Synthesis of novel conformationally constrained pyrazolo[4,3-c]quinoline derivatives as potential ligands for the estrogen receptor

Article abstract of DOI:10.1055/s-2006-926466

The preparation of three novel classes of pyrazolo[4,3-c]quinoline derivatives is reported. The easily accessible 2,3-dihydro-1H-quinolin-4-ones were used as the starting materials and were functionalized with three different acylating agents affording th

Full text of DOI:10.1055/s-2006-926466

PAPER
1791
Synthesis of Novel Conformationally Constrained Pyrazolo[4,3-c]quinoline
Derivatives as Potential Ligands for the Estrogen Receptor
Conformationally
oConstrained
n
Pyrazolo[4,3
s
-
c
]quinoli
t
ne
D
er
a
ivatives ntinos M. Kasiotis,a Nikolas Fokialakis,b Serkos A. Haroutounian*a
a
Chemistry Laboratory, Agricultural University of Athens, Iera odos 75, Athens 11855, Greece
Fax +30(210)5294265; E-mail: sehar@aua.gr
b
Division of Pharmacology and Chemistry of Natural Products, Faculty of Pharmacy, University of Athens, Panepistimiopolis, Zografou
15771, Athens, Greece
Received 10 August 2005; revised 11 January 2006
pyrazole derivatives, exemplified by the propylpyrazole
triol (PPT, Figure 1), have emerged as particularly inter-
esting targets. The latter was found to possess particularly
high ERa-selective binding affinity and potency.13–15 On
Abstract: The preparation of three novel classes of pyrazolo[4,3-
c]quinoline derivatives is reported. The easily accessible 2,3-dihy-
dro-1H-quinolin-4-ones were used as the starting materials and
were functionalized with three different acylating agents affording
their respective constrained core substrates. The latter by condensa- the other hand, other research groups have reported that
the substitution pattern of the pyrazole derivatives16 great-
tion with phenyl(or 4-methoxyphenyl)hydrazines and subsequent
debenzylation or demethylation provided the desired pyrazole de-
rivatives. Some interesting features emerged with respect to the re-
ly affects their binding affinity to the ERb.
gioselectivity and mechanism of these reactions.
X
Key words: quinolines, fused ring-systems, acylations, pyrazole,
estrogens
N
N
Estrogens are known to exert various biological effects
OH
via their molecular target, the estrogen receptor (ER). The
latter functions as a ligand-activated transcriptional regu-
R
HO
lator that binds with a wide range of steroidal and non-ste-
R = n-Pr, X = H
roidal ligands.1 In this context, the high ER affinity
R = n-Pr, X = OH (PPT)
R = Et, X = H
R = Et, X = OH
synthetic estrogens – especially those of a non-steroidal
nature – generally retain the phenolic function of natural
estradiol but exhibit tolerance with regard to their struc-
tural motifs. Thus, they can encompass either simple acy-
clic core structures of various lengths and sizes and/or a
wide ring-size range of fused or non-fused carbocyclic
and heterocyclic systems.2–4
Figure 1 1,3,5-Triaryl-4-alkyl substituted pyrazole derivatives.
We were interested in investigating the ER binding selec-
tivity pattern, and thus envisioned the synthesis of novel
fused pyrazolo[4,3-c]quinoline derivatives. Recent re-
An appreciable number of these ligands have been utilized ports have established that similar ring systems display
as hormonal agents, exhibiting mixed agonist-antagonist significant biological activities, such as good affinity and/
and tissue selective activities that are useful in hormone or selectivity to adenosine, benzodiazepine, and NMDA
replacement therapy, fertility regulation, and the preven- receptors.17–19 The rationale to design these molecules is
tion or treatment of breast cancer.5–8 Some of these agents to combine in a single molecule the known pharmaco-
(Selective Estrogen Receptor Modulators, SERMs) dis- phore quinoline ring with a tetrasubstituted pyrazole ring
play a mixed endocrine profile that is expressed by ago- backbone that inherently displays high affinity and selec-
nistic or antagonistic activity, depending on the tissue
tivity to the ER. This was achieved through the initial
target.9 The characterization of a second form of estrogen preparation of the 2,3-dihydro-1H-quinolin-4-one moi-
receptor (ERb subtype), by Gustafsson and coworkers,10–12 ety,20–22 providing the constrained core substrate for the
directed research interest towards the synthesis of ligands consecutive construction of the desired substituted pyra-
able to selectively activate or inhibit each of the ER sub- zole derivatives. Herein, we describe the substrate-depen-
types.
dent/directed regioselective synthesis of various
pyrazolo[4,3-c]quinolines, that can act as potential
ligands for the estrogen receptor.
In the course of investigations aimed at developing novel
SERMs that possess high affinity and selectivity for an
ER subtype, a broad variety of diverse ligands have been 1-Benzyl-7-methoxy-2,3-dihydro-1H-quinolin-4-one (3)
considered. Among them, 1,3,5-triaryl-4-alkyl substituted was synthesized via condensation of m-anisidine with
acrylic acid and subsequent acid-promoted ring closure.20
On the other hand, the condensation of m-anisidine with
ethylacetoacetate provided the corresponding enamine,
which by subsequent hydrogenation furnished compound
SYNTHESIS 2006, No. 11, pp 1791–1802
Advanced online publication: 27.04.2006
DOI: 10.1055/s-2006-926466; Art ID: T10905SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
6

1792
K. M. Kasiotis et al.
PAPER
1. The latter was cyclized in a solution of polyphosphonic responds to H-3. These results were further confirmed by
1
acid (PPA) to give the corresponding qionolin-4-one 2, gradient inverse-detected long range H-15N correlation
which after benzylation produced the 1-benzyl-7-meth- experiments. In this regard, for compound 7b a four-bond
oxy-2-methyl-2,3-dihydro-1H-quinolin-4-one (compound correlation was observed between the aromatic proton H-
4; Scheme 1).
9 (7.36 ppm) and the nitrogen atom that resonates at 198.7
ppm. The latter corresponds to the shielded N-1, which
also correlates with the aromatic protons of the N-(p-
methoxyphenyl) ring. It must also be noted that according
to the assigned structure the other two nitrogen atoms bear
double bonds and resonate at 294.8 and 324.6 ppm.
A general route to access the target pyrazole derivatives is
via a-acylation of the corresponding quinolinone sub-
strate and the subsequent condensation with a phenylhy-
drazine derivative. However, the outcome of this
acylation reaction depends greatly on the nature of both
the quinolinone substrate and the acylating agent.23 In this The second pathway involves the reaction of lithium eno-
context, three distinct pathways were investigated.
lates of quinolin-4-ones with pyruvonitrile. More specifi-
cally, the reaction of compound 3 furnished exclusively
the diacetylation product 11, presumably because of the
increased acidity of its a-hydrogens. However, in the case
of the 2-methyl-substituted derivative, it is evident that
the presence of a bulky methyl group on the vicinal C-2
hinders the addition of a second acetyl group, leading to
the formation of 1,3-diketone 10 as the only product
(Scheme 3). In both cases, however, some of the starting
material (22–29%) was recovered intact. Finally, the con-
densation of carbonyl intermediates 10 and 11 with phe-
nylhydrazines led to the exclusive formation of the
pyrazole regioisomers 14a–c, as depicted in Scheme 3.
The regioselectivity of compounds 14a–c was confirmed
to be in accordance with the previously described spec-
troscopy experiments. More specifically, for compound
14a, 2D NOE showed a strong cross-peak between the
pyrazole methyl group and the N-aryl hydrogens, as well
as the absence of enhancement with H-9, are indicative of
the assigned regiochemistry. This assignment was con-
The first pathway involves the formylation of quinolinone
which afforded the hydroxymethylene quinolin-4-ones 5a
and 5b. Double condensation of the latter with phenyl (or
4-methoxyphenyl)hydrazine furnished predominantly the
pyrazoles 6a–c (Scheme 2), while only a small amount
(2–13%) of the regioisomeric pyrazoles 6d–f was ob-
tained. The regioselectivity of this condensation may be
rationalized considering that the formyl carbons of com-
pounds 5 react predominantly with the most nucleophilic
terminal NH2 of phenylhydrazines to form an imine inter-
mediate. The latter by intramolecular ring closure provid-
ed the corresponding quinolinone derivatives.
Subsequently, the initial demethylation of quinoline 6a
and the removal of the benzyl protecting group resulted in
the aromatization of the molecule to afford the desired
pyrazolo[4,3-c]quinolinone derivative 8a. Similar results
were obtained by performing the aromatization before the
demethylation reaction (pyrazoles 8b, 8c and 9b, 9c).
1
firmed by H–15N correlation experiments. The aromatic
The configuration of the pyrazole products was elucidat-
ed, through 2D NOE NMR spectroscopy. More specifi-
cally, the assigned stereochemistry of compounds 6a–c is
consistent with the observed strong cross peak between H-
9 and the phenyl group. On the contrary, for compounds
6d–f the observed enhancement of the phenyl protons cor-
proton H-9 (7.36 ppm) showed a characteristic four-bond
correlation with the nitrogen atom that resonates at 290.3
ppm, corresponding to the deshielded N-1 atom bearing a
double bond.
O
OH
O
a
b
85%
77%
MeO
79%
NH2
MeO
MeO
N
N
H
H
d
88%
c
OEt
O
O
MeO
N
H
MeO
N
R
Bn
e
73%
3, R = H
4, R = Me
c
OEt
O
O
84%
b
73%
MeO
N
MeO
N
H
H
1
2
Scheme 1 Reagents and conditions: (a) acrylic acid (1.5 equiv), toluene, reflux; (b) PPA, 90 °C; (c) K2CO3, BnBr, DMF, 60 °C; (d)
CH3COCH2CO2Et, AcOH; (e) Pd/C, H2, MeOH.
Synthesis 2006, No. 11, 1791–1802 © Thieme Stuttgart · New York

PAPER
Conformationally Constrained Pyrazolo[4,3-c]quinoline Derivatives
1793
6a, R = H, R' = H, (81%)
6b, R = H, R' = OMe, (65%)
6c, R = Me, R' = OMe, (75%)
R'
R'
O
O
OH
R
N
N
N
N
a
b
d
+
MeO
N
R
MeO
N
Bn
Bn
MeO
R
N
R
MeO
N
5a, R = H, (75%)
5b, R = Me, (85%)
Bn
3, R = H
4, R = Me
Bn
6d, R = H, R' = H, 2%
6e, R = H, R' = OMe, 13%
6f, R = Me, R' = OMe, 3%
c
R'
N
N
7b, R = H, R' = OMe, (80%)
7c, R = Me, R' = OMe, (79%)
N
N
HO
N
R
MeO
N
R
Bn
7a, (70%)
c
d
N
N
HO
MeO
HO
N
N
4
N
N
8a, (70%)
N
3
+
HO
N
R
HO
N
R
8b, R = H, (30%)
8c, R = Me, (50%)
9b, R = H, (40%)
9c, R = Me, (35%)
Scheme 2 Reagents and conditions: (a) NaH, HCOOEt, DMF, THF; (b) R¢C6H4NHNH2·HCl, DMF–THF 3:1, 120 °C; (c) Pd/C, H2, MeOH
or EtOAc–AcOH; (d) BBr3, CH2Cl2, –78 °C.
O
O
O
R
O
O
a
O
MeO
MeO
N
N
R
MeO
N
R
Bn
Bn
Bn
3, R = H
4, R = Me
10, R = Me, (78%)
b
11, R = H, (70%)
b
R'
R'
R'
N
N
N
N
N
N
d
c
MeO
N
R
MeO
HO
N
R
N
R
Bn
12a, R = H, R' = H, (80%)
12b, R = H, R' = OMe, (80%)
12c, R = Me, R' = OMe, (81%)
13a, R = H, R' = H, (72%)
13b, R = H, R' = OMe, (80%)
13c, R =Me, R' = OMe, (91%)
14a, R = H, R' = H, (71%)
14b, R = H, R' = OH, (68%)
14c, R = Me, R' = OH, (63%)
Scheme 3 Reagents and conditions: (a) LHMDS, CH3COCN THF; (b) R¢C6H4NHNH2·HCl, DMF–THF (3:1), 120 °C; (c) Pd/C, H2, MeOH
or EtOAc; (d) BBr3, CH2Cl2, –78 °C.
Synthesis 2006, No. 11, 1791–1802 © Thieme Stuttgart · New York

1794
K. M. Kasiotis et al.
PAPER
The third synthetic route, which is presented in Scheme 4, compounds 17b and 18b. The regioselectivity of com-
involves the acylation of the lithium enolate of 1-benzyl- pounds 17 and 18 was assigned based on gradient-inverse-
1
7-methoxy-2,3-dihydro-1H-quinolin-4-one (3) with ben- detected long-range H–15N correlation experiments. For
zoyl cyanide to produce an inseparable mixture example, for compound 17b we observed a four bond cor-
(Scheme 4) of triketone 15 and 1,3-diketone 16 (15/16, relation between the aromatic proton H-9 (6.67 ppm) and
5:1). These derivatives were identified and analyzed after the deshielded nitrogen atom N-1 (291.8 ppm), which
separation by semi-preparative HPLC.
bears a double bond. On the contrary, for compound 18b,
this four-bond correlation was observed with a shielded
nitrogen atom, indicating that N-1 does not bear a double
bond.
Since the main goal of this synthetic route was the prepa-
ration of pyrazole derivatives, a mixture of 15 and 16 was
condensed with phenylhydrazine to give a 1:1 mixture of
17a and its regioiosmer 18a, which were separated by pre- The manganese dioxide oxidation of these compounds
parative HPLC. Condensation of the same mixture with 4- provided in almost quantitative yield the respective pyra-
methoxyphenylhydrazine produced a similar mixture of zoles 19a, 19b, 20a, 20b. Finally, debenzylation (aroma-
R
O
O
2
N
1
N
O
3
9
6
3a
8
7
O
MeO
N
Bn
5
4
MeO
N
15
a
17a, R = H, (35%)
17b, R = OMe, (35%)
b
Bn
+
MeO
N
+
Bn
R
O
O
N
3
18a, R = H, (31%)
18b, R = OMe, (31%)
2
N
1
N
MeO
3
9
6
9a
Bn
3a
8
7
16
5
4
MeO
N
Bn
R
R
R
c
N
N
N
N
N
N
MeO
N
MeO
N
22a, R = H, (71%)
22b, R = OMe, (75%)
21a, R = H, (71%)
21b, R = OMe, (75%)
N
MeO
Bn
19a, R = H, (95%)
19b, R = OMe, (92%)
R
d
e
N
N
R
R
MeO
N
Bn
20a, R = H, (96%)
20b, R = OMe, (89%)
N
N
N
N
HO
N
HO
N
23a, R = H, (72%)
23b, R = OH, (77%)
24a, R = H, (72%)
24b, R = OH, (72%)
Scheme 4 Reagents and conditions: (a) LHMDS, C6H4COCN, THF; (b) R¢C6H4NHNH2·HCl, DMF–THF (3:1), 120 °C; (c) MnO2, benzene,
100 °C; (d) Pd/C, H2, MeOH or EtOAc; (e) BBr3, CH2Cl2, –78 °C.
Synthesis 2006, No. 11, 1791–1802 © Thieme Stuttgart · New York

PAPER
Conformationally Constrained Pyrazolo[4,3-c]quinoline Derivatives
1795
Anal. Calcd for C13H19NO3: C, 63.14; H, 7.23; N, 6.69. Found: C,
63.28; H, 7.31; N, 6.60.
tization) and subsequent removal of the methoxy
protecting groups produced in good yields the conforma-
tionally constrained pyrazoles 23a, 23b, 24a, 24c. It is
noteworthy that the configuration of compounds 23a, 23b
and 24a, 24b were elucidated considering the chemical
shift of N-1, since this nitrogen atom correlates (through
three or four bonds) with the aromatic proton H-9 or the
aromatic protons of the N-(phenyl) or the N-(p-hydroxy-
phenyl) ring. More specifically, in the case of compounds
23a and 23b, the nitrogen atom N-1 is deshielded (297
ppm), presumably because of the attached double bond.
On the contrary, in compounds 24a and 24b the nitrogen
atom (N-1) does not bear a double bond and thus resonates
7-Methoxy-2-methyl-2,3-dihydro-1H-quinolin-4-one (2)
PPA (10 g) was heated to 90 °C with mechanical stirring. Ester 1
(0.5 g, 2.1 mmol) was added in one portion, and the mixture was
stirred for 2 h. After cooling to 60 °C, ice (50 g) was added and the
reaction mixture was stirred until the reaction was complete (ca. 15
min). Then the product was extracted with EtOAc (4 × 30 mL). The
combined organic layers were washed with H2O (30 mL) and aq
NaOH (5%, 15 mL). Then the organic layer was washed with H2O
(20 mL) until the pH of the solution was neutral. The combined or-
ganic layers were washed with brine (30 mL), dried over MgSO4,
and concentrated under reduced pressure. The resulting brown oil
was purified by flash column chromatography (EtOAc–hexane 1:1)
at 209 ppm. The latter configuration assignment is rein- to afford the title compound as a yellow solid; yield: 0.29 g (73%);
mp 137–138 (dec.).
IR (neat): 3230, 1681 cm–1.
forced by the observed correlation between the N-1 and
all N-attached phenolic protons.
1H NMR (CDCl3): d = 1.21 (d, J = 6.8 Hz, 3 H, CHCH3), 2.49 (dd,
J = 6.8, 2.9 Hz, 1 H, H-3), 3.02 (dd, J = 11.3, 5.9 Hz, 1 H, H-3),
3.43 (m, 1 H, H-2), 3.77 (s, 3 H, OCH3), 4.25 (s, 1 H, NH), 6.05 (d,
J = 2.2 Hz, 1 H, H-8), 6.30 (dd, J = 8.8, 2.2 Hz, 1 H, H-6), 7.76 (d,
J = 8.8 Hz, 1 H, H-5).
All anhydrous reactions were carried out under an argon atmo-
sphere. Solvents were dried by distillation prior to use. Starting ma-
terials were purchased from Aldrich (analytical reagent grades) and
were used without further purification. Analytical TLC was con-
ducted on Merck glass plates coated with silica gel 60 F254 and spots
were visualized with UV light and/or an alcohol solution of anisal-
dehyde. Flash column chromatography was performed using Merck
silica gel 60 (230–400 mesh).
Anal. Calcd for C11H13NO2: C, 65.80; H, 8.07; N, 5.90. Found: C,
65.89; H, 7.91; N, 5.80.
1-Benzyl-7-methoxy-2,3-dihydro-1H-quinolin-4-one (3)20
1H NMR (CDCl3): d = 2.68 (t, J = 7.1 Hz, 2 H, H-3), 3.56 (t, J = 7.1
Hz, 2 H, H-2), 3.69 (s, 3 H, OCH3), 4.52 (s, 2 H, NCH2), 6.09 (d,
J = 2.5 Hz, 1 H, H-8), 6.32 (dd, J = 8.7, 2.5 Hz, 1 H, H-6), 7.23–
7.37 (m, 5 H, Ar), 7.87 (d, J = 8.7 Hz, 1 H, H-5).
Melting points were determined on a Büchi melting point apparatus
and are uncorrected. 1H and 2D NMR spectra were recorded at 400
MHz on a Bruker DRX-400 spectrometer in the indicated solvents.
The chemical shifts are reported in ppm with TMS as an internal
standard. IR spectra were obtained on a Nicolet Magna 750, series
II spectrometer.
1-Benzyl-7-methoxy-2-methyl-2,3-dihydro-1H-quinolin-4-one
(4)20
HPLC separations were performed using a Hewlett Packard 1100
series instrument with a variable wavelength UV detector coupled
to a HP ChemStation utilizing the manufactorer’s software package
(version 5.01). A Kromasil column with pore size 100 Å, internal
diameter of 5 mm, and a C-18 bond phase was used. Compounds 15
and 16 were eluted with H2O–MeCN (30:70) at a flow rate of 1.6
mL/min. Compounds 17 and 18 were eluted with H2O–MeCN
(50:50) at a flow rate of 3 mL/min.
1H NMR (CDCl3): d = 1.21 (d, J = 6.8 Hz, 3 H, CHCH3), 2.49 (dd,
J = 6.8, 2.9 Hz, 1 H, H-3), 3.02 (dd, J = 11.3, 5.9 Hz, 1 H, H-3),
3.68 (s, 3 H, OCH3), 3.81 (m, 1 H, H-2), 4.35 (d, J = 16.5 Hz, 1 H,
NCHHPh), 4.64 (d, J = 16.5 Hz, 1 H, NCHHPh), 6.01 (d, J = 2.4
Hz, 1 H, H-8), 6.28 (dd, J = 8.8, 2.4 Hz, 1 H, H-6), 7.23–7.37 (m, 5
H, Ph), 7.87 (d, J = 8.8 Hz, 1 H, H-5).
Formylation of 2,3-Dihydro-1H-quinolin-4-ones; General Pro-
cedure
1
The H–15N GHMQC spectral data were acquired as 3072 × 400
data points with a total of 290 transients accumulated/t1 increment.
Pulse widths were 8.55 ms for 1H and 27.7 ms for the 15N at 0 and
–3 dB. The F1 spectral window employed was set from 100–400
ppm. Pulsed field gradients, gt1–gt3, had durations of 0.8 ms. Gra-
dient pairs were optimized as 70:30:50 for 15N spectroscopy.
To a stirred solution of NaH (60% dispersion in oil, 1.5 mmol) in
anhyd DMF (4 mL) under a N2 atmosphere, was added a solution of
the corresponding quinolinone (1.5 mmol) in anhyd THF (8 mL)
dropwise. After stirring for 4 h, HCOOEt (1.64 mmol) was added,
and the mixture was stirred for an additional 4 h. A sat. solution of
NH4Cl (10 mL) was added to quench the reaction and the product
was extracted with EtOAc (2 × 20 mL). The combined organic lay-
ers were concentrated under vacuum; the resulting orange solid was
purified by flash chromatography (EtOAc–hexane, 4:1) and recrys-
tallized (Et2O) to furnish the desired product.
3-(3-Methoxyphenylamino)butyric Acid Ethyl Ester (1)
3-(3-Methoxyphenylamino)but-2-enoic acid ethyl ester (4.0 g, 17
mmol) was dissolved in MeOH (80 mL) and hydrogenated over
10% Pd/C (0.4 g) at 1 atm for 8 h in the absence of sunlight. The
mixture was filtered through celite, dried over MgSO4, and concen-
trated. Purification by flash column chromatography (EtOAc–hex-
ane, 1:1) afforded the title compound as an off-white oil; yield: 2.94
g (73%).
IR (neat): 3230, 1729 cm–1.
1H NMR (CDCl3): d = 1.25 (t, J = 7.1 Hz, 3 H, OCH2CH3), 1.28 (d,
3 H, J = 7.1 Hz, CHCH3), 2.32 (dd, J = 14.9, 5.1 Hz, 1 H,
N-Benzyl-3-hydroxymethylene-7-methoxy-2,3-dihydro-1H-
quinolin-4-one (5a)
Quinolinone 3 (2.0 g, 7.5 mmol) was reacted according to the gen-
eral procedure to afford 5a as a yellow solid; yield: 1.65 g (75%);
mp 187–189 (dec.).
IR (neat): 3487, 1679 cm–1.
COCHHCHCH3), 2.36 (dd,
J
=
14.9, 5.1 Hz,
1
H,
1H NMR (CDCl3): d = 3.71 (s, 3 H, OCH3), 4.09 (s, 2 H, H-2), 4.48
(s, 2 H, NCH2), 6.09 (d, J = 2.5 Hz, 1 H, H-8), 6.33 (dd, J = 8.7, 2.5
Hz, 1 H, H-6), 7.25–7.37 (m, 5 H, Ph), 7.72 (s, 1 H, C=CH), 7.83
(d, J = 8.7 Hz, 1 H, H-5), 14.70 (br s, 1 H, OH).
COCHHCHCH3), 3.74 (s, 3 H, OCH3), 3.79 (s, 1 H, NH), 3.81–3.84
(m, 1 H, CHCH3), 4.11 (q, J = 7.1 Hz, 2 H, OCH2CH3), 6.00 (d,
J = 2.2 Hz, 1 H, H-2¢), 6.03 (d, J = 8.8, 1.4 H, H-6¢), 6.30 (dd, J =
8.8, 2.2 Hz, 1 H, H-4¢), 7.06 (dd, J = 8.8, 8.8 Hz, 1 H, H-5¢).
Synthesis 2006, No. 11, 1791–1802 © Thieme Stuttgart · New York

1796
K. M. Kasiotis et al.
PAPER
Anal. Calcd for C18H17NO3: C, 73.20; H, 5.80; N, 4.74. Found: C,
73.44; H, 5.91; N, 4.59.
3,3-Dibenzoyl-1-benzyl-7-methoxy-2,3-dihydro-1H-quinolin-4-
one (15) and 3-Benzoyl-1-benzyl-7-methoxy-2,3-dihydro-1H-
quinolin-4-one (16)
1-Benzyl-3-hydroxymethylene-7-methoxy-2-methyl-2,3-dihy-
dro-1H-quinolin-4-one (5b)
Quinolinone 4 (2 g, 7.11 mmol) was reacted according to the gener-
al procedure to afford 5b as a light-yellow crystalline solid; yield:
1.87 g (85%); mp 178–180 (dec.).
Column chromatography (EtOAc–hexanes, 1:4) gave unreacted
quinolinone 3 (15%) and an inseparable mixture of triketone 15 and
diketone 16 (0.29 g), which were separated by semi-preparative
HPLC.
15
IR (neat): 3415, 1672 cm–1.
IR (neat): 1694 (br) cm–1.
1H NMR (CDCl3): d = 1.27 (d, J = 6.3 Hz, 3 H, CHCH3), 3.69 (s, 3
H, OCH3), 4.20 (q, J = 6.3 Hz, 1 H, H-2), 4.38 (d, J = 16.0 Hz, 1 H,
NCHH), 4.51 (d, J = 16.0 Hz, 1 H, NCHH), 6.02 (d, J = 1.9 Hz, 1
H, H-8), 6.33 (dd, J = 9, 1.9 Hz, 1 H, H-6), 7.28–7.37 (m, 5 H, Ph),
7.81 (d, J = 9.0 Hz, 1 H, H-5), 7.98 (s, 1 H, C=CH), 14.75 (br s, 1
H, OH).
1H NMR (CDCl3): d = 3.78 (s, 3 H, OCH3), 4.25 (s, 2 H, H-2), 4.43
(s, 2 H, NCH2), 6.09 (d, J = 2.1 Hz, 1 H, H-8), 6.39 (dd, J = 8.5, 1.7
Hz, 1 H, H-6), 7.25–7.39 (m, 12 H, Ph), 7.47 (t, J = 8.7 Hz, 1 H,
Ph), 7.89 (t, J = 8.7 Hz, 1 H, Ph), 7.92 (d, J = 8.5 Hz, 1 H, H-5), 8.01
(d, J = 8.2 Hz, 1 H, Ph).
Anal. Calcd for C19H19NO3: C, 73.77; H, 6.19; N, 4.53. Found: C,
73.64; H, 6.06; N, 4.67.
16
1H NMR (CDCl3): d = 3.71 (m, 1 H, H-2), 3.72 (m, 1 H, H-2), 3.78
(s, 3 H, OCH3), 4.12 (t, J = 2.1 Hz, 1 H, H-3), 4.43 (s, 2 H, CH2N),
6.09 (d, J = 2.1 Hz, 1 H, H-8), 6.39 (dd, J = 8.5, 1.7 Hz, 1 H, H-6),
7.25–7.39 (m, 8 H, Ar), 7.55 (t, 1 H, J = 8.7 Hz, Ar), 7.91 (t, 1 H,
J = 8.7 Hz, Ar), 8.42 (d, J = 8.5 Hz, 1 H, Ar).
Acylation of Quinolin-4-ones; General Procedure
A solution of the appropriate 2,3-dihydro-1H-quinolin-4-one (0.71
mmol) in THF (10 mL) was added dropwise to a stirred solution of
LHMDS (1 M, THF; 0.71 mmol) over a period of 30 min. The re-
sulting solution was stirred for a further 15 min prior to the addition
of a solution of the acylating agent (0.71 mmol) in THF (2 mL). The
reaction mixture was stirred for 30 min, quenched with a solution of
NH4Cl (5 mL), and extracted with EtOAc (3 × 20 mL). The com-
bined organic solvents were dried over MgSO4, concentrated under
vacuum, and the residue was purified by chromatography.
Pyrazole Synthesis; General Procedure
To a solution of the appropriate quinolin-4-one substrate (1.0 mmol;
keto, diketo, or hydroxymethylene derivative) in DMF (30 mL) and
THF (10 mL) was added the appropriate phenylhydrazine hydro-
chloride (3–5 equiv). The mixture was heated at reflux (oil bath
temperature 120 °C) until the starting material had disappeared
(TLC analysis). The reaction mixture was then allowed to cool to r.t.
and diluted with H2O (30 mL). The product was extracted with
EtOAc (3 × 25 mL) and the combined organic layers were washed
with a sat. solution of LiCl (25 mL), a sat. solution of NaHCO3 (25
mL), and brine (25 mL). The organic layer was dried over MgSO4
and concentrated under reduced pressure to afford the crude product
as an oil, which was purified by flash chromatography or by filtra-
tion through a short plug of silica gel (EtOAc–hexanes).
3-Acetyl-1-benzyl-7-methoxy-2,3-dihydro-1H-quinolin-4-one
(10)
Column chromatography (EtOAc–hexanes, 1:4) gave unreacted
quinolinone 4 (22%) and, after recrystalization (Et2O), the desired
diketone 10 as a yellowish solid; yield: 0.18 g (78%); mp 113–114
(dec.).
IR (neat): 1703, 1695 cm–1.
1H NMR (CDCl3): d = 1.27 (d, J = 6.3 Hz, 3 H, CH3), 1.98 (s, 3 H,
COCH3), 3.69 (s, 3 H, OCH3), 4.28 (q, J = 7.1 Hz, 1 H, H-4), 4.34
(d, J = 15.3 Hz, 1 H, NCH2), 4.65 (d, J = 15.3 Hz, 1 H, NCH2), 4.78
(d, J = 7.1 Hz, 1 H, H-3), 5.99 (d, J = 2.2 Hz, 1 H, H-8), 6.31 (dd,
J = 8.8, 2.2 Hz, 1 H, H-6), 7.24–7.27 (m, 1 H, Ph), 7.30–7.36 (m, 4
H, Ph), 7.79 (d, J = 8.8 Hz, 1 H, H-5).
5-Benzyl-7-methoxy-1-phenyl-4,5-dihydro-1H-pyrazolo[4,3-
c]quinoline (6a)
Quinolinone 5a and phenylhydrazine hydrochloride were reacted
according to the general procedure. Flash chromatography (EtOAc–
hexanes, 1:4) gave 6a as an amorphous yellow solid; yield: 0.37 g
(81%); mp 124–125 (dec.).
1H NMR (CDCl3): d = 3.63 (s, 3 H, OCH3), 4.47 (s, 2 H, H-2), 4.53
(s, 2 H, NCH2), 6.01 (dd, J = 8.7, 2.3 Hz, 1 H, H-8), 6.22 (d, J = 2.3
Hz, 1 H, H-6), 6.67 (d, J = 8.7 Hz, 1 H, H-9), 7.23–7.27 (m, 2 H,
Ph), 7.34 (m, 3 H, Ph), 7.42 (s, 1 H, H-3), 7.45–7.52 (m, 5 H, Ph).
13C NMR (CDCl3): d = 53.3 (C-4), 57.1 (OCH3), 62.9 (NCH2), 97.2
(C-6), 105.2 (C-8), 115.8, 117.9, 119.3, 123.6, 125.5, 129.2 (C-9),
132.2, 137.8, 144.4 (C=N), 146.3, 172.2 (C-7).
Anal. Calcd for C20H21NO3: C, 74.28; H, 6.55; N, 4.33. Found: C,
74.11; H, 6.69; N, 4.41.
3,3-Diacetyl-1-benzyl-7-methoxy-2,3-dihydro-1H-quinolin-4-
one (11)
Column chromatography (EtOAc–hexanes, 1:4) gave unreacted
quinolinone 3 (29%) and, after recrystalization (Et2O), the desired
triketone 11 as a yellowish solid; yield: 0.29 g (70%); mp 97–98
(dec.).
Anal. Calcd for C24H21N3O: C, 78.45; H, 5.76; N, 11.44. Found: C,
78.32; H, 5.87; N, 11.27.
IR (neat): 1700 (br), 1693 cm–1.
1H NMR (CDCl3): d = 2.22 (s, 3 H, COCH3), 2.85 (s, 3 H, COCH3),
3.44 (s, 2 H, H-2), 3.80 (s, 3 H, OCH3), 4.39 (d, J = 16.1 Hz, 1 H,
NHHPh), 4.56 (d, J = 16.1 Hz, 1 H, NHHPh), 6.71 (d, J = 2.1 Hz, 1
H, H-8), 7.01 (dd, J = 8.5, 2.1 Hz, 1 H, H-6), 7.32–7.40 (m, 5 H,
Ph), 7.70 (d, J = 8.5 Hz, 1 H, H-5).
5-Benzyl-7-methoxy-1-(4-methoxyphenyl)-4,5-dihydro-1H-
pyrazolo[4,3-c]quinoline (6b) and 5-Benzyl-7-methoxy-2-(4-
methoxyphenyl)-4,5-dihydro-2H-pyrazolo[4,3-c] quinoline (6e)
Quinolinone 5a and 4-methoxyphenylhydrazine hydrochloride
were reacted according to the general procedure. Flash chromatog-
raphy (EtOAc–hexanes, 1:4) gave 6b and 6e as amorphous yellow
solids.
Anal. Calcd for C21H21NO4: C, 71.78; H, 6.02; N, 3.99. Found: C,
71.65; H, 5.85; N, 4.15.
6b
Yield: 65%.
1H NMR (CDCl3): d = 3.66 (s, 3 H, OCH3), 3.90 (s, 3 H, OCH3),
4.53 (s, 2 H, H-4), 4.57 (s, 2 H, NCH2), 6.06 (dd, J = 8.8, 2.4 Hz, 1
Synthesis 2006, No. 11, 1791–1802 © Thieme Stuttgart · New York

PAPER
Conformationally Constrained Pyrazolo[4,3-c]quinoline Derivatives
1797
H, H-8), 6.26 (d, J = 2.4 Hz, 1 H, H-6), 6.70 (d, J = 8.3 Hz, 2 H,
Ph), 7.03 (d, J = 8.8 Hz, 1 H, H-9), 7.35–7.38 (m, 3 H, Ph), 7.41–
7.44 (m, 4 H, Ph), 7.45 (s, 1 H, H-3).
Anal. Calcd for C26H25N3O2: C, 75.89; H, 6.12; N, 10.21. Found: C,
75.75; H, 6.02; N, 10.39.
5-Benzyl-7-methoxy-2-(4-methoxyphenyl)-3,4-dimethyl-4,5-di-
hydro-2H-pyrazolo [4,3-c]quinoline (12c)
Quinolinone 10 and 4-methoxyphenylhydrazine hydrochloride
were reacted according to the general procedure. Flash chromatog-
raphy (EtOAc–hexanes, 1:4) gave 12c as an amorphous yellow sol-
id; yield: 81%; mp 177–179 (dec.).
1H NMR (CDCl3): d = 1.27 (d, J = 6.2 Hz, 3 H, CH3), 2.88 (s, 3 H,
CH3), 3.54 (s, 3 H, OCH3), 3.78 (s, 3 H, OCH3), 4.36 (d, J = 15.8
Hz, 1 H, NCHH), 4.52–4.58 (m, 2 H, NCHH, H-4), 5.95 (dd, J =
8.5, 2.3 Hz, 1 H, H-8), 6.07 (d, J = 2.3 Hz, 1 H, H-6), 6.62 (d, J =
8.8 Hz, 1 H, H-9), 6.90 (d, J = 9.1 Hz, 2 H, Ph), 7.18 (d, J = 9.1 Hz,
2 H, Ph), 7.22–7.33 (m, 5 H, Ph).
13C NMR (CDCl3): d = 53.9 (C-4), 57.3 (OCH3), 58.1 (OCH3), 62.9
(NCH2), 97.9 (C-6), 105.2 (C-8), 115.8, 117.9 (C=C), 118.1, 119.2,
123.6, 126.5, 130.2 (C-9), 132.2, 136.8, 145.1 (C=N), 146.3, 161.2
(COCH3), 170.1 (C-7).
Anal. Calcd for C25H23N3O2: C, 75.54; H, 5.83; N, 10.57. Found: C,
75.72; H, 5.97; N 10.47.
6e
Yield: 13%.
1H NMR (CDCl3): d = 3.68 (s, 3 H, OCH3), 3.87 (s, 3 H, OCH3),
4.49 (s, 2 H, H-4), 4.59 (s, 2 H, NCH2), 6.26 (d, J = 2.1 Hz, 1 H, H-
6), 6.36 (dd, J = 8.8, 2.1 Hz, 1 H, H-8), 6.98 (d, J = 8.3 Hz, 1 H, H-
9), 7.13 (d, J = 8.3 Hz, 2 H, Ph) 7.32–7.37 (m, 5 H, Ph), 7.53 (s, 1
H, H-3), 7.63 (d, J = 8.3 Hz, 2 H, Ph).
Anal. Calcd for C27H27N3O2: C, 76.21; H, 6.40; N, 9.87. Found: C,
76.09; H, 6.54; N, 10.03.
Anal. Calcd for C25H23N3O2: C, 75.54; H, 5.83; N, 10.57. Found: C,
75.37; H, 5.96; N, 10.35.
5-Benzyl-7-methoxy-2,3-diphenyl-3,3a,4,5-tetrahydro-2H-
pyrazolo[4,3-c]quinoline (17a) and 5-Benzyl-7-methoxy-1,3-
diphenyl-3a,4,5,9a-tetrahydro-1H-pyrazolo[4,3-c]quinoline
(18a)
A mixture of triketone 15 and diketone 16 (0.28 g), and phenylhy-
drazine hydrochloride (0.34 g, 2.2 mmol) were reacted according to
the general procedure. Preparative HPLC (H2O–MeCN, 1:1) gave
17a and 18a as yellow amorphous solids.
5-Benzyl-7-methoxy-1-(4-methoxyphenyl)-4-methyl-4,5-dihy-
dro-1H-pyrazolo[4,3-c]quinoline (6c)
Quinolinone 5b and 4-methoxyphenylhydrazine hydrochloride
were reacted according to the general procedure. Flash chromatog-
raphy (EtOAc–hexanes, 3:7) gave 6c as an amorphous yellow solid;
yield: 90 mg (75%).
1H NMR (CDCl3): d = 1.27 (d, J = 6.2 Hz, 3 H, CHCH3), 3.59 (s, 3
H, OCH3), 3.89 (s, 3 H, OCH3), 4.51 (d, J = 16.1 Hz, 1 H, NCHH),
4.68 (d, J = 16.1 Hz, 1 H, NCHH), 4.85 (q, J = 6.2 Hz, 1 H, H-4),
6.03 (dd, J = 8.8, 2.3 Hz, 1 H, H-8), 6.19 (d, J = 2.3 Hz, 1 H, H-6),
6.67 (d, J = 8.8 Hz, 1 H, H-9), 7.09 (d, J = 9.1 Hz, 2 H, Ph), 7.24 (t,
J = 7.3 Hz, 1 H, Ph), 7.31–7.41 (m, 6 H, Ph), 7.43 (s, 1 H, H-3).
13C NMR (CDCl3): d = 23.1 (CCH3), 52.9 (C-4), 56.2 (OCH3), 56.9
(OCH3), 59.9 (NCH2), 98.4 (C-6), 105.2 (C-8), 115.1, 117.9 (C=C),
120.1, 125.5, 127.4, 128.5, 130.2 (C-9), 132.2, 136.8, 142.3 (C=N),
146.3, 163.1 (COCH3), 166.1 (C-7).
17a
Yield: 90 mg (35%); tR 14.7 min.
1H NMR (CDCl3): d = 3.62 (s, 3 H, OCH3), 3.65–3.68 (m, 1 H, H-
4), 3.78–3.81 (m, 1 H, H-4), 3.95 (ddd, J = 3.1 Hz, 1 H, H-3a), 4.78
(d, J = 16.7 Hz, 1 H, NCH2), 4.87 (d, J = 16.7 Hz, 1 H, NCH2), 5.36
(d, J = 3.1 Hz, 1 H, H-3), 5.97 (dd, J = 8.2, 2.2 Hz, 1 H, H-8), 6.19
(d, J = 2.2 Hz, 1 H, H-6), 6.67 (d, J = 8.8 Hz, 1 H, H-9), 7.26–7.33
(m, 5 H, Ph), 7.36–7.39 (m, 3 H, Ph), 7.43–7.49 (m, 3 H, Ph), 7.54
(d, J = 7.0 Hz, 2 H, Ph), 7.74 (d, J = 7.0 Hz, 2 H, Ph).
13C NMR (CDCl3): d = 45.6 (C-3a), 52.9 (C-4), 54.3 (C-3), 58.5
(OCH3), 59.9 (NCH2), 98.4 (C-6), 105.2 (C-8), 110.2, 112.4, 116.1,
126.9, 127.4, 128.1, 128.5, 129.5, 132.2, 134.1 (C-9), 136.8, 144.2,
146.3, 153.4 (C=N), 169.2 (C-7).
Anal. Calcd for C26H25N3O2: C, 75.89; H, 6.12; N, 10.21. Found: C,
75.75; H, 5.94; N, 10.07.
1H–15N NMR (CDCl3): d = 292.3 (N-1), 194.2 (N-2), 322.6 (N-5).
5-Benzyl-7-methoxy-3-methyl-2-phenyl-4,5-dihydro-2H-pyra-
zolo[4,3-c]quinoline (12a)
Quinolinone 11 and phenylhydrazine hydrochloride were reacted
according to the general procedure. Flash chromatography (EtOAc–
hexanes, 1:4) gave 12a as an amorphous yellow solid; yield: 0.14 g
(80%); mp 139–142 (dec.).
1H NMR (CDCl3): d = 2.19 (s, 3 H, CH3) 3.63 (s, 3 H, OCH3), 4.47
(s, 2 H, H-4), 4.53 (s, 2 H, CH2N), 5.97 (dd, J = 8.4, 2.1 Hz, 1 H, H-
8), 6.19 (d, J = 2.1 Hz, 1 H, H-6), 6.63 (d, J = 8.4 Hz, 1 H, H-9),
7.28–7.35 (m, 5 H, Ph), 7.44–7.51 (m, 5 H, Ph).
Anal. Calcd for C30H27N3O: C, 80.87; H, 6.11; N, 9.43. Found: C,
81.05; H, 6.24; N, 9.32.
18a
Yield: 90 mg (35%); tR 19.9 min.
1H NMR (CDCl3): d = 3.61–3.65 (m, 1 H, H-4), 3.67–3.70 (m, 4 H,
OCH3, H-4), 3.92 (q, J = 7.0 Hz, 1 H, H-3a), 4.63 (d, J = 8.3 Hz, 1
H, H-9a), 4.75 (d, J = 14.9 Hz, 1 H, NCHH), 4.87 (d, J = 14.9 Hz,
1 H, NCHH), 6.08 (dd, J = 8.3, 2.2 Hz, 1 H, H-8), 6.38 (d, J = 2.2
Hz, 1 H, H-6), 6.75 (d, J = 8.8 Hz, 1 H, H-9), 7.26–7.31 (m, 4 H,
Ph), 7.34–7.38 (m, 2 H, Ph), 7.42–7.48 (m, 5 H, Ph), 7.51–7.58 (m,
4 H, Ph).
13C NMR (CDCl3): d = 48.6 (C-9a), 52.9 (C-4), 58.5 (OCH3), 63.2
(NCH2), 97.9 (C-6), 105.2 (C-8), 110.2, 112.4, 116.1, 126.9, 127.4,
128.1, 128.5, 129.5, 130.1, 132.9, 133.8 (C-9), 138.4, 145.4, 146.8,
154.9 (C-3), 162.5 (C-7).
Anal. Calcd for C25H23N3O: C, 78.71; H, 6.00; N, 11.02. Found: C,
78.92; H, 5.85; N, 11.17.
5-Benzyl-7-methoxy-2-(4-methoxyphenyl)-3-methyl-4,5-dihy-
dro-2H-pyrazolo[4,3-c]quinoline (12b)
Quinolinone 11 and 4-methoxyphenylhydrazine hydrochloride
were reacted according to the general procedure. Flash chromatog-
raphy (EtOAc–hexanes, 1:4) gave 12b as an amorphous yellow sol-
id; yield: (80%).
1H NMR (CDCl3): d = 2.22 (s, 3 H, CH3) 3.64 (s, 3 H, OCH3), 3.74
(s, 3 H, OCH3), 4.43 (s, 2 H, H-4), 4.55 (s, 2 H, NCH2), 6.02 (dd,
J = 8.3, 2.1 Hz, 1 H, H-8), 6.19 (d, J = 2.1 Hz, 1 H, H-6), 6.71 (d,
J = 8.3 Hz, 1 H, H-9), 6.85 (d, J = 8.2 Hz, 2 H, Ph), 7.29–7.34 (m,
2 H, Ph), 7.44–7.51 (m, 5 H, Ph).
1H–15N NMR (acetone-d6): d = 197.7 (N-1), 295.5 (N-2), 323.4 (N-
5).
Anal. Calcd for C30H27N3O: C, 80.87; H, 6.11; N, 9.43. Found: C,
81.01; H, 6.22; N, 9.29.
Synthesis 2006, No. 11, 1791–1802 © Thieme Stuttgart · New York

1798
K. M. Kasiotis et al.
PAPER
5-Benzyl-7-methoxy-2-(4-methoxyphenyl)-3-phenyl-3,3a,4,5-
tetrahydro-2H-pyrazolo[4,3-c]quinoline (17b) and 5-Benzyl-7-
methoxy-1-(4-methoxyphenyl)-3-phenyl-3a,4,5,9a-tetrahydro-
1H-pyrazolo[4,3-c]quinoline (18b)
A mixture of triketone 15, diketone 16, and 4-methoxyphenylhydra-
zine hydrochloride were reacted according to the general procedure.
Preparative HPLC (H2O–MeCN, 1:1) gave 17b and 18b as yellow
amorphous solids.
128.1, 128.6, 129.5, 130.1, 133.1 (C-9), 136.8, 138.9, 144.2 (C-3),
146.3, 157.4 (C=N), 165.2 (C-7).
Anal. Calcd for C30H25N3O: C, 81.24; H, 5.68; N, 9.47. Found: C,
81.02; H, 5.49; N, 9.65.
5-Benzyl-7-methoxy-2-(4-methoxyphenyl)-3-phenyl-4,5-dihy-
dro-2H-pyrazolo[4,3-c]quinoline (19b)
Quinoline 17b was oxidized according to the general procedure to
give 19b as an amorphous yellow solid; yield: 0.18 g (92%).
17b
1H NMR (CDCl3): d = 3.62 (s, 3 H, OCH3), 3.67 (s, 3 H, OCH3),
4.23 (s, 2 H, H-4), 4.72 (d, J = 16.7 Hz, 1 H, NCHH), 4.82 (d, J =
16.7 Hz, 1 H, NCHH), 5.99 (dd, J = 8.7, 2.1 Hz, 1 H, H-8), 6.18 (d,
J = 2.1 Hz, 1 H, H-6), 6.76 (d, J = 8.7 Hz, 1 H, H-9), 6.92 (d, J =
7.7 Hz, 2 H, Ph), 7.22 (d, J = 7.7 Hz, 2 H, Ph), 7.27–7.33 (m, 4 H,
Ph), 7.43–7.52 (m, 3 H, Ph), 7.63–7.72 (m, 3 H, Ph).
13C NMR (CDCl3): d = 45.5 (C-4), 56.9 (OCH3), 57.2 (OCH3), 63.9
(NCH2), 100.3 (C-6), 106.2 (C-8), 110.8, 113.2, 113.9, 118.1
(C=C), 120.1, 126.5, 128.1, 128.6, 129.5, 130.4 (C-9), 131.7, 137.3,
138.8, 144.9 (C-3), 146.3, 157.4 (C=N), 161.5 (COCH3), 165.2 (C-
7).
Yield: (31%); tR13.7 min.
1H NMR (CDCl3): d = 3.63 (s, 3 H, OCH3), 3.64 (s, 3 H, OCH3),
3.66–3.69 (m, 1 H, H-4), 3.79–3.81 (m, 1 H, H-4), 3.96 (m, 1 H, H-
3a), 4.81 (d, J = 16.7 Hz, 1 H, NCHH), 4.89 (d, J = 16.7 Hz, 1 H,
NCHH), 5.36 (d, J = 3.1 Hz, 1 H, H-3), 5.99 (dd, J = 8.2, 2.2 Hz, 1
H, H-8), 6.28 (d, J = 2.2 Hz, 1 H, H-6), 6.67 (d, J = 8.8 Hz, 1 H, H-
9), 7.26–7.31 (m, 5 H, Ph), 7.33–7.39 (m, 3 H, Ph), 7.43–7.49 (m, 2
H, Ph), 7.57 (d, J = 7.0 Hz, 2 H, Ph), 7.76 (d, J = 7.0 Hz, 2 H, Ph).
13C NMR (CDCl3): d = 45.6 (C-3a), 52.9 (C-4), 54.3 (C-3), 57.6
(OCH3), 57.9 (OCH3), 61.3 (NCH2), 100.1 (C-6), 105.2 (C-8),
110.2, 113.7, 115.3, 127.4, 128.7, 129.2, 129.8, 132.2, 132.7 (C-9),
136.8, 144.2, 145.6, 151.9 (COCH3), 157.9 (C=N), 170.1 (C-7).
Anal. Calcd for C31H27N3O2: C, 78.62; H, 5.75; N, 8.87. Found: C,
78.82; H, 5.56; N, 8.77.
1H–15N NMR (CDCl3): d = 291.8 (N-1), 193.1 (N-2), 322.2 (N-5).
Anal. Calcd for C31H29N3O2: C, 78.29; H, 6.15; N, 8.84. Found: C,
78.49; H, 6.29; N, 8.99
5-Benzyl-7-methoxy-1,3-diphenyl-4,5-dihydro-1H-pyrazo-
lo[4,3-c]quinoline (20a)
Quinoline 18a was oxidized according to the general procedure to
give 20a as an amorphous yellow solid; yield: 0.1 g (96%).
18b
Yield: 31%; tR 19.1 min.
1H NMR (CDCl3): d = 3.63 (s, 3 H, OCH3), 4.27 (s, 2 H, H-4), 4.74
(s, 2 H, NCH2), 6.04 (dd, 1 H, J = 8.8, 2.2 Hz, H-8), 6.20 (d, 1 H,
J = 2.2 Hz, H-6), 6.77 (d, 1 H, J = 8.8 Hz, H-9), 7.29–7.41 (m, 8 H,
Ph), 7.44–7.56 (m, 3 H, Ph), 7.59 (d, J = 7.2 Hz, 2 H, Ph), 7.73 (d,
J = 7.2 Hz, 2 H, Ph).
1H NMR (CDCl3): d = 3.61–3.68 (m, 1 H, H-4), 3.67–3.70 (m, 4 H,
OCH3, H-4), 3.72 (s, 3 H, OCH3) 3.96 (q, J = 7.0 Hz, 1 H, H-3a),
4.69 (d, J = 8.3 Hz, 1 H, H-9a), 4.77 (d, J = 14.9 Hz, 1 H, NCHH),
4.87 (d, J = 14.9 Hz, 1 H, NCHH), 6.12 (dd, J = 8.3, 2.2 Hz, 1 H,
H-8), 6.37 (d, J = 2.2 Hz, 1 H, H-6), 6.76 (d, J = 8.8 Hz, 1 H, H-9),
7.26–7.31 (m, 4 H, Ph), 7.34–7.38 (m, 2 H, Ph), 7.42–7.48 (m, 4 H,
Ph), 7.63 (d, J = 7.3 Hz, 2 H, Ph), 7.83 (d, J = 7.3 Hz, 2 H, Ph).
Anal. Calcd for C30H25N3O: C, 81.24; H, 5.68; N, 9.47. Found: C,
80.99; H, 5.54; N, 9.65.
13C NMR (CDCl3): d = 46.4 (C-3a), 48.9 (C-9a), 54.4 (C-4), 57.6
(OCH3), 57.9 (OCH3), 61.3 (NCH2), 100.1 (C-6), 105.2 (C-8),
110.2, 113.7, 115.8, 127.8, 128.7, 129.2, 129.8, 130.7 (C-9), 132.2,
138.4, 144.9, 151.2 (COCH3), 155.6 (C-3), 162.3 (C-7).
5-Benzyl-7-methoxy-1-(4-methoxyphenyl)-3-phenyl-4,5-dihy-
dro-1H-pyrazolo[4,3-c]quinoline (20b)
Quinoline 18b was oxidized according to the general procedure to
give 20b as an amorphous yellow solid; yield: 0.16 g (89%).
1H–15N NMR (CDCl3): d = 198.2 (N-1), 296.5 (N-2), 325.9 (N-5).
1H NMR (CDCl3): d = 3.62 (s, 3 H, OCH3), 3.67 (s, 3 H, OCH3),
4.19 (s, 2 H, H-4), 4.69 (d, J = 16.7 Hz, 1 H, NCHH), 4.78 (d, J =
16.7 Hz, 1 H, NCHH), 6.07 (dd, J = 8.7, 2.1 Hz, 1 H, H-8), 6.22 (d,
J = 2.1 Hz, 1 H, H-6), 6.88 (d, J = 8.7 Hz, 1 H, H-9), 6.94 (d, J =
7.9 Hz, 2 H, Ph), 7.20 (d, J = 7.9 Hz, 2 H, Ph), 7.29–7.33 (m, 3 H,
Ph), 7.45–7.52 (m, 4 H, Ph), 7.63–7.72 (m, 3 H, Ph).
Anal. Calcd for C31H29N3O2: C, 78.29; H, 6.15; N, 8.84. Found: C,
78.12; H, 6.29; N, 9.02.
Oxidation; General Procedure
To a stirred solution of tetrahydro-2H-pyrazolo[4,3-c]quinoline
(0.45 mmol) in anhyd benzene (25 mL) was added MnO2 (0.51 g,
5.85 mmol). A Dean–Stark trap was attached, the solution was heat-
ed to 100 °C for 2 h, cooled to r.t., filtered through celite, and con-
centrated. The crude product was purified by chromatography
(EtOAc–hexanes, 1:4) to afford the desired pyrazole derivatives.
Anal. Calcd for C31H27N3O2: C, 78.62; H, 5.75; N, 8.87. Found: C,
78.43; H, 5.63; N, 8.71.
Hydrogenolysis; General Procedure
Pyrazolo[4,3-c]quinolines (0.2 mmol) in MeOH (18 mL) or
MeOH–AcOH (5:1, 25 mL) were hydrogenated over 10% Pd/C (10
mg) at 1 atm in the absence of sunlight. The progress of the reaction
was monitored by TLC, when the reaction was complete the result-
ing mixture was filtered through celite, and concentrated under re-
duced pressure. Purification by flash chromatography (EtOAc–
hexanes) gave the desired products as yellow solids, which were re-
crystallized (CH2Cl2–MeOH or Et2O) to afford pale-yellow/white
needles.
5-Benzyl-7-methoxy-2,3-diphenyl-4,5-dihydro-2H-pyrazo-
lo[4,3-c]quinoline (19a)
Quinoline 17a was oxidized according to the general procedure to
give 19a as an amorphous yellow solid; yield: 0.19 g (95%).
1H NMR (CDCl3): d = 3.62 (s, 3 H, OCH3), 4.23 (s, 2 H, H-4), 4.72
(d, J = 16.7 Hz, 1 H, NCHH), 4.82 (d, J = 16.7 Hz, 1 H, NCHH),
6.05 (dd, J = 8.7, 2.1 Hz, 1 H, H-8), 6.21 (d, J = 2.1 Hz, 1 H, H-6),
6.81 (d, J = 8.7 Hz, 1 H, H-9), 7.29–7.34 (m, 4 H, Ph), 7.39–7.43
(m, 4 H, Ph), 7.45 (d, J = 7.7 Hz, 2 H, Ph), 7.48–7.56 (m, 3 H, Ph),
7.73 (d, J = 7.7 Hz, 2 H, Ph).
7-Methoxy-2,3-diphenyl-2H-pyrazolo[4,3-c]quinoline (21a)
Pyrazolo[4,3-c]quinoline 19a in MeOH was hydrogenated accord-
ing to the general procedure. Flash chromatography (EtOAc–hex-
anes, 1:9) and recrystallization (Et2O) gave 21a as a yellow solid;
yield: 71%; mp 144–145 (dec.).
13C NMR (CDCl3): d = 44.4 (C-4), 58.5 (OCH3), 63.9 (NCH2), 98.4
(C-6), 105.2 (C-8), 110.8, 113.2, 117.6 (C=C), 120.1, 126.5, 127.2,
Synthesis 2006, No. 11, 1791–1802 © Thieme Stuttgart · New York

PAPER
Conformationally Constrained Pyrazolo[4,3-c]quinoline Derivatives
1799
1H NMR (CDCl3): d = 3.70 (s, 3 H, OCH3), 6.84 (d, J = 2.4 Hz, 1
H, H-6), 7.09 (dd, J = 8.9, 2.4 Hz, 1 H, H-8), 7.26 (d, J = 8.9 Hz, 1
H, H-9), 7.31–7.38 (m, 6 H, Ph), 7.41–7.48 (m, 4 H, Ph), 8.30 (s, 1
H, H-4).
7-Methoxy-1-(4-methoxyphenyl)-1H-pyrazolo[4,3-c]quinoline
(7b)
Pyrazolo[4,3-c]quinoline 6b (0.16 g, 0.4 mmol) in MeOH–AcOH
(5:1, 45 mL) was hydrogenated according to the general procedure
for 1.5 h. Flash chromatography (EtOAc–hexanes, 3:2) and recrys-
talization (CH2Cl2–acetone) gave 7b as a yellow solid; yield: 98 mg
(80%); mp 139–141 (dec.).
Anal. Calcd for C23H17N3O: C, 78.61; H, 4.88; N, 11.96. Found: C,
78.76; H, 4.77; N, 11.83.
7-Methoxy-2-(4-methoxyphenyl)-3-phenyl-2H-pyrazolo[4,3-
c]quinoline (21b)
Pyrazolo[4,3-c]quinoline 19b in MeOH was hydrogenated accord-
ing to the general procedure. Flash chromatography (EtOAc–hex-
anes, 1:9) and recrystallization (Et2O) gave 21b as a yellow solid;
yield: 75%; mp 204–205 (dec.).
1H NMR (CDCl3): d = 3.69 (s, 3 H, OCH3), 3.81 (s, 3 H, OCH3),
6.89 (d, J = 2.3 Hz, 1 H, H-6), 6.96 (d, J = 8.2 Hz, 2 H, Ph), 7.10
(dd, J = 8.8, 2.3 Hz, 1 H, H-8), 7.22 (d, J = 8.2 Hz, 2 H, Ph), 7.29
(d, J = 8.8 Hz, 1 H, H-9), 7.33–7.35 (m, 3 H, Ph), 7.40–7.43 (m, 2
H, Ph), 8.25 (s, 1 H, H-4).
1H NMR (acetone-d6): d = 3.87 (s, 3 H, OCH3), 3.89 (s, 3 H, OCH3),
7.09 (dd, J = 8.3, 2.4 Hz, 2 H, Ar), 7.16 (d, J = 8.8 Hz, 2 H, Ar),
7.36 (d, J = 8.3 Hz, 1 H, H-9), 7.52–7.58 (m, 2 H, Ar), 8.49 (s, 1 H,
H-4), 9.21 (s, 1 H, H-3).
13C NMR (acetone-d6): d = 57.6 (OCH3), 58.3 (OCH3), 109.1 (C-6),
115.8, 117.9 (C=C), 118.1, 118.8 (C-8), 119.9, 123.6, 124.5, 130.5
(C-9), 137.2, 147.1 (C=N), 152.5 (C-4), 161.2 (COCH3), 162.8 (C-
7).
1H–15N NMR (acetone-d6): d = 198.7 (N-1), 294.8 (N-2), 324.6 (N-
5).
Anal. Calcd for C18H15N3O2: C, 70.81; H, 4.95; N, 13.76. Found: C,
71.09; H, 4.72; N, 13.92.
Anal. Calcd for C24H19N3O2: C, 75.57; H, 5.02; N, 11.02. Found: C,
75.74; H, 5.20; N, 11.15.
7-Methoxy-1-(4-methoxyphenyl)-4-methyl-1H-pyrazolo[4,3-
c]quinoline (7c)
Pyrazolo[4,3-c]quinoline 6c (80 mg, 0.19 mmol) in MeOH–AcOH
(5:1, 20 mL) was hydrogenated according to the general procedure.
Flash chromatography (EtOAc–hexanes, 3:2) gave 7c as a dark-yel-
low crystalline solid; yield: 49 mg (79%); mp 187–189 (dec.).
1H NMR (CDCl3): d = 2.62 (s, 3 H, CH3), 3.61 (s, 3 H, OCH3), 3.89
(s, 3 H, OCH3), 6.89 (d, J = 9.1 Hz, 2 H, Ph), 7.02 (dd, J = 8.9, 2.4
Hz, 1 H, H-8), 7.25 (d, J = 8.9 Hz, 1 H, H-9), 7.29 (d, J = 9.1 Hz, 2
H, Ph), 7.53 (d, J = 2.4 Hz, 1 H, H-6), 8.63 (s, 1 H, H-3).
13C NMR (CDCl3): d = 20.1 (CCH3), 56.9 (OCH3), 57.3 (OCH3),
109.1 (C-6), 115.8, 116.2, 117.9 (C=C), 118.5 (C-8), 119.9, 123.6,
124.5, 128.2 (C-9), 132.2, 135.4, 142.2 (C-3), 147.1 (C=N), 156.5
(C-4), 159.7 (COCH3), 162.4 (C-7).
7-Methoxy-1,3-diphenyl-1H-pyrazolo[4,3-c]quinoline (22a)
Pyrazolo[4,3-c]quinoline 20a in MeOH was hydrogenated accord-
ing to the general procedure. Flash chromatography (EtOAc–hex-
anes, 3:2) and recrystallization (CH2Cl2–MeOH) gave 22a as white
needles; yield: 71%.
1H NMR (CDCl3): d = 3.70 (s, 3 H, OCH3), 6.79 (d, J = 2.4 Hz, 1
H, H-6), 7.07 (dd, J = 8.9, 2.4 Hz, 1 H, H-8), 7.26 (d, J = 8.9 Hz, 1
H, H-9), 7.36–7.44 (m, 5 H, Ph), 7.49–7.53 (m, 3 H, Ph), 7.55–7.59
(m, 2 H, Ph), 8.36 (s, 1 H, H-4).
13C NMR (CDCl3): d = 44.7 (C-4), 58.5 (OCH3), 61.9 (NCH2), 98.4
(C-6), 103.6 (C-8), 113.2, 117.6 (C=C), 117.9, 120.1, 126.5, 127.2,
128.1, 128.6, 129.5, 130.1, 133.1 (C-9), 136.8, 137.6, 139.5, 145.3,
146.3, 157.9 (C=N), 164.2 (C-7).
Anal. Calcd for C23H17N3O: C, 78.61; H, 4.88; N, 11.96. Found: C,
78.41; H, 4.76; N, 12.14.
1H–15N NMR (acetone-d6): d = 197.6 (N-1), 292.8 (N-2), 321.7 (N-
5).
Anal. Calcd for C19H17N3O2: C, 71.46; H, 5.37; N, 13.16. Found: C,
71.58; H, 5.29; N, 13.30.
7-Methoxy-1-(4-methoxyphenyl)-3-phenyl-1H-pyrazolo[4,3-
c]quinoline (22b)
Pyrazolo[4,3-c]quinoline 20b in MeOH was hydrogenated accord-
ing to the general procedure. Flash chromatography (EtOAc–hex-
anes, 3:2) and recrystallization (CH2Cl2–MeOH) gave 22b as white
needles; yield: 75%.
1H NMR (CDCl3): d = 3.65 (s, 3 H, OCH3), 3.79 (s, 3 H, OCH3),
6.89 (d, J = 2.3 Hz, 1 H, H-6), 6.92 (d, J = 8.2 Hz, 2 H, Ph), 7.15
(dd, J = 8.7, 2.3 Hz, 1 H, H-8), 7.30 (d, J = 8.7 Hz, 1 H, Ph), 7.35
(d, J = 8.8 Hz, 1 H, H-9), 7.37–7.40 (m, 2 H, Ph), 7.42–7.48 (m, 4
H, Ph), 8.21 (s, 1 H, H-4).
7-Methoxy-3-methyl-2-phenyl-2H-pyrazolo[4,3-c]quinoline
(13a)
Pyrazolo[4,3-c]quinoline 12a (0.1 g, 0.26 mmol) in MeOH (20 mL)
was hydrogenated according to the general procedure. Flash chro-
matography (EtOAc–hexanes, 2:3) gave 7c as a dark-yellow crys-
talline solid; yield: 54 mg (72%); mp 135–137 (dec.).
1H NMR (CDCl3): d = 2.72 (s, 3 H, CH3), 3.75 (s, 3 H, OCH3), 6.99
(dd, J = 8.4, 2.1 Hz, 1 H, H-8), 7.17 (d, J = 2.1 Hz, 1 H, H-6), 7.21–
7.28 (m, 5 H, Ph), 7.49 (d, J = 8.4 Hz, 1 H, H-9), 8.27 (s, 1 H, H-4).
13C NMR (CDCl3): d = 7.8 (CCH3), 56.9 (OCH3), 110.1 (C-6),
118.1, 119.2, 120.5 (C-8), 122.2, 123.6, 124.5, 128.2 (C-9), 132.2,
138.7, 140.9 (C-3), 147.2, 151.5 (C-4), 159.8 (C-7).
Anal. Calcd for C24H19N3O2: C, 75.57; H, 5.02; N, 11.02. Found: C,
75.77; H, 4.88; N, 10.86.
1-Phenyl-1H-pyrazolo[4,3-c]quinolin-7-ol (8a)
Pyrazolo[4,3-c]quinoline 7a in MeOH was hydrogenated accord-
ing to the general procedure. Flash chromatography (EtOAc–hex-
anes, 3:2) and recrystallization (CH2Cl2–MeOH) gave 8a as white
needles; yield: 70%; mp 181–182 (dec.).
1H NMR (DMSO-d6): d = 6.92 (dd, J = 8.9, 2.4 Hz, 1 H, H-8), 7.30
(d, J = 8.9 Hz, 1 H, H-9), 7.42 (d, J = 2.4 Hz, 1 H, H-6), 7.61–7.68
(m, 5 H, Ph), 8.48 (s, 1 H, H-3), 9.18 (s, 1 H, H-4), 10.18 (br s, 1 H,
HH).
Anal. Calcd for C18H15N3O: C, 74.72; H, 5.23; N, 14.52. Found: C,
74.50; H, 5.36; N, 14.39.
5-Benzylo-7-methoxy-2-(4-methoxyphenyl)-3-methyl-4,5-dihy-
dro-2H-pyrazolo[4,3-c]quinoline (13b)
Pyrazolo[4,3-c]quinoline 12b (0.1 g, 0.24 mmol) in MeOH (20 mL)
was hydrogenated according to the general procedure. Purification
by flash chromatography (EtOAc–hexanes, 2:3) afforded 13b as
yellowish needles; yield: 80%.
Anal. Calcd for C16H11N3O: C, 73.55; H, 4.24; N, 16.08. Found: C,
73.69; H, 4.42; N, 15.93.
1H NMR (CDCl3): d = 2.19 (s, 3 H, CH3), 3.63 (s, 3 H, OCH3), 3.73
(s, 3 H, OCH3), 4.47 (s, 2 H, H-4), 5.97 (dd, J = 8.4, 2.1 Hz, 1 H, H-
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1800
K. M. Kasiotis et al.
PAPER
8), 6.19 (d, J = 2.1 Hz, 1 H, H-6), 6.63 (d, J = 8.4 Hz, 1 H, H-9),
7.18 (d, J = 8.7 Hz, 2 H, Ph), 7.40–7.42 (d, J = 8.7 Hz, 2 H, Ph).
8b
Yield: 16 mg (30%); mp 271–272 (dec.).
13C NMR (CDCl3): d = 6.7 (CH3), 56.9 (OCH3), 58.5 (OCH3), 109.1
(C-6), 113.8, 118.1, 119.2, 120.5 (C-8), 122.2, 123.6, 125.7, 128.2
(C-9), 132.7, 138.7, 140.9 (C-3), 149.8, 153.2 (C-4), 159.6
(COCH3), 161.9 (C-7).
1H NMR (DMSO-d6): d = 6.99 (d, J = 8.9 Hz, 2 H, Ph), 7.03 (d, J =
2.1 Hz, 1 H, H-6), 7.34 (d, J = 8.9 Hz, 1 H, H-9), 7.40 (dd, J = 8.9,
2.1 Hz, 1 H, H-8), 7.42 (d, J = 8.9 Hz, 2 H, Ph), 8.44 (s, 1 H, H-3),
9.17 (s, 1 H, H-4), 10.19 (br s, 2 H, OH).
Anal. Calcd for C18H15N3O: C, 75.89; H, 6.12; N, 10.21. Found: C,
75.75; H, 5.95; N, 10.39.
Anal. Calcd for C16H11N3O2: C, 69.31; H, 4.00; N, 15.15. Found: C,
69.52; H, 4.14; N, 14.97.
7-Methoxy-2-(4-methoxyphenyl)-3,4-dimethyl-2H-pyrazo-
lo[4,3-c]quinoline (13c)
9b
Yield: 22 mg (40%); mp 241–243 (dec.).
Pyrazolo[4,3-c]quinoline 12c (24 mg, 0.06 mmol) in MeOH–AcOH
(5:1, 25 mL) was hydrogenated according to the general procedure.
Purification by flash chromatography (EtOAc–hexanes, 1:1) af-
forded 13c as a yellowish solid; yield: 91%.
1H NMR (CDCl3): d = 2.71 (s, 3 H, CH3), 2.90 (s, 3 H, CH3), 3.87
(s, 3 H, OCH3), 3.89 (s, 3 H, OCH3), 7.01 (dd, J = 8.9, 2.7 Hz, 1 H,
H-8), 7.19 (d, J = 8.9 Hz, 2 H, Ph), 7.25 (d, J = 8.9 Hz, 1 H, H-9),
7.46 (d, J = 2.7 Hz, 1 H, H-6), 7.52 (d, J = 8.9 Hz, 2 H, Ph).
1H NMR (DMSO-d6): d = 3.89 (s, 3 H, OCH3), 7.05 (d, J = 8.5 Hz,
2 H, Ph), 7.17 (dd, J = 9.2, 2.4 Hz, 1 H, H-8), 7.41 (d, J = 9.2 Hz,
1 H, H-9), 7.45 (d, J = 8.5 Hz, 2 H, Ph), 7.59 (d, J = 2.4 Hz, 1 H,
H-6), 8.71 (s, 1 H, H-4), 9.24 (s, 1 H, H-4), 10.19 (br s, 1 H, OH).
Anal. Calcd for C17H13N3O2: C, 70.09; H, 4.50; N, 14.42. Found: C,
69.95; H, 4.37; N, 14.56.
1-(4-Hydroxyphenyl)-4-methyl-1H-pyrazolo[4,3-c]quinolin-7-
ol (8c) and 1-(4-Methoxyphenyl)-4-methyl-1H-pyrazolo[4,3-
c]quinolin-7-ol (9c)
Anal. Calcd for C20H19N3O2: C, 72.05; H, 4.95; N, 13.76. Found: C,
72.25; H, 4.84; N, 13.61.
A stirred CH2Cl2 solution of 7c (60 mg, 0.19 mmol) was deprotect-
ed using BBr3 according to the general demethylation procedure.
Flash chromatography (MeOH–CH2Cl2, 1:20) gave 8c and 9c as
yellow solids, which were recrystallized (Et2O) to afford the title
compounds as small off-white crystals.
Demethylation; General Procedure
To a stirred solution of methyl-protected pyrazole (1 equiv) in
CH2Cl2 (35 mL/mmol) at –78 °C, a solution of BBr3 (1 M, CH2Cl2;
10–15 equiv) was added dropwise. After complete addition of BBr3,
the reaction was maintained at –78 °C for 1 h and then the temper-
ature was allowed to rise to r.t. and stirring continued for an addi-
tional 16 h. The mixture was cooled to 0 °C and carefully quenched
with H2O (15–25 mL). The product was then extracted with EtOAc
(3 × 20 mL) and the organic layers were dried over MgSO4. After
removal of the solvent the crude phenolic products were purified by
flash chromatography and/or recrystallization (MeOH–CH2Cl2 or
Et2O).
8c
Yield: 50% yield; mp 221–222 (dec.).
1H NMR (DMSO-d6): d = 2.55 (s, 3 H, CH3), 6.87 (d, J = 8.5 Hz, 2
H, Ph), 7.17 (dd, J = 9.2, 2.4 Hz, 1 H, H-8), 7.25 (d, J = 8.5 Hz, 2
H, Ph), 7.41 (d, J = 9.2 Hz, 1 H, H-9), 7.59 (d, J = 2.4 Hz, 1 H, H-
6), 8.11 (s, 1 H, H-3), 9.05 (br s, 1 H, OH), 9.15 (br s, 1 H, OH).
Anal. Calcd for C17H13N3O2: C, 70.09; H, 4.50; N, 14.42. Found: C,
69.92; H, 4.61; N, 14.28.
5-Benzyl-1-phenyl-4,5-dihydro-1H-pyrazolo[4,3-c]quinolin-7-
ol (7a)
A stirred CH2Cl2 solution of 6a (100 mg, 0.27 mmol) was deprotect-
ed using BBr3 according to the general demethylation procedure.
Flash chromatography (EtOAc–hexanes, 2:3) afforded a yellow sol-
id which was recrystallized (Et2O) to afford the title compound as
small off-white crystals; yield: 67 mg (70%); mp 169–171 (dec.).
1H NMR (acetone-d6): d = 4.52 (s, 2 H, H-4), 4.55 (s, 2 H, HCH2),
5.95 (dd, J = 8.7, 2.1 Hz, 1 H, H-8), 6.22 (d, J = 2.1 Hz, 1 H, H-6),
6.56 (d, J = 8.7 Hz, 1 H, H-9), 7.24–7.28 (m, 1 H, Ph), 7.31–7.40
(m, 4 H, Ph), 7.41 (s, 1 H, H-3), 7.45–7.55 (m, 5 H, Ph).
9c
Yield: 35%; mp 191–193 (dec.).
1H NMR (DMSO-d6): d = 2.59 (s, 3 H, CH3), 3.83 (s, 3 H, OCH3),
7.06 (d, J = 8.5 Hz, 2 H, Ph), 7.17 (dd, J = 9.2, 2.4 Hz, 1 H, H-8),
7.41 (d, J = 9.2 Hz, 1 H, H-9), 7.45 (d, J = 8.5 Hz, 2 H, Ph), 7.59
(d, J = 2.4 Hz, 1 H, H-6), 8.59 (s, 1 H, H-3), 10.21 (br s, 1 H, OH).
Anal. Calcd for C18H15N3O2: C, 70.81; H, 4.95; N, 13.76. Found: C,
70.96; H, 4.79; N, 13.63.
13C NMR (acetone-d6): d = 52.9 (C-4), 61.2 (NCH2), 99.7 (C-6),
104.4 (C-8), 115.1, 118.5 (C=C), 120.1, 125.5, 127.4, 128.5, 128.9,
129.3 131.1 (C-9), 132.2, 136.8, 142.3 (C=N), 145.4, 160.1 (C-7).
1H–15N NMR (acetone-d6): d = 199.8 (N-1), 295.2 (N-2), 327.6 (N-
5).
3-Methyl-2-phenyl-2H-pyrazolo[4,3-c]quinolin-7-ol (14a)
A stirred CH2Cl2 solution of 13a (0.1 g, 0.34 mmol) was deprotect-
ed using BBr3 according to the general demethylation procedure.
Flash chromatography (EtOAc–hexanes, 2:1) afforded 14a as white
needles; yield: 71%; mp 211–213 (dec.).
1H NMR (acetone-d6): d = 2.68 (s, 3 H, CH3), 6.75 (d, J = 8.3 Hz, 2
H, Ph), 6.89 (dd, J = 8.4, 2.1 Hz, 1 H, H-8), 7.13 (d, J = 2.1 Hz, 1
H, H-6), 7.20 (d, J = 8.3 Hz, 2 H, Ph), 7.33 (m, 1 H, Ph), 7.53 (d,
J = 8.4 Hz, 1 H, H-9), 7.92 (s, 1 H, H-4).
13C NMR (DMSO-d6): d = 6.2 (C=CCH3), 108.2 (C-6), 116.4, 117.9
(C=C), 118.7 (C-8), 119.6, 123.6, 124.5, 128.2 (C-9), 129.4, 130.7,
134.8, 140.2 (C-3), 147.8, 152.9 (C-4), 158.9 (C-7).
1H–15N NMR (acetone-d6): d = 290.3 (N-1), 195.4 (N-2), 319.5 (N-
5).
Anal. Calcd for C23H19N3O: C, 78.16; H, 5.42; N, 11.84. Found: C,
78.28; H, 5.31; N, 11.71.
1-(4-Hydroxyphenyl)-1H-pyrazolo[4,3-c]quinolin-7-ol (8b) and
1-(4-Methoxyphenyl)-1H-pyrazolo[4,3-c]quinolin-7-ol (9b)
A stirred CH2Cl2 solution of 7b (60 mg, 0.2 mmol) was deprotected
using BBr3 according to the general demethylation procedure. Flash
chromatography (MeOH–CH2Cl2, 1:20) gave 8b and 9b as yellow
solids, which were recrystallized (Et2O) to afford the title com-
pounds as small off-white crystals.
Anal. Calcd for C17H13N3O: C, 74.17; H, 4.76; N, 15.26. Found: C,
73.93; H, 4.52; N, 15.43.
Synthesis 2006, No. 11, 1791–1802 © Thieme Stuttgart · New York

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Conformationally Constrained Pyrazolo[4,3-c]quinoline Derivatives
1801
2-(4-Hydroxyphenyl)-3-methyl-2H-pyrazolo[4,3-c]quinolin-7-
ol (14b)
A stirred CH2Cl2 solution of 13b (0.1 g, 0.32 mmol) was deprotect-
ed using BBr3 according to the general demethylation procedure.
Flash chromatography (EtOAc–hexanes, 2:1) afforded 14b as white
needles; yield: 68%); mp 321–322 (dec.)
1H NMR (DMSO-d6): d = 2.68 (s, 3 H, CH3), 6.75 (d, J = 8.3 Hz, 2
H, Ph), 7.01 (dd, J = 8.4, 2.1 Hz, 1 H, H-8), 7.13 (d, J = 2.1 Hz, 1
H, H-6), 7.20 (d, J = 8.3 Hz, 2 H, Ph), 7.45 (d, J = 8.4 Hz, 1 H, H-
9), 7.95 (s, 1 H, H-4).
1,3-Diphenyl-1H-pyrazolo[4,3-c]quinolin-7-ol (24a)
A stirred CH2Cl2 solution of 22a (0.1 g, 0.29 mmol) was deprotect-
ed using BBr3 according to the general demethylation procedure.
Flash chromatography (CH2Cl2–MeOH, 97:3) afforded 24a as an
off-white solid; yield: 72%.
1H NMR (acetone-d6): d = 7.09 (dd, J = 8.8, 2.2 Hz, 1 H, H-8), 7.22
(d, J = 2.2 Hz, 1 H, H-6), 7.32–7.37 (m, 6 H, Ph), 7.46–7.51 (m, 4
H, Ph), 7.58 (d, J = 8.8 Hz, 1 H, H-9), 8.32 (s, 1 H, H-4), 9.19 (s, 1
H, OH).
Anal. Calcd for C22H15N3O: C, 78.32; H, 4.48; N, 12.46. Found: C,
78.31; H, 4.60; N, 12.74.
1H–15N NMR (DMSO-d6): d = 294.9 (N-1), 197.2 (N-2), 323.9 (N-
5).
1-(4-Hydroxyphenyl)-3-phenyl-1H-pyrazolo[4,3-c]quinolin-7-
ol (24b)
A stirred CH2Cl2 solution of 22b (0.1 g, 0.27 mmol) was deprotect-
ed using BBr3 according to the general demethylation procedure.
Flash chromatography (CH2Cl2–MeOH, 97:3) afforded 24b as an
off-white solid; yield: 72%.
1H NMR (DMSO-d6): d = 6.69 (d, J = 8.7 Hz, 2 H, Ph), 6.98 (d,
J = 8.7 Hz, 2 H, Ph), 7.15 (dd, J = 8.6, 1.9 Hz, 1 H, H-8) 7.39 (d,
J = 8.6 Hz, 1 H, H-9), 7.43 (d, J = 1.9 Hz, 1 H, H-6), 8.60 (s, 1 H,
H-4).
Anal. Calcd for C17H13N3O2: C, 70.09; H, 4.50; N, 14.42. Found: C,
69.85; H, 4.65; N, 14.34.
2-(4-Hydroxyphenyl)-3,4-dimethyl-2H-pyrazolo[4,3-c]quino-
lin-7-ol (14c)
A stirred CH2Cl2 solution of 13c (15 mg, 0.04 mmol) was deprotect-
ed using BBr3 according to the general demethylation procedure.
Flash chromatography (CH2Cl2–MeOH, 97:3) afforded 14c as a
yellowish solid; yield: 63%.
1H NMR (DMSO-d6): d = 2.71 (s, 3 H, CH3), 2.90 (s, 3 H, CH3),
7.01 (dd, J = 8.9, 2.7 Hz, 1 H, H-8), 7.20 (d, J = 8.9 Hz, 2 H, Ph),
7.25 (d, J = 8.9 Hz, 1 H, H-9), 7.38 (d, J = 2.7 Hz, 1 H, H-6), 7.52
(d, J = 8.9 Hz, 2 H, Ph), 8.52 (br s, 2 H, OH).
Anal. Calcd for C22H15N3O2: C, 74.78; H, 4.28; N, 11.89. Found: C,
74.58; H, 4.43; N, 11.65.
13C NMR (DMSO-d6): d = 6.8 (C=CCH3), 19.9 (N=CCH3), 108.2
(C-6), 116.4, 116.9, 117.9 (C=C), 118.7 (C-8), 119.9, 123.6, 124.5,
128.2 (C-9), 132.2, 135.4, 140.8 (C-3), 147.8, 158.1 (C-7), 160.2
(C-4).
References
(1) Gao, H.; Katzenellenbogen, J. A.; Garg, R.; Hansch, C.
Chem. Rev. 1999, 99, 723.
(2) Magarian, R. A.; Overaacre, L. B.; Singh, S. Curr. Med.
Chem. 1994, 1, 61.
(3) Grundy, J. Chem. Rev. 1957, 57, 281.
1H–15N NMR (DMSO-d6): d = 295.1 (N-1), 196.2 (N-2), 324.8 (N-
5).
Anal. Calcd for C18H15N3O2: C, 70.81; H, 4.95; N, 13.76. Found: C,
70.96; H, 4.75; N, 13.54.
(4) Compton, D. R.; Carlson, K. E.; Katzenellenbogen, J. A.
Bioorg. Med. Chem. Lett. 2004, 14, 5681.
(5) Jordan, V. C. Trends Endocrinol. Metab. 1999, 10, 312.
(6) Meegan, M. J.; Hughes, R. B.; Lloyd, D. G.; Williams, D. C.;
Zisterer, D. M. J. Med. Chem. 2001, 44, 1072.
(7) Arnal, J. F.; Gourdy, P.; Bayard, L. F.; Filippe, C. Drug
Discov. Today: Dis. Model. 2004, 23, 213.
(8) Delmas, P. D.; Bjarnason, N. H.; Mitlak, B. H.; Ravoux, A.
C.; Shah, A. S.; Huster, W. J.; Draper, M.; Christianson, C.
N. Engl. J. Med. 1997, 337, 1641.
(9) Grese, T. A.; Dogde, J. A. Curr. Pharm. Des. 1998, 4, 71.
(10) Kuiper, G. G.; Enmark, E.; Pelto-Huikko, M.; Nilsson, S.;
Gustafsson, J.-A. Proc. Natl. Acad. Sci. U.S.A. 1996, 93,
5925.
(11) Pettersson, K.; Gustafsson, J. A. Ann. Rev. Physiol. 2001, 63,
165.
2,3-Diphenyl-2H-pyrazolo[4,3-c]quinolin-7-ol (23a)
A stirred CH2Cl2 solution of 21a (0.1 g, 0.29 mmol) was deprotect-
ed using BBr3 according to the general demethylation procedure.
Flash chromatography (CH2Cl2–MeOH, 97:3) afforded 23a as an
off-white solid; yield: 72%.
1H NMR (acetone-d6): d = 7.09 (dd, J = 8.8, 2.2 Hz, 1 H, H-8), 7.22
(d, J = 2.2 Hz, 1 H, H-6), 7.32–7.37 (m, 4 H, Ph), 7.42 (d, J = 8.2
Hz, 2 H, Ph), 7.46–7.51 (m, 4 H, Ph), 7.58 (d, J = 8.8 Hz, 1 H, H-
9), 8.82 (s, 1 H, H-4).
Anal. Calcd for C22H15N3O: C, 78.32; H, 4.48; N, 12.46. Found: C,
78.51; H, 4.63; N, 12.19.
2-(4-Hydroxyphenyl)-3-phenyl-2H-pyrazolo[4,3-c]quinolin-7-
ol (23b)
A stirred CH2Cl2 solution of 21b (0.1 g, 0.27 mmol) was deprotect-
ed using BBr3 according to the general demethylation procedure.
Flash chromatography (CH2Cl2–MeOH, 97:3) afforded 23b as off-
white needles; yield: 77%.
1H NMR (DMSO-d6): d = 6.82 (d, J = 7.8 Hz, 2 H, Ph), 7.02 (dd,
J = 8.6, 1.9 Hz, 1 H, H-8) 7.14 (d, J = 7.8 Hz, 2 H, Ph), 7.30–7.35
(m, 5 H, Ph), 7.39 (d, J = 8.6 Hz, 1 H, H-9), 7.43 (d, J = 1.9 Hz, 1
H, H-6), 8.92 (s, 1 H, H-4), 9.15 (s, 2 H, OH).
(12) Nilsson, S.; Kuiper, G.; Gustafsson, J. A. Trends
Endocrinol. Metab. 1998, 9, 387.
(13) Stauffer, S. R.; Coletta, C. J.; Tedesco, R.; Nishigushi, G.;
Carlson, K.; Sun, J.; Katzenellenbogen, B. S.;
Katzenellenbogen, J. A. J. Med. Chem. 2000, 44, 4934.
(14) Fink, B. E.; Mortensen, D. S.; Stauffer, S. R.; Aron, Z. D.;
Katzenellenbogen, J. A. Chem. Biol. 1999, 6, 205.
(15) Stauffer, S. R.; Huang, Y. R.; Aron, Z. D.; Coletta, C. J.;
Sun, J.; Katzenellenbogen, B. S.; Katzenellenbogen, J. A.
Bioorg. Med. Chem. 2001, 9, 151.
(16) Lin, X.; Huebner, V. Curr. Opin. Drug Discov. Dev. 2000,
Anal. Calcd for C22H15N3O2: C, 74.78; H, 4.28; N, 11.89. Found: C,
74.98; H, 4.39; N, 12.06.
3, 383.
(17) Baraldi, P. G.; Borea, P. A. Trends Pharmacol. Sci. 2000,
21, 456.
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PAPER
(18) Colleta, V.; Catarzi, D.; Varano, F.; Cecchi, L.; Filacchiono,
G.; Martini, C.; Lucacchini, A. J. Med. Chem. 2000, 43,
3118.
(19) Eskildsen, J.; Østergaard, N.; Vedsø, P.; Begtrup, M.
Tetrahedron 2002, 58, 7635.
(20) Kuo, S.-C.; Lee, H.-Z.; Juang, J.-P.; Lin, Y.-T.; Wu, T.-S.;
Chang, J.-J.; Lednicer, D.; Paull, K. D.; Lin, C.-M.; Hamel,
E.; Lee, K.-H. J. Med. Chem. 1993, 36, 1146.
(21) Edwards, J. P.; Higuchi, R. I.; Winn, D. T.; Pooley, C. L. F.;
Caferro, T. R. Bioorg. Med. Chem. Lett. 1999, 7, 1003.
(22) Booker-Milburn, K. I.; Dunkin, I. R.; Kelly, F. C.; Khalaf, A.
I.; David, A. J. Chem. Soc., Perkin Trans. 1 1997, 3261.
(23) Wiles, C.; Watts, P.; Haswell, S. J.; Pombo-Villar, E.
Tetrahedron Lett. 2002, 43, 2945.
Synthesis 2006, No. 11, 1791–1802 © Thieme Stuttgart · New York