New heterocycles from 8-hydroxyquinoline via dipolar 1,3-cycloadditions: Synthesis & biological evaluation

Article abstract of DOI:10.1002/jhet.5570400207

Diarylnitrilimine and arylnitriloxide dipoles react with two 8-hydroxyquinoline substrates to give respectively pyrazolinic and isoxazolinic derivatives. The structure of these new heterocycles was established on the basis of their spectroscopic data and by chemical methods. The inhibition activity of one of these heterocycles was evaluated in vitro against 8 pathogenic μ-organisms.

Full text of DOI:10.1002/jhet.5570400207

Mar-Apr 2003
243
New Heterocycles from 8-Hydroxyquinoline via Dipolar
1,3-Cycloadditions: Synthesis & Biological Evaluation
Abdelmejid Bahloul [a], Abdelfatah Sebban [a], Zainaba Dardari [b], Mohammed
Boudouma [b], Said Kitane* [c], Touria Belghiti [d] and Jean-Pierre Joly [d]
[a] Laboratoire de Chimie des Polymères et de Synthèse Organique, Faculté des Sciences Ben M'Sik,
Université Hassan II - Mohammedia, Casablanca, Morocco [b] Laboratoire de Microbiologie et de Biologie
Moléculaire, Faculté des Sciences Ben M'Sik, Université Hassan II - Mohammedia, Casablanca, Morocco [c]
Laboratoire de Chimie Appliquée, Ecole Nationale de l'Industrie Minérale, BP 753, Agdal, Rabat, Morocco [d]
Groupe SUCRES, UMR CNRS 7565, Université Henri Poincaré - Nancy I, F-54506 Vandœuvre, France.
Received October 7, 2002
Diarylnitrilimine and arylnitriloxide dipoles react with two 8-hydroxyquinoline substrates to give respec-
tively pyrazolinic and isoxazolinic derivatives. The structure of these new heterocycles was established on
the basis of their spectroscopic data and by chemical methods. The inhibition activity of one of these hetero-
cycles was evaluated in vitro against 8 pathogenic µ-organisms.
J. Heterocyclic Chem., 40, 243 (2003).
Scheme 1
Introduction.
Although 8-hydroxyquinoline derivatives are endowed
with some interesting biological properties [1], they are
more often known as selective metal extractants [2]. In the
course of the research completed in our respective labora-
tories for the development of heterocyclic compounds of
both synthetic and biological interest [3], we report here
about new polycyclic derivatives synthesized by 1,3-dipo-
lar cycloadditions of diarylnitrilimines (DANI) and arylni-
triloxides (ANO) with 7-(2'-propenyl)-8-hydroxyquinoline
2 and 7-(1'-propenyl)-8-hydroxyquinoline 3.
1
2
3
The E configuration of 3 was ascertained by the high cou-
pling constant (ie. 16 Hz) connecting H-1' and H-2'. The Z
isomer would imply a coupling constant of only ca. 8 Hz by
comparison to related described structures [8]. The reaction
of 2 and 3 with nitrilimine 1,3-dipoles 4 [9] in refluxing ben-
zene for 48 hours led respectively to cycloadducts 5a-d and
6a-c in 60-80% yields of pure isolated products.
The chemical structure of 7-[5'-(3'-aryl-4',5'-dihydro-1'-
phenyl-pyrazolo)-methyl]-8-hydroxyquinolines 5a-d was
established on the basis of their H- and C-NMR data
(see Table 1). This common structure is in favor of a highly
regioselective reaction.
Results and Discussion.
Allyl derivative 2 has been briefly claimed in two
German patents [4] and was obtained by a Williamson syn-
thesis from 8-hydroxyquinoline [5] and allyl bromide via
allyloxyquinoline 1 which underwent a Claisen rearrange-
ment to yield 2 [6]. Dipolarophile 3 was obtained by iso-
merization of 2 in a strong basic medium [7] as depicted in
Scheme 1.
1
13
Scheme 2

244
A. Bahloul, A. Sebban, Z. Dardari, M. Boudouma, S. Kitane, T. Belghiti and J.-P. Joly
Vol. 40
Table 1
1
13
H- and C-NMR Data of Adducts 5a-d in CDCl , δ (ppm/TMS), J (Hz)
3
Adducts H-4'A H-4'B
H-5'
H-6'
R = CH
C-4'
C-5'
C-6'
R = H, CH
3
3
or OCH
or OCH
3
3
5a
5b
5c
5d
3.56 2.72 (dd)
= 13.4
4.94 (m)
3.15 (d)
-
37.4
59.2
2.5
-
J
J
J
J
J
= 7.5
AB
5'-6'
J
= 3.3
4'A-5'
J
= 10.3
4'B-5'
3.63 2.75 (dd)
= 13.3
4.90 (m)
4.90 (m)
5.10 (m)
3.13 (d)
= 6.9
5'-6'
2.35 (s)
3.80 (s)
-
37.5
38.0
36.6
59.1
59.0
60.0
32.5
31.7
32.0
21.1
55.0
-
J
AB
J
= 3.3
4'A-5'
J
= 10.3
4'B-5'
3.62 2.72 (dd)
= 13.1
3.15 (d)
= 6.3
5'-6'
J
AB
J
= 3.2
4'A-5'
J
= 10.3
4'B-5'
3.62 2.75 (dd)
3.20 (d)
= 7.6
5'-6'
J
= 13.4
AB
J
J
= 3.1
= 10.1
4'A-5'
4'B-5'
1
1
The H-NMR spectrum of 5c in CDCl (see Table 1)
lines 10a-c. All H-NMR spectra in CDCl displayed a
3
3
displays a peculiar doublet at 3.15 ppm which was
assigned to the two isochronous protons H-6' coupled with
H-5'. The two protons H-4' and H-5' form an ABM system,
the two split doublets at 3.62 and 2.72 ppm being respec-
tively assigned to H-4'A and H-4'B, and the multiplet
downfield shifted at 4.90 ppm by an adjacent heteroatom
assigned to H-5' [10]. This resonance has been already
observed on products resulting from the addition of nitrile
imine derivatives on allyl dipolarophiles [11].
singlet around 6.4 ppm assigned to H-4 ‘ in good agree-
ment with literature values [9b,14].
1
13
Altogether H- and C-NMR data of isolated adducts
6a-c (see Table 2) indicate that this 1,3-dipolar cycloaddi-
tion reaction led to a single regioisomer (see Scheme 2).
Usually, similar reactions yield both regioisomers with a
prevalence of those resulting from weaker steric effects
[9a,11a,15]. Of particular significance were a multiplet
around 3.5 ppm and a doublet around 5.6 ppm. These reso-
nances were assigned respectively to vicinal protons H-4'
and H-5' which are obviously trans in all these adducts
judging from their low coupling constant (< 4 Hz).
Substituting CDCl for DMSO-d made the two protons
3
6
H-6' anisochronous and thus led protons H-4', -5', and -6'
to form an ABMXY system in 5c [12]. It is well known
that the nature of solvent, concentration and temperature
affect the resonance of certain nuclei in a given structure
In order to enlighten the regiospecificity of the cycload-
dition products of N-phenyl-C-arylnitrilimines, dipo-
larophile 2 was reacted with two arylaldoximes (7a: R =
H; 7b: R = Me) in a two-phase medium (ie. aqueous
[13]. In DMSO-d , H-5' appears in the form of a 16 transi-
6
tions resonance at 4.89 ppm, H-6'A and H-6'B as two split
doublets centered respectively at 3.15 and 3.28 ppm. The
NaClO and CHCl [16]) at -10 °C for 1 hour (see Scheme
3
1
13
2). Comparison of H- and C-NMR chemical shifts at 4'-
and 5'-positions in both kinds of adducts are in favor of the
postulated structure taking into account that replacement
of the nitrogen by an oxygen in 9a-b led to an important
shielding of ca. 21 ppm. From all these data, it appears that
the regiochemistry of the reaction of DANI and ANO with
dipolarophiles 2 and 3 does not depend on the nature of the
1,3-dipoles used but on steric hindrance effects [11a,15].
In vitro antimicrobial activity of compound 9a was eval-
uated against seven pathogenic strains and one yeast (C.
albicans) by the disc-diffusion method [17]. As indicated
in Table 3, compound 9a displays a measurable antibacter-
ial activity against all the microorganisms tested, the low-
est activity being observed against Gram-negative bacteria
and especially Salmonella enterica which developed
recently multidrug-resistance [18]. The largest diameters
of inhibition (m/m) were measured against Enterococcus
feacalis and Mycobacterium smegmatis, which is an acid-
coupling constants between these three protons were: J
6'A-
= 17 Hz, J
= 5 Hz, and J
= 10.5 Hz, these two
6'B
6'A-5'
6'B-5'
last values suggesting H-6'B and H-6'A are respectively cis
and trans in respect to H-5'.
To ascertain this regiochemistry adducts 5a-c were sub-
jected to a reaction of heteroaromatization (see Scheme 3).
p-Chloranil mild dehydrogenation of 5a-c yielded only
7-[5'-(1'-phenyl-3'-arylpyrazolo)methyl]-8-hydroxyquino-
Scheme 3

Mar-Apr 2003
New Heterocycles from 8-Hydroxyquinoline via Dipolar 1,3-Cycloadditions
245
Table 2
1
13
H- and C-NMR Data of Adducts 6a-c in CDCl δ (ppm/TMS), J (Hz)
3,
Adducts
H-4'
H-5'
CH
R = CH
C-4'
C-5'
CH
R = H, CH
3
3
3
3
on C-4'
or OCH
on C-4'
or OCH
3
3
6a
6b
6c
3.55 (m)
J = 7.1
5.60 (d)
1.55 (d)
J = 7.1
-
49.6
49.6
49.7
65.3
65.4
65.4
19.1
-
3
3
J
J
= 3.5
4'-5'
3.57 (m)
5.60 (d)
= 3.6
1.55 (d)
2.36 (s)
3.83 (s)
19.2
19.1
21.3
55.2
3
3
J = 7.1
J = 7.2
4'-5'
3.54 (m)
5.57 (d)
= 3.6
1.55 (d)
3
3
J = 7.1
J
J = 7.1
4'-5'
fast staining rod [19]. The higher in vitro activity of 9a
against Gram-positive bacteria was not surprising since
Gram-negative rods are endowed with an outer membrane
that decreases the transfer of drugs through the cytoplas-
mic membrane. It has been suggested that hydroxyquino-
line and its derivatives could exert their biological activi-
ties as membrane-active agents via metal ion chelation
[20,21]. Our preliminary results are in good agreement
with those reported by Shen et al. [20] and Lentz et al.
[22]. A signicative fungistatic activity was also observed
against Candida albicans, the sole yeast of our test.
Further investigations of compound 9a on other bacte-
ria, fungi, and protozoa are in progress to throw light on its
antimicrobial spectrum.
Table 3
In Vitro Activities of 7-[5'-(3'-Phenyl-isoxazolino)-methyl]-8-hydroxy-
quinoline 9a vs Penicillin G or Amphothericine B
Strains
Inhibition-zone diameter (m/m)
9a
Penicillin G
Amphotericine B
Escherichia coli (ATCC 10536)
12
25
-
Escherichia coli (ATCC 8739)
11
25
-
Conclusion.
Pseudomonas aeruginosa (CIP 105526)
11
1,3-Dipolar cycloaddition reactions of DANI and ANO
with two isomers, namely the 7-(2'-propenyl)-8-hydrox-
yquinoline 2 and the 7-(1'-propenyl)-8-hydroxyquinoline 3,
were used to synthesize new chelating molecules from
8-hydroxyquinoline. The regiochemistry of this reaction
relies on already discussed steric effects. Some of these new
heteroadducts behave like selective extractants of metal ions
in liquid-liquid extraction [23] and compound 9a is
endowed with interesting in vitro antimicrobial activity
against both Gram-positive and Gram-negative bacteria.
25
-
Pseudomonas aeruginosa (ATCC 9027)
11
25
-
Salmonella enterica (CIP 80.39)
10
25
-
Staphylococcus aureus (ATCC 9144)
15
26
-
EXPERIMENTAL
Staphylococcus aureus (ATCC 6538)
15
25
-
Chemistry.
Enterococcus feacalis (ATCC 10541)
Melting points were measured with a Buchi 510 apparatus and
18
26
-
are uncorrected. NMR spectra were recorded in CDCl using a
3
1
Bruker AC200 spectrometer operating at 200 MHz for H and 50
13
MHz for C with TMS as internal standard. Assignments of the
Bacillus subtilis (ATCC 6633)
various protons were supported by successive irradiations. IR
spectra were recorded with a Perkin Elmer 577 spectrometer,
solid products being palletized in KBr. DANI precursors were
prepared according to Huisgen [9a,15]. Elemental analyses were
carried out by the 'Service Central de Microanalysis' of the CNRS
in Vernaison, France.
11
25
-
Mycobacterium smegmatis (CIP 73.26)
18
25
-
Candida albicans (ATCC 10231)
Microbiology.
13
-
22
Strains were purchased from the American Type Culture
Collection (ATCC), Manassas, VA 20108, USA and from the

246
A. Bahloul, A. Sebban, Z. Dardari, M. Boudouma, S. Kitane, T. Belghiti and J.-P. Joly
Vol. 40
Institut Pasteur de Paris (IPP), 25-28 rue du Docteur Roux, 75724
Paris, France. Sterile paper discs of 6 m/m diameter (Wattmann
eliminated by filtration through a sinter glass under an efficient
fume board. The solvents were evaporated and the residue diluted
in a small volume of an ether-ethanol mixture (1:1) in which the
cycloadducts solidified on standing in the refrigerator.
N°3) were impregnated with a 3 mg/mL CH Cl solution of the
2
2
compound to be tested and dried at 37 °C before use. The rest of
the procedure was identical to the method reported in § 2.8. of
ref. [17].
Adducts from Dipolarophile 2.
7-(2,5-Diphenyl-3,4-dihydro-2H-pyrazol-3-ylmethyl)-quinolin-
8-ol (5a).
7-(2-Propenyl)-8-hydroxyquinoline (2).
A suspension of 0.2 mole of 8-hydroxyquinoline and 0.3 mole
Compound 5a was obtained in 82% yield; mp 218 °C; IR:
3300-3400, 1580 cm ; H- and C-NMR, see Table 1.
of K CO in 300 mL of anhydrous acetone was refluxed for 15
2
3
-1
1
13
minutes in a 0.5 L reactor equipped with a drying funnel (CaCl ).
2
Anal. Calcd. for C
H N O: C, 79.16; H, 5.54. Found: C,
25 21 3
Allyl bromide (18 mL, ~ 1 eq.) was then dropped and the mixture
stirred and refluxed for 24 additional hours. After cooling, the
suspension was filtered under a fume board and the resulting
solids washed with acetone (3 x 100 mL). The solvent was evap-
orated under reduced pressure to an oily residue which was dis-
solved in ether (200 mL), washed successively with 5% aq. KOH
78.94; H 5.40.
7-(2-Phenyl-5-p-tolyl-3,4-dihydro-2H-pyrazol-3-ylmethyl)-
quinolin-8-ol (5b).
Compound 5b was obtained in 80% yield; mp 205 °C; IR:
-1
1
13
3300-3400, 1580 cm ; H- and C-NMR, see Table 1.
and water until neutral, dried with Na SO , and finally concen-
2
4
Anal. Calcd. for C
H N O: C, 79.39; H, 5.85. Found: C,
26 23 3
trated under vacuo to yield the crude allyl ether 1 (~ 37 g, 100%)
79.18; H 5.71.
1
as a brown oil. H-NMR: 4.86 (d, 2H, J
5.4 Hz, H-1'), 5.34
1'-X
(dd, 1H, J
17.3 Hz, J
1.2 Hz, H-A), 5.4 (dd, 1H, J
10.4
7-[5-(4-Methoxy-phenyl)-2-phenyl-3,4-dihydro-2H-pyrazol-3-
ylmethyl]-quinolin-8-ol (5c).
A-X
A-B
B-X
Hz, H-B), 6.2 (m, 1H, H-X), 7.0-8.8 (m, 6H, Ar.). The Claisen
rearrangement of ether 1 was initiated by heating at approxi-
mately 160 °C on a sand bath under a nitrogen atmosphere. An
exothermic reaction took place and the temperature raised up to
200 °C in a few minutes [6]. After cooling, the residue was dis-
tilled under reduced pressure (bp 165-170 °C/0.5) to give 2
(29.63 g, 80%) as a yellowish oil which crystallized on standing:
Compound 5c was obtained in 76% yield; mp 212 °C; IR:
-1
1
13
3300-3400, 1595 cm ; H- and C-NMR, see Table 1.
Anal. Calcd. for C
H N O : C, 76.28; H, 5.63. Found: C,
26 23 3 2
76.42; H 5.50.
7-(5-(4-Nitrophenyl)-2-phenyl-3,4-dihydro-2H-pyrazol-3-
ylmethyl)-quinolin-8-ol (5d).
1
mp 42 °C (n-heptane), Litt. [6] mp 41.5-42 °C (pentane); H-
NMR: 3.68 (d, 2H, J
6.5 Hz, H-1'), 5.1 (dd, 1H, J
1.8 Hz,
1'-X
A-B
Compound 5d was obtained in 70% yield; mp > 260 °C; IR:
J
16.6 Hz , H-A), 5.18 (dd, 1H, J
10.0 Hz, H-B), 6.1 (m,
A-X
B-X
-1
1
13
3300-3400, 1590 cm ; H- and C-NMR, see Table 1.
13
1H, H-X), 8.58 (bs, 1H, OH), 7.3-8.9 (m, 5H, Ar.); C-NMR:
149.1 (C-8), 147.6 (C-2), 137.8 (C-8a), 136.4 (C-2'), 136.1 (C-4),
129.5 (C-6), 127.1 (C-4a), 122.0 (C-7), 120.9 (C-3), 117.3 (C-5),
115.7 (C-3'), 34.0 (C-1').
Anal. Calcd. for C
H N O : C, 70.75; H, 4.72. Found: C,
25 20 4 3
70.53; H 4.61.
Adducts from Dipolarophile 3.
7-(1-Propenyl)-8-hydroxyquinoline (3).
In the same manner, adducts 6a-c were isolated after evapora-
tion of benzene, purified by chromatography on silica gel column
with chloroform as the mobile phase, and finally crystallized
from 96% ethanol.
A solution of 2 (20.0 g) in 200 mL of n-butanol was refluxed
for 4 h with KOH pellets (34.0 g). After cooling, the solvent was
evaporated under reduced pressure, the residue carefully neutral-
ized with 6 N HCl and extracted with ether (3 x 100 mL). The
organic phases were combined, washed twice with water, and
7-(4-Methyl-2,5-diphenyl-3,4-dihydro-2H-pyrazol-3-yl)-quino-
lin-8-ol (6a).
dried on Na SO . Evaporation of solvents and crystallization of
2
4
Compound 6a was obtained in 54% yield; mp 192 °C; IR:
the residue from hot ethanol gave compound 3 (14.4 g, 72%) as
yellow needles: mp 86-88 °C, Litt. [7] 86-87 °C; H-NMR: 2.0
-1
1
13
3300-3400, 1580 cm ; H- and C-NMR, see Table 2.
1
Anal. Calcd. for C
H N O: C, 79.16; H, 5.54. Found: C,
25 21 3
(dd, 3H, J
1.5 Hz, J
6.6 Hz, Me), 6.4 (dq, 1H, J
16.0
1'-3'
2'-3'
1'-2'
79.37; 5.46.
Hz, H-2'), 6.95 (m, 1H, H-1'), 8.6 (bs, 1H, OH), 7.2-7.8 (m, 5H,
13
Ar.); C-NMR: 148.0 (C-2, -8), 138.5 (C-8a), 135.5 (C-4), 127.2
7-(4-Methyl-2-phenyl-5-p-tolyl-3,4-dihydro-2H-pyrazol-3-yl)-
quinolin-8-ol (6b).
(C-6), 127.0 (C-4a), 126.0 (C-1'), 125.0 (C-2'), 121.0 (C-3),
120.0 (C-7), 117.0 (C-5), 19.0 (C-3').
Compound 6b was obtained in 60% yield; mp 156 °C; IR:
Addition of N-Phenyl-C-arylnitrilimines on Dipolarophiles 2
and 3.
-1
1
13
3300-3400, 1590 cm ; H- and C-NMR, see Table 2.
Anal. Calcd. for C
H N O: C, 79.39; H, 5.85. Found: C,
26 23 3
79.16; H, 5.61.
Onto a magnetically stirred solution of the dipolarophile (2 or
3, 10 mmoles) and 13 mmoles of the selected hydrazonoyl
hydrochloride precursor of DANI [3c,9a,24] in 30 mL of
anhydrous benzene in a 100 mL reactor equipped with a reflux
7-[5-(4-Methoxy-phenyl)-4-methyl-2-phenyl-3,4-dihydro-2H-
pyrazol-3-yl]-quinolin-8-ol (6c).
Compound 6c was obtained in 65% yield; IR: 3300-3400,
1580 cm ; mp 163 °C; H- and C-NMR, see Table 2.
condenser and a drying funnel (CaCl ) were dropped 2 mL of
2
-1
1
13
triethylamine over 15 minutes as the mixture was heated to
reflux. The reflux was kept for 48 hours. After complete cooling,
20 mL of anhydrous benzene was added and the hydrochloride
Anal. Calcd. for C
H N O : C, 76.28; H, 5.63. Found: C,
26 23 3 2
76.51; H, 5.46.

Mar-Apr 2003
New Heterocycles from 8-Hydroxyquinoline via Dipolar 1,3-Cycloadditions
247
Cycloaddition of ANO 8 with Dipolarophile 2.
7-[5-(4-Methoxy-phenyl)-2-phenyl-2H-pyrazol-3-yl-
methyl]quinolin-8-ol (10c).
Commercial bleach (40 mL, 24° ~ 23% NaClO w/w) was
slowly dropped under magnetic stirring onto a solution of
1
Compound 10c was obtained in 60% yield; mp 180 °C; H-
oxime 7 in 20 mL of CHCl kept at -10 °C. The resulting two-
phase system was vigorously stirred for one hour after complete
addition at the same temperature. The organic phase was
NMR: 4.4 (s, 2H, H-6'), 6.4 (s, 1H, H-4'), 7.4-8.6 (m, 15H, Ar. +
OH); C-NMR (selected datum): 105.1 (C-4').
3
13
Anal. Calcd. for C
H N O : C, 71.09; H, 4.26. Found: C,
25 18
4 3
decanted, washed with water (3 x 10 mL), dried (Na SO ), and
70.89; H, 4.19.
2
4
REFERENCES NOTES
finally concentrated to a gum which was chromatographied on
silica gel with cyclohexane/ethyl acetate (9:1) as the eluent.
Compounds 9a-b were finally crystallized from a mixture
ether/petroleum ether (2:3).
[1a] M. Yamato, K. Hashigaki, Y. Yasumoto, J. Sakai, S.
Tsukagoshi, T. Tashiro, and T. Tsuruo, Chem. Pharm. Bull., 34, 3496
(1986); [b] Z. H. Khalil, A. S. Yanni, A. A. Abdel-Hafez, and A. A.
Khalaf, J. Indian Chem. Soc., 67, 821 (1990).
7-(3-Phenyl-4,5-dihydroisoxazol-5-ylmethyl)-quinolin-8-
ol (9a).
[2a] J. Helgorsky and A. Lévèque, Eur. Pat. Appl. N° 4 226 (1979);
[b] P. Mourier, G. Cote, and D. Bauer, Analusis, 10, 468 (1982); [c]
T. Sato and K. Sato, Hydrometallurgy, 26, 299 (1991); [d] N. Su,
J. S. Bradshaw, X. X. Zhang, H. Song, P. B. Savage, G. Xue, K. E.
Krakowiak, and R. M. Izaat, J. Org. Chem., 64, 8855 (1999).
[3a] S. Kitane, M. Berrada, J. Vebrel, and B. Laude, Bull. Soc.
Chim. Belg., 94, 163 (1985); [b] S. Kitane, A. Sebban, J. Vebrel, and
B. Laude, Bull. Soc. Chim. Belg., 98, 105 (1989); [c] A. Eddaif, S. Kitane,
M. Soufiaoui, and P. Mison, Tetrahedron Lett., 32, 3709 (1991); [d] S.
Kitane, L. Chraibi, and M. Soufiaoui, Tetrahedron, 48, 8935 (1992); [e]
A. Bahloul, S. Kitane, and M. Soufiaoui, J. Soc. Mar. Chim., 2, 12 (1993);
[f] A. Bahloul, S. Kitane, A. Sebban, and M. Berrada, J. Soc. Alger.
Chim., 10, 131 (2000); [g] S. Kitane, A. Taimi, A. Bahloul, A. Sebban, M.
Berrada, and J.-P. Joly, J. Heterocyclic Chem., 37, 1641 (2000).
[4a] H. Hahl, Germ. Pat. N° 433 182 (1926); Chem. Abstr., 20,
19621 (1926); [b] H. Timmler and H. Andersag, Germ. Pat. N° 937 588
(1956); Chem. Abstr., 52, 113831 (1958).
Compound 9a was obtained in 50% yield; mp 115 °C; IR:
-1
1
3300-3400, 1580 cm ; H-NMR: 3.19 (dd, 1H, J
16.7 Hz,
A-B
J
7.8 Hz, H-4'A), 3.31 (dd, 1H, J
9.9 Hz, H-4'B), 5.25
4'A-5'
4'B-5'
(m, 1H, H-5'), 3.38 (d, 2H, H-6'), 7.1-8.8 (m, 11H, Ar. +
13
OH); C-NMR (selected data): 117-158 (Ar.), 81.0 (C-5'), 39.0
(C-4'), 35.0 (C-6').
Anal. Calcd. for C
H N O : C, 75.00; H, 5.26. Found: C,
19 16 2 2
75.24; H, 5.13.
7-(3-p-Tolyl-4,5-dihydro-isoxazol-5-ylmethyl)-quinolin-
8-ol (9b).
Compound 9b was isolated in 56% yield; mp 120 °C; IR:
-1
1
3300-3400, 1590 cm ; H-NMR: 2.35 (s, 3H, Me); 3.19 (dd, 1H,
17.0 Hz, J 7.8 Hz, H-4'A), 3.3 (dd, 1H, J 10 Hz,
J
A-B
4'A-5 ‘
4'B-5'
H-4'B), 5.15 (m, 1H, H-5'), 3.27 (d, 2H, H-6'), 7.1-8.8 (m, 10H,
13
Ar. + OH); C-NMR (selected data): 117-158 (Ar.), 80.7 (C-5'),
[5a] B. Mander-Jones and V. M. Trikojus, J. Proc. Roy. Soc. N. S.
Wales, 66, 300 (1932); [b] N. P. Buu-Hoi, H. K. Wei, and R. Royer, Bull.
Soc. Chim. Fr., 866 (1945).
39.5 (C-4'), 35.1 (C-6'), 21.4 (Me).
Anal. Calcd. for C
H N O : C, 75.45; H, 5.66. Found: C,
20 18 2 2
75.45; H, 5.81.
[6] C. Pène, P. Demerseman, A. Cheutin, and R. Royer, Bull. Soc.
Chim. Fr., 586 (1966).
Heteroaromatization of Adducts 5a-c into Pyrazoles
10a-c.
[7] H. Fiedler, Arch. Pharm., 297, 108 (1964).
[8a] S. Ananda Weerawarna, M. Guha-Biswas, and W. L. Nelsen,
J. Heterocyclic Chem., 28, 1395 (1991); [b] M. Rivière, Dissertation,
Toulouse, France (1970); [c] J. Sauer, and H. Prahl, Tetrahedron Lett., 25,
2863 (1966).
An equimolar mixture of 5 (10 mmoles) and p-chloranil in 40
mL anhydrous benzene was refluxed for 48 hours. After com-
plete cooling, the mixture was washed with 5% aq. KOH, the
[9a] R. Huisgen, M. Seidel, G. Wallbillich, and H. Knupfer,
Tetrahedron, 17, 3 (1962); [b] B. Laude, M. Soufiaoui, and J. Arriau, J.
Heterocyclic Chem., 14, 1183 (1977).
organic phase was separed, dried on Na SO , and the solvent
evaporated under reduced pressure. Crude solid materials were
recrystallized from 96% ethanol.
2
4
[10a] A. Hassner and M. J. Michelson, J. Org. Chem., 27, 3974
(1962); [b] A. Padwa, S. Nahm, and E. Sato, J. Org. Chem., 43, 1664
(1978).
7-(2,5-Diphenyl-2H-pyrazol-3-ylmethyl)-quinolin-8-ol
(10a).
[11a] R. Sustmann, Dissertation, Munich, Germany (1966); [b] B.
Bennani, Dissertation, Belfort, France (1981).
[12] N. Naji, M. Soufiaoui, and P. Moreau, J. Fluorine Chem., 79,
179 (1996).
[13] T. D. W. Claridge, Tetrahedron Org. Ser., Vol. 19, ‘'High-
Resolution NMR Techniques in Organic Chemistry'', Pergamon Press,
Elsevier Science (1999).
Compound 10a was obtained in 72% yield; mp 176 °C; IR:
-1
1
3300-3400, 1610, 1590 cm ; H-NMR: 4.26 (s, 2H, H-6'), 6.63
13
(s, 1H, H-4'), 7.4-8.6 (m, 16H, Ar. + OH); C-NMR (selected
datum): 105.04 (C-4').
Anal. Calcd. for C
H N O: C, 79.57; H, 5.04. Found: C,
25 19 3
79.75; H, 5.13.
[14] B. Daou, M. Soufiaoui, and R. Carrié, J. Heterocyclic Chem.,
26, 1485 (1989).
[15] R. Huisgen, Bull. Soc. Chim. Fr, 3431 (1965) and references
cited therein.
[16a] G. A. Lee, Synthesis, 508 (1982); [b] M. Soufiaoui, B. Syassi,
B. Daou, and N. Baba, Tetrahedron Lett., 32, 3699 (1991).
[17] P. Jaiarj, P. Khoohaswan, Y. Wongkrajang, P. Peungvicha,
P. Suriyawong, M. L. Sumal Saraya, and O. Ruangsomboon,
J. Ethnopharmacol., 67, 203 (1999).
7-(2-Phenyl-5-p-tolyl-2H-pyrazol-3-ylmethyl)-quinolin-8-
ol (10b).
Compound 10b was obtained in 80% yield; mp 187 °C; IR:
-1 1
3300-3400, 1610, 1595 cm ; H-NMR: 2.41 (s, 3H, Me), 4.25 (s,
13
2H, H-6'), 6.38 (s, 1H, H-4'), 7.4-8.6 (m, 15H, Ar. + OH); C-
NMR (selected data): 105.0 (C-4'), 21.5 (Me).
Anal. Calcd. for C
H N O: C, 79.79; H, 5.37. Found: C,
26 21 3
79.62; H, 5.28.

248
A. Bahloul, A. Sebban, Z. Dardari, M. Boudouma, S. Kitane, T. Belghiti and J.-P. Joly
Vol. 40
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