Synthesis of 6- or 4-functionalized indoles via a reductive cyclization approach and evaluation as aromatase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2008.06.094

Two new series of benzonitrile derivatives on position 6 or 4 of indole ring were successfully synthesized via a Leimgruber-Batcho reaction. All the compounds were evaluated in vitro on the inhibition of aromatase (CYP19) and 17α-hydroxylase-C17,20-lyase

Full text of DOI:10.1016/j.bmcl.2008.06.094

Bioorganic & Medicinal Chemistry Letters 18 (2008) 4713–4715
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis of 6- or 4-functionalized indoles via a reductive cyclization
approach and evaluation as aromatase inhibitors
Marie-Pierre Lézé a, Anja Palusczak b, Rolf W. Hartmann b, Marc Le Borgne a,
*
a Université de Nantes, Nantes Atlantique Universités, Département de Pharmacochimie, IICiMed UPRES EA 1155, UFR de Sciences Pharmaceutiques, 1 rue Gaston Veil,
Nantes, F-44035 Cedex 1, France
b Fachrichtung 8.5 Pharmaceutische und Medizinische Chemie, Universität des Saarlandes, PO Box 151150, D-66041 Saarbrücken, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Two new series of benzonitrile derivatives on position 6 or 4 of indole ring were successfully synthesized
via a Leimgruber–Batcho reaction. All the compounds were evaluated in vitro on the inhibition of aroma-
tase (CYP19) and 17a-hydroxylase-C17,20-lyase (CYP17). The racemate, 4-[(1H-imidazol-1-yl)(1H-indol-
Received 1 May 2008
Revised 27 June 2008
Accepted 28 June 2008
Available online 3 July 2008
4-yl)methyl]benzonitrile 9, showed high level of inhibitory activity towards CYP19 (IC50 = 11.5 nM).
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Breast cancer
Aromatase inhibitors
Indole
Azoles
Benzonitrile derivatives
Reductive cyclization
About two-thirds of breast cancers are dependent on estrogens
for growth, so endocrine therapies are widely used for the treat-
ment of hormone-dependent breast cancer (HDBC).1 Amongst
endocrine therapies available today, we find (i) selective estrogen
receptor modulators (SERMs), (ii) estrogen deprivation therapy
using LHRH agonists and aromatase inhibitors, and (iii) estrogen
receptor downregulators and complete antagonists.2 Recent stud-
ies3–5 have shown that aromatase inhibitors (AIs) are superior to
SERMs, such as tamoxifen in terms of survival and side effects.
So, the reduction or blockade of estradiol (E2) biosynthesis be-
comes an important strategy of treatment. The efficacy of AIs can
be explained by the fact that they block both genomic and non
genomic activities of the estrogen receptor.2 Then aromatase
(CYP19) is a prime target and many researchers intensively worked
to find selective AIs.6 Two non steroidal AIs, letrozole and anastroz-
ole, are daily used in postmenopausal women with HDBC (Fig. 1).
In previous works,7,8 we presented diverse synthetic routes to 5
or 7-aroylindoles. In series 5, racemic compound 1 and chloro
derivative 2 exerted aromatase inhibitory activity at nanomolar
level.
N
N
N
N
N
NH2
NC
.HCl
O
N
O
CN
CN
Fadrozole
Aminoglutethimide
N
Anastrozole
N
N
N
N
N
N
N
H
N
H
CN NC
Cl
NC
Letrozole
2
1
Figure 1. Non steroidal aromatase inhibitors (NSAIs).
were evaluated in vitro for inhibitory activity against CYP19 and
CYP17 enzymes.
As outlined in Scheme 1, the key intermediate 7 was prepared
in three steps. First, an acylation of bromobenzene followed by a
Leimgruber–Batcho reaction involving (i) the formation of enamine
6 and (ii) the catalytic reduction of the nitro group followed by
spontaneous cyclization to provide the 6-aroylindole 7.
For the Friedel-Crafts acylation, the bromobenzene 3 was trea-
ted with the 4-methyl-3-nitrobenzoyl chloride 4 in the presence
of aluminium chloride at 80–85 °C to afford the benzophenone
derivative 5 in 66% yield.9,10 The condensation of 5 with N,N-
In this letter, we describe a synthetic route to access to 6- and 4-
aroylindoles, key intermediates in the synthesis of 4-[(azol-1-
yl)(indol-6 or 4-yl)methyl)]-benzonitriles. All target compounds
* Corresponding author. Tel.: +33 2 40 41 11 14; fax: +33 2 40 41 28 76.
E-mail address: marc.le-borgne@univ-nantes.fr (M. Le Borgne).
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.06.094

4714
M.-P. Lézé et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4713–4715
14 which was directly used in the catalytic hydrogenation using
Br
Br
Br
a
+
Raney Nickel in ethanol to afford the key intermediate 15 in 15%
yield.11,13 The latter was subjected to a bromine/cyano exchange
reaction in the presence of zinc cyanide and Pd(PPh3)4 as catalyst
under microwave irradiation to afford nitrile derivative 16 in 79%
yield.17 As described above, the target compounds 17, 18 were ob-
tained after reduction of ketone derivative 16 and fixation of azole
moieties using CDI (48% yield) or CDT (13% yield).20,24
Cl
NO2
NO2
O
O
4
5
3
b
Br
N
c
N
NO2
H
O
O
Determination of the in vitro anti-aromatase activity of 9, 10
and 17, 18 was carried out using microsomal fraction of human
7
6
placental tissue,25 according to a previously described procedure.26
Scheme 1. Reagents and conditions: (a) AlCl3, 80–85 °C, 17 h, 66%; (b) DMFDMA,
DMF, 110 °C, 15 h, 73%; (c) Raney-Ni, H2, EtOH, rt, 3 h, 32%.
3
[1b ꢀ H]Androstenedione (0.08
lCi, 15 nM), unlabeled andro-
stenedione (485 nM), NADPH-generating system, and inhibitor
dimethylformamide dimethyl acetal at 110 °C provided the corre-
sponding enamine 6 in 73% yield.11,12 The latter was subjected to
reductive cyclization with catalytic hydrogenation using Raney
nickel in ethanol to afford the key intermediate 7 in 32% yield.13,14
Other reducing agents, such as zinc dust in acetic acid15 or aqueous
titanium (III) chloride in ammonium acetate,16 were used unsuc-
cessfully. Contrary to palladium on carbon, Raney Nickel is the cat-
alyst of choice to avoid hydrogenolysis of bromine atom.
The compound 7 was used as a precursor to afford the nitrile
derivative 8 by a bromine/cyano exchange reaction in the presence
of zinc cyanide and Pd(PPh3)4 as catalyst under microwave irradi-
ation (Scheme 2).17,18
The synthesis of target compounds 9 and 10 (Scheme 2) was
carried out by reduction of the ketone derivative 8 in the presence
of sodium borohydride in methanol,19 followed by the fixation of
imidazole or triazole moiety using 1,10-carbonyldiimidazole (CDI,
61% yield) or 1,10-carbonyldi(1H-1,2,4-triazole) (CDT, 10% yield)
in dry acetonitrile or tetrahydrofuran.20,21
The same approach, via a Leimgruber–Batcho reaction, was em-
ployed to synthesize parent compounds in series 4 (Scheme 3). The
commercially available acid 11 was treated with thionyl chloride
to afford the corresponding acid chloride 12 in 98% yield.22,23 Then,
the bromobenzene 3 was acylated by compound 12 in the presence
of aluminium chloride at 85 °C to afford the benzophenone deriv-
ative 13 in 70% yield.9 The condensation of 13 with N,N-dimethyl-
formamide dimethyl acetal at 110 °C provided the crude enamine
(0–100 M, DMSO as solvent) in phosphate buffer (pH 7.4) were
l
preincubated for 5 min at 30 °C in a shaking water bath. Micro-
somal protein was added to start the enzymatic reaction. After
incubation for 14 min at 30 °C, a cold HgCl2 1 mM solution and a
Norit A 2% suspension were added. After shaking and centrifuga-
tions, aliquots of the supernatant were assayed for 3H2O by count-
ing in a scintillation mixture using LKB-Wallac b-counter. The IC50
values were determined by plotting the percent inhibition versus
the concentration of inhibitor on a semilog plot.
The CYP17 assay was performed in vitro using membrane frac-
tions of recombinant E. coli pJL17/OR coexpressing human CYP17/
rat NADPH-P450 reductase and progesterone as a substrate.27 Re-
sults are summarized in Table 1.
All target compounds were inactive towards CYP17. The highest
inhibition was 26% at 2.5 lM.
In the aromatase inhibition assay, the triazole derivatives 10
and 18 were less active than the corresponding imidazole ana-
logues 9 and 17. This results confirmed our previous studies.7,8,28
The fixation site of (benzonitrile)(4-cyanophenyl)(1H-imidazol-
1-yl)methyl chain on indole ring influenced the pharmacological
activities. Thus, the compound 9 in series 6 (IC50 = 11.5 nM) was
1.6-fold more potent than its analogue 17 in series
4
(IC50 = 18.7 nM). In the same way, compound 9 is more active than
the benzonitrile derivative 1 in series 5 (IC50 = 19.3 nM).8
Table 1
In vitro CYP19 and CYP17 inhibitions by benzonitrile derivatives
NC
Br
a
Compound
Series
Y
CYP19
CYP17
N
H
IC50 (l
M)a
RPb
% Inhibitionc
N
H
O
O
9
10
17
18
AG
Fadrozole
6
6
4
4
—
—
CH
N
CH
N
—
—
0.0115 ( 0.0006)
0.0938 ( 0.0066)
0.0187 ( 0.0021)
1.6200 ( 0.1800)
29.75
2587
0317
1591
0018
0001
992
026
na
018
<10
—
7
8
NC
b, c or d
N
H
9: Y = CH
10: Y = N
00.03
na
N
Y
a
Values are the mean of at least two experiments performed in duplicate,
standard deviation is given in parentheses.
Relative potency RP=IC50(AG)/IC50 (tested compound).
Progesterone: 25 lM, inhibitor: 2.5 lM. Values are the mean of two experi-
ments performed in duplicate (na, not active).
N
b
Scheme 2. Reagents and conditions: (a) Zn(CN)2, Pd(PPh3)4, DMF, microwaves,
60 W, 153 °C, 4 min, 67%; (b) NaBH4, CH3OH, 1 h, rt; (c) CDI, CH3CN, rt, 24 h, 61%;
(d) CDT/THF/N2/rt, 43 h, 10%.
c
Br
Br
X
NC
f, g or h
N
HO
O
Cl
O
O
O
O
N
Y
Br
a
b
c
d
+
N
NO2
NO2
N
H
15: X = Br
N
H
NO2
NO2
12
3
13
14
11
17: Y = CH
18: Y = N
e
16: X = CN
Scheme 3. Reagents and conditions: (a) SOCl2, 60 °C, 24 h, 98%; (b) AlCl3, 85 °C, 17 h, 70%; (c) DMFDMA, DMF, 110 °C, 39 h; (d) Raney-Ni, H2, EtOH, rt, 2.25 h, 15%; (e) Zn(CN)2,
Pd(PPh3)4, DMF, microwaves, 60 W, 153 °C, 4 min, 79%; (f) NaBH4, CH3OH, rt; 1 h (g) CDI, CH3CN, rt, 19 h, 48%; (h) CDT/THF/N2/rt, 17 h, 13%.

M.-P. Lézé et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4713–4715
4715
183–184 °C; 1H NMR (500 MHz, DMSO-d6): d 6.61 (d, J = 2.84 Hz, 1H, indolyl H-
3), 7.51 (dd, J = 1.58 Hz, J = 8.20 Hz, 1H, indolyl H-5), 7.68 (dd, J = J = 2.84 Hz,
1H, indolyl H-2), 7.71 (d, J = 8.51 Hz, 2H, 4-bromophenyl H-3, H-5), 7.72 (d,
J = 8.20 Hz, 1H, indolyl H-4) 7.81 (d, J = 8.51 Hz, 2H, 4-bromophenyl H-2, H-6),
7.86 (s, 1H, indolyl H-7), 11.53 (s, 1H, NH); IR (KBr): 3226 (NH), 3050 (CHarom),
In comparison to our lead racemate inhibitor
2
(IC50 = 15.3 nM),8 the compound 9 showed the highest anti-aroma-
tase activity, with an IC50 of 11.5 nM.
All tested molecules were more active than standard compound
aminoglutethimide AG (IC50 = 29.75 lM). The imidazole derivatives
1607 (C@O), 1560 (C@Carom) cmꢀ1
.
15. Moyer, M. P.; Shiurba, J. F.; Rapoport, H. . J. Org. Chem. 1986, 51, 5106.
16. Schumacher, R. W.; Davidson, B. S. . Tetrahedron 1999, 55, 935.
17. Alterman, M.; Hallberg, A. J. Org. Chem. 2000, 65, 7984.
9 and 17 exhibited an inhibitory activity superior to that of fadrozole
(IC50 = 30 nM) whereas triazole analogues 10 and 18 were inferior.
Furthermore, letrozole and anastrozole, third generation of NSAIs,
exhibited inhibition of aromatase activity with IC50 values from 10
to 15 nM.29 So our compound 9 displayed in vitro anti-aromatase
activity comparable to that of letrozole (IC50 = 11.5 nM).
In summary, the introduction of (benzonitrile)(4-cyano-
phenyl)(1H-imidazol-1-yl)methyl chain at position 6 or 4 of the in-
dole ring led to potent and selective CYP19 inhibitors. We
confirmed that the imidazole core was more favourable than tria-
zole moiety in vitro. Further investigations are required in due
course to confirm these above results. We have to separate enanti-
omers to test them on CYP19 inhibition and to study their in vivo
potency.
18. Characteristics of 4-(1H-indol-6-ylcarbonyl)benzonitrile 8. The residue was
purified on silica gel (CH2Cl2) to afford compound 8 in 67% overall yield. Mp
198–199 °C; 1H NMR (500 MHz, DMSO-d6): d 6.62 (d, J = 2.84 Hz, 1H, indolyl H-
3), 7.53 (dd, J = 1.51 Hz, J = 8.51 Hz, 1H, indolyl H-5), 7.71 (dd, J = J = 2.84 Hz,
1H, indolyl H-2), 7.74 (d, J = 8.51 Hz, 1H, indolyl H-4), 7.85 (s, 1H, indolyl H-7),
7.90 (d, J = 8.20 Hz, 2H, benzonitrile H-2, H-6), 8.08 (d, J = 8.20 Hz, 2H,
benzonitrile H-3, H-5), 11.57 (s, 1H, NH); IR (KBr): 3290 (NH), 3070 (CHarom),
2233 (C„N), 1632 (C@O), 1560, 1504 (C@Carom) cmꢀ1
19. Robinson, B. Chem. Rev. 1969, 69, 785.
.
20. Njar, V. C. O. Synthesis 2000, 14, 2019.
21. Preparation of 4-[(1H-indol-6-yl)(1H-1,2,4-triazol-1-yl)methyl]benzonitrile
10. Sodium borohydride (262 mg, 6.92 mmol) was added portionwise to a
stirred solution of 8 (427 mg, 1.73 mmol) in 30 mL of methanol. The reaction
mixture was stirred for 1 h at rt prior to quenching with H2O. The aqueous
layer was extracted with Et2O. The organic layer was dried over Na2SO4 and the
solvent was evaporated to give a light white oil. The corresponding alcohol
(381 mg, 1.54 mmol) and CDT (554 mg, 3.08 mmol) in 30 mL THF were stirred
for 43 h at rt under N2 atmosphere. The solvent was removed and the residue
was dissolved in H2O and CH2Cl2. The layers were separated, the organic layer
was washed with H2O, and dried over Na2SO4. The solvent was evaporated and
the residue was purified on silica gel (ethyl acetate-hexane, 7:3 v/v) to afford a
beige powder 10 in 10% overall yield. Mp 68–69 °C; 1H NMR (500 MHz, DMSO-
d6): d 6.43 (d, J = 2.21 Hz, 1H, indolyl H-3), 6.97 (dd, J = 1.26, J = 8.20 Hz, 1H,
indolyl H-5), 7.30 (s, 1H, indolyl H-7), 7.33 (s, 1H, CH), 7.42-7.44 (m, 3H, indolyl
H-2, benzonitrile H-3, H-5), 7.58 (d, J = 8.20 Hz, 1H, indolyl H-4), 7.89 (d,
J = 8.51 Hz, 2H, benzonitrile H-2, H-6), 8.13 (s, 1H, triazolyl H), 8.64 (s, 1H,
triazolyl H), 11.19 (s, 1H, NH); 13C NMR (500 MHz, DMSO-d6): d 65.75 (CH),
101.17 (C-3), 110.72 (benzonitrile C-1), 111.69 (C-7), 118.73 (C„N), 119.5 (C-
5), 120.5 (C-4), 126.71 (C-2), 127.64 (C-4a), 128.97 (2C, benzonitrile C-3, C-5),
130.71 (C-6), 132.64 (2C, benzonitrile C-2, C-6), 135.82 (C-7a), 144.75 (triazolyl
C), 145.42 (benzonitrile C-4), 152.18 (triazolyl C); IR (KBr): 3370 (NH), 3123
(CHarom), 2229 (C„N), 1502 (C@Carom, C@N), 1245 (C–N) cmꢀ1. Anal. calcd for
Acknowledgments
A doctoral fellowship from the ‘‘Ministère de l’Enseignement
Supérieur et de la Recherche” to M.-P. Lézé is gratefully acknowl-
edged. This work was also managed within the framework ‘‘Pro-
gramme Cotutelle” between Nantes Atlantique Universities
(France) and Saarland University (Germany).
References and notes
1. Spicer, J.; Ellis, P. Cancer Lett. 2007, 248, 165.
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4. Ingle, J. N.; Suman, V. J. J. Steroid Biochem. Mol. Biol. 2005, 95, 113.
5. Perez, E. A. The Oncologist 2006, 11, 1058.
C18H13N5: C, 72.23; H, 4.38; N, 23.40. Found: C, 72.20; H, 4.37; N, 23.44.
22. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamagughi, M. Bull. Chem. Soc. Jap.
1979, 52, 1989.
23. Preparation of 2-methyl-3-nitrobenzoyl chloride 12. A solution of 2-methyl-3-
nitrobenzoic acid 11 (1 g, 5.52 mmol) in thionyl chloride (8.8 mL, 0.12 mmol)
was stirred for 24 h at 60 °C. After cooling, thionyl chloride was evaporated
under reduced pressure to afford a beige powder 12 in 98% overall yield. Mp
158–159 °C; 1H NMR (500 MHz, DMSO-d6): d 2.60 (s, 3H, CH3), 7.70 (dd,
J = J = 8.0 Hz, 1H, H-5), 8.18 (d, J = 8.0 Hz, 1H, H-6), 8.45 (d, J = 8.0 Hz, 1H, H-4);
IR (KBr): 3094 (CHarom), 2964 (CHalkane), 1748 (C@O), 1522 (C@Carom, NO2),
6. Jordan, V. C.; Brodie, A. M. H. Steroids 2007, 72, 7.
7. Marchand, P.; Le Borgne, M.; Palzer, M.; Le Baut, G.; Hartmann, R. W. Bioorg.
Med. Chem. Lett. 2003, 13, 1553.
8. Lézé, M.-P.; Le Borgne, M.; Pinson, P.; Palusczak, A.; Duflos, M.; Le Baut, G.;
Hartmann, R. W. Bioorg. Med. Chem. Lett. 2006, 16, 1134.
9. Astoin, J.; Lepage, F.; Fromantin, J-P.; Poisson, M. Eur. J. Med. Chem. 1980, 15,
457.
1357 (NO2) cmꢀ1
.
10. Preparation of 40-bromo-4-methyl-3-nitrobenzophenone 5. Aluminium choride
(2.23 g, 18.20 mmol) was added portionwise to a stirred solution of 4-methyl-
3-nitrobenzoyl chloride (2.55 mL, 17.50 mmol) and bromobenzene (2.90 mL,
27.47 mmol). The reaction mixture was stirred for 17 h at 80–85 °C prior to
quenching with H2O and ethyl acetate. The mixture was poured onto crushed
ice, water and ethyl acetate. The layers were separated and the aqueous layer
was extracted with ethyl acetate. The combined organic fractions were washed
with brine and dried over Na2SO4. The solvent was removed and the residue
was purified on silica gel (hexane-ethylacetate, 8:2 v/v) to afford a beige solid 5
in 66% overall yield. Mp 107–108 °C; 1H NMR (500 MHz, DMSO-d6): d 2.66 (s,
3H, CH3), 7.74 (d, J = 7.60 Hz, 1H, H-5), 7.75 (d, J = 8.20 Hz, 2H, H-30, H-50), 7.84
(d, J = 8.20 Hz, 2H, H-20, H-60), 8 (dd, J = 1.58 Hz, J = 7.60 Hz, 1H, H-6), 8.29 (d,
J = 1.58 Hz, 1H, H-2); IR (KBr): 3084 (CHarom), 2957 (CHalkane), 1652 (C@O),
24. Preparation of 4-[(1H-imidazol-1-yl)(1H-indol-4-yl)methyl]benzonitrile 17.
Sodium borohydride (92 mg, 2.44 mmol) was added portionwise to a stirred
solution of 16 (150 mg, 0.61 mmol) in 20 mL of methanol. The reaction mixture
was stirred for 1 h at rt prior to quenching with H2O. The aqueous layer was
extracted with Et2O. The organic layer was dried over Na2SO4 and the solvent
was evaporated to give a light white oil. The corresponding alcohol (151 mg,
0.61 mmol) and CDI (168 mg, 1.04 mmol) in 15 mL CH3CN were stirred for 19 h
at rt. The solvent was removed and the residue was dissolved in H2O and
CH2Cl2. The layers were separated, the organic layer was washed with H2O, and
dried over Na2SO4. The solvent was evaporated and the residue was purified on
silica gel (ethyl acetate-hexane, 8:2 v/v) to afford a white powder 17 in 48%
overall yield. Mp 107–108 °C; 1H NMR (500 MHz, DMSO-d6):
d 6.21 (d,
1578 (C@Carom, NO2), 1340 (NO2) cmꢀ1
.
J = 2.84 Hz, 1 H, indolyl H-3), 6.59 (d, J = 7.25, 1H, indolyl H-5), 6.99 (s, 1H,
imidazolyl H), 7.12 (dd, J = 7.25, J = 7.88 Hz, 1H, indolyl H-6), 7.14 (s, 1H,
imidazolyl H), 7.34 (s, 1H, CH), 7.35 (d, J = 8.20 Hz, 2H, benzonitrile H-3, H-5),
7.37 (dd, J = J = 2.84 Hz, 1H, indolyl H-2), 7.46 (d, J = 7.88 Hz, 1H, indolyl H-7),
7.71 (s, 1H, imidazolyl H), 7.89 (d, J = 8.20 Hz, 2H, benzonitrile H-2, H-6), 11.34
(s, 1H, NH); 13C NMR (500 MHz, DMSO-d6): d 61.60 (CH), 99.45 (C-3), 110.74
(benzonitrile C-1), 112.13 (C-7), 118.25 (C-5), 118.70 (C„N), 119.53
(imidazolyl C), 121.03 (C-6), 126.05 (C-2), 126.46 (C-4a), 128.66 (2C,
benzonitrile C-3, C-5), 128.75 (imidazolyl C), 130 (C-4), 132.75 (2C,
benzonitrile C-2, C-6), 136.22 (C-7a), 137.47 (imidazolyl C), 145.69
(benzonitrile C-4); IR (KBr): 3107 (NH), 3060 (CHarom), 2229 (C„N), 1501
(C@Carom, C@N), 1281 (C–N) cmꢀ1. Anal. calcd for C19H14N4: C, 76.49; H, 4.73;
N, 18.78. Found: C, 76.51; H, 4.71; N, 18.79.
11. Clark, R. D.; Repke, D. B. Heterocycles 1984, 22, 195.
12. Preparation of 40-bromo-4-[(E)-2-(dimethylamino)vinyl]-3-nitrobenzophenone 6.
A solution of 5 (2.50 g, 7.80 mmol) and DMFDMA (2.07 mL, 16.60 mmol) in
10 mL of DMF was stirred for 15 h at 110 °C. After cooling, the reaction mixture
was filtered. The precipitate 6 was washed with diethyl ether and dried. The
filtrate was washed with water and dried over Na2SO4. The solvent was removed
and the residue was recrystallized from diethyl ether to afford a purple powder
6 in 73% overall yield. Mp 140–141 °C; 1H NMR (400 MHz, DMSO-d6): d 3.04 (s,
6H, CH3), 5.86 (d, J = 13.10 Hz, 1H, CH@CHN), 7.69 (d, J = 8.10 Hz, 2H, H-30, H-50),
7.77 (d, J = 8.85 Hz, 1H, H-6), 7.81 (d, J = 8.10 Hz, 2H, H-20, H-60), 7.87 (d,
J = 8.85 Hz, 1H, H-5), 7.89 (d, J = 13.10 Hz, 1H, CH@CHN), 8.15 (s, 1H, H-2); IR
(KBr): 3034 (CHarom), 2900 (CHalkane), 1612 (C@O), 1261 (NO2) cmꢀ1
.
25. Thompson, E. A.; Siiteri, P. K. J. Biol. Chem. 1974, 249, 5364.
13. Dellar, G.; Djura, P.; Sargent, M. V. J. Chem. Soc. Perkin I 1981, 1679.
14. Preparation of (4-bromophenyl)(1H-indolyl-6-yl)methanone 7. Raney nickel
(catalytic amount, 1/2 spatula) was added to a stirred solution of 6 (2.50 g,
2.12 mmol) in 50 mL of ethanol. The reaction mixture was stirred during 3 h at
rt under hydrogen atmosphere. The reaction mixture was filtered and the
filtrate was evaporated under reduced pressure. The residue was dissolved in
ethyl acetate and the organic layer was washed with H2O, brine and dried over
Na2SO4. The solvent was removed and the residue was purified on silica gel
(hexane-ethylacetate, 7:3 v/v) to afford a brown solid 7 in 32% overall yield. Mp
26. Graves, P. E.; Salhanick, H. A. Endocrinology 1979, 105, 52; Foster, A. B.; Jarman,
M.; Leung, C.-S.; Rowlands, M. G.; Taylor, G. N. J. Med. Chem. 1983, 26, 50.
27. Ehmer, P. B.; Jose, J.; Hartmann, R. W. J. Steroid Biochem. Mol. Biol. 2000, 75, 57;
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