Synthesis and evaluation of azole-substituted 2-aryl-6-methoxy-3,4- dihydronaphthalenes and -naphthalenes as inhibitors of 17α-hydroxylase- C17,20-Lyase (P450 17)

Article abstract of DOI:10.1002/(SICI)1521-4184(19991)332:1<25::AID-ARDP25>3.0.CO;2-7

The synthesis and biological evaluation of azole-substituted 3,4- dihydronaphthalenes (7a, 7b, 14a, 14b) and naphthalenes (12a, 12b, 16a, 16b) as nonsteroidal inhibitors of 17α-hydroxylase-C17,20-lyase (P450 17, CYP 17) are described. In the case of the dihydronaphthalenes, introduction of the phenyl substituent into the 2-position was accomplished by coupling 2- hydroxy-3,4-dihydronaphthalene-2-trifluoromethanesulfonate 1 with the corresponding aryl-Zn-bromides 4a and 4b in the presence of Pd(PPh₃)₄ as catalyst yielding 5a and 5b as key intermediates. In the case of the naphthalenes, 2-bromonaphthalene 9 was reacted with the corresponding Grignard reagents yielding 10a and 10b. After transformation of the intermediate acetals 5a, 5b, 10a, 10b into the corresponding aldehydes, the latter compounds were reacted with tosylmethyl isocyanide and K₂CO₃ to give the oxazoles 7a, 7b, 12a, and 12b. The imidazoles 14a, 14b, 16a, and 16b were prepared by heating the corresponding 4-tosyloxazolines in ammonia, which were prepared by reacting the aldehydes with tosylmethyl isocyanide and NaCN. Using a microsomal fraction of human testicular enzyme, the title compounds did not inhibit the target enzyme.

Full text of DOI:10.1002/(SICI)1521-4184(19991)332:1<25::AID-ARDP25>3.0.CO;2-7

Substituted 2-Aryl-6-methoxy-3,4-dihydronaphthalenes
25
Synthesis and Evaluation of Azole-substituted
2-Aryl-6-methoxy-3,4-dihydronaphthalenes and -naphthalenes as
Inhibitors of 17α-Hydroxylase-C17,20-Lyase (P450 17)✩
Yan Zhuang and Rolf W. Hartmann*
FR 12.1 Pharmazeutische und Medizinische Chemie, Universität des Saarlandes, P.O. Box 15 11 50, D-66041 Saarbrücken, Germany
Key Words: Nonsteroidal P450 17 inhibitors; 17α-hydroxylase-C17,20-lyase (P450 17; CYP 17);
azole-substituted 2-aryl-3,4-dihydronaphthalenes and 2-aryl-naphthalene
[7,15]
steroidal compounds, it has recently been shown
that an
Summary
imidazole ring at the C-17 position leads to potent inhibitors
as well (e.g., III, Chart 1 ). The present paper describes the
[7]
The synthesis and biological evaluation of azole-substituted
3,4-dihydronaphthalenes (7a, 7b, 14a, 14b) and naphthalenes
(12a, 12b, 16a, 16b) as nonsteroidal inhibitors of 17α-hydroxy-
lase-C17,20-lyase (P450 17, CYP 17) are described. In the case of
the dihydronaphthalenes, introduction of the phenyl substituent
into the 2-position was accomplished by coupling 2-hydroxy-3,4-
dihydronaphthalene-2-trifluoromethanesulfonate 1 with the corre-
sponding aryl-Zn-bromides4a and 4b in the presence of Pd(PPh3)4
as catalyst yielding 5a and 5b as key intermediates. In the case of
the naphthalenes, 2-bromonaphthalene 9 was reacted with the
corresponding Grignard reagents yielding 10a and 10b. After
transformation of the intermediate acetals5a, 5b, 10a, 10b into the
corresponding aldehydes, the latter compounds were reacted with
tosylmethyl isocyanide and K2CO3 to give the oxazoles 7a, 7b,
12a, and12b. Theimidazoles 14a, 14b, 16a, and 16b wereprepared
by heating the corresponding 4-tosyloxazolines in ammonia,
which were prepared by reacting the aldehydes with tosylmethyl
isocyanide and NaCN. Using a microsomal fraction of human
testicular enzyme, the title compounds did not inhibit the target
enzyme.
synthesis of imidazole and oxazole-substituted 3,4-dihydro-
naphthalenes and naphthalenes (7a, 7b, 12a, 12b, 14a, 14b,
16a, and 16b, Chart 1) and their biological evaluation. A
phenyl ring instead of a methylene group is used as a spacer
between the two ring systems leading to conformationally
constrained compounds.
Introduction
Chart 1. Selected inhibitors of P450 17 (I–III) and the title compounds.
Two strategies are conceivable for the therapy of hormone
dependent tumors: The use of hormone antagonists and the
application of inhibitors of hormone biosynthesis. In the case
of estrogen dependent breast cancer both methods have been
Synthesis
[1]
realized in the meantime . As an alternative to antiestrogen
6-Methoxy-2-tetralone was used as starting material for the
synthesis of the dihydronaphthalenes 7 and 14 (Scheme 1).
[2]
treatment , highly potent inhibitors of estrogen biosynthesis
have been developed recently, some of which already have Reaction with trifluoromethanesulfonic acid anhydride gave
[16]
been admitted to the market (fadrozole, anastrozole, letro-
the corresponding trifluoromethanesulfonate 1 . After pro-
[3–5]
zole)
. Efforts are currently being undertaken to develop
tection of the aldehyde group in the bromo compounds 2a and
[6,7]
inhibitors of androgen biosynthesis
antiandrogens (flutamide, cyproterone acetate)
, as alternatives to 2b, the corresponding acetals 3a and 3b were reacted with
[8,9]
[17]
and
t-BuLi and ZnCl . Using a described procedure , the in situ
2
[10]
GnRH analogs (such as busereline) . The enzyme in ques-
formed compounds 4a and 4b were converted with 1, using
tion is 17α-hydroxylase-C17,20-lyase (P450 17) which cata- the palladium complex Pd(PPh ) as catalyst, to yield com-
3 4
lyzes the conversion of progesterone and pregnenolone into pounds 5a and 5b. After deprotection, the aldehydes 6a and
the androgens, androstenedione and dehydroepiandrosterone 6b were either transformed to the oxazole compounds 7a and
[11,12]
[6,13,14]
(DHEA), respectively
. Recently we have shown
7b using equimolar quantities of tosylmethyl isocyanide
[18]
that a dihydro- or tetrahydronaphthalene nucleus is able to (TosMIC) , or were converted to the imidazole derivatives
give – after linkage with an N containing heterocycle such as 14a and 14b. For the synthesis of the latter compounds,
imidazole, pyrazine, or pyridine – highly potent inhibitors of reaction of the aldehydes 6a and 6b with TosMIC and sodium
[6]
P450 17 (e.g., I and II, Chart 1 ). While the heterocyclic N cyanide to yield the corresponding 4-tosyloxazolines 13a and
is complexing the heme iron of P450 17, the rest of the 13b and subsequent heating of 13a and 13b in saturated
[19]
molecule interacts with the apoprotein moiety. In the case of methanolic ammonia was performed
.
Arch. Pharm. Pharm. Med. Chem.
© WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0365-6233/99/0101/0025 $17.50 +.50/0

26
Zhuang and Hartmann
a: meta substitution
b: para substitution
Ts: p-tolylsulfonyl
i) O(SO2CF3)2, Py, CH2Cl2, N2, rt, 2 d;
iii) t-BuLi, ZnCl2, THF, N2, –78 °C;
v) 10% HCl, THF, rt, 10 h;
ii) ethylene glycol, TsOH, toluene, reflux, 4 d;
iv) Pd(PPh3)4, THF, N2, 65 °C, 2 h;
vi) TosMIC, K2CO3, CH3OH, reflux, 3 h;
viii) NH3, CH3OH, THF, 110–120 °C, 24 h.
vii) TosMIC, NaCN, EtOH, THF, 0 °C , 2 h;
Scheme 1. Synthesis of 7a, 7b, 14a, and 14b.
Arch. Pharm. Pharm. Med. Chem. 332, 25–30 (1999)

Substituted 2-Aryl-6-methoxy-3,4-dihydronaphthalenes
27
a: meta substitution
b: para substitution
Ts: p-tolylsulfonyl
i) Mg, I2, THF, N2, rt, 2 h;
ii) Pd(PPh3)4, THF, N2, 65 °C, 2 h;
iii) 10% HCl, THF, rt, 10 h;
iv) TosMIC, K2CO3, CH3OH, reflux, 3 h;
vi) NH3, CH3OH, THF, 110–120 °C, 24 h.
v) TosMIC, NaCN, EtOH, THF, 0 °C , 2 h;
Scheme 2. Synthesis of 12a, 12b, 16a, and 16b.
For the synthesis of the naphthalene compounds 12 and 16, compounds and the highly potent steroidal inhibitor III.
a different coupling reaction was used (Scheme 2). The Superimposition of these compounds is shown in Figure 1. It
acetals 3a and 3b were converted to the Grignard reagents 8a becomes apparent that the D ring and the heterocycle of the
and 8b which were reacted with 2-bromo-6-methoxy- meta substituted compounds fit well with the steroidal tem-
naphthalene 9 using Pd(PPh ) as catalyst. The resulting plate. A large difference, however, can be seen with respect
3 4
2-arylnaphthalenes 10a and 10b were further converted to the to the A and B ring systems. This is true for the para substi-
title compounds using the same reactions as for the dihydro- tuted compounds as well. The different orientation of the keto
naphthalenes.
group of the steroidal compound III and the methoxy group
of the title compounds seems to be a plausible reason for their
poor inhibitory activity.
Results and Discussion
Compounds 7a, 7b, 12a, 12b, 14a, 14b, 16a, and 16b were
tested for inhibition of P450 17 using human testicular en-
zyme as well as progesterone as substrate (25 µM) employing
Acknowledgements
Thanks are due to the Fonds der Chemischen Industrie, who supported this
work by a grant. We thank Dr. Markus Hector and Mr. Bertil Wachall for
discussions, Mr. Jochim Schröder for providing the mass spectra, and Ms
Anja Palusczak for performing the P450 17 inhibitory assay.
[20]
the procedure recently described . Tested at a concentra-
tion of 2.5 µM, the title compounds showed no inhibitory
activity (7a, –19.6%, 7b, –13.5%, 12a, –10.2% and 12b,
3.9%, 14a, –4.0%, 14b, –9.9%, 16a, –4.6% and 16b, 2.8%).
This result is probably due to the fact that there is no ener-
getically preferred conformation of these azoles to fit prop-
erly into the active site of the enzyme. In order to find an
explanation for this, molecular modeling studies were per-
formed using energy-minimized conformations of the title
Experimental Section
Melting points were determined on a Kofler microscope (Reichert; Vi-
enna) and are not corrected. Elemental analyses were performed at the
Inorganic Chemistry Department of the Universität des Saarlandes and were
within ±0.4% of the calculated values. Mass spectra (EI) were recorded on
Arch. Pharm. Pharm. Med. Chem. 332, 25–30 (1999)

28
Zhuang and Hartmann
6-Methoxy-2-3-(1,3-dioxolan-2-yl)phenyl-3,4-dihydronaphthalene (5a)
A stirred solution of 3a (3.65 g, 15 mmol, 2.5 eq) in THF (50 ml) was
treated with t-BuLi (20 ml, 30 mmol, 5 eq) under dry nitrogen at –75 °C.
Then a slurry of ZnCl2 (2.04 g, 15 mmol, 2.5 eq) in THF (10 ml) was added.
The mixture was warmed to room temperature, before triflate 1 (1.85 g,
6.0 mmol, 1 eq) and Pd(PPh3)4 (0.23 g, 0.2 mmol) were added and then
heated under reflux for 2 h. The solution was worked up with 3 N HCl and
extracted three times with CH2Cl2 (100 ml). The organic layer was washed
with brine, dried over Na2SO4 and the solvent was removed in vacuo. The
crude product was purified by silica gel column chromatography using 4%
EtOAc/petroleum ether as eluent to give 1.3 g (70%) of 5a (white crystals).–
Mp 98–99 °C.– IR (KBr): ν = 3020 (w, Ar-H), 3000 (m, CH), 2960 (m, CH),
2880 (m, CH), 1600 (s), 1570 (s, C=C), 1500 (s, C=C) (vs)cm–1;– 1H NMR
(CDCl3): δ = 2.73 (t, J = 8.4 Hz, 2H, ArCH2CH2), 2.93 (t, J = 8.4 Hz, 2H,
ArCH2), 3.82 (s, 3H, OCH3), 4.06 (t, J = 7.08 Hz, 2H, CH2O), 4.16 (t, J =
7.08 Hz, 2H, CH2O), 5.85(s, 1H, HC(OCH2)2), 6.72 (d, J = 7.96 Hz, 1H,
Ar-H, -H7), 6.74 (s, 1H, Ar-H, -H5), 6.84 (s, 1H, =CH), 7.07 (d, J = 7.96 Hz,
1H, Ar-H, -H8), 7.37–7.38 (m, 2H, Ar′-H, -H4′, -H6′), 7.52 (m, 1H, Ar′-H,
-H5′), 7.64 (s, 1H, Ar′-H, -H2′);– MS m/z (%) = 308 (100) (M+), 145 (70),
73 (50).
6-Methoxy-2-4-(1,3-dioxolan-2-yl)phenyl-3,4-dihydronaphthalene (5b)
3.65 g (15.9 mmol) of 3b gave 1.2 g of 5b (65%, white crystals).– Mp
112–114 °C;– IR (KBr): ν = 3000 (w, Ar-H), 2980 (m, CH), 2800 (m, CH),
1600 (s), 1570 (s), 1500 (s, C=C) (vs) cm–1;– 1H NMR (CDCl3): δ = 2.72 (t,
J = 8.4 Hz, 2H, ArCH2CH2), 2.95 (t, J = 8.4 Hz, 2H, ArCH2), 3.82 (s, 3H,
OCH3), 4.03–4.06 (t, J = 6.86 Hz, 2H, CH2O), 4.13–4.17 (t, J = 6.86 Hz, 2H,
CH2O), 5.83 (s, 1H, HC(OCH2)2), 6.71–6.73 (d, J = 7.96 Hz, 1H, Ar-H, -H7),
6.73 (s, 1H, Ar-H, -H5), 6.83 (s, 1H, =CH),), 7.06–7.08 (d, J = 7.96 Hz, 1H,
Ar-H, -H8), 7.46-7.48 (d, J = 8.4 Hz, 2H, Ar′-H, -H2′, -H6′), 7.53–7.56 (d,
J = 8.4 Hz, 2H, Ar′-H, -H3′, -H5′);– MS m/z (%) = 308 (100) (M+), 236 (60),
145 (70), 91(40).
Figure 1. Superimposition of the lowest-energy conformation of the title
compounds with III (red); top: from β side; bottom: from front side.
a HP G1800A GCD. 1H-NMR spectra were measured on a Bruker AM 400
(400 MHz) and are consistent with the assigned structures. IR spectra of KBr
disks were measured on a Perkin-Elmer Infrared Spectrometer 398. Silica
gel 60 from Macherey & Nagel was used for column chromatography.
Petroleum ether refers to petroleum ether (40-60 °C).
6-Methoxy-2-3-(1,3-dioxolan-2-yl)phenylnaphthalene (10a)
3a (1.7 g, 7.4 mmol) was slowly added to a solution containing Mg (0.18 g,
7.4 mmol) in THF (5 ml)under dry nitrogen at 90 °C with a trace of I2 as
catalyst. The mixture was stirred under reflux for 2 h, then cooled to room
temperature, prior to addition of 9 (2-bromo-6-methoxynaphthalene) (0.85 g,
3.5 mmol) and Pd(PPh3)4 (0.23 g, 0.2 mmol). The mixture was then heated
under reflux for another 2 h. The solution was worked up with 1 N HCl and
extracted three times with CH2Cl2 (100 ml). The organic layer was washed
with brine, dried over Na2SO4, and the solvent was removed in vacuo. The
crude product was purified by silica gel column chromatography using 4%
EtOAc/petroleum ether as eluent to give 0.55 g (50%) of 10a (white crys-
tals).– Mp 118–119.5 °C.– IR (KBr): ν = 3030 (w, Ar-H), 2980, 2890 (m,
CH), 1630, 1610 (s, C=C), 1600, 1490 (s, C=C) (vs)cm–1;– 1H NMR
(CDCl3): δ = 3.95 (s, 3H, OCH3), 4.08 (m, 2H, CH2O), 4.17 (m, 2H, CH2O),
5.92 (s, 1H, HC(OCH2)2), 7.16 (s, 1H, Ar-H, -H5), 7.17 (d, J = 7.96 Hz, 1H,
Ar-H, -H7), 7.48 (m, 1H, Ar-H, -H4), 7.49 (d, J = 7.96 Hz, 1H, Ar-H, -H8),
7.70–7.73 (m, 2H, Ar-H, -H3, Ar′-H, -H5′), 7.79–7.82 (m, 3H, Ar′-H, -H2′,
-H4′, -H6′), 7.99 (s, 1H, Ar-H, -H1).
2-Hydroxy-6-methoxy-3,4-dihydronaphthalene-2-trifluoromethanesulfon-
ate (1)
Trifluoromethanesulfonic acid anhydride (5.4 ml, 32 mmol) was added
slowly to a stirred solution of 6-methoxy-2-tetralone (4.2 g, 24 mmol) and
pyridine (3.2 g, 40 mmol) in CH2Cl2 (250 ml) under nitrogen atmosphere at
0 °C. The mixture was stirred at room temperature for 2 days. The end of
reaction was determined by TLC control. Then 200 ml water was added
slowly in an ice-bath. The reaction mixture was worked up with saturated
NaHCO3 and extracted three times with CH2Cl2 (150 ml). The organic layer
was washed with H2O, dried over Na2SO4 and the solvent was removed in
vacuo. The crude product was purified by silica gel column chromatography
using 4% EtOAc / petroleum ether as eluent to give 4.3 g (60%) of compound
1.– Mp 35–37 °C.– 1H NMR (CDCl3): δ = 2.66 (t, J = 8.4 Hz, 2H,
ArCH2CH2), 3.03 (t, J = 8.4 Hz, 2H, ArCH2), 3.80 (s, 3H, OCH3), 6.43 (s,
1H, HC=), 6.68 (m, 2H, Ar-H, -H5, -H7), 6.70 (d, J = 8.4, Hz, 1H, Ar-H,
-H8).
6-Methoxy-2-4-(1,3-dioxolan-2-yl)phenylnaphthalene (10b)
1.4 g (6.1 mmol) of 3b gave 0.52 g (55%) of 10b (white crystals).– Mp
151–153 °C.– IR (KBr): ν = 3020 (w, Ar-H), 2960, 2880 (m, CH), 1630,
1610 (s, C=C), 1600 (s, C=C) (vs) cm–1;– 1H NMR (CDCl3): δ = 3.96 (s, 3H,
OCH3), 4.03–4.06 (m, 2H, CH2O), 4.17 (m, 2H, CH2O), 5.89 (s, 1H,
HC(OCH2)2), 7.18 (s, 1H, Ar-H, -H5), 7.20 (d, J = 8.84 Hz, 1H, Ar-H, -H7),
7.74 (d, J = 8.84 Hz, 1H, Ar-H, -H8), 7.81–7.84 (m, 2H, Ar-H, -H3, -H4),
7.87 (d, J = 8.4 Hz, 2H, Ar′-H, -H3′, -H5′), 7.98 (d, J = 8.4 Hz, 2H, Ar′-H,
-H2′, -H6′), 8.05 (s, 1H, Ar-H, -H1).
2-(3-Bromophenyl)-1,3-dioxolane (3a)
A mixture of 3-bromobenzaldehyde 2a (39.8 g, 25 ml, 214 mmol), ethyl-
ene glycol (14 g, 226 mmol), and toluene sulfonic acid (p-TsOH-H2O)
(714 mg, 3.75 mmol) in toluene (200 ml) was heated at reflux in a flask
equipped with a Dean-Stark apparatus. After 8 h, ethylene glycol (4.65 g,
75 mmol) was added and the mixture was refluxed for 4 days. The reaction
mixture was cooled to room temperature, washed with 1N NaHCO3, brine,
and dried over Na2SO4. After the solvent was removed in vacuo, the residue
was distilled to give 33 g (68%) of 3a, oil, bp 132–133 °C/8.0 Torr.
2-(3-Formylphenyl)-6-methoxy-3,4-dihydronaphthalene (6a)
10% HCl (5 ml) was added to a stirred solution of 5a (1.0 g, 3.24 mmol)in
THF (20 ml). The mixture was stirred at room temperature for 10 h, before
it was worked up with saturated NaHCO3 and extracted three times with
CH2Cl2 (50 ml). The organic layer was washed with H2O and dried over
2-(4-Bromophenyl)-1,3-dioxolane (3b)
23 g (124 mmol) of 2b gave 24.5 g of 3b (86%), oil, bp 107 °C/2 Torr.
Arch. Pharm. Pharm. Med. Chem. 332, 25–30 (1999)

Substituted 2-Aryl-6-methoxy-3,4-dihydronaphthalenes
29
Na2SO4. Evaporation of the solvent in vacuo gave the crude product 6a
(0.81 g, 95%) which was purified by recrystallization from EtOH.– Mp
52–53°C (white crystals).– IR (KBr): ν = 3010 (w, Ar-H), 2990 (m, CH),
2890 (m, CH), 2720 (m, CHO), 1700 (s, C=O), 1610, 1600, 1500 (s, C=C)
(vs)cm–1;– 1H NMR (CDCl3): δ = 2.76 (t, J = 8.18 Hz, 2H, ArCH2CH2), 2.96
(t, J = 8.18 Hz, 2H, ArCH2), 3.83 (s, 3H, OCH3), 6.74 (d, J = 7.96 Hz, 1H,
Ar-H, -H7), 6.76 (s, 1H, Ar-H, -H5), 6.91 (s, 1H, =CH), 7.09 (d, J = 7.96 Hz,
1H, Ar-H, -H8), 7.52 (t, J = 7.52 Hz, 1H, Ar′-H, -H5′), 7.75 (d, J = 7.52 Hz,
1H, Ar′-H, -H4′), 7.79 (d, J = 7.52, 1H, Ar′-H, -H6′), 8.02 (s, 1H, Ar′-H,
-H2′), 10.05 (s, 1H, -CHO);– MS m/z (%) = 264 (95) (M+), 145 (100), 119
(30).
= 7.96 Hz, 2H, ArCH2CH2), 2.95 (t, J = 7.96 Hz, 2H, ArCH2), 3.83 (s, 3H,
OCH3), 6.74 (d, J = 7.96 Hz, 1H, Ar-H, -H7), 6.75 (s, 1H, Ar-H, -H5), 6.89
(s, 1H, =CH), 7.09 (d, J = 7.96 Hz, 1H, Ar-H, -H8), 7.37 (s, 1H, oxazole–H4),
7.59 (d, J = 8.4 Hz, 2H, Ar′-H, -H2′, -H6′), 7.65 (d, J = 7.52, 2H, Ar′-H, -H3′,
-H5′), 7.95 (s, 1H, oxazole-H2);– MS m/z (%) = 303 (95) (M+), 158 (100),
145 (41); Anal. (C20H17NO2) C,H,N.
6-Methoxy-2-3-(5-oxazolyl)phenylnaphthalene (12a)
0.1 g (0.38 mmol) of 11a gave 104 mg of 12a (90%, white crystals).– Mp
164–165.5 °C;– IR (KBr): ν = 3120 (w), 3100 (w, Ar-H), 2900 (m, CH),
1630, 1610, 1600 (s), 1580 (s), 1500 (s, Ar) (vs)cm–1;– 1H NMR (CDCl3): δ
= 3.96 (s, 3H, OCH3), 7.18 (s, 1H, Ar-H, -H5), 7.20 (d, J = 8.4 Hz, 1H, Ar-H,
-H7), 7.45 (s, 1H, oxazole-H4), 7.53 (t, J = 7.96 Hz, 1H, Ar′-H, -H5′), 7.65
(d, J = 7.96 Hz, 1H, Ar′-H, -H6′), 7.68 (d, J = 7.96, 1H, Ar′-H, -H4′), 7.74
(d, J = 8.4 Hz, 1H, Ar-H, -H8), 7.82 (d, J = 7.96 Hz, 1H, Ar-H, -H3), 7.84
(d, J = 7.96 Hz, 1H, Ar-H, -H4), 7.97 (s, 1H, oxazole-H2), 7.98 (s, 1H, Ar′-H,
-H2′), 8.01 (s, 1H, -H1);– MS m/z (%) = 301 (100) (M+), 258 (45), 202 (35);
Anal. (C20H15NO2) C,H,N.
2-(4-Formylphenyl)-6-methoxy-3,4-dihydronaphthalene (6b)
0.46 g of 5b gave 0.375 g of 6b (95%, yellow crystals).– Mp 85–87 °C.–
IR (KBr): ν = 3020 (w), 2950, 2840 (m, CH), 1700 (s, C=O), 1600, 1570 (s,
C=C) (vs)cm–1;– 1H NMR (CDCl3): δ = 2.77 (t, J = 8.18 Hz, 2H,
ArCH2CH2), 2.96 (t, J = 8.18 Hz, 2H, ArCH2), 3.83 (s, 3H, OCH3), 6.74 (d,
J = 8.4 Hz, 1H, Ar-H, -H7), 6.76 (s, 1H, Ar-H, -H5), 6.98 (s, 1H, =CH), 7.11
(d, J = 8.4 Hz, 1H, Ar-H, -H8), 7.67 (d, J = 8.4 Hz, 2H, Ar′-H, -H2′, -H6′),
7.87 (d, J = 8.4 Hz, 2H, Ar′-H, -H3′, -H5′), 10.0 (s, 1H, CHO);– MS m/z (%)
= 264 (70) (M+), 145 (100).
6-Methoxy-2-4-(5-oxazolyl)phenylnaphthalene (12b)
0.35 g (1.33 mmol) of 11b gave 0.37 g of 12b (92%, yellow crystals).– Mp
222.5–224 °C (dec.);– IR (KBr): ν = 3120 (w), 3005 (w, Ar-H), 2980 (m,
CH), 1630, 1600 (s), 1500 (s, Ar) (vs)cm–1;– 1H NMR (DMSO(d6)): δ = 3.92
(s, 3H, OCH3), 7.21 (d, J = 7.96 Hz, 1H, Ar-H, -H7), 7.34 (s, 1H, Ar-H, -H5),
7.68 (s, 1H, oxazole-H4), 7.82-7.84 (m, 3H, Ar-H, -H8, Ar′-H, -H2′, -H6′),
7.89-7.93 (m, 4H, Ar-H, -H3, -H4, Ar′-H, -H3′, -H5′), 8.18 (s, 1H, Ar-H,
-H1), 8.38 (s, 1H, oxazole-H2);– MS m/z (%) = 301 (100) (M+), 258 (40),
202 (25); Anal. (C20H15NO2) C,H,N.
2-(3-Formylphenyl)-6-methoxynaphthalene (11a)
0.55 g (1.8 mmol) of 10a gave the crude product 11a (0.35 g, 75%) which
was purified by recrystallization from EtOAc / petroleum ether (white
crystals).– Mp 102–104°C;– IR (KBr): ν = 3040 (w, Ar-H), 2960 (m, CH),
2800 (m, CH), 2720 (m, CHO), 1710 (s, C=O), 1620, 1600 (s, C=C), 1585
(s, C=C) (vs)cm–1;– 1H NMR (CDCl3): δ = 3.95 (s, 3H, OCH3), 7.19 (s, 1H,
Ar-H, -H5), 7.20 (d, J = 8.4 Hz, 1H, Ar-H, -H7), 7.64 (t, J = 7.52 Hz, 1H,
Ar′-H, -H5′), 7.74 (d, J = 8.4 Hz, 1H, Ar-H, -H8), 7.82 (d, J = 8.4 Hz, 1H,
Ar-H, -H4), 7.84-7.88 (m, 2H, Ar′-H, -H4′, -H6′), 7.98 (d, J = 8.4 Hz, 1H,
Ar-H, -H3), 8.02 (s, 1H, Ar′-H, -H2′), 8.21 (s, 1H, Ar-H, -H1), 10.12 (s, 1H,
-CHO);– MS m/z (%) = 262 (100) (M+), 219 (50), 189 (30).
6-Methoxy-2-3-(4-tosyl-5-oxazolinyl)phenyl-3,4-dihydronaphthalene (13a)
To a stirred suspension of tosylmethyl isocyanide (TosMIC) (0.38 g,
2.0 mmol) and 6a (0.5 g, 2.1 mmol) in dry ethanol (15 ml) and THF (5 ml)
was added finely powdered sodium cyanide (10 mg, 0.2 mmol). Within
minutes the slightly exothermic reaction mixture became clear, and white
crystals of oxazoline quickly began to deposit from solution (20 min).
Stirring was continued for an additional 2 h. The mixture was filtered and
the crystals were washed with diethyl ether:n-hexane (1:1) (15 ml) to give,
after drying, 0.68 g of 13a (71%, white powder).– Mp 139–141 °C;– IR
(KBr): ν = 3020 (w, Ar-H), 2940 (m, CH), 1620 (s), 1600, 1500 (s) (Ar),
2-(4-Formylphenyl)-6-methoxynaphthalene (11b)
0.47 g (1.54 mmol) of 10b gave 0.35 g of 11b (86%, white crystals).– Mp
141–143 °C.– IR (KBr): ν = 3020 (w, Ar-H), 2980 (m, CH), 2940 (m, CH),
2840 (m, CHO), 1690 (s, C=O), 1620, 1600 (s, C=C), 1565 (s, C=C)
1
(vs)cm–1;– H NMR (CDCl3): δ = 3.96 (s, 3H, OCH3), 7.18 (s, 1H, Ar-H,
1380 (s), 1320, 1150 (SO2) (vs)cm–1
.
-H5), 7.20 (d, J = 8.84 Hz, 1H, Ar-H, -H7), 7.74 (d, J = 8.84 Hz, 1H, Ar-H,
-H8), 7.81–7.84 (m, 2H, Ar-H, -H3, -H4), 7.87 (d, J = 8.4 Hz, 2H, Ar′-H,
-H2′, -H6′), 7.97 (d, J = 8.4 Hz, 2H, Ar′-H, -H3′, -H5′), 8.05 (s, 1H, Ar-H,
-H1), 10.07 (s, 1H, -CHO);– MS m/z (%) = 262 (100) (M+), 219 (60), 189
(40).
6-Methoxy-2-4-(4-tosyl-5-oxazolinyl)phenyl-3,4-dihydronaphthalene (13b)
475 mg (1.8 mmol) of 6b gave 0.64 g of 13b (78%, white powder).– Mp
134–135 °C;– IR (KBr): ν = 3060, 3020 (w, Ar-H), 2940 (m, CH), 1620 (s),
1600, 1540 (s) (Ar), 1495, 1320 (SO2), 1250, 1140 (SO2) (vs)cm–1
.
6-Methoxy-2-3-(5-oxazolyl)phenyl-3,4-dihydronaphthalene (7a)
Tosylmethyl isocyanide (TosMIC) (0.27 g, 1.4 mmol) was added to a
stirred solution of 6a (0.37 g, 1.4 mmol) and of K2CO3 (0.28 g, 2.0 mmol)in
20 ml of CH3OH. The mixture was refluxed for 3 h, before it was worked up
with saturated NaHCO3 and extracted three times with CH2Cl2 (50 ml). The
organic layer was washed with H2O and dried over Na2SO4. Evaporation of
the solvent in vacuo gave 0.39 g of 7a (92%, white crystals).– Mp 112.5–
114 °C;– IR (KBr): ν = 3020 (w, Ar-H), 2980 (w), 2900 (m, CH), 1600 (s),
1570 (s, C=C), 1500 (s, C=C) (vs)cm–1;– 1H NMR (CDCl3): δ = 2.76 (t, J =
7.96 Hz, 2H, ArCH2CH2), 2.96 (t, J = 7.96 Hz, 2H, ArCH2), 3.83 (s, 3H,
OCH3), 6.74 (d, J = 7.96 Hz, 1H, Ar-H, -H7), 6.75 (s, 1H, Ar-H, -H5), 6.88
(s, 1H, =CH), 7.10 (d, J = 7.96 Hz, 1H, Ar-H, -H8), 7.40 (s, 1H, oxazole–H4),
7.42 (t, J = 7.52 Hz, 1H, Ar′-H, -H5′), 7.50 (d, J = 7.52 Hz, 1H, Ar′-H, -H6′),
7.54 (d, J = 7.52, 1H, Ar′-H, -H4′), 7.80 (s, 1H, oxazole-H2), 7.96 (s, 1H,
Ar′-H, -H2′);– MS m/z (%) = 303 (98) (M+), 158 (35), 145 (100); Anal.
(C20H17NO2) C,H,N.
6-Methoxy-2-3-(4-tosyl-5-oxazolinyl)phenylnaphthalene (15a)
0.3 g (1.14 mmol) of 11a gave 0.41 g of 15a (78%, white powder).– Mp
134–135 °C;– IR (KBr): ν = 3060 (w, Ar-H), 2920 (m, CH), 1620 (s), 1600,
1500 (s)(Ar), 1320, 1140 (SO2) (vs)cm–1
.
6-Methoxy-2-4-(4-tosyl-5-oxazolinyl)phenylnaphthalene (15b)
0.25 g (0.95 mmol) of 11b gave 0.68 g of 15b (69%, white powder).– Mp
138–140 °C;– IR (KBr): ν = 3060 (w, Ar-H), 2970 (m, CH), 1630 (s), 1605,
1500 (s)(Ar), 1320, 1130 (SO2) (vs)cm–1
.
2-3-(4-Imidazolyl)phenyl-6-methoxy-3,4-dihydronaphthalene (14a)
In a resealable pressure tube, a solution of 13a (0.6 g, 1.3 mmol) and a
saturated solution of ammonia in dry methanol (20 ml) and dry THF (20 ml)
was heated between 100–120 °C for 24 h. TLC (CH2Cl2/MeOH: 9/1) of the
reaction mixture indicated a clean transformation. Concentration and chro-
matography (CH2Cl2/MeOH: 9/1) of the residue gave 123 mg of 14a (31%,
light brown powder).– Mp 176–178 °C;– IR (KBr): ν = 3100(s, NH), 3020
(w, Ar-H), 2940 (m, CH), 1600, 1580, 1500 (s) (Ar), 1465 (s), 1250 (s)
(vs)cm–1;– 1H NMR (DMSO(d6)): δ = 2.70 (t, J = 8.4 Hz, 2H, ArCH2CH2),
6-Methoxy-2-4-(5-oxazolyl)phenyl-3,4-dihydronaphthalene (7b)
0.3 g (1.14 mmol) of 6b gave 0.32 g of 7b (93%, yellow crystals).– Mp
167–169 °C;– IR (KBr): ν = 3080, 3030 (w, Ar-H), 2960 (w), 2890 (m, CH),
1610, 1600, 1570, 1500 (s, Ar) (vs)cm–1;– 1H NMR (CDCl3): δ = 2.76 (t, J
Arch. Pharm. Pharm. Med. Chem. 332, 25–30 (1999)

30
Zhuang and Hartmann
2.90 (t, J = 8.4 Hz, 2H, ArCH2), 3.77 (s, 3H, OCH3), 6.76 (d, J = 7.96 Hz,
1H, Ar-H, -H7), 6.81 (s, 1H, Ar-H, -H5), 6.97 (s, 1H, =CH), 7.15 (d, J = 7.96
Hz, 1H, Ar-H, -H8), 7.34–7.37 (m, 2H, Ar′-H, -H5′, imidazole–H2), 7.68–
7.70 (m, 3H, Ar′-H, -H4′, -H6′, imidazole–H5), 7.80 (s, 1H, Ar′-H, -H2′);–
MS m/z (%) = 302 (100) (M+), 207 (80), 157 (43); Anal. (C20H18N2O) C,H,N.
Molecular Modeling
The energy minimization of the compounds was carried out using
CHARm22 in Quanta-Release 97 software package, run on Silicon Graphics
INDY (SGI) O2 with R 10000 workstation with default setting value.
Molecular Similarity (rigid and flexible method) fitting operation was se-
lected to perform a least-squares fit between two molecules, matching the
pairs of atoms, using energy-minimized steroid III as a template and C8, C9,
C14 as fit atoms.
2-4-(4-Imidazolyl)phenyl-6-methoxy-3,4-dihydronaphthalene (14b)
0.62 g (1.35 mmol) of 13b gave 95 mg of 14b (23%, light yellow pow-
der).– Mp 243–245 °C;– IR (KBr): ν = 3120 (NH), 3060 (w, Ar-H), 2930
(m, CH), 1610, 1570, 1500 (s) (Ar), 1430 (s), 1250 (s) (vs)cm–1;– 1H NMR
(DMSO(d6)): δ = 2.66 (t, J = 8.4 Hz, 2H, ArCH2CH2), 2.88 (t, J = 8.4 Hz,
2H, ArCH2), 3.76 (s, 3H, OCH3), 6.74 (d, J = 7.96 Hz, 1H, Ar-H, -H7), 6.78
(s, 1H, Ar-H, -H5), 6.92 (s, 1H, =CH), 7.11 (d, J = 7.96 Hz, 1H, Ar-H, -H8),
7.51 (d, J = 8.4 Hz, 1H, imidazole–H2), 7.55 (d, J = 8.4 Hz, 2H, Ar′-H, -H2′,
-H6′), 7.66 (s, 1H, imidazole–H5), 7.74 (d, J = 8.4 Hz, 2H, Ar′-H, -H3′,
-H5′);– MS m/z (%) = 302 (100) (M+), 287 (15), 207 (20), 157 (70); Anal.
(C20H18N2O) C,H,N.
References
✩
Dedicated to Professor Kallmayer on the occasion of his 60th birthday.
[1] R.W. Hartmann, H. Schönenberger in Arzneimittel-Fortschritte 1972
bis 1985 (Eds.: A. Kleemann, E. Lindner, J. Engel), Verlag Chemie,
Weinheim, 1987, 1308–1366.
[2] V.C. Jordan, J.I. MacGregor, D.A. Tonetti, Clin. Oncol. R. Coll. Radiol.
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2-3-(4-Imidazolyl)phenyl-6-methoxynaphthalene (16a)
[3] M. Lang, Ch. Batzl, P. Furet, R. Bowmann, A. Häusler, A. Bhatnager,
J. Steroid Biochem. Molec. Biol. 1993, 44, 421–428.
0.8 g (1.75 mmol) of 15a gave 126 mg of 15a (24%, brown powder).– Mp
197–199 °C;– IR (KBr): ν = 3120 (NH), 3060, 3000 (w, Ar-H), 2940 (m,
CH), 1630, 1610, 1580 (s) (Ar), 1485, 1460 (s), 1240 (s) (vs)cm–1;– 1H NMR
(DMSO(d6)): δ = 3.90 (s, 3H, OCH3), 7.11 (s, 1H, Ar-H, -H5), 7.12 (d, J =
8.4 Hz, 1H, Ar-H, -H7), 7.36 (s, 1H, imidazole–H5), 7.42 (d, J = 7.96 Hz,
1H, Ar′-H, -H3′), 7.55 (d, J = 7.96 Hz, 1H, Ar′-H, -H4′), 7.63 (d, J = 7.96
Hz, 1H, Ar′-H, -H5′), 7.68 (d, J = 8.4 Hz, 2H, Ar-H, -H3, -H8), 7.72 (s, 1H,
imidazole–H2), 7.74 (d, J = 8.4 Hz, 1H, Ar-H, -H4), 7.95 (s, 1H, Ar′-H, -H2′),
8.05 (s, 1H, Ar-H, -H1);– MS m/z (%) = 300 (100) (M+), 285 (10), 257 (32),
150 (30); Anal. (C20H16N2O) C,H,N.
[4] G. M. Higa, N. Alkhouri, Am. J. Health-Syst. Pharm. 1998, 55, 445–
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[5] For reviews, see: A. Brodie, H.B. Brodie, G. Callard, C. Robinson, C.
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2-4-(4-Imidazolyl)phenyl-6-methoxynaphthalene (16b)
0.2 g (0.44 mmol) of 15b gave 43 mg of 16b (33%, light yellow powder).–
Mp 266–268 °C;– IR (KBr): ν = 3120 (NH), 3040 (w, Ar-H), 2995 (m, CH),
1635, 1605, 1500 (s) (Ar), 1250 (s), 1200 (s) (vs)cm–1;– 1H NMR
(DMSO(d6)): δ = 3.90 (s, 3H, OCH3), 7.19 (d, J = 8.84 Hz, 1H, Ar-H, -H7),
7.35 (s, 1H, Ar-H, -H5), 7.68 (s, 1H, imidazole–H5), 7.73 (s, 1H, imidazole–
H2), 7.78 (d, J = 8.4 Hz, 2H, Ar′-H, -H2′, -H6′), 7.83 (d, J = 8.4 Hz, 1H,
Ar-H, -H3), 7.90 (d, J = 8.4 Hz, 1H, Ar-H, -H4), 7.91 (d, J = 8.4 Hz, 2H,
Ar′-H, -H3′, -H5′), 7.92 (d, J = 8.84 Hz, 1H, Ar-H, -H8), 8.17 (s, 1H, Ar-H,
-H1);– MS m/z (%) = 300 (100) (M+), 285 (18), 257 (40), 150 (45); Anal.
(C20H16N2O) C,H,N.
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Enzyme Preparation: The enzyme was prepared using human testes. For
the determination of enzyme inhibition, microsomes were incubated with
excess progesterone as substrate (25 µM), NADPH (500 µM) and inhibitor
(2.5 µM) in phosphate buffer (temperature: 32 °C, termination after 20 min
by addition of 1 N HCl)[20]. After extraction of the steroids, fluorocortisol
acetate was added as internal standard. The samples were submitted to HPLC
(RP-8 column, CH3OH:H2O = 1:1, v/v) and detected by UV. Peak areas
(fluorocortisol, progesterone, 17α-hydroxyprogesterone, androstenedione
and testerone) were determined using a data evaluation software (JCL 6000,
Chromatography Data System, Vision 5.07).
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R. W. Hartmann, Synth. Commun. 1998, 28, 2725–2729.
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[20] T. F. Sergejew, R.W. Hartmann, J. Enz. Inhib. 1994, 8, 113–122.
Statistical limits: The inhibitory activity data are mean values of two
experiments. The deviations were within ±10%.
Received: October 12, 1998 [FP338]
Arch. Pharm. Pharm. Med. Chem. 332, 25–30 (1999)