Synthesis of aryl-substituted or aryl-fused N-hydroxyethyl and N-hydroxymethypyrazole derivatives as potential ligands for the estrogen receptor

Article abstract of DOI:10.1007/s13738-012-0126-z

A new series of N-hydroxyethylpyrazole (12a-f) and N-hydroxymethylpyrazole derivatives (15a-f) were designed for their estrogenic activities, having a 11.0 ± 0.5 A distance between their two hydroxyl groups, aliphatic-OH and phenolic-OH similar to 17β-estradiol (E2) as an endogenous hormone. To synthesize the title compounds, the key intermediate 1,3-dicarbonyl derivatives (2 and 8), were treated with hydrazine hydrate to produce the pyrazole ring 5 and 9. Further hydroxyalkylation of the latter produced the title pyrazoles. The position of hydroxyethyl or hydroxymethyl substituents in the products was determined through 2D NOE NMR spectroscopy.

Full text of DOI:10.1007/s13738-012-0126-z

J IRAN CHEM SOC (2013) 10:43–53
DOI 10.1007/s13738-012-0126-z
ORIGINAL PAPER
Synthesis of aryl-substituted or aryl-fused N-hydroxyethyl
and N-hydroxymethypyrazole derivatives as potential
ligands for the estrogen receptor
•
Maryam Allahyari-Devin Behnam Abedi
•
•
Latifeh Navidpour Abbas Shafiee
Received: 30 May 2012 / Accepted: 8 June 2012 / Published online: 29 June 2012
Ó Iranian Chemical Society 2012
Abstract A new series of N-hydroxyethylpyrazole (12a–f)
and N-hydroxymethylpyrazole derivatives (15a–f) were
designed for their estrogenic activities, having a 11.0
important physiological roles, such as maintenance of bone
mineral density, cardiovascular health, neuroprotection, the
development and function of the female reproduction sys-
tem [1–3]. Recent evidences suggest that estrogen may also
mediate non-reproductive events including learning and
memory [1–3]. The most potent endogenous ligand for
both estrogen receptors is 17b-estradiol (E2). The tradi-
tional utility of ER ligands has been reported for such
therapies as hormone replacement therapy (HRT) and
contraception that is mediated primarily via ERa [4].
The structure of high ER affinity synthetic estrogens,
especially those of non-steroidal nature, generally consists
of a phenolic functionality that mimics the phenol moiety
of natural estradiol, and is tolerant to other target structural
motifs that can be encompassed [5–7].
˚
0.5 A distance between their two hydroxyl groups, ali-
phatic–OH and phenolic–OH similar to 17b-estradiol (E2)
as an endogenous hormone. To synthesize the title com-
pounds, the key intermediate 1,3-dicarbonyl derivatives (2
and 8), were treated with hydrazine hydrate to produce the
pyrazole ring 5 and 9. Further hydroxyalkylation of the latter
produced the title pyrazoles. The position of hydroxyethyl or
hydroxymethyl substituents in the products was determined
through 2D NOE NMR spectroscopy.
Keywords 17b-Estradiol ꢀ Pyrazole ꢀ Estrogen receptor ꢀ
2D NOE NMR spectroscopy
There are so many efforts to find a new series of safe
and selective estrogenic compounds. In the course of
investigations aimed at developing novel selective estrogen
receptor modulators (SERMs) that possess high affinity and
selectivity for an ER subtype, a broad variety of diverse
ligands have been considered. In this work, the incorpo-
ration of a pyrazole moiety in the structures represents an
intriguing case [8], since the propylpyrazoletriol (PPT)
(Fig. 1), a 1,3,5-triaryl-4-alkyl-substituted pyrazole deriv-
ative, has been found to possess particularly high ERa
selective binding affinity and potency [9–11], while
cycloalkylpyrazoles (Fig. 1) have shown higher binding
affinity for ERb [12].
Introduction
The estrogen receptors (ERs) are ligand-dependent tran-
scription factors that exert their physiological effects by
binding of endogenous steroid hormones, such as 17b-
estradiol (E2) or synthetic estrogens. There are two sub-
types of estrogen receptor, ERa and ERb, which are
members of the nuclear receptor (NR) that regulates many
The affinity of ligand binding to either form of ER
primarily reflects the presence of two hydroxyl groups with
an O–O distance close to that between the 3- and 17b-
hydroxyl groups of estradiol [12]. In general, it is thought
that for optimum hydrogen bonding this distance should be
M. Allahyari-Devin ꢀ B. Abedi ꢀ L. Navidpour (&) ꢀ
A. Shafiee (&)
Department of Medicinal Chemistry, Faculty of Pharmacy
and Pharmaceutical Sciences Research Center,
Tehran University of Medical Sciences, 14176 Tehran, Iran
e-mail: navidpur@sina.tums.ac.ir
˚
11.0 0.5 A [13]. Since the O–O distances for PPT are
˚
12.3 and 13.1 A, the rationale to design these molecules is
A. Shafiee
e-mail: ashafiee@ams.ac.ir
123

44
J IRAN CHEM SOC (2013) 10:43–53
Fig. 1 17b-Estradiol (E2),
Propylpyrazoletriol (PPT),
cycloalkylpyrazoles and
designed structures
OH
OH
OH
N
N
N
N
OH
HO
HO
OH
HO
n = 1,2
17β-Estradiol (E2)
PPT
OH
N
N
N
N
R2
R2
HO
HO
12c-f, 15c-f
designed structures
12a-b, 15a-b
m,n= 1, 2
R2= H, CH3
to substitute one of the phenol rings with CH2CH2OH or
CH2OH in order to decrease the O–O distance of the
hydroxyl groups according to the suitable range for opti-
mum hydrogen binding. Therefore, herein we describe the
synthesis of N-hydroxyethyl and N-hydroxymethypyrazole
derivatives as potential ligands for the estrogen receptor.
in this temperature and kept in 0 °C overnight. The pre-
cipitate was filtered and washed with diethyl ether and
dissolved in water, neutralized with HCl and the precipitate
was filtered and washed with water and dried to give
acylated derivatives (2 and 8). The spectral data of 2a–c and
2e–f were similar with those reported [14–18].
2-Acetyl-5-methoxy-2,3-dihydro-1H-inden-1-one (2d):
Yield 60 %; mp 89–91 °C; IR (KBr): m 1,655 cm-1 (C=O);
1H NMR (CDCl3): d 7.75 (d, J = 8.2 Hz, 0.67H, H7), 7.65
(d, J = 8.2 Hz, 0.33H, H7), 6.96 (s, 1H, H4), 6.93 (d,
J = 8.2 Hz, 1H, H6), 3.94 (dd, J = 3.2, 7.6 Hz, 0.33H,
H2), 3.89 (s, 3H, OCH3), 3.67 (dd, J = 3.2, 17.5 Hz,
0.33H, H3), 3.54 (s, 1.34H, H3), 3.05 (dd, J = 7.6, 17.5 Hz,
0.33H, H3), 2.48 (s, 1H), 2.12 ppm (s, 2H).
Experimental
Commercially available chemicals were purchased from
the Fluka, Aldrich or Merck Chemical Companies and used
without further purification. Melting points were deter-
mined with a Reichert-Jung hot-stage microscope and are
uncorrected. Infrared spectra were recorded on a Nicolet
Magna 550-FT spectrometer. 1H NMR spectra were
measured on a Bruker 500 MHz spectrometer (Bruker,
Rheinstatten, Germany), in CDCl3, CD3OD or DMSO-d6
with TMS as the internal standard, where J (coupling
constant) values are estimated in Hertz. Mass spectra were
obtained with an Agilent Technologies 5975C spectrome-
ter (Agilent Technologies, USA) at 70 eV.
General procedure B. Preparation of pyrazole
derivatives from 1,3-dicarbonyl compounds
To a solution of the appropriate 1,3-dicarbonyl compound
(2 or 8, 1 mmol) in ethanol was added hydrazine mono-
hydrate (4 mmol) and glacial acetic acid (4 mmol). The
mixture was refluxed in an oil bath and the progress of the
reaction was monitored by TLC. After cooling to room
temperature the solution was poured into ice-water and the
resulting precipitate was filtered, washed with cold water,
dried and recrystallized from ethyl acetate to give 5 or 9
[19]. The spectral data of 5a–b [20–23] and 5e [24] were
similar with those reported.
General procedure A. Acylation of acetophenone,
indanone and tetralone derivatives
A solution of appropriate starting material (1 or 7,
10 mmol) in methyl formate (for formylation) or methyl
acetate (for acetylation) (25 ml) was added dropwise to a
stirring suspension of freshly prepared sodium ethoxide
(1 g, 15 mmol) in dry diethyl ether (25 ml) in an ice bath
(0 °C), over a period of 30 min. The resulting mixture was
warmed up to room temperature and stirred for further 1 h
6-Methoxy-2,4-dihydroindeno[1,2-c]pyrazole (5c): Yield
1
80 %; mp 185–187 °C; IR (KBr): m 3,129 cm-1 (NH); H
NMR (CDCl3): d 7.72 (d, J = 8.4 Hz, 1H, H8), 7.52 (s, 1H,
H3), 7.08 (d, J = 2.3 Hz, 1H, H5), 6.92 (dd, J = 2.3, 8.4 Hz,
1H, H7), 3.86 (s, 3H, OCH3), 3.67 ppm (s, 2H, H4).
123

J IRAN CHEM SOC (2013) 10:43–53
45
6-Methoxy-3-methyl-2,4-dihydroindeno[1,2-c]pyrazole
(5d): Yield 83 %; mp 198–200 °C; IR (KBr): m 3,145 cm-1
(NH); H NMR (CDCl3): d 7.65 (d, J = 7.9 Hz, 1H, H8),
7.05 (s, 1H, H5), 6.90 (d, J = 7.9 Hz, 1H, H7), 3.86 (s, 3H,
OCH3), 3.54 (s, 2H, H4), 2.3 ppm (s, 3H, CH3).
NMR (CDCl3): d 7.73 (d, J = 7.8 Hz, 1H, H9), 7.18 (s, 1H,
H3), 6.81 (d, J = 7.8 Hz, 1H, H8), 6.78 (s, 1H, H6), 4.22 (t,
J = 5.2 Hz, 2H, CH2CH2OH), 4.01 (t, J = 5.2 Hz, 2H,
CH2CH2OH), 3.83 (s, 3H, OCH3), 2.90 (t, J = 7.0 Hz, 2H,
H5), 2.75 ppm (t, J = 7.0 Hz, 2H, H4).
1
7-Methoxy-3-methyl-4,5-dihydro-2H-benzo[g]indazole
(5f): Yield 90 %; mp 171–173 °C; IR (KBr): m 3,170 cm-1
(NH); H NMR (CDCl3): d 7.66 (d, J = 8.2 Hz, 1H, H9),
6.81 (d, J = 8.2 Hz, 1H, H8), 6.80 (s, 1H, H6), 3.82 (s, 3H,
OCH3), 2.92 (t, J = 9.0 Hz, 2H, H5), 2.65 (t, J = 9.0 Hz,
2H, H4), 2.26 ppm (s, 3H, CH3).
2-(7-Methoxy-3-methyl-4,5-dihydro-2H-benzo[g]indazol-
2-yl)ethanol (3f): mp 123–125 °C; IR (KBr): m 3,227 cm-1
(OH); 1H NMR (CDCl3): d 7.71 (d, J = 8.0 Hz, 1H, H9), 6.81
(d, J = 8.0 Hz, 1H, H8), 6.78 (s, 1H, H6), 4.13 (t, J = 4.6 Hz,
2H, CH2CH2OH), 4.03 (t, J = 4.6 Hz, 2H, CH2CH2OH), 3.82
(s, 3H, OCH3), 2.90 (t, J = 7.4 Hz, 2H, H5), 2.64 (t,
J = 7.4 Hz, 2H, H4), 2.21 ppm (s, 3H, CH3).
1
General procedure C. Preparation
2-[5-(4-Methoxyphenyl)pyrazol-1-yl]ethanol (4a): mp
135–137 °C; IR (KBr): m 3,269 cm-1 (OH); 1H NMR
(CDCl3): d 7.47 (d, J = 1.6 Hz, 1H, H3), 7.33 (d,
J = 8.8 Hz, 2H, H2,6), 6.95 (d, J = 8.8 Hz, 2H, H3,5), 6.22
(d, J = 1.6 Hz, 1H, H4), 4.21 (t, J = 5.1 Hz, 2H,
CH2CH2OH), 3.97 (t, J = 5.1 Hz, 2H, CH2CH2OH),
3.85 ppm (s, 3H, OCH3).
of N-hydroxylethylpyrazoles
To a stirred mixture of protected pyrazole (5 or 9, 1 mmol),
sodium hydroxide (1.5 mmol), dioxane (50 ml) and ben-
zyltriethylammonium chloride (0.05 mmol) was dropwise
added to 2-bromoethanol (1 mmol) within 1 h at 80 °C.
The reaction mixture was stirred for further 1.5 h then the
mixture was then cooled, filtered and the solid were washed
with dioxane (3 9 10 ml). The solvent was evaporated
under reduced pressure and the residue was purified by
preparative TLC to give 3, 4, 10 or 11 [25].
2-[5-(4-Methoxyphenyl)-3-methylpyrazol-1-yl]ethanol
1
(4b): mp 149–151 °C; IR (KBr): m 3,289 cm-1 (OH); H
NMR (CDCl3): d 7.30 (d, J = 8.0 Hz, 2H, H2,6), 6.96 (d,
J = 8.0 Hz, 2H, H3,5), 6.05 (s, 1H, H4), 4.12 (t,
J = 4.7 Hz, 2H, CH2CH2OH), 3.93 (t, J = 4.7 Hz, 2H,
CH2CH2OH), 3.84 (s, 3H, OCH3), 2.29 ppm (s, 3H, CH3).
2-(6-Methoxyindeno[1,2-c]pyrazol-1(4H)-yl)ethanol (4c):
2-[3-(4-Methoxyphenyl)pyrazol-1-yl]ethanol (3a): mp
79–80 °C; IR (KBr): m 3,269 cm-1 (OH); 1H NMR
(CDCl3): d 7.67 (d, J = 8.5 Hz, 2H, H2,6), 7.60 (d,
J = 1.6 Hz, 1H, H5), 6.94 (d, J = 8.5 Hz, 2H, H3,5), 6.53
(d, J = 1.6 Hz, 1H, H4), 4.15 (t, J = 4.5 Hz, 3H,
CH2CH2OH), 4.01 (t, J = 4.5 Hz, 2H, CH2CH2OH),
3.84 ppm (s, 3H, OCH3).
1
mp 142–144 °C; IR (KBr): m 3,277 cm-1 (OH); H NMR
(CDCl3): d 7.44 (d, J = 8.2 Hz, 1H, H8), 7.39 (s, 1H, H3),
7.07 (s, 1H, H5), 6.87 (d, J = 8.2 Hz, 1H, H7), 4.47 (t,
J = 4.4 Hz, 2H, CH2CH2OH), 4.10 (t, J = 4.4 Hz, 2H,
CH2CH2OH), 3.85 (s, 3H, OCH3), 3.53 ppm (s, 2H, H4).
2-(6-Methoxy-3-methylindeno[1,2-c]pyrazol-1(4H)-yl)eth-
anol (4d): mp 165–166 °C; IR (KBr): m 3,293 cm-1 (OH); 1H
NMR (CDCl3): d 7.40 (d, J = 8.2 Hz, 1H, H8), 7.07 (s, 1H,
H5), 6.86 (d, J = 8.2 Hz, 1H, H7), 4.39 (t, J = 4.4 Hz, 2H,
CH2CH2OH), 4.06 (t, J = 4.4 Hz, 2H, CH2CH2OH), 3.84 (s,
3H, OCH3), 3.45 (s, 2H, H4), 2.29 ppm (s, 3H, H3).
2-[3-(4-Methoxyphenyl)-5-methylpyrazol-1-yl]ethanol
1
(3b): mp 128–129 °C; IR (KBr): m 3,284 cm-1 (OH); H
NMR (CDCl3): d 7.69 (d, J = 8.5 Hz, 2H, H2,6), 6.92 (d,
J = 8.5 Hz, 2H, H3,5), 6.28 (s, 1H, H4), 4.16 (t,
J = 4.4 Hz, 2H, CH2CH2OH), 4.05 (t, J = 4.4 Hz, 2H,
CH2CH2OH), 3.83 (s, 3H, OCH3), 2.31 ppm (s, 3H, CH3).
2-(6-Methoxyindeno[1,2-c]pyrazol-2(4H)-yl)ethanol (3c):
2-(7-Methoxy-4,5-dihydro-2H-benzo[g]indazol-1-yl)etha-
nol (4e): mp 109–110 °C; IR (KBr): m 3,211 cm-1 (OH); 1H
NMR (CDCl3): d 7.48 (d, J = 8.4 Hz, 1H, H9), 7.36 (s, 1H,
H3), 6.89 (d, J = 2.8 Hz, 1H, H6), 6.82 (dd, J = 2.8, 8.4 Hz,
1H, H8), 4.48 (t, J = 4.6 Hz, 2H, CH2CH2OH), 4.14 (t,
J = 4.6 Hz, 2H, CH2CH2OH), 3.84 (s, 3H, OCH3), 2.87 (t,
J = 7.0 Hz, 2H, H5), 2.68 ppm (t, J = 7.0 Hz, 2H, H4).
2-(7-Methoxy-3-methyl-4,5-dihydro-2H-benzo[g]indazol-
1-yl)ethanol (4f): mp 108–110 °C; IR (KBr): m 3,220 cm-1
(OH); 1H NMR (CDCl3): d 7.44 (d, J = 8.4 Hz, 1H, H9), 6.88
(d, J = 2.4 Hz, 1H, H6), 6.80 (dd, J = 2.4, 8.4 Hz, 1H, H8),
4.42 (t, J = 4.8 Hz, 2H, CH2CH2OH), 4.09 (t, J = 4.8 Hz,
2H, CH2CH2OH), 3.83 (s, 3H, OCH3), 2.86 (t, J = 7.2 Hz,
2H, H5), 2.57 (t, J = 7.2 Hz, 2H, H4), 2.22 ppm (s, 3H, H3).
mp 149–151 °C; IR (KBr): m 3,250 cm-1 (OH); H NMR
1
(CDCl3): d 7.63 (d, J = 7.9 Hz, 1H, H8), 7.25 (s, 1H, H3), 7.03
(s, 1H, H5), 6.88 (d, J = 7.9 Hz, 1H, H7), 4.29 (t, J = 4.5 Hz,
2H, CH2CH2OH), 4.03 (t, J = 4.5 Hz, 2H, CH2CH2OH), 3.84
(s, 3H, OCH3), 3.59 ppm (s, 2H, H4).
2-(6-Methoxy-3-methylindeno[1,2-c]pyrazol-2(4H)-yl)eth-
anol (3d): mp 123–125 °C; IR (KBr): m 3,257 cm-1 (OH); 1H
NMR (CDCl3): d 7.62 (d, J = 8.0 Hz, 1H, H8), 7.04 (s, 1H,
H5), 6.89 (d, J = 8.0 Hz, 1H, H7), 4.19 (t, J = 5.2 Hz, 2H,
CH2CH2OH), 4.05 (t, J = 5.2 Hz, 2H, CH2CH2OH), 3.85 (s,
3H, OCH3), 3.52 (s, 2H, H4), 2.33 ppm (s, 3H, CH3).
2-(7-Methoxy-4,5-dihydro-2H-benzo[g]indazol-2-yl)etha-
nol (3e): mp 135–137 °C; IR (KBr): m 3,203 cm-1 (OH); 1H
123

46
J IRAN CHEM SOC (2013) 10:43–53
General procedure D. Demethylation with BBr3
2.87 (t, J = 7.2 Hz, 2H), 2.74 ppm (t, J = 7.2 Hz, 2H);
MS m/z (%): 294 (M??2, 63), 292 (M?, 63), 230 (52), 199
(100), 187 (36), 169 (14), 147 (16), 128 (23), 107 (31), 91
(20), 77 (22), 41 (18).
To a stirred solution of methyl protected pyrazole (3a–f,
1 mmol) in dry CH2Cl2 (35 mL) at -78 °C, a solution of
BBr3 (1 M in dry CH2Cl2; 10–15 eq) was added dropwise.
After complete addition of BBr3, the reaction was main-
tained at -78 °C for 1 h and then the temperature was
allowed to rise to room temperature and stirred for 16 h in
this temperature. The mixture was cooled to 0 °C and
carefully quenched with H2O. The product was then
extracted with EtOAc (3 9 20 ml) and the organic layers
were dried over Na2SO4. After evaporation of the solvent
the residue was purified by chromatography (EtOAc/n-
hexane, 1:1) to give (6a–f).
2-(2-Bromoethyl)-3-methyl-4,5-dihydro-2H-benzo[g]
indazol-7-ol (6f): Yield 65 %; mp 224–226 °C; IR (KBr):
1
m 3,250 cm-1 (OH); H NMR (CDCl3): d 9.35 (bs, 1H,
OH), 7.44 (d, J = 8.2 Hz, 1H, H9), 6.65 (d, J = 2.2 Hz,
1H, H6), 6.62 (dd, J = 2.2, 8.2 Hz, 1H, H8), 4.39 (t,
J = 6.3 Hz, 2H, CH2CH2Br), 3.81 (t, J = 6.3 Hz, 2H,
CH2CH2Br), 2.76 (t, J = 7.2 Hz, 2H, H5), 2.55 ppm (t,
J = 7.2 Hz, 2H, H4); MS m/z (%): 308 (M??2, 19), 306
(M?, 19), 279 (24), 227 (5), 212 (28), 200 (29), 167 (84),
149 (100), 128 (54), 115 (35), 104 (22), 83 (35), 78 (55), 57
(66), 43 (36).
1-(2-Bromoethyl)-3-(4-hydroxyphenyl)pyrazole (6a): Yield
96 %; mp 109–110 °C; IR (KBr): m3,235 cm-1 (OH); 1HNMR
(DMSO-d6): d 7.36 (d, J = 8.6 Hz, 2H, H2,6), 7.29 (d,
J = 2.3 Hz, 1H, H5), 6.61 (d, J = 8.6 Hz, 2H, H3,5), 6.21 (d,
J = 2.3 Hz, 1H, H4), 4.28 (t, J = 6.2 Hz, 2H, CH2CH2Br),
3.54 ppm (t, J = 6.2 Hz, 2H, CH2CH2Br); MS m/z (%): 268
(M??2, 90), 266 (M?, 90), 239 (3), 237 (3), 219 (6), 190 (12),
173 (100), 161 (92), 131 (57), 107 (51), 77 (34), 51 (12).
1-(2-Bromoethyl)-3-(4-hydroxyphenyl)-5-methylpyrazole
(6b): Yield 90 %; mp 153–154 °C; IR (KBr): m 3,341 cm-1
(OH); 1H NMR (DMSO-d6): d 7.28 (t, J = 8.0 Hz, 2H, H2,6),
6.92 (d, J = 8.0 Hz, 2H, H3,5), 6.05 (s, 1H, H4), 4.38 (t,
J = 5.8 Hz, 2H, CH2CH2Br), 3.68 (t, J = 5.8 Hz, 2H,
CH2CH2Br), 2.32 ppm (s, 3H, CH3); MS m/z (%): 282
(M??2, 64), 280 (M?, 64), 248 (4), 201 (11), 188 (51), 174
(100), 146 (34), 115 (36), 91 (12), 65 (10).
3-(4-Benzyloxyphenyl)-3-oxopropanal (8a): It was
prepared according to ‘‘General procedure A’’ and was
completely enolized to 1-(4-benzyloxyphenyl)-3-hydroxy-
2-propen-1-one. Yield 67 %, mp 80–83 °C; IR (KBr): m
3,289 (OH), 1,633 cm-1 (C=O); 1H NMR (CDCl3): d
15.35 (bs, 1H, OH), 8.15 (d, J = 4.0 Hz, 1H, H3-vinylic),
7.89 (d, J = 8.2 Hz, 2H, H2,6), 7.50–7.28 (m, 5H, Ph), 7.02
(d, J = 8.2 Hz, 2H, H3,5), 6.16 (d, J = 4.0 Hz, 1H, H2-
vinylic), 5.14 (s, 2H, CH2).
1-(4-Benzyloxyphenyl)butane-1,3-dione (8b): It was
prepared according to ‘‘General procedure A’’ and was
partially enolized. Yield 73 %, mp 100–102 °C; IR (KBr):
1
m 3,346 (OH), 1,712 cm-1 (C=O); H NMR (CDCl3): d
7.91 (d, J = 8.4 Hz, 0.4H, H2,6), 7.86 (d, J = 8.4 Hz,
1.6H, H2,6), 7.45–7.30 (m, 5H, Ph), 7.01 (d, J = 8.4 Hz,
2H, H3,5), 6.12 (s, 0.8H, H-vinylic), 5.13 (s, 2H, CH2), 4.01
(s, 0.4H, CH2), 2.17 ppm (s, 3H, CH3).
2-(2-Bromoethyl)-2,4-dihydroindeno[1,2-c]pyrazol-6-ol
(6c): Yield 68 %; mp 144–146 °C; IR (KBr): m 3,251 cm-1
1
(OH); H NMR (CDCl3): d 7.57 (d, J = 8.1 Hz, 1H, H8),
6-Benzyloxy-3-hydroxy-1H-indene-2-carbaldehyde (8c):
It was prepared according to ‘‘General procedure A’’ and was
partially enolized to 5-benzyloxy-2-hydroxymethylene-2,3-
dihydroinden-1-one. Yield 72 %; mp 145–147 °C; IR (KBr):
m 3,307 (OH), 1,685 cm-1 (C=O); 1H NMR (CDCl3): d 7.77
(d, J = 8.8 Hz, 0.67H, H7), 7.69 (d, J = 8.8 Hz, 0.33H, H7),
7.44–7.32 (m, 6H, Ph, H-vinylic), 7.04–6.98 (m, 2H, H4,6),
5.15 (s, 2H, CH2-Ph), 3.55 ppm (s, 2H, H3).
7.32 (s, 1H, H3), 7.00 (s, 1H, H5), 6.83 (dd, J = 2.3,
8.1 Hz, 1H, H7), 4.57 (t, J = 6.2 Hz, 2H, CH2CH2Br), 3.77
(t, J = 6.2 Hz, 2H, CH2CH2Br), 3.59 ppm (s, 2H, H4); MS
m/z (%): 280 (M??2, 71), 278 (M?, 71), 201 (15), 185
(100), 173 (23), 158 (17), 135 (13), 115 (29), 89 (13), 63
(11).
2-(2-Bromoethyl)-3-methyl-2,4-dihydroindeno[1,2-c]pyr-
azol-6-ol (6d): Yield 70 %; mp 235–236 °C; IR (KBr): m
3,290 cm-1 (OH); 1H NMR (CDCl3): d 7.57 (d, J = 8.2 Hz,
1H, H8), 6.99 (d, J = 2.0 Hz, 1H, H5), 6.81 (dd, J = 2.0,
8.2 Hz, 1H, H7), 4.49 (t, J = 5.2 Hz, 2H, CH2CH2Br), 3.78 (t,
J = 5.2 Hz, 2H, CH2CH2Br), 3.52 (s, 2H, H4), 2.38 ppm (s,
3H, CH3); MS m/z (%): 294 (M??2, 86), 292 (M?, 86), 213
(20), 199 (100), 186 (46), 172 (28), 158 (19), 145 (17), 128
(58), 107 (16), 77 (22), 43 (19).
2-Acetyl-5-benzyloxy-2,3-dihydroinden-1-one (8d): It
was prepared according to ‘‘General procedure A’’ and was
partially enolized. Yield 76 %; mp 132–134 °C; IR (KBr):
1
m 3,320 (OH), 1,660 cm-1 (C=O); H NMR (CDCl3): d
7.75 (d, J = 8.5 Hz, 0.67H, H7), 7.65 (d, J = 8.5 Hz,
0.33H, H7), 7.45–7.35 (m, 5H, Ph), 7.03–6.96 (m, 2H,
H
4,6), 5.14 (s, 2H, CH2–Ph), 3.94 (dd, J = 3.2, 7.6 Hz,
0.33H, H2), 3.67 (dd, J = 3.2, 17.5 Hz, 0.33H, H3), 3.54 (s,
1.34H, H3), 3.05 (dd, J = 7.6, 17.5 Hz, 0.33H, H3), 2.48 (s,
1H, CH3), 2.12 ppm (s, 2H, CH3).
2-(2-Bromoethyl)-4,5-dihydro-2H-benzo[g]indazol-7-ol
(6e): Yield 72 %; mp 119–121 °C; IR (KBr): m 3,230 cm-1
1
(OH); H NMR (CDCl3): d 7.68 (d, J = 8.4 Hz, 1H, H9),
6-Benzyloxy-1-hydroxy-3,4-dihydronaphthalene-2-
carbaldehyde (8e): It was prepared according to
‘‘General procedure A’’ and was comletely enolized to
7.23 (s, 1H, H3), 6.72 (m, 2H, H6,8), 4.49 (t, J = 6.2 Hz,
2H, CH2CH2Br), 3.74 (t, J = 6.2 Hz, 2H, CH2CH2Br),
123

J IRAN CHEM SOC (2013) 10:43–53
47
6-benzyloxy-2-hydroxymethylene-3,4-dihydronaphthalen-
7-Benzyloxy-3-methyl-4,5-dihydro-2H-benzo[g]indazole
1(2H)-one. Yield 69 %; mp 88–90 °C; IR (KBr): m 3,400
(9f): It was prepared according to ‘‘General procedure B’’.
Yield 82 %; mp 141–142 °C; IR (KBr): m 3,219 cm-1 (NH);
1H NMR (CDCl3): d 7.66 (d, J = 8.0 Hz, 1H, H9), 7.45–7.31
(m, 5H, Ph), 6.88 (m, 2H, H6,8), 5.08 (s, 2H, CH2–Ph), 2.91 (t,
J = 7.2 Hz, 2H, H5), 2.65 (t, J = 7.2 Hz, 2H, H4), 2.26 ppm
(s, 3H, CH3).
1
(OH), 1,643 cm-1 (C=O); H NMR (CDCl3): d 14.66 (s,
1H, OH), 7.94 (d, J = 8.6 Hz, 1H, H8), 7.49–7.33 (m,
6H, Ph, H-vinylic), 6.93 (dd, J = 2.2, 8.6 Hz, 1H, H7),
6.81 (d, J = 2.2 Hz, 1H, H5), 5.12 (s, 2H, CH2-Ph), 2.86
(t, J = 7.0 Hz, 2H, H4), 2.55 ppm (t, J = 7.0 Hz, 2H, H3).
2-Acetyl-6-benzyloxy-3,4-dihydronaphthalen-1(2H)-one
(8f): It was prepared according to ‘‘General procedure A’’
and was partially enolized. Yield 75 %; mp 118–120 °C; IR
(KBr): m 3,310 (OH), 1,600 cm-1 (C=O); 1H NMR (CDCl3):
d 7.91 (d, J = 8.6 Hz, 1H, H9), 7.43–7.33 (m, 5H, Ph), 6.91
(dd, J = 2.4, 8.6 Hz, 1H, H8), 6.78 (d, J = 2.4 Hz, 1H, H6),
5.11 (s, 2H, CH2–Ph), 2.84 (t, J = 7.2 Hz, 2H, H5), 2.61 (t,
J = 7.2 Hz, 2H, H4), 2.19 ppm (s, 3H, CH3).
2-[3-(4-Benzyloxyphenyl)pyrazol-1-yl]ethanol (10a): It
was prepared according to ‘‘General procedure C’’. Yield
1
77 %; mp 117–119 °C; IR (KBr): m 3,248 cm-1 (OH); H
NMR (CDCl3): d 7.71 (d, J = 8.7 Hz, 2H, H2,6), 7.45 (d,
0
J = 7.2 Hz, 2H, H2 ,6 ), 7.41 (d, J = 2.2 Hz, 1H, H5-pyra-
0
0
zole), 7.39 (t, J = 7.2 Hz, 2H, H3 ,5 ), 7.33 (t, J = 7.2 Hz,
0
0
1H, H4 ), 7.01(d, J = 8.7 Hz, 2H, H3,5), 6.48(d, J = 2.2 Hz,
1H, H4-pyrazole), 5.10 (s, 2H, CH2), 4.25 (t, J = 4.5 Hz, 2H,
CH2CH2OH), 4.02 ppm (t, J = 4.5 Hz, 2H, CH2CH2OH).
2-[3-(4-Benzyloxyphenyl)-5-methylpyrazol-1-yl]ethanol
(10b): It was prepared according to ‘‘General procedure C’’.
Yield 72 %; mp 104–106 °C; IR (KBr): m 3,306 cm-1 (OH);
1H NMR (CDCl3): d 7.68 (d, J = 8.7 Hz, 2H, H2,6), 7.44 (d,
3-(4-Benzyloxyphenyl)-1H-pyrazole (9a): It was pre-
pared according to ‘‘General procedure B’’. Yield 73 %;
1
mp 113–115 °C; IR (KBr): m 3,425 cm-1 (NH); H NMR
(CDCl3): d 7.66 (d, J = 8.4 Hz, 2H, H2,6), 7.60 (s, 1H, H5-
0
0
pyrazole), 7.45 (d, J = 7.2 Hz, 2H, H2 ,6 ), 7.40 (t,
0
0
0
0
0
0
0
J = 7.2 Hz, 2H, H2 ,6 ), 7.39 (t, J = 7.2 Hz, 2H, H3 ,5 ), 7.32
J = 7.2 Hz, H3 ,5 ), 7.34 (t, J = 7.2 Hz, 1H, H4 ), 7.02 (d,
J = 8.4 Hz, 2H, H3,5), 6.54 (s, 1H, H4-pyrazole), 5.11 (s,
2H, CH2).
0
(t, J = 7.2 Hz, 1H, H4 ), 6.99 (d, J = 8.7 Hz, 2H, H3,5), 6.27
(s, 1H, H4-pyrazole), 5.09 (s, 2H, CH2), 4.13 (t, J = 4.4 Hz,
2H, CH2CH2OH), 4.05 (t, J = 4.4 Hz, 2H, CH2CH2OH),
2.30 ppm (s, 3H, CH3).
3-(4-Benzyloxyphenyl)-5-methyl-1H-pyrazole (9b): It
was prepared according to ‘‘General procedure B’’. Yield
87 %; mp 149–150 °C; IR (KBr): m 3,381 cm-1 (NH); H
NMR (CDCl3): d 7.64 (d, J = 8.5 Hz, 2H, H2,6), 7.44 (d,
0
J = 7.2 Hz, 2H, H2 ,6 ), 7.39 (t, J = 7.2 Hz, 2H, H3 ,5 ),
1
2-(6-Benzyloxyindeno[1,2-c]pyrazol-2(4H)-yl)ethanol
(10c): It was prepared according to ‘‘General procedure
C’’. Yield 27 %; mp 118–120 °C; IR (KBr): m 3,415 cm-1
0
0
0
1
0
7.32 (t, J = 7.2 Hz, 1H, H4 ), 7.00 (d, J = 8.5 Hz, 2H,
(OH); H NMR (CDCl3): d 7.63 (d, J = 8.2 Hz, 1H, H8),
H
3,5), 6.29 (s, 1H, H4-pyrazole), 5.09 (s, 2H, CH2), 2.35 (s,
3H, CH3).
6-Benzyloxy-2,4-dihydroindeno[1,2-c]pyrazole (9c): It
7.48–7.32 (m, 6H, Ph, H3), 7.16 (s, 1H, H5), 6.96 (d,
J = 8.2 Hz, 1H, H7), 5.11 (s, 2H, CH2-Ph), 4.30 (t,
J = 4.7 Hz, 2H, CH2CH2OH), 4.03 (t, J = 4.7 Hz, 2H,
CH2CH2OH), 3.55 ppm (s, 2H, H4).
was prepared according to ‘‘General procedure B’’. Yield
1
84 %; mp 189–191 °C; IR (KBr): m 3,129 cm-1 (NH); H
2-(6-Benzyloxy-3-methylindeno[1,2-c]pyrazol-2(4H)-
yl)ethanol (10d): Yield 3 %; mp 128–130 °C; IR (KBr,
cm-1): m 3,320 (OH); 1H NMR (CDCl3): d 7.65 (d,
J = 8.4 Hz, 1H, H8), 7.46–7.34 (m, 5H, Ph), 7.10 (d,
J = 2.4 Hz, H5), 6.94 (dd, J = 2.4, 8.4 Hz, 1H, H7), 5.10
(s, 2H, CH2-Ph), 4.18 (t, J = 4.8 Hz, 2H, CH2CH2OH),
4.04 (t, J = 4.8 Hz, 2H, CH2CH2OH), 3.48 (s, 2H, H4),
2.32 ppm (s, 3H, CH3).
NMR (CDCl3): d 7.64 (d, J = 8.4 Hz, 1H, H8), 7.47–7.32
(m, 6H, Ph, H3), 7.16 (d, J = 2.4 Hz, 1H, H5), 6.98 (dd,
J = 2.4, 8.4 Hz, 1H, H7), 5.11 (s, 2H, CH2–Ph), 3.63 ppm
(s, 2H, H4).
6-Benzyloxy-3-methyl-2,4-dihydroindeno[1,2-c]pyra-
zole (9d): It was prepared according to ‘‘General pro-
cedure B’’. Yield 83 %; mp 198–200 °C; IR (KBr): m
3,114 cm-1 (NH); 1H NMR (CDCl3): d 7.64 (d,
J = 8.3 Hz, 1H, H8), 7.46–7.32 (m, 5H, Ph), 7.14 (d,
J = 2.2 Hz, 1H, H5), 6.93 (dd, J = 2.4, 8.3 Hz, 1H, H7),
5.11 (s, 2H, CH2–Ph), 3.53 (s, 2H, H4), 2.36 ppm (s, 3H,
CH3).
2-(7-Benzyloxy-4,5-dihydro-2H-benzo[g]indazol-2-yl)
ethanol (10e): It was prepared according to ‘‘General pro-
cedure C’’. Yield 43 %; mp 112–114 °C; IR (KBr): m
3,203 cm-1 (OH); 1H NMR (CDCl3):
d 7.73 (d,
J = 8.1 Hz, 1H, H9), 7.47–7.32 (m, 5H, Ph), 7.17 (s, 1H,
H3), 6.89–6.87 (m, 2H, H6,8), 5.07 (s, 2H, CH2–Ph), 4.20 (t,
J = 4.7 Hz, 2H, CH2CH2OH), 3.99 (t, J = 4.7 Hz, 2H,
CH2CH2OH), 2.89 (t, J = 7.2 Hz, 2H, H5), 2.74 ppm (t,
J = 7.2 Hz, 2H, H4).
7-Benzyloxy-4,5-dihydro-2H-benzo[g]indazole (9e): It
was prepared according to ‘‘General procedure B’’. Yield
89 %; mp 152–154 °C; IR (KBr): m 3,270 cm-1 (NH); H
NMR (CDCl3): d 7.62 (d, J = 7.4 Hz, 1H, H9), 7.45–7.33
(m, 6H, Ph, H3), 6.89 (s, 1H, H6), 6.87 (d, J = 8.6 Hz, 1H,
H8), 5.12 (s, 2H, CH2–Ph), 2.92 (t, J = 7.2 Hz, 2H, H5),
2.78 ppm (t, J = 7.2 Hz, 2H, H4).
1
2-(7-Benzyloxy-3-methyl-4,5-dihydro-2H-benzo[g]indazol
-2-yl)ethanol (10f): It was prepared similar to ‘‘General
procedure C’’. Yield 37 %; mp 123–125 °C; IR (KBr): m
123

48
J IRAN CHEM SOC (2013) 10:43–53
3,227 cm-1 (OH); 1H NMR (CDCl3):
d
7.72 (d,
6.87 (dd, J = 2.6, 8.2 Hz, 1H, H8), 5.09 (s, 2H, CH2–Ph),
4.42 (t, J = 4.8 Hz, 2H, CH2CH2OH), 4.09 (t, J = 4.8 Hz,
2H, CH2CH2OH), 2.86 (t, J = 7.0 Hz, 2H, H5), 2.57 (t,
J = 7.0 Hz, 2H, H4), 2.23 ppm (s, 3H, CH3).
J = 8.0 Hz, 1H, H9), 7.46–7.33 (m, 5H, Ph), 6.88 (m, 2H,
6,8), 5.09 (s, 2H, CH2–Ph), 4.12 (t, J = 4.6 Hz, 2H,
H
CH2CH2OH), 3.96 (t, J = 4.6 Hz, 2H, CH2CH2OH), 2.90
(t, J = 7.2 Hz, 2H, H5), 2.64 (t, J = 7.2 Hz, 2H, H4),
2.10 ppm (s, 3H, CH3).
General procedure E. Hydrogenolysis of benzyl-
protected pyrazoles
2-[3-(5-Benzyloxyphenyl)pyrazol-1-yl]ethanol (11a): It
was prepared according to ‘‘General procedure C’’. Yield
12 %; mp 138–140 °C; IR (KBr): m 3,282 cm-1 (OH); H
NMR (CDCl3): d 7.70 (d, J = 8.8 Hz, 2H, H2,6), 7.54 (d,
J = 2.2 Hz, 1H, H5-pyrazole), 7.47 (d, J = 7.2 Hz, 2H,
1
N-Hydroxylethylpyrazole derivatives (10a–f, 0.2 mmol) in
MeOH–AcOH (5:1, 20 ml) were hydrogenated over 10 %
Pd/C (10 mg) at 60 psi and the progress of the reaction was
monitored by TLC. When the reaction was complete, the
resulting mixture was filtered through Celite, and concen-
trated under reduced pressure to give debenzylated residues
(12a–f) [12].
0
2 ,6 ), 7.39 (t, J = 7.2 Hz, 2H, H3 ,5 ), 7.35 (t, J = 7.2 Hz,
0
0
0
H
0
1H, H4 ), 7.04 (d, J = 8.8 Hz, 2H, H3,5), 6.27 (d,
J = 2.2 Hz, 1H, H4-pyrazole), 5.12 (s, 2H, CH2–Ph), 4.20
(t, J = 4.7 Hz, 2H, CH2CH2OH), 3.97 ppm (t, J = 4.7 Hz,
2H, CH2CH2OH).
2-(3-(4-Hydroxyphenyl)pyrazol-1-yl)ethanol (12a):
Yield 89 %; mp 152–153 °C; IR (KBr): m 3,229 cm-1 (OH);
1H NMR (CD3OD): d 7.61 (d, J = 2.2 Hz, 1H, H5-pyra-
zole), 7.59 (d, J = 8.5 Hz, 2H, H2,6), 6.81 (d, J = 8.5 Hz,
2H, H3,5), 6.49 (d, J = 2.2 Hz, 1H, H4-pyrazole), 4.25 (t,
J = 4.5 Hz, 2H, CH2CH2OH), 3.91 ppm (t, J = 4.5 Hz,
2H, CH2CH2OH); MS m/z (%): 204 (M?, 72), 173 (100), 161
(40), 146 (20), 119 (12), 91 (10), 77 (10), 65 (12).
2-[3-(5-Benzyloxyphenyl)-5-methylpyrazol-1-yl]ethanol
(11b): It was prepared according to ‘‘General procedure
C’’. Yield 19 %; mp 137–139 °C; IR (KBr): m 3,265 cm-1
(OH); 1H NMR (CDCl3): d 7.69 (d, J = 8.7 Hz, 2H, H2,6),
0
7.45 (d, J = 7.2 Hz, 2H, H2 ,6 ), 7.37 (t, J = 7.2 Hz, 2H,
0
0 0 0
3 ,5 ), 7.30 (t, J = 7.2 Hz, 1H, H4 ), 7.03 (d, J = 8.7 Hz,
H
2H, H3,5), 6.05 (s, 1H, H4-pyrazole), 5.11 (s, 2H, CH2-Ph),
4.18 (t, J = 4.4 Hz, 2H, CH2CH2OH), 3.95 (t, J = 4.4 Hz,
2H, CH2CH2OH), 2.29 ppm (s, 3H, CH3).
2-(3-(4-Hydroxyphenyl)-5-methylpyrazol-1-yl)ethanol
(12b): Yield 92 %; mp 123–125 °C; IR (KBr): m 3,227 cm-1
(OH); 1H NMR (CD3OD): d 7.57 (d, J = 9.0 Hz, 2H, H2,6),
6.83 (d, J = 9.0 Hz, 2H, H3,5), 6.40 (s, 1H, H4-pyrazole),
4.22 (t, J = 5.5 Hz, 2H, CH2CH2OH), 3.90 (t, J = 5.5 Hz,
2H, CH2CH2OH), 3.28 ppm (s, 3H, CH3); MS m/z (%): 218
(M?, 72), 187 (100), 173 (55), 146 (33), 127 (10), 107 (34),
86 (32), 77 (22), 57 (20).
2-(6-Benzyloxyindeno[1,2-c]pyrazol-1(4H)-yl)ethanol
(11c): It was prepared according to ‘‘General procedure
C’’. Yield 45 %; mp 128–130 °C; IR (KBr): m 3,300 cm-1
1
(OH); H NMR (CDCl3): d 7.45–7.32 (m, 7H, Ph, H3,8),
7.15 (dd, J = 2.3, 8.4 Hz, H7), 5.11 (s, 2H, CH2–Ph), 4.47
(t, J = 4.8 Hz, 2H, CH2CH2OH), 4.10 (t, J = 4.8 Hz, 2H,
CH2CH2OH), 3.54 ppm (s, 2H, H4).
2-(2-Hydroxyethyl)-2,4-dihydroindeno[1,2-c]pyrazol-6-ol
(12c): Yield 72 %; mp 216–218 °C; IR (KBr): m 3,229,
3,218 cm-1 (OH); 1H NMR (CD3OD): d 7.50 (d, J = 8.2 Hz,
1H, H8), 7.35 (s, 1H, H3), 6.96 (s, 1H, H5), 6.77 (d, J = 8.2 Hz,
1H, H7), 4.24 (t, J = 5.3 Hz, CH2CH2OH), 3.90 (t,
J = 5.3 Hz, CH2CH2OH), 3.55 ppm (s, 2H, H4); MS m/z (%):
216 (M?, 85), 185 (100), 172 (76), 141 (34), 77 (42), 85 (31).
2-(2-Hydroxyethyl)-4,5-dihydro-2H-benzo[g]indazol-7-
ol (12e): Yield 65 %; mp 202–204 °C; IR (KBr): m 3,203,
2-(6-Benzyloxy-3-methylindeno[1,2-c]pyrazol-1(4H)-
yl)ethanol (11d): Yield 83 %; mp 116–118 °C; IR (KBr): m
3,320 cm-1 (OH); 1H NMR (CDCl3): d 7.45–7.33 (m, 6H,
Ph, H8), 7.14 (d, J = 2.3 Hz, 1H, H5), 6.94 (dd, J = 2.3,
8.3 Hz, 1H, H7), 5.10 (s, 2H, CH2–Ph), 4.39 (t, J = 4.8 Hz,
2H, CH2CH2OH), 4.06 (t, J = 4.8 Hz, 2H, CH2CH2OH),
3.45 (s, 2H, H4), 2.29 ppm (s, 3H, CH3).
2-(7-Benzyloxy-4,5-dihydro-2H-benzo[g]indazol-1-
yl)ethanol (11e): It was prepared according to ‘‘General
procedure C’’. Yield 30 %; mp 87–89 °C; IR (KBr): m
1
3,118 cm-1 (OH); H NMR (DMSO-d6): d 9.35 (s, 1H,
Ph–OH), 7.44 (d, J = 8.2 Hz, 1H, H9), 7.42 (s, 1H, H3),
6.63–6.61 (m, 2H, H6,8), 4.88 (t, J = 5.0 Hz, 1H,
CH2CH2OH), 4.07 (t, J = 5.0 Hz, 2H, CH2CH2OH), 3.70
(q, J = 5.0 Hz, 2H, CH2CH2OH), 2.73 (t, J = 7.2 Hz, 2H,
H5), 2.61 ppm (t, J = 7.2 Hz, 2H, H4); MS m/z (%): 230
(M?, 87), 199 (100), 186 (15), 128 (9), 115 (10).
3,203 cm-1 (OH); 1H NMR (CDCl3):
d 7.73 (d,
J = 8.1 Hz, 1H, H9), 7.46–7.30 (m, 6H, Ph, H3), 6.97 (d,
J = 2.4 Hz, 1H, H6), 6.88 (dd, J = 2.4, 8.1 Hz, 1H, H8),
5.09 (s, 2H, CH2–Ph), 4.46 (t, J = 4.8 Hz, 2H,
CH2CH2OH), 4.12 (t, J = 4.8 Hz, 2H, CH2CH2OH), 2.85
(t, J = 7.2 Hz, 2H, H5), 2.66 ppm (t, J = 7.2 Hz, 2H, H4).
2-(7-Benzyloxy-3-methyl-4,5-dihydro-2H-benzo[g]inda-
zol-1-yl)ethanol (11f): It was prepared according to ‘‘Gen-
eral procedure C’’. Yield 37 %; mp 123–125 °C; IR (KBr): m
3,227 cm-1 (OH); 1H NMR (CDCl3): d 7.71 (d, J = 8.2 Hz,
H9), 7.45–7.34 (m, 5H, Ph), 6.97 (d, J = 2.6 Hz, 1H, H6),
2-(2-Hydroxyethyl)-3-methyl-4,5-dihydro-2H-benzo
[g]indazol-7-ol (12f): Yield 68 %; mp 209–211 °C; IR
(KBr): m 3,313, 3,120 cm-1 (OH); 1H NMR (DMSO-d6): d
9.31 (bs, 1H, Ph–OH), 7.59 (d, J = 8.2 Hz, 1H, H9), 6.63
(d, J = 2.4 Hz, 1H, H6), 6.60 (dd, J = 2.4, 8.2 Hz, 1H,
H8), 4.48 (t, J = 5.6 Hz, 2H, CH2CH2OH), 4.02 (t,
123

J IRAN CHEM SOC (2013) 10:43–53
49
J = 5.6 Hz, 2H, CH2CH2OH), 3.68 (q, J = 5.6 Hz, 2H,
CH2CH2OH), 2.73 (t, J = 7.4 Hz, 2H, H5), 2.61 (t,
J = 7.4 Hz, 2H, H4), 2.18 ppm (s, 3H, CH3); MS m/z (%):
244 (M?, 74), 213 (96), 200 (100), 159 (24), 131 (16), 115
(25), 77 (12).
3-Methyl-2,4-dihydroindeno[1,2-c]pyrazol-6-ol (14d):
Yield 67 %; mp 299–301 °C; IR (KBr): m 3,300 (OH),
1
3,243 cm-1 (NH); H NMR (DMSO-d6): d 12.08 (bs, 1H,
NH), 9.32 (bs, 1H, OH), 7.32 (d, J = 8.0 Hz, 1H, H8), 6.88
(d, J = 2.2 Hz, 1H, H5), 6.69 (dd, J = 2.2, 8.0 Hz, 1H,
H7), 3.40 (s, 2H, H4), 2.23 ppm (s, 3H, CH3).
General procedure F. Demethylation of methyl
protected pyrazoles with HBr
3-Methyl-4,5-dihydro-2H-benzo[g]indazol-7-ol (14f):
Yield 70 %; mp 250–252 °C; IR (KBr): m 3,300 (OH),
1
3,252 cm-1 (NH); H NMR (DMSO-d6): d 12.18 (bs, 1H,
Pyrazole derivatives (5a–f, 5 mmol) were boiled in aque-
ous 48 % hydrobromic acid (25 ml) for 12 h under nitro-
gen. The mixture was then cooled and filtered. The
precipitate was dissolved in sodium hydroxide (20 ml,
6 %). The solution was neutralized with sodium bicar-
bonate solution (10 %) and filtered, dried and recrystallized
to give 14a–f. The spectral data of 14e were similar with
those reported [11].
NH), 9.32 (bs, 1H, OH), 7.40 (d, J = 8.2 Hz, 1H, H9), 6.64
(s, 1H, H6), 6.61 (d, J = 8.2 Hz, 1H, H8), 2.74 (t, J = 7.2 Hz,
2H, H5),2.51 (t, J = 7.2 Hz, 2H, H4), 2.10 ppm (s, 3H, CH3).
General procedure G. Preparation
of N-hydroxymethylpyrazoles (15a–f)
Demethylated-pyrazole derivatives (14a–f, 1 mmol) and
paraformaldehyde (1.3 mmol) were placed under nitrogen.
The interior of the flask was flushed with dry nitrogen three
times. Dry THF (30 ml) was added to give a suspension.
The suspension was kept well stirred at 45 °C until the
starting material disappeared by TLC control. Evaporation
of THF under reduced pressure gave residues which were
recrystallized from ethyl acetate to give 15a–f [14].
1-Hydroxymethyl-3-(4-hydroxyphenyl)pyrazole (15a):
Yield 84 %; mp 177–178 °C; IR (KBr): m 3,280, 3,230 cm-1
(OH); 1H NMR (DMSO-d6): d 9.56 (bs, 1H, Ph–OH), 7.23
(d, J = 2.5 Hz, 1H, H5), 7.22 (d, J = 8.7 Hz, 2H, H2,6), 6.43
(d, J = 8.7 Hz, 2H, H3,5), 6.09 (d, J = 2.5 Hz, 1H, H4),
5.06 ppm (s, 2H, CH2OH); MS m/z (%): 190 (M?, 3), 160
(100), 131 (96), 103 (25), 77 (42), 51 (21).
3-(4-Hydroxyphenyl)-1H-pyrazole (14a): Yield 93 %;
mp 184–185 °C; IR (KBr): m 3,396 (OH), 3,263 cm-1 (NH);
1H NMR (CDCl3): d 9.60 (bs, 1 H, Ph–OH), 7.59 (d,
J = 8.0 Hz, 2H, H2,6), 7.55 (d, J = 1.6 Hz, 1H, H5), 6.88 (d,
J = 8.0 Hz, 2H, H3,5), 6.45 ppm (d, J = 1.6 Hz, 1H, H4).
3-(4-Hydroxyphenyl)-5-methyl-1H-pyrazole (14b):
Yield 95 %; mp [ 300 °C; IR (KBr): m 3,310 (OH),
1
3,255 cm-1 (NH); H NMR (DMSO-d6): d 9.53 (bs, 1 H,
OH), 7.53 (d, J = 8.3 Hz, 2H, H2,6), 6.77 (d, J = 8.3 Hz,
2H, H3,5), 6.31 (s, 1H, H4), 2.22 ppm (s, 3H, CH3).
2,4-Dihydroindeno[1,2-c]pyrazol-6-ol (14c): Yield
60 %; mp 171–173 °C; IR (KBr): m 3,300 (OH), 3,225 cm-1
(NH); 1H NMR (DMSO-d6): d 12.43 (bs, 1H, NH), 9.37 (bs,
1H, OH), 7.50 (s, 1H, H3), 7.38 (d, J = 8.1 Hz, 1H, H8), 6.92
(s, J = 2.1 Hz, 1H, H5), 6.72 (dd, J = 2.1, 8.1 Hz, 1H, H7),
3.50 ppm (s, 2H, H4).
1-Hydroxymethyl-3-(4-hydroxyphenyl)-5-methyl-pyra-
zole (15b): Yield 98 %; mp [300 °C; IR (KBr): m
OH
HO
N
O
N
N
N
O
O
a
R1
a
R1
CH3
R1
a
b
+
H3CO
H3CO
H3CO
H3CO
1a
4a, R1 = H (72%)
4b, R1 = CH3 (65%)
3a, R1 = H (12%)
3b, R1 = CH3 (18%)
2a, R1 = H
2b, R1 = CH3
HO
N
N
a
OH
O
O
N
a
N
O
b
a
R1
+
R1
H3CO
R1
H3CO
H3CO
H3CO
1b, n = 1
1c, n = 2
4c, R1 = H, n = 1 (48%)
4d, R1 = CH3, n = 1 (90%)
4e, R1 = H, n = 2 (91%)
4f, R1 = CH3, n = 2 (43%)
3c, R1 = H, n = 1 (41%)
2c, R1 = H, n = 1
3d, R1 = CH3, n = 1 (1%)
3e, R1 = H, n = 2 (1%)
3f, R1 = CH3, n = 2 (49%)
2d, R1 = CH3, n = 1
2e, R1 = H, n = 2
2f, R1 = CH3, n = 2
Scheme 1 Reagents and conditions: a R1COOCH3, C2H5ONa, 0 °C to r.t.; b NH2NHCH2CH2OH, THF, DMF (1:1), reflux
123

50
J IRAN CHEM SOC (2013) 10:43–53
3,226 cm-1 (OH); 1H NMR (DMSO-d6): d 9.46 (bs, 1H, Ph–
OH), 7.56 (d, J = 8.2 Hz, 2H, H2,6), 6.76 (d, J = 8.2 Hz,
2H, H3,5), 6.35 (s, 1 H, H4), 5.32 (s, 2H, CH2OH), 2.31 ppm
(s, 3H, CH3); MS m/z (%): 204 (M?, 4), 174 (100), 145 (40),
131 (60), 115 (83), 91 (31), 77 (12), 63 (23), 42 (23).
2-Hydroxymethyl-2,4-dihydroindeno[1,2-c]pyrazol-6-ol
9.43 (bs, 1H, Ph–OH), 7.35 (d, J = 8.0 Hz, 1H, H8), 6.90
(d, J = 1.7 Hz, 1H, H5), 6.71 (dd, J = 1.7, 8.0 Hz, 1H,
H7), 6.47 (t, J = 7.3 Hz, CH2–OH), 5.33 (d, J = 7.3 Hz,
2H, CH2–OH), 3.44 (s, 2H, H4), 2.32 ppm (s, 3H, CH3);
MS m/z (%): 216 (M?, 5), 186 (100), 171 (74), 145 (64),
116 (27), 89 (37), 42 (25).
(15c): Yield 84 %; mp 170–172 °C; IR (KBr):
m
2-Hydroxymethyl-4,5-dihydro-2H-benzo[g]indazol-7-ol
(15e): Yield 80 %; mp 203–205 °C; IR (KBr): m 3,392,
3,232 cm-1 (OH). H NMR (DMSO-d6): d 9.46 (bs, 1H,
Ph–OH), 7.60 (bs, 1H, H3), 7.38 (d, J = 7.7 Hz, 1H, H8),
6.91 (s, 1H, H5), 6.72 (d, J = 7.7 Hz, 1H, H7), 6.64 (t,
J = 7.4 Hz, 1H, CH2-OH), 5.36 (d, J = 7.4 Hz, 2H, CH2–
OH), 3.50 ppm (s, 2H, H4). MS m/z (%): 202 (M?, 4), 172
(100), 145 (82), 115 (62), 89 (82), 63 (50).
1
1
3,262 cm-1 (OH); H NMR (DMSO-d6): d 9.39 (bs, 1H,
Ph–OH), 7.51 (bs, 1H, H3), 7.46 (d, J = 8.2 Hz, 1H, H9),
6.63 (m, 3H, H6,8 and CH2–OH), 5.30 (s, 2H, CH2–OH),
2.75 (t, J = 7.2 Hz, 2H, H5), 2.63 ppm (t, J = 7.2 Hz, 2H,
H4). MS m/z (%): 216 (M?, 3), 186 (100), 185 (95), 158
(80), 131 (55), 103 (33), 84 (57), 66 (29).
2-Hydroxymethyl-3-methyl-2,4-dihydroindeno[1,2-c]
pyrazol-6-ol (15d): Yield 85 %; mp 283–285 °C; IR
(KBr): m 3,414, 3,206 cm-1 (OH); 1H NMR (DMSO-d6): d
2-Hydroxymethyl-3-methyl-4,5-dihydro-2H-benzo[g]
indazol-7-ol (15f): Yield 70 %; mp 248–250 °C; IR (KBr): m
Br
N
N
R1
HO
6a, R1 = H
6b, R1 = CH3
e
OH
HO
N
N
N
N
NH
N
a
R1
O
O
a
R1
R1
+
d
R1
c
H3CO
H3CO
H3CO
H3CO
4a, R1 = H (22%)
4b, R1 = CH3 (9%)
5a, R1 = H
5b, R1 = CH3
3a, R1 = H (78%)
3b, R1 = CH3 (73%)
2a, R1 = H
2b, R1 = CH3
HO
N
N
OH
a
N
N
a
O
N
NH
O
d
c
R1
+
R1
R1
H3CO
H3CO
H3CO
R1
H3CO
4c, R1 = H, n = 1 (37%)
4d, R1 = CH3, n = 1 (41%)
4e, R1 = H, n = 2 (42%)
4f, R1 = CH3, n = 2 (37%)
3c, R1 = H, n = 1 (34%)
5c, R1 = H, n = 1
2c, R1 = H, n = 1
3d, R1 = CH3, n = 1 (29%)
3e, R1 = H, n = 2 (34%)
3f, R1 = CH3, n = 2 (41%)
5d, R1 = CH3, n = 1
5e, R1 = H, n = 2
5f, R1 = CH3, n = 2
2d, R1 = CH3, n = 1
2e, R1 = H, n = 2
2f, R1 = CH3, n = 2
e
Br
N
N
R1
HO
6c, R1 = H, n = 1
6d, R1 = CH3, n = 1
6e, R1 = H, n = 2
6f, R1 = CH3, n = 2
Scheme 2 Reagents and conditions: c NH2NH2ꢀH2O, CH3COOH, C2H5OH, reflux; d BrCH2CH2OH, NaOH, benzyltriethylammonium
chloride, dioxane, 80 °C; e BBr3, CH2Cl2, -78 °C
123

J IRAN CHEM SOC (2013) 10:43–53
51
3,300 cm-1 (OH); 1H NMR (DMSO-d6): d 9.34 (bs, 1H, Ph–
OH), 7.45 (d, J = 8.2 Hz, 1H, H9), 6.63 (m, 3H, H6,8 and
CH2–OH), 5.31 (s, 2H, CH2–OH), 2.76 (t, J = 7.2 Hz, 2H,
H5), 2.55 (t, J = 7.2 Hz, 2H, H4), 2.26 ppm (s, 3H, CH3);
MS m/z (%): 230 (M?, 4), 200 (100), 199 (95), 158 (55), 131
(58), 115 (60), 77 (76), 42 (58).
subsequent condensation with the appropriate hydrazine
derivative.
The first pathway involved the acylation of methoxy-
substituted acetophenone (1a), indanone (1b) and tetralone
(1c) which afforded the 1,3-dicarbonyl compounds (4a–f)
[7–10]. Sunsequent condensation of the latters with
hydroxyethylhydrazine furnished for some derivatives (4a,
4b, 4d and 4e) predominantly the hydroxylethylpyrazoles 4
(Scheme 1) [26]. However, it is noteworthy that the main
goal of this synthetic route was the preparation of 3a–f.
The configuration of the pyrazole products was eluci-
dated through 2D NOE NMR spectroscopy. More specifi-
cally, the assigned regiochemistry of compounds 4a–f were
consistent with the observed strong cross peak between Ha
and the ethyl group. On the contrary, for compounds
Results and discission
The synthetic reactions used for the preparation of
N-hydroxyethyl (12a–f) and N-hydroxymethylpyrazole
derivatives (15a–f) are illustrated in Schemes 1, 2, 3 and 4.
A general route to access the target pyrazole derivatives
is via acylation of the corresponding substrates 1a–c and
OH
N
N
R1
O
HO
12a, R1 = H
12b, R1 = CH3
BnO
7a
OH
i
f
HO
N
N
N
N
NH
N
a
R1
O
O
a
R1
R1
+
h
R1
g
BnO
BnO
BnO
BnO
11a, R1 = H (12%)
11b, R1 = CH3 (19%)
10a, R1 = H (77%)
10b, R1 = CH3 (72%)
8a, R1 = H
8b, R1 = CH3
9a, R1 = H
9b, R1 = CH3
HO
N
OH
a
N
N
a
N
O
N
NH
R1
O
h
g
R1
+
R1
BnO
BnO
BnO
R1
BnO
11c, R1 = H, n = 1 (45%)
11d, R1 = CH3, n = 1 (83%)
11e, R1 = H, n = 2 (30%)
11f, R1 = CH3, n = 2 (42%)
10c, R1 = H, n = 1 (27%)
10d, R1 = CH3, n = 1 (3%)
10e, R1 = H, n = 2 (43%)
10f, R1 = CH3, n = 2 (37%)
9c, R1 = H, n = 1
8c, R1 = H, n = 1
9d, R1 = CH3, n = 1
9e, R1 = H, n = 2
9f, R1 = CH3, n = 2
8d, R1 = CH3, n = 1
8e, R1 = H, n = 2
8f, R1 = CH3, n = 2
i
f
OH
N
O
N
R1
HO
BnO
12c, R1 = H, n = 1
12d, R1 = CH3, n = 1
12e, R1 = H, n = 2
12f, R1 = CH3, n = 2
7b, n = 1
7c, n = 1
Scheme 3 Reagents and conditions: f R1COOCH3, C2H5ONa, 0 °C to r.t.; g NH2NH2.H2O, CH3COOH, C2H5OH, reflux; h BrCH2CH2OH,
NaOH, benzyltriethylammonium chloride, dioxane, 80 °C; i Pd/C, H2 (60 psi), MeOH–AcOH, r.t
123

52
J IRAN CHEM SOC (2013) 10:43–53
3a–f the observed enhancement of the ethyl protons cor-
responds to R1 hydrogens (H or methyl) substituted on
pyrazole ring (Scheme 1).
considering that the hydroxyl groups on aliphatic chains in
the presence of a lewis acid would be susceptible for
substitution with bromide as a nucleophile.
The second pathway involved the condensation of the
1,3-dicarbonyl compounds (2a–f) with hydrazine hydrate
in the presence of acetic acid which produced the pyrazole
compounds 5a–f (Scheme 2) [8–13]. The substitution
reaction of pyrazole with 2-bromoethanol in basic media in
the presence of benzyltriethylammonium chloride fur-
nished a mixture of 3a–f and their regioisomer 4a–f, which
were separated by preparative TLC. Finally, removal of the
methoxy protecting groups of 3a–f promoted by BBr3
resulted in compounds 6a–f, as depicted in Scheme 2,
which their characterization by mass spectrometry showed
that as well as demethylation, the aliphatic hydroxyl group
was displaced with bromine. This can be rationalized
The third synthetic route refers to the use of benzyl
substituent as the protecting group of phenol moiety to
avoid the latter substitution of hydroxyl with bromine.
Similarly, the acylation of benzyloxy-substituted aceto-
phenone (7a), indanone (7b) and tetralone (7c) afforded the
1,3-dicarbonyl compounds (8a–f). Subsequent condensa-
tion of the latters with hydrazine hydrate and further
alkylation of the resulted pyrazole with 2-bromoethanol
furnished a mixture of regioisomers 10a–f and 11a–f,
which were separated by preparative TLC. Final hydrog-
enolysis of 10a–f for removal of the benzyloxy-protecting
groups produced in good yields of the title hydrox-
yethylpyrazoles 12a–f.
OH
R2
NH
N
N
N
R2
a
k
HO
H3CO
j
14a, R1 = H
13a, R1 = H
NH
N
14b, R1 = CH3
13b, R1 = CH3
R2
OH
NH
N
H3CO
N
N
R2
a
l
R2
j
5a, R1 = H
5b, R1 = CH3
HO
HO
14a, R1 = H
14b, R1 = CH3
15a, R1 = H
15b, R1 = CH3
OH
N
NH
N
N
a
k
R2
R2
HO
H3CO
j
13c, R1 = H, n = 1
13d, R1 = CH3, n = 1
13e, R1 = H, n = 2
14c, R1 = H, n = 1
14d, R1 = CH3, n = 1
14e, R1 = H, n = 2
14f, R1 = CH3, n = 2
N
NH
R2
13f, R1 = CH3, n = 2
H3CO
5c, R1 = H, n = 1
N
OH
5d, R1 = CH3, n = 1
5e, R1 = H, n = 2
5f, R1 = CH3, n = 2
NH
l
N
a
j
N
R2
R2
HO
HO
14c, R1 = H, n = 1
14d, R1 = CH3, n = 1
14e, R1 = H, n = 2
14f, R1 = CH3, n = 2
15c, R1 = H, n = 1
15d, R1 = CH3, n = 1
15e, R1 = H, n = 2
15f, R1 = CH3, n = 2
Scheme 4 Reagents and conditions: j paraformaldehyde, THF, 45 °C; k BBr3, CH2Cl2, -78 °C; l HBr 48 %, reflux
123

J IRAN CHEM SOC (2013) 10:43–53
53
3. R.E. McDevitt, M.S. Malamas, E.S. Manas, R.J. Unwalla, Z.B.
Xu, C.P. Miller, H.A. Harris, Bioorg. Med. Chem. Lett. 15, 3137
(2005)
4. M. Waibel, K.J. Kieser, K.E. Carlson, F. Stossi, B.S. Katzenel-
lenbogen, J.A. Katzenellenbogen, Eur. J. Med. Chem. 44, 3560
(2009)
5. R.A. Magarian, L.B. Overaacre, S. Singh, Curr. Med. Chem. 1,
61 (1994)
6. J. Grundy, Chem. Rev. 57, 281 (1957)
7. D.R. Compton, K.E. Carlson, J.A. Katzenellenbogen, Bioorg.
Med. Chem. Lett. 14, 5681 (2004)
8. M. Shekarchi, M. Pirali-Hamedani, L. Navidpour, N. Adib, A.
Shafiee, J. Iran. Chem. Soc. 5, 150 (2008)
9. S.R. Stauffer, C.J. Coletta, R. Tedesco, G. Nishigushi, K. Carlson,
J. Sun, B.S. Katzenellenbogen, J.A. Katzenellenbogan, J. Med.
Chem. 43, 4934 (2000)
10. B.E. Fink, D.S. Mortensen, S.R. Stauffer, Z.D. Aron, J.A.
Katzenellenbogen, Chem. Biol. 6, 205 (1999)
11. S.R. Stauffer, Y.R. Huang, Z.D. Aron, C.J. Coletta, J. Sun, B.S.
Katzenellenbogen, J.A. Katzenellenbogen, Bioorg. Med. Chem.
9, 151 (2001)
The fourth synthetic route, which is presented in
Scheme 4, involves the hydroxymethylation of pyrazole
compounds 5a–f [27]. The condensation of latter pyrazoles
with paraformaldehyde led to the exclusive formation of
the pyrazole regioisomers 13a–f. The regioselectivity of
compound 13 was confirmed to be in accordance with the
previously described spectroscopy experiments. More
specifically, 2D NOE showed a strong cross peak between
the methylene group (of CH2OH) and the R1 (H or methyl)
substituents on pyrazole ring, as well as the absence of
enhancement with Ha, are indicative of the assigned
regiochemistry (Scheme 4). However, in subsequent
demethylation promoted by BBr3, the hydroxymethyl
moiety was removed. Finally, prior removal of methoxy-
protecting group of pyrazole 5a–f [17], followed by
hydroxymethylation by paraformaldehyde afforded the title
hydroxymethylpyrazoles 15a–f.
12. X. Alexi, K.M. Kasiotis, N. Fokialakis, G. Lambrinidis, A.K.
meligova, E. Mikros, S.A. Haroutounian, M.N. Alexis. J. steroid
Biochem. Mol. Biol. 117, 159 (2009)
13. J.S. Wright, H. Shadnia, J.M. Anderson, J.M. Anderson, J.M.
Anderson, T. Durst, M. Assim, M. El-salfiti, C. Choueiri, M.A.C.
Pratt, S.C. Ruddy, R. Lau, K.E. Carlson, J.A. Katzenellenbogen,
P.J. O’Brien, L. Wan, J. Med. Chem. 54, 433 (2011)
14. N. Minami, Y. Suzuki, Yakugaku Zasshi 95, 815 (1975)
15. M.T. Di Parsia, C. Suarez, M.J. Vitolo, V.E. Marquez, J. Med.
Chem. 24, 117 (1981)
Finally as previously reported, ERa and ERb are known
to bind with high affinity steroidal and non-steroidal
compounds having two hydroxyl groups with an O–O
˚
distance similar or even higher than estradiol (10.8 A) such
as propylpyrazoletriol (PPT) and 1,3-diarylcyclopentapyr-
azole that reportedly possess particularly high ERa and
ERb selective binding affinity and potency, respectively
[8–12]. The O–O distance of the OH pair of compounds
16. E.C. Taylor, A. Mc Killop, Y. Shvo, G.H. Hawks, Tetrahedron
23, 2081 (1967)
17. J.G. Morgan, K. Darrell Berlin, N.N. Durham, R.W. Chesnut, J.
Heterocycl. Chem. 8, 61 (1971)
18. J.A. may, P.W. Zinke, US Pat., 2003, 2003/83346
19. Z.-F. Tao, G, Li, Y. Tong, Z. Chen, P. Merta, P. Kovar, H. Zhang,
S.H. Rosenberg, H.L. Sham, T.J. Sowin, N.-H. Lin, Bioorg. Med.
Chem. Lett. 17, 4308 (2007)
20. V.K. Aggarwal, J. de Vicente, R.V. Bonnert, J. Org. Chem. 68,
5381 (2003)
˚
12a–f and 15a–f estimated was equal to 10.7 and 9.6 A,
respectively, while the compounds 11a–f does not provide
suitable distance. The compounds 11a–f were differenti-
ated from 10a–f (precursor of 12a–f) by 2D NOE NMR
spectroscopy (see above). However, compound 15 might
provide suitable distance by help of a water molecule as a
bridge. So, compounds 12 and 15 deserve to be evaluated
as possible estrogen receptor ligands.
21. L. Levi, C. Boersch, C.F. Gers, E. Merkul, T.J.J. Mu¨ller, Mole-
cules 16, 9340 (2011)
22. C.J. Valduga, H.S. Braibante, M.E.F. Braibante, J. Heterocycl.
Chem. 34, 1453 (1997)
Acknowledgments This research was supported by a grant from
National Elite Foundation.
23. R.G. Parker, J.D. Roberts, J. Org. Chem. 35, 996 (1970)
24. S. Sivaprasad, R. Sridhar, P.T. Perumal, J. Heterocycl. Chem. 43,
389 (2006)
References
25. A.O. Baltayan, V.I. Rstakyan, S.K. Antanosyan, F.S. Kinoyan,
O.S. Attaryan, G.V. Asratyan, Russ. J. Gen. Chem. 79, 2417
(2009)
1. S.W. Landvatter, J.A. Katzenellenbogen, J. Med. Chem. 25, 1300
(1982)
26. K.M. Kasiotis, N. Fokialakis, S.A. Haroutounian, Synthesis 11,
1791 (2006)
27. A.R. Katritzky, P. Lue, K. Akutagawa, Tetrahedron 45, 4253
(1989)
2. S. Bertini, A. De Cupertinis, C. Granchi, B. Bargagli, T. Tucci-
nardi, A. Martinelli, M. Macchia, J.R. Gunther, K.E. Carlson, J.A.
Katzenellenbogen, F. Minutolo, Eur. J. Med. Chem. 46, 2453
(2011)
123