Synthesis and antifungal activity of new 1-halogenobenzyl-3-imidazolylmethylindole derivatives

Article abstract of DOI:10.1016/S0223-5234(02)00005-3

A series of 1-benzyl-3-(imidazol-1-ylmethyl)indole derivatives 35-46 were prepared under mild reaction conditions and tested for their antifungal activity. Pharmacomodulation at N¹, C² and C⁵ of the indole ring and at the level of the alkyl chain (R₁) was carried out starting from the corresponding 3-acylindoles 6, 7 or 3-formylindoles 11-22. Target imidazolyl compounds 35-46 were obtained in satisfactory yields by CO₂ elimination from the intermediate carbamates. All of the compounds were evaluated in vitro against two human fungal pathogens, Candida albicans (CA980001) and Aspergillus fumigatus (AF980003); amphotericin B, fluconazole and itraconazole were used as references. Seven out of 27 compounds (35b, 35e, 35g, 35h, 36a, 38a and especially 40a) exerted significant antifungal activity against C. albicans, with MIC in the range of 1-6 μg mL^-1. As regards inhibitory activity against A. fumigatus, the MIC figures of most of our compounds were in excess of 20 μg mL^-1 in contrast to the reference drugs, amphotericin B and itraconazole, whose MIC₉₀ and MIC₈₀ values were 0.14 and 0.50 μg mL^-1, respectively. The most potent compound, 45a, exhibited MIC value (8±1 μg mL^-1) 16-fold higher than that of itraconazole.

Full text of DOI:10.1016/S0223-5234(02)00005-3

European Journal of Medicinal Chemistry 38 (2003) 75ꢀ87
/
www.elsevier.com/locate/ejmech
Original article
Synthesis and antifungal activity of new 1-halogenobenzyl-3-
imidazolylmethylindole derivatives
Young-Min Na a,c,*, Marc Le Borgne a, Fabrice Pagniez b, Guillaume Le Baut a,
Patrice Le Pape b
a Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, 1, rue Gaston Veil, 44035 Nantes cedex, France
b Department of Parasitology, Faculty of Pharmacy, 1, rue Gaston Veil, 44035 Nantes cedex, France
c YangJi Chemicals Co., 638-6 Sunggok-dong, Ansan, 425-110 Kyoungki-do, South Korea
Received 30 July 2002; received in revised form 5 November 2002; accepted 14 November 2002
Abstract
A series of 1-benzyl-3-(imidazol-1-ylmethyl)indole derivatives 35ꢀ
their antifungal activity. Pharmacomodulation at N1, C2 and C5 of the indole ring and at the level of the alkyl chain (R1) was carried
out starting from the corresponding 3-acylindoles 6, 7 or 3-formylindoles 11ꢀ22. Target imidazolyl compounds 35ꢀ46 were
/
46 were prepared under mild reaction conditions and tested for
/
/
obtained in satisfactory yields by CO2 elimination from the intermediate carbamates. All of the compounds were evaluated in vitro
against two human fungal pathogens, Candida albicans (CA980001) and Aspergillus fumigatus (AF980003); amphotericin B,
fluconazole and itraconazole were used as references. Seven out of 27 compounds (35b, 35e, 35g, 35h, 36a, 38a and especially 40a)
exerted significant antifungal activity against C. albicans, with MIC in the range of 1ꢀ
6 mg mLꢁ1. As regards inhibitory activity
/
against A. fumigatus, the MIC figures of most of our compounds were in excess of 20 mg mLꢁ1 in contrast to the reference drugs,
amphotericin B and itraconazole, whose MIC90 and MIC80 values were 0.14 and 0.50 mg mLꢁ1, respectively. The most potent
compound, 45a, exhibited MIC value (89
1 mg mLꢁ1) 16-fold higher than that of itraconazole.
/
´
# 2002 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
Keywords: Imidazolylmethylindoles; Azoles; Antifungal activity; Candida albicans; Aspergillus fumigatus
1. Introduction
conazole (Fig. 1) are currently used for both superficial
and systemic fungal infections [7ꢀ11]. However, their
/
In recent years, fungal infection became an important
complication and a major cause of morbidity and
mortality in immunocompromised individuals such as
those suffering from tuberculosis, cancer or AIDS and
in organ transplant cases [1,2]. Amphotericin B has been
widely used to treat fungal infections, but it can cause
serious side effects notably due to its renal toxicity [3,4].
The conazoles, which include the imidazole and triazole
compounds (Fig. 1) inhibit the synthesis of sterols in
fungi by inhibiting cytochrome P450-dependent 14a-
lanosterol demethylase (P-45014DM), which removes the
methyl group on C-14 of lanosterol [5,6], a key inter-
mediate step in the formation of ergosterol in the fungal
cell membrane. Among azoles, ketoconazole and itra-
clinical value has been limited by their relatively high
risk of toxicity, the emergence of drug resistance,
pharmacokinetic deficiencies, and/or insufficiencies in
their antifungal activities. Despite recent developments
[12], there is still a need for a genuinely broad-spectrum
fungicidal agent.In the research field of conazole anti-
fungal agents, investigations with an indole core have
been few reported [13,14]. More recently, a new
antifungal N-reverse prenylated indole alkaloid, isolated
from the basidiomycete Asporpium caryae, and its
derivative having a 2,3-dihydroxy-1,1-dimethylpropyl
unit, have been studied for their interesting antifungal
abilities [15,16]. In relation with these works, we
synthesised new 1-benzyl-3-(1-imidazolylmethyl)indoles
for investigating the importance of: (i) an alkyl sub-
stituent at the methylene bridge; (ii) a methyl group at
position 2 on indole nucleus and a bromine atom at
* Corresponding author.
E-mail address: youngminna@hotmail.com (Y.-M. Na).
´
0223-5234/02/$ - see front matter # 2002 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
PII: S 0 2 2 3 - 5 2 3 4 ( 0 2 ) 0 0 0 0 5 - 3

76
Y.-M. Na et al. / European Journal of Medicinal Chemistry 38 (2003) 75ꢀ
/87
Fig. 1. Imidazole and triazole derivatives used in fungal infections.
position 5. The antifungal activity of the target com-
pounds was then evaluated against Candida albicans and
Aspergillus fumigatus, the two most clinically important
fungi responsible for the majority of systemic fungal
infections.
and 5d, g which were N1-benzylated using the couple
NaHꢀDMSO, and reduced by LiAlH4 to give the
/
corresponding 3-(1-hydroxyalkyl)indole derivatives 23
and 34. In order to avoid the generally moderate or low
yield of the acylation step, the Grignard reaction was
applied to 3-formylindole 8, 3-formyl-2-methylindole 9
and 5-bromo-3-formylindole 10, obtained by Vilsmeierꢀ
Haack reaction [24]. Alcohols 23c, d, f and 24ꢀ29
belonging to subseries b (R1ꢂCH3) were obtained by
this sequence in overall yields ranging from 50 to 60%.
The 1-benzyl-3-hydroxymethylindole derivatives 23ꢀ28
and 30ꢀ34 belonging to subseries a (R1ꢂH) were
obtained by LiAlH4 reduction of the corresponding 1-
benzyl-3-formylindoles 11ꢀ16 and 18-22. The physico-
chemical properties of all these compounds are de-
scribed in the experimental part and in Table 1 for 35ꢀ
/
/
2. Chemistry
/
Preparation of the target 1-benzyl-3-(1-imidazolyl-
methyl)indoles 35ꢀ46 (Fig. 2) was carried out by two
methods: (i) reduction of 1-benzyl-3-acylindoles 6, 7
afforded the intermediate alcohols 23 and 34 which were
condensed with 1,1-carbonyldiimidazole [17] leading to
carbamates undergoing in situ decarboxylation to afford
the expected compounds; (ii) an alternative pathway
/
/
/
/
/
/
46.
consisted in synthesising the alcohols 23ꢀ
Grignard reaction starting from the 1-benzyl-3-formy-
lindoles 11ꢀ22.
/
34 by
/
3-Acylindoles have been obtained by alkaline hydro-
lysis of 3-acetoacetylindole derivatives [18], under
3. Pharmacology
VilsmeierꢀHaack conditions [19] involving dialkyla-
/
The target 1-benzyl-3-imidazolylmethylindole deriva-
mides and phosphorus oxychloride, by Cu2O-catalyzed
cyclisation of 2-acylmethylphenylisocyanides [20] or
palladium-catalysed indole cyclisation of b-(2-haloani-
lino)-a,b-unsaturated ketones [21]. Selective 3-acylation
of indole with acetic anhydride in the presence of
aluminium chloride necessitates previous N-protection
[22]. The reaction of the indole magnesium salt with acid
chlorides gives often a mixture of N-1 and 3-substituted
products; using the zinc salt of indole (obtained by
exchange with the magnesium salt) and facilitating
formation of the carbonyl ion complex by Lewis acid
like AlCl3, allowed selective 3-acylation in fair yields
[23]. Direct acylation of indole, 1, and 5-bromoindole, 3,
by this method afforded the 3-acylindoles 4b, d, e, g, h
tives 35ꢀ46 were tested for antifungal activity against C.
/
albicans and A. fumigatus. The growth inhibition test
for drug screening against C. albicans and A. fumigatus
was carried out by the method based on the fluorometric
properties of alamar Blue [25]. Amphotericin B, fluco-
nazole and itraconazole were used as positive controls.
The minimum inhibitory concentration (MIC) values (in
mg mLꢁ1) of 35ꢀ
/
46, together with their structure, are
gathered in Table 2.
Pharmacomodulation aimed at evaluating the influ-
ence of (i) the steric bulk and the lipophilicity resulting
from alkyl substitution at R1, (ii) the nature and
position of halogen group(s) fixed at the benzyl unit

Y.-M. Na et al. / European Journal of Medicinal Chemistry 38 (2003) 75ꢀ
/87
77
Fig. 2. Reagents: (i) ZnCl2, EtMgBr, AlCl3, CH2Cl2, r.t.; (ii) NaH, halogenated benzylchloride, DMSO; (iii) POCl3, DMF; (iv) LiAlH4, THF; (v)
R1MgX, THF, ꢁ78 8C; (vi) CDI, THF, reflux.
/
and (iii) a bromine atom at C5 of indole and a methyl
group at C2 of indole.
The results of the MIC tests against C. albicans can be
summarised as follows. SAR resulting from introduc-
tion of an alkyl group (R1) were explored in the
subseries of 1-(4-chlorobenzyl)indole derivatives
35. Replacing hydrogen by methyl exerted a favourable
maintained with a bulky group, such as i-Pr, n- and t-
Bu (35e, g, h), indicating that high lipophilicity did
not prevent activity; astonishingly the propenyl deriva-
tive 34f was a very moderate inhibitor and the
n-propyl analogue 34d was devoid of activity at 100
mg mLꢁ1
.
Replacing the 4-chloro at the benzyl moiety of 35a by
a fluorine atom, leading to 36a, exerted a positive effect
and the same increase was observed after dihalogenation
effect: 35b was 10-fold as active as 35a (39
/
0.1 and
1 mg mLꢁ1) and this level of activity could be
279
/

78
Y.-M. Na et al. / European Journal of Medicinal Chemistry 38 (2003) 75ꢀ87
/
Table 1
Physical constants of 3-imidazolylmethylindole compounds 35ꢀ46
/
Number
Z
R2
X
R1
M.p. (8C)
55ꢀ57
Oil
Oil
Oil
Formula
Yield (%)
35a
35b
35c
35d
35e
35f
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Br
Br
Br
Br
Br
Br
H
4-Cl
4-Cl
H
/
C19H16ClN3
C20H18ClN3
C21H20ClN3
83
52
64
53
45
43
47
62
17
68
30
62
40
79
30
45
51
54
50
63
26
34
50
53
53
71
H
Methyl
Ethyl
n-Propyl
i-Propyl
Propenyl
n-Butyl
t-Butyl
H
H
4-Cl
4-Cl
H
C22H22ClN3
C22H22ClN3
C22H20ClN3
H
4-Cl
4-Cl
126ꢀ
Oil
Oil
/
127
145
H
35g
35h
36a
36b
37a
37b
38a
38b
39a
39b
40a
41b
42a
42b
43a
44a
45a
46a
46d
46g
H
4-Cl
4-Cl
C23H24ClN3
H
142ꢀ
91ꢀ
Oil
/
C23H24ClN3
C19H16FN3
C20H18FN3
H
4-F
/
92
H
4-F
Methyl
H
H
2,4-diF
2,4-diF
2,4-diCl
2,4-diCl
4-F
62ꢀ
Oil
Oil
Oil
/
63
C19H15F2N3
C20H17F2N3
C19H15Cl2N3
C20H17Cl2N3
C20H18FN3
H
Methyl
H
H
H
Methyl
H
CH3
CH3
CH3
CH3
CH3
CH3
H
157ꢀ
137ꢀ
147ꢀ
Oil
/
158
140
148
4-F
4-Cl
Methyl
H
/
C21H20FN3
/
C20H18ClN3
C21H20BrN3
C20H17Cl2N3
C21H19Cl2N3
C19H15BrFN3
C19H15BrFN3
4-Br
Methyl
H
2,4-diCl
2,4-diCl
2-F
157ꢀ
/
160
Methyl
H
Oil
101ꢀ
123ꢀ
98ꢀ
145ꢀ
/
102
124
H
4-F
H
/
H
2-Cl
4-Cl
H
/
100
147
C19H15BrClN3
C19H15BrClN3
C22H21BrClN3
H
H
/
H
4-Cl
4-Cl
n-Propyl
n-Butyl
Oil
Oil
H
C23H23BrClN3
(2,4-dichloro or 2,4-difluoro) in 37a and 38a; but
compared with the 1-(4-chlorobenzyl) subseries, the
parent methyl (R1) counterparts, 36b, 37b and 38b
were less active.
Results of the MIC tests against A. fumigatus were
not very promising; 13 compounds out of 26 displayed
MIC in the range of about 15ꢀ
30 mg mLꢁ1; although
compounds issued from the 5-bromoindole series were
generally inefficient (MICꢀ
100 mg mLꢁ1), 5-bromo-1-
(2-chlorobenzyl)-3-(1H-imidazol-1-ylmethyl)indole 45a
exhibited the lightest activity with a MIC value of 89
1 mg mLꢁ1
/
The presence of a bromine atom at C5 of indole
exerted a constant detrimental effect: 43a, 44a, 45a, and
/
46a, d, g. In the 2-methylindole series (39ꢀ
/
42, R2ꢂCH3)
/
/
comparison with the corresponding unsubstituted (R2ꢂ
/
.
H) derivatives brought to the fore that this pharmaco-
modulation usually exerted a negative effect; never-
theless a clear-cut increase of activity was observed in
the 1-(4-chlorobenzyl)-3-imidazolylmethylindole sub-
series: 40a was about 30-fold as active as 35a; this
First approach in the series of new imidazolylmethy-
lindoles bearing different structural features on the
indole moiety and the intercyclic methylene points out
that the 1-(4-chlorobenzyl)-2-methyl-3-(1H-imidazol-1-
ylmethyl)indole 40a and the 5-bromo-1-(2-chloroben-
zyl)-3-(1H-imidazol-1ylmethyl)indole 45a exert signifi-
cant in vitro antifungal activity against C. albicans and
A. fumigatus, respectively. Although less potent than the
reference drugs, they could represent new lead com-
compound, with a MIC of 19
0.2 mg mLꢁ1, was the
/
most potent antifungal against C. albicans in the studied
series. This encouraging result justified ongoing investi-
gation.

Y.-M. Na et al. / European Journal of Medicinal Chemistry 38 (2003) 75ꢀ
/87
79
Table 2
In vitro antifungal activity of 3-imidazolylmethylindole derivatives 35
/
46
ꢀ
Number
Z
R2
X
R1
MIC
Candida albicans (CA980001) (mg mLꢁ1
)
Aspergillus fumigatus (AF980003) (mg mLꢁ1
)
35a
35b
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Br
Br
Br
Br
Br
Br
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-F
H
279
3.09
159
100
0.1
/
1
259
249
249
100
259
299
/
2
a
Methyl
Ethyl
n-Propyl
/0.1
/2
b
35c
/4
/5
35da
35e
ꢀ/
ꢀ
/
i-Propyl 5.09
/
/3
a
35f
35f
Allyl
Allyl
n-Butyl
t-Butyl
H
349
289
3.59
6.19
49
259
169
269
59
159
100
229
1.09
100
109
239
/1
/1
b
/2
ꢀ
ꢀ
ꢀ
/
100
100
100
a
35g
/0.1
/
35h
36a
/0.2
/
/
1
139
289
199
/1
a
36b
37a
4-F
2,4-diF
Methyl
H
/1
/1
/2
/2
b
37b
38a
2,4-diF Methyl
2,4-diCl
2,4-diCl Methyl
/5
ꢀ
/
100
100
100
H
/
1
209
/
8
a
38b
/3
319
/1
39a
39b
40a
41b
42a
CH3 4-F
CH3 4-F
H
ꢀ/
ꢀ
/
Methyl
H
/1
239
/1
CH3 4-Cl
CH3 4-Br
CH3 2,4-diCl
/0.2
199
/2
Methyl
H
ꢀ/
ꢀ
/
/2
2491
/
b
42b
CH3 2,4-diCl Methyl
/1
ꢀ
ꢀ
ꢀ
/
100
100
100
43a
44a
45a
46a
H
H
H
H
H
H
2-F
4-F
H
ꢀ/100
/
H
ꢀ/100
/
2-Cl
4-Cl
4-Cl
4-Cl
H
329
/
14
891
/
H
ꢀ/100
ꢀ
ꢀ
ꢀ
/
100
100
100
a
46d
46g
n-Propyl
n-Butyl
ꢀ/100
/
a
459
0.129
0.029
/
2
/
Amphotericin B
Fluconazole
/
0.01
0.149
/
0.04
/0.001
ꢀ/
Itraconazole
ꢀ/
0.59
/
0.1
a
Fumarate salt.
Nitrate salt.
b
pounds for further pharmacomodulation in the series of
indole-based imidazole or 1,2,4-triazole derivatives.
5-bromo-3-formylindole 10 have been previously de-
scribed [24].
4. Experimental
4.2. Chemistry
4.1. Materials
4.2.1. General procedure for ketones 4, 5
Melting points, as determined in open tubes with a
To a suspension of indole 1 or 5-bromoindole 3 (4.3
mmol) and zinc chloride (1 M solution in diethyl ether,
8.6 mL) in 20 mL of CH2Cl2 was added dropwise a
solution of EtMgBr (1M in THF, 4.3 mL) over 20 min.
The mixture was stirred for 1 h and acyl chloride (5.4
mmol) was added. The suspension was stirred for
another h and AlCl3 (0.98 g) was added. The resultant
TottoliꢀBuchi apparatus, are uncorrected. Infrared
/
¨
spectra were obtained on a Beckman IR 4230 spectro-
1
photometer using KBr pellets or NaCl disk. The H-
NMR spectra were recorded on a Bruker AC-250
instrument (250 MHz); chemical shifts are expressed in
d units (ppm) using the solvent signal as reference.
Elemental analyses of the target compounds, indicated
mixture was stirred until the reaction was complete (1ꢀ4
/
by the element symbols, were within 9
theoretical values.
The synthesis of 3-acetylindole 4b [23], 3-n-butyrylin-
dole 4d [18], 3-isobutyrylindole 4e [19], 3-valerylindole
4g [24], 3-isovalerylindole [23] and 3-pivaloylindole 4h
[23] have been previously reported; 3-formylindole 8 and
/
0.4% of the
h) and it was cautiously quenched with sat. NH4Cl (20
mL). The organic layer was washed with saturated
NaHCO3 and brine, dried over Na2SO4 and filtered.
The solvent was removed under vacuum. The product
was treated with cold ether, filtered and dried to give 4
or 5 as a white powder.

80
Y.-M. Na et al. / European Journal of Medicinal Chemistry 38 (2003) 75ꢀ87
/
4.2.1.1. 3-Butyryl-5-bromo-1H-indole (5d). White pow-
der (16%), m.p. 160ꢀ161 8C; IR nmax 3402, 2934, 2930,
1636 cmꢁ1. H-NMR (DMSO-d6) d 0.96 (t, Jꢂ
7.30
Hz, 3H, CH3), 1.69 (m, 2H, CH2), 2.85 (t, Jꢂ7.30 Hz,
2H, CH2), 7.37 (dd, Jꢂ8.55 Hz, J?ꢂ 1.85 Hz, 1H, 6-
CH), 7.48 (d, Jꢂ8.55 Hz, 1H, 7-CH), 8.37 (d, Jꢂ1.85
Hz, 1H, 4-CH), 8.42 (d, Jꢂ3.05 Hz, 1H, 2-CH), 12.14
(d, Jꢂ3.05 Hz, 1H, NH).
4.2.2.4. 3-Valeryl-1-(4-chlorobenzyl)-1H-indole (6g).
Brown powder (90%), m.p. 103ꢀ104 8C; IR nmax 1632,
1254, 1058 cmꢁ1. H-NMR (DMSO-d6) d 0.97 (t, Jꢂ
7.30 Hz, 3H, CH3), 1.39 (m, 2H, CH2), 1.65 (tt, Jꢂ7.30
Hz, 2H, CH2), 2.88 (t, Jꢂ7.30 Hz, 2H, CH2), 5.53 (s,
2H, CH2), 7.23 (m, 2H, 5,6-CH), 7.34 (d, Jꢂ8.50 Hz,
2H, Ph-H), 7.43 (d, Jꢂ8.50 Hz, 2H, Ph-H), 7.53 (m,
/
/
1
1
/
/
/
/
/
/
/
/
/
/
/
/
/
1H, 7-CH), 8.25 (m, 1H, 4-CH), 8.62 (s, 1H, 2-CH).
4.2.1.2. 3-Valeryl-5-bromo-1H-indole (5g). White pow-
der (20%), m.p. 169ꢀ170 8C; IR nmax 3394, 2897, 2802,
1657 cmꢁ1. H-NMR (DMSO-d6) d 0.96 (t, Jꢂ
7.30
Hz, 3H, CH3), 1.37 (m, 2H, CH2), 1.65 (m, 2H, CH2),
2.86 (t, Jꢂ7.30 Hz, 2H, CH2), 7.36 (dd, Jꢂ8.55 Hz,
J?ꢂ1.80 Hz, 1H, 6-CH), 7.47 (d, Jꢂ8.55 Hz, 1H, 7-
CH), 8.36 (d, Jꢂ1.80 Hz, 1H, 4-CH), 8.42 (d, Jꢂ3.05
Hz, 1H, 2-CH), 12.13 (d, Jꢂ3.05 Hz, 1H, NH).
4.2.2.5. 3-Pivaloyl-1-(4-chlorobenzyl)-1H-indole (6h).
/
White powder (15%), m.p. 118ꢀ120 8C; IR nmax 1674,
/
1
1
/
1233, 1087 cmꢁ1. H-NMR (DMSO-d6) d 1.40 (s, 9H,
CH3), 5.56 (s, 2H, CH2), 7.21 (m, 2H, 5,6-CH), 7.34 (d,
/
/
Jꢂ
/
8.40 Hz, 2H, Ph-H), 7.44 (d, Jꢂ8.40 Hz, 2H, Ph-
/
/
/
H), 7.51 (m, 1H, 7-CH), 8.33 (m, 1H, 4-CH), 8.72 (s, 1H,
2-CH).
/
/
/
4.2.2.6. 3-Butyryl-5-bromo-1-(4-chlorobenzyl)-1H-
4.2.2. General procedure for N1-substituted ketones 6 and
7
indole (7g). White powder (65%), m.p. 124ꢀ
/
126 8C; IR
nmax 1628, 1239, 1076 cmꢁ1. H-NMR (DMSO-d6) d
0.98 (t, Jꢂ7.30 Hz, 3H, CH3), 1.70 (m, 2H, CH2), 2.86
(t, Jꢂ7.30 Hz, 2H, CH2), 5.54 (s, 2H, CH2), 7.34 (d,
Jꢂ
Jꢂ
Jꢂ
1
Sodium hydride (60% in dispersion, 1.5 g, 37.8 mmol)
was added to a solution of 4 or 5 (34.4 mmol) in 200 mL
of anhydrous DMSO at room temperature (r.t.) with
stirring. After 1 h stirring at the same temperature,
benzyl chloride (41.28 mmol) was added to the solution.
The mixture was stirred at the same temperature for 2 h.
After addition of water, the mixture was extracted with
dichloromethane. The organic layer was washed with
brine, dried over anhydrous Na2SO4 and evaporated
under reduced pressure. The residue was chromato-
graphed on a silica gel column using CH2Cl2: n-hexane
(1:1) to give 6 or 7.
/
/
/
8.50 Hz, 2H, Ph-H), 7.37 (m, 1H, 6-CH), 7.44 (d,
8.50 Hz, 2H, Ph-H), 7.55 (m, 1H, 7-CH), 8.38 (d,
1.50 Hz, 1H, 4-CH), 8.67 (s, 1H, 2-CH).
/
/
4.2.2.7. 3-Valeryl-5-bromo-1-(4-chlorobenzyl)-1H-
indole (7h). Yellow powder (88%), m.p. 127ꢀ128 8C; IR
nmax 1658, 1263, 1088 cmꢁ1. H-NMR (DMSO-d6) d
0.94 (t, Jꢂ7.30 Hz, 3H, CH3), 1.38 (m, 2H, CH2), 1.65
/
1
/
(m, 2H, CH2), 2.88 (m, 2H, CH2), 5.54 (s, 2H, CH2),
7.37 (m, 1H, 6-CH), 7.37 (m, 2H, Ph-H), 7.42 (m, 2H,
Ph-H), 7.53 (m, 1H, 7-CH), 8.37 (d, Jꢂ1.50 Hz, 1H, 4-
/
4.2.2.1. 3-Acetyl-1-(4-chlorobenzyl)-1H-indole
(6b).
CH), 8.67 (s, 1H, 2-CH).
Brown powder (54%), m.p. 170ꢀ172 8C; IR nmax 1659,
/
1
1299, 1090 cmꢁ1. H-NMR (DMSO-d6) d 2.50 (s, 3H,
CH3), 5.54 (s, 2H, CH2), 7.24 (m, 2H, 5,6-CH), 7.35 (d,
4.2.3. 3-Formyl-2-methyl-1H-indole (9)
A solution of 1 g (7.62 mmol) of 2-methyl-1H-indole
Jꢂ
/
8.40 Hz, 2H, Ph-H), 7.44 (d, Jꢂ/8.40 Hz, 2H, Ph-
2 in 5 mL of N,N-dimethylformamide was added at 5ꢀ
/
H), 7.55 (m, 1H, 7-CH), 8.23 (m, 1H, 4-CH), 8.58 (s, 1H,
2-CH).
10 8C over 1 h to a mixture of 0.79 mL (8.46 mmol) of
phosphorus oxychloride and 2.6 mL of N,N-dimethyl-
formamide. The orange solution was stirred at r.t. for 1
h. Ice (12 g) was added, followed by a solution of 3.38 g
(84.5 mmol) of potassium hydroxide in 30 mL of water.
The mixture was heated at 93 8C for 30 min and then
stored at r.t. overnight. The precipitate was collected,
washed with water, and dried to afford 1.1 g (90%) of 9
4.2.2.2. 3-Butyryl-1-(4-chlorobenzyl)-1H-indole (6d).
White powder (35%), m.p. 140ꢀ
/
141 8C; IR nmax 1625,
1256, 1088 cmꢁ1. H-NMR (DMSO-d6) d 1.05 (t, Jꢂ
/
1
7.30 Hz, 3H, CH3), 1.70 (m, 2H, CH2), 2.76 (m, 2H,
CH2), 5.55 (s, 2H, CH2), 7.22 (m, 2H, 5,6-CH), 7.34 (m,
2H, Ph-H), 7.43 (m, 2H, Ph-H), 7.53 (m, 1H, 7-CH),
8.23 (m, 1H, 4-CH), 8.61 (s, 1H, 2-CH).
as a white powder, m.p. 202ꢀ
/
203 8C. IR nmax 1635,
1290, 1095 cmꢁ1. H-NMR (DMSO-d6) d 2.72 (s, 3H,
CH3), 7.17 (dd, Jꢂ8.80 Hz, Jꢂ7.35 Hz, 1H, 5-CH),
7.23 (dd, Jꢂ8.80 Hz, J?ꢂ7.35 Hz, 1H, 6-CH), 7.73 (d,
Jꢂ8.80 Hz, 1H, 7-CH), 8.08 (d, Jꢂ8.80 Hz, 1H, 4-
CH),10.09 (s, 1H, CHO), 12.02 (s, 1H, NH).
1
/
/
4.2.2.3. 3-iso-Butyryl-1-(4-chlorobenzyl)-1H-indole
/
/
(6e). White powder (79%), m.p. 119ꢀ
1668, 1258, 1092 cmꢁ1. 1H-NMR (DMSO-d6) d 1.17 (d,
Jꢂ6.00 Hz, 6H, CH3), 3.44 (m, 1H, CH), 5.53 (s, 2H,
/
120 8C; IR nmax
/
/
/
CH2), 7.24 (m, 2H, 5,6-CH), 7.33 (m, 2H, Ph-H), 7.38
(m, 2H, Ph-H), 7.53 (m, 1H, 7-CH), 8.24 (m, 1H, 4-CH),
8.64 (s, 1H, 2-CH).
4.2.4. General procedure for compounds 11ꢀ22
The procedure is the same as that employed for
compounds 6 and 7.
/

Y.-M. Na et al. / European Journal of Medicinal Chemistry 38 (2003) 75ꢀ
/87
81
4.2.4.1. 1-(4-Chlorobenzyl)-3-formyl-1H-indole
Brown powder (89%), m.p. 117ꢀ119 8C; IR nmax 3389,
1650 cmꢁ1. H-NMR (DMSO-d6) d 5.59 (s, 2H, CH2),
7.30 (m, 2H, 5,6-CH), 7.36 (d, Jꢂ8.60 Hz, 2H, Ph-H),
7.45 (d, Jꢂ8.60 Hz, 2H, Ph-H), 7.60 (m, 1H, 7-CH),
(11).
Ph-H), 7.28 (m, 2H, 5,6-CH), 7.33 (dd, Jꢂ
J?ꢂ2.10 Hz, 1H, Ph-H), 7.46 (d, Jꢂ
CH), 8.20 (d, Jꢂ7.60 Hz, 1H, 4-CH), 10.19 (s, 1H,
CHO).
/
8.55 Hz,
/
/
/
7.20 Hz, 1H, 7-
1
/
/
/
8.15 (m, 1H, 4-CH), 8.51 (s, 1H, 2-CH), 9.99 (s, 1H,
CHO).
4.2.4.9. 5-Bromo-1-(2-fluorobenzyl)-3-formyl-1H-indole
(19). Brown powder (70%), m.p. 131ꢀ132 8C; IR nmax
/
1
3392, 1649 cmꢁ1. H-NMR (DMSO-d6) d 5.65 (s, 2H,
CH2), 7.20 (m, 1H, Ph-H), 7.30 (m, 1H, Ph-H), 7.39 (dd,
4.2.4.2. 1-(4-Fluorobenzyl)-3-formyl-1H-indole
(12).
Brown powder (76%), m.p. 116ꢀ
/
117 8C; IR nmax 3230,
Jꢂ
Hz, J?ꢂ
7-CH), 8.28 (d, Jꢂ
/
7.20 Hz, J?ꢂ
1.80 Hz, 1H, 6-CH), 7.64 (d, Jꢂ
1.80 Hz, 1H, 4-CH), 8.49 (s, 1H, 2-
/
1.90 Hz, 1H, Ph-H), 7.48 (dd, Jꢂ
/
8.80
1633 cmꢁ1. H-NMR (DMSO-d6) d 5.57 (s, 2H, CH2),
7.27 (m, 4H, 5,6-CH and Ph-H), 7.42 (m, 2H, Ph-H),
7.64 (m, 1H, 7-CH), 8.15 (m, 1H, 4-CH), 8.52 (s, 1H, 2-
CH), 9.98 (s, 1H, CHO).
1
/
/
8.80 Hz, 1H,
/
CH), 9.96 (s, 1H, CHO).
4.2.4.10. 5-Bromo-1-(4-fluorobenzyl)-3-formyl-1H-
4.2.4.3. 1-(2,4-Difluorobenzyl)-3-formyl-1H-indole
indole (20). Brown powder (76%), m.p. 132ꢀ133 8C; IR
/
1
nmax 3412, 1648 cmꢁ1. H-NMR (DMSO-d6) d 5.57 (s,
2H, CH2), 7.21 (m, 2H, Ph-H), 7.40 (m, 2H, Ph-H), 7.46
(13). Brown powder (84%), m.p. 120ꢀ121 8C; IR nmax
/
1
3256, 1658 cmꢁ1. H-NMR (DMSO-d6) d 5.61 (s, 2H,
CH2), 7.12 (m, 1H, Ph-H), 7.35 (m, 4H, Ph-H and 5,6,7-
CH), 7.65 (m, 1H, Ph-H), 8.43 (s, 1H, 4-CH), 9.98 (s,
1H, CHO).
(dd, Jꢂ
/
8.75 Hz, J?ꢂ
/
1.85 Hz, 1H, 6-CH), 7.65 (d, Jꢂ
/
8.75 Hz, 1H, 7-CH), 8.27 (d, Jꢂ/1.85 Hz, 1H, 4-CH),
8.56 (s, 1H, 2-CH), 9.96 (s, 1H, CHO).
4.2.4.4. 1-(2,4-Dichlorobenzyl)-3-formyl-1H-indole
4.2.4.11. 5-Bromo-1-(2-chlorobenzyl)-3-formyl-1H-
(14). Brown powder (87%), m.p. 121ꢀ
/
123 8C; IR nmax
3400, 1628 cmꢁ1. H-NMR (DMSO-d6) d 5.57 (s, 2H,
CH2), 7.32 (m, 2H, 5,6-CH), 7.42 (d, Jꢂ8.35 Hz, 1H,
Ph-H), 7.45 (dd, Jꢂ8.35 Hz, J?ꢂ2.10 Hz, 1H, Ph-H),
7.56 (m, 1H, 7-CH), 8.19 (d, Jꢂ7.20 Hz, 1H, 4-CH),
indole (21). Brown powder (80%), m.p. 128ꢀ
/
129 8C; IR
nmax 3375, 1644 cmꢁ1. H-NMR (DMSO-d6) d 5.68 (s,
2H, CH2), 6.97 (dd, Jꢂ7.55 Hz, J?ꢂ1.70 Hz, 1H, Ph-
H), 7.35 (m, 2H, Ph-H), 7.47 (dd, Jꢂ8.75 Hz, J?ꢂ1.80
Hz, 1H, 6-CH), 7.54 (d, Jꢂ8.75 Hz, 1H, 7-CH), 8.30 (d,
Jꢂ1.80 Hz, 1H, 4-CH), 8.44 (s, 1H, 2-CH), 9.97 (s, 1H,
CHO).
1
1
/
/
/
/
/
/
/
/
/
8.40 (s, 1H, 2-CH), 9.98 (s, 1H, CHO).
/
4.2.4.5. 1-(4-Fluorobenzyl)-3-formyl-2-methyl-1H-
indole (15). White powder (75%), m.p. 121ꢀ123 8C; IR
/
nmax 3452, 1655 cmꢁ1. H-NMR (DMSO-d6) d 2.74 (s,
3H, CH3), 5.61 (s, 2H, CH2), 7.18 (m, 2H, 5,6-CH), 7.21
(m, 2H, Ph-H), 7.25 (m, 2H, Ph-H), 7.56 (m, 1H, 7-CH),
8.17 (m, 1H, 4-CH), 10.16 (s, 1H, CHO).
1
4.2.4.12. 5-Bromo-1-(4-chlorobenzyl)-3-formyl-1H-
indole (22). Brown powder (55%), m.p. 200ꢀ201 8C; IR
nmax 3279, 1634 cmꢁ1. H-NMR (DMSO-d6) d 5.59 (s,
2H, CH2), 7.35 (d, Jꢂ8.45 Hz, 2H, Ph-H), 7.45 (d, Jꢂ
8.45 Hz, 2H, Ph-H), 7.48 (m, 1H, 6-CH), 7.61 (d, Jꢂ
8.75 Hz, 1H, 7-CH), 8.28 (d, Jꢂ1.80 Hz, 1H, 4-CH),
/
1
/
/
/
/
4.2.4.6. 1-(4-Chlorobenzyl)-3-formyl-2-methyl-1H-
8.36 (s, 1H, 2-CH), 9.97 (s, 1H, CHO).
indole (16). Brown powder (80%), m.p. 116ꢀ
/
118 8C; IR
nmax 3403, 1676 cmꢁ1. H-NMR (DMSO-d6) d 2.73 (s,
3H, CH3), 5.59 (s, 2H, CH2), 7.13 (d, Jꢂ8.45 Hz, 2H,
Ph-H), 7.26 (m, 2H, 5,6-CH), 7.43 (d, Jꢂ8.45 Hz, 2H,
1
4.2.5. General procedure for alcohols 23 and 34 from
ketones 6 and 7
/
/
To a solution of 6 or 7 in anhydrous tetrahydrofuran
(15 mL), LiAlH4 (1.1 equiv.) was slowly added with
vigorous stirring under nitrogen atmosphere at r.t. The
reaction mixture was stirred for 30 min and then
quenched with water. The mixture was extracted with
CH2Cl2 and the organic layer was washed with brine,
dried over Na2SO4 and evaporated under vacuum. The
crude product was purified by chromatography.
Ph-H), 7.55 (m, 1H, 7-CH), 8.17 (m, 1H, 4-CH), 10.17
(s, 1H, CHO).
4.2.4.7. 1-(4-Bromobenzyl)-3-formyl-2-methyl-1H-
indole (17). Brown powder (75%), m.p. 122ꢀ123 8C; IR
/
1
nmax 3400, 1659 cmꢁ1. H-NMR (DMSO-d6) d 2.74 (s,
3H, CH3), 5.56 (s, 2H, CH2), 7.12 (m, 2H, Ph-H), 7.20
(m, 2H, 5,6-CH), 7.43 (m, 2H, Ph-H), 7.51 (m, 1H, 7-
CH), 8.10 (m, 1H, 4-CH), 10.17 (s, 1H, CHO).
4.2.5.1. 1-(4-Chlorobenzyl)-3-(1-hydroxyethyl)-1H-
indole (23b). Green oil (97%); IR nmax 3369, 1265, 1079
4.2.4.8. 1-(2,4-Dichlorobenzyl)-3-formyl-2-methyl-1H-
indole (18). White powder (80%), m.p. 165ꢀ
/
166 8C; IR
nmax 3388, 1655 cmꢁ1. H-NMR (DMSO-d6) d 2.68 (s,
3H, CH3), 5.60 (s, 2H, CH2), 6.37 (d, Jꢂ8.55 Hz, 1H,
cmꢁ1. 1H-NMR (DMSO-d6) d 1.52 (d, Jꢂ
/
6.30 Hz, 3H,
4.65 Hz, 1H, OH), 5.03 (m, 1H, CH),
5.39 (s, 2H, CH2), 7.08 (m, 2H, 5,6-CH), 7.35 (d, Jꢂ
1
CH3), 4.94 (d, Jꢂ
/
/
/

82
Y.-M. Na et al. / European Journal of Medicinal Chemistry 38 (2003) 75ꢀ87
/
8.50 Hz, 2H, Ph-H), 7.44 (d, Jꢂ
7.55 (m, 1H, 7-CH), 7.69 (d, Jꢂ
8.25 (s, 1H, 2-CH).
/
8.50 Hz, 2H, Ph-H),
7.80 Hz, 1H, 4-CH),
1H, CH), 5.41 (s, 2H, CH2), 7.37 (d, Jꢂ
Ph-H), 7.44 (d, Jꢂ8.50 Hz, 2H, Ph-H), 7.49 (s, 1H, 2-
CH), 7.64 (m, 2H, 6,7-CH), 7.70 (m, 1H, 4-CH).
/
8.50 Hz, 2H,
/
/
4.2.5.2. 1-(4-Chlorobenzyl)-3-(1-hydroxybutyl)-1H-
indole (23d). Yellow oil (96%); IR nmax 3200, 1235, 1082
4.2.6. General procedure for compounds 23aꢀ
/
28a and
30aꢀ34a from 11 to 16 and 18 to 22
/
cmꢁ1. 1H-NMR (DMSO-d6) d 0.97 (t, Jꢂ
/
7.10 Hz, 3H,
CH3), 1.25 (m, 2H, CH2), 1.90 (m, 2H, CH2), 4.98 (d,
Jꢂ4.70 Hz, 1H, OH), 5.03 (m, 1H, CH), 5.40 (s, 2H,
CH2), 7.15 (m, 2H, 5,6-CH), 7.40 (d, Jꢂ8.55 Hz, 2H,
Ph-H), 7.47 (d, Jꢂ 8.55 Hz, 2H, Ph-H), 7.52 (m, 1H, 7-
These compounds were prepared according to the
procedure used (LiAlH4 reduction) for ketones 6 and 7.
/
/
4.2.6.1. 1-(4-Chlorobenzyl)-3-(1-hydroxymethyl)-1H-
/
indole (23a). White powder (85%), m.p. 75ꢀ
/
76 8C; IR
nmax 3385 cmꢁ1. H-NMR (DMSO-d6) d 4.68 (d, Jꢂ
5.40 Hz, 2H, CH2), 4.87 (t, Jꢂ5.40 Hz, 1H, OH), 5.42
(s, 2H, CH2), 7.08 (m, 2H, 5,6-CH), 7.25 (d, Jꢂ8.60 Hz,
2H, Ph-H), 7.41 (m, 3H, 2-CH, Ph-H), 7.45 (d, Jꢂ7.45
Hz, 1H, 7-CH), 7.64 (d, Jꢂ7.60 Hz, 1H, 4-CH).
1
CH), 7.64 (s, 1H, 2-CH), 7.69 (m, 1H, 4-CH).
/
/
4.2.5.3. 1-(4-Chlorobenzyl)-3-(1-hydroxy-2-
methylpropyl)-1H-indole (23e). Light yellow oil (95%);
IR nmax 3250, 1237, 1075 cmꢁ1. 1H-NMR (DMSO-d6) d
/
/
/
0.81 (d, Jꢂ
(m, 1H, CH), 4.99 (m, 1H, OH), 5.39 (s, 2H, CH2), 7.06
(m, 2H, 5,6-CH), 7.25 (d, Jꢂ8.35 Hz, 2H, Ph-H), 7.40
(d, Jꢂ8.35 Hz, 2H, Ph-H), 7.45 (m, 2H, 4,7-CH), 7.76
(s, 1H, 2-CH).
/
6.60 Hz, 6H, CH3), 1.80 (m, 1H, CH), 4.89
4.2.6.2. 1-(4-Fluorobenzyl)-3-(1-hydroxymethyl)-1H-
indole (24a). Yellow powder (80%), m.p. 91ꢀ92 8C; IR
nmax 3385 cmꢁ1. H-NMR (DMSO-d6) d 4.85 (t, Jꢂ
5.35 Hz, 1H, OH), 4.67 (d, Jꢂ5.35 Hz, 2H, CH2), 5.51
(s, 2H, CH2), 7.05 (m, 2H, 5,6-CH), 7.18 (m, 2H, Ph-H),
7.33 (m, 2H, Ph-H), 7.43 (s, 1H, 2-CH), 7.47 (d, Jꢂ8.10
Hz, 1H, 7-CH), 7.64 (d, Jꢂ7.60 Hz, 1H, 4-CH).
/
/
/
1
/
/
4.2.5.4. 1-(4-Chlorobenzyl)-3-(1-hydroxypentyl)-1H-
indole (23g). Yellow oil (98%); IR nmax 3128, 1285, 1085
/
/
cmꢁ1. 1H-NMR (DMSO-d6) d 0.88 (t, Jꢂ
/
6.60 Hz, 3H,
CH3), 1.24 (m, 4H, CH2), 1.83 (m, 2H, CH2), 4.83 (m,
1H, CH), 4.91 (d, Jꢂ4.50 Hz, 1H, OH), 5.40 (s, 2H,
CH2), 7.02 (dd, Jꢂ7.90 Hz, J?ꢂ7.05 Hz, 1H, 5-CH),
7.11 (dd, Jꢂ7.90 Hz, J?ꢂ7.05 Hz, 1H, 6-CH), 7.24 (d,
Jꢂ8.40 Hz, 2H, Ph-H), 7.36 (m, 2H, Ph-H), 7.68 (m,
4.2.6.3. 1-(2,4-Difluorobenzyl)-3-(1-hydroxymethyl)-
1H-indole (25a). Yellow oil (97%); IR nmax 3287 cmꢁ1
/
.
/
/
1H-NMR (DMSO-d6) d 4.68 (m, 1H, CH2), 4.77 (m,
1H, OH), 5.54 (s, 2H, CH2), 7.09 (m, 2H, 5,6-CH), 7.12
(m, 1H, Ph-H), 7.35 (m, 1H, Ph-H), 7.40 (s, 1H, 2-CH),
7.44 (m, 1H, 7-CH), 7.60 (m, 1H, 4-CH), 7.65 (m, 1H,
Ph-H).
/
/
/
1H, 7-CH), 8.15 (m, 1H, 4-CH), 8.51 (s, 1H, 2-CH).
4.2.5.5. 1-(4-Chlorobenzyl)-3-(1-hydroxy-2,2-
dimethylpropyl)-1H-indole (23h). Light yellow oil
(96%); IR nmax 3255, 1255, 1079 cmꢁ1
.
1H-NMR
4.60 Hz,
1H, OH), 5.06 (m, 1H, CH), 5.44 (s, 2H, CH2), 7.08 (m,
2H, 5,6-CH), 7.27 (d, Jꢂ8.40 Hz, 2H, Ph-H), 7.38 (m,
4.2.6.4. 1-(2,4-Dichlorobenzyl)-3-(1-hydroxymethyl)-
1H-indole (26a). Brown powder (98%); IR nmax 3215
cmꢁ1. 1H-NMR (DMSO-d6) d 4.60 (m, 2H, CH2), 4.68
(DMSO-d6) d 1.00 (s, 9H, CH3), 4.84 (d, Jꢂ
/
(m, 1H, OH), 5.41 (s, 2H, CH2), 6.18 (d, Jꢂ
1H, Ph-H), 7.09 (m, 2H, 5,6-CH), 7.24 (m, 1H, Ph-H),
7.35 (s, 1H, 2-CH), 7.38 (m, 1H, 7-CH), 7.64 (d, Jꢂ7.60
Hz, 1H, 4-CH), 7.70 (d, Jꢂ2.00 Hz, 1H, Ph-H).
/
8.30 Hz,
/
2H, Ph-H), 7.43 (m, 1H, 7-CH), 7.58 (m, 1H, 4-CH),
7.60 (s, 1H, 2-CH).
/
/
4.2.5.6. 5-Bromo-1-(4-chlorobenzyl)-3-(1-
hydroxybutyl)-1H-indole (34d). Yellow oil (96%); IR
4.2.6.5. 1-(4-Fluorobenzyl)-3-(1-hydroxymethyl)-2-
methyl-1H-indole (27a). Yellow oil (95%); IR nmax 3198
1
nmax 3198, 1257, 1087 cmꢁ1. H-NMR (DMSO-d6) d
1
cmꢁ1. H-NMR (DMSO-d6) d 2.36 (s, 3H, CH3), 4.68
0.97 (t, Jꢂ
(t, Jꢂ7.00 Hz, 2H, CH2), 4.87 (d, Jꢂ
OH), 5.15 (m, 1H, CH), 5.41 (s, 2H, CH2), 7.30 (d, Jꢂ
8.50 Hz, 2H, Ph-H), 7.31 (s, 1H, 2-CH), 7.40 (d, Jꢂ8.50
/
7.00 Hz, 3H, CH3), 1.23 (m, 2H, CH2), 1.74
(m, 3H, CH2 and OH), 5.46 (s, 2H, CH2), 7.06 (m, 2H,
5,6-CH), 7.11 (m, 2H, Ph-H), 7.18 (m, 2H, Ph-H), 7.38
(m, 1H, 7-CH), 7.58 (m, 1H, 4-CH).
/
/
4.70 Hz, 1H,
/
/
Hz, 2H, Ph-H), 7.56 (m, 2H, 6,7-CH), 7.63 (m, 1H, 4-
CH).
4.2.6.6. 1-(4-Chlorobenzyl)-3-(1-hydroxymethyl)-2-
methyl-1H-indole (28a). Yellow powder (97%), m.p.
1
4.2.5.7. 5-Bromo-1-(4-chlorobenzyl)-3-(1-
hydroxypentyl)-1H-indole (34g). Green oil (97%); IR
75ꢀ
/
77 8C; IR nmax 3362 cmꢁ1. H-NMR (DMSO-d6) d
2.35 (s, 3H, CH3), 4.65 (m, 3H, CH2 and OH), 5.46 (s,
2H, CH2), 7.05 (m, 2H, 5,6-CH), 7.25 (m, 2H, Ph-H),
1
nmax 3258, 1237, 1072 cmꢁ1. H-NMR (DMSO-d6) d
0.90 (t, Jꢂ
(m, 2H, CH2), 4.99 (d, Jꢂ
/
7.00 Hz, 3H, CH3), 1.30 (m, 4H, CH2), 1.85
4.65 Hz, 1H, OH), 5.11 (m,
7.37 (m, 1H, 7-CH), 7.43 (m, 2H, Ph-H), 7.60 (d, Jꢂ
7.85 Hz, 1H, 4-CH).
/
/

Y.-M. Na et al. / European Journal of Medicinal Chemistry 38 (2003) 75ꢀ
/87
83
4.2.6.7. 1-(2,4-Diclorobenzyl)-3-(1-hydroxymethyl)-2-
methyl-1H-indole (30a). White powder (96%), m.p.
evaporated under reduced pressure and the residue was
chromatographed on silica gel.
110ꢀ
d6) d 2.32 (s, 3H, CH3), 4.67 (m, 2H, CH2), 4.72 (m, 1H,
OH), 5.46 (s, 2H, CH2), 6.17 (d, Jꢂ8.55 Hz, 1H, Ph-H),
/
112 8C; IR nmax 3258 cmꢁ1 1H-NMR (DMSO-
.
4.2.7.1. 1-(4-Chlorobenzyl)-3-(1-hydroxypropyl)-1H-
indole (23c). Yellow oil (97%); IR nmax 3386, 1263, 1078
/
7.06 (m, 2H, 5,6-CH), 7.28 (m, 2H, Ph-H and 7-CH),
7.77 (m, 2H, Ph-H and 4-CH).
cmꢁ1. 1H-NMR (DMSO-d6) d 0.88 (t, Jꢂ
/
7.00 Hz, 3H,
CH3), 1.93 (m, 2H, CH2), 4.93 (m, 1H, CH), 4.95 (d, Jꢂ
4.70 Hz, 1H, OH), 5.42 (s, 2H, CH2), 7.07 (m, 2H, 5,6-
/
CH), 7.36 (d, Jꢂ
Hz, 2H, Ph-H), 7.50 (m, 1H, 7-CH), 7.77 (d, Jꢂ
Hz, 1H, 4-CH), 7.81 (s, 1H, 2-CH).
/
8.40 Hz, 2H, Ph-H), 7.43 (d, Jꢂ
/
8.40
4.2.6.8. 5-Bromo-1-(2-fluorobenzyl)-3-(1-
hydroxymethyl)-1H-indole (31a). Yellow oil (97%); IR
/
7.60
1
nmax 3319 cmꢁ1. H-NMR (DMSO-d6) d 4.63 (d, Jꢂ
/
5.40 Hz, 2H, CH2), 4.94 (t, Jꢂ5.40 Hz, 1H, OH), 5.46
/
4.2.7.2. 1-(4-Chlorobenzyl)-3-(1-hydroxybut-3-enyl)-
1H-indole (23f). Brown oil (96%); IR nmax 3360, 1248,
(s, 2H, CH2), 7.09 (m, 1H, Ph-H), 7.18 (m, 2H, Ph-H),
?
8.90 Hz, JHF
7.26 (dd, Jꢂ
/
ꢂ/8.90 Hz, 1H, Ph-H), 7.42
1
1083 cmꢁ1. H-NMR (DMSO-d6) d 0.98 (m, 1H, CH),
(s, 1H, 2-CH), 7.48 (d, Jꢂ/8.70 Hz, 1H, 7-CH), 7.82 (d,
1.61 (d, Jꢂ
and 5.16 (d, Jcis
CH2), 5.08 (d, Jꢂ
CH2), 7.03 (dd, Jꢂ7.60 Hz, J?ꢂ
7.12 (dd, Jꢂ7.70 Hz, J?ꢂ7.05 Hz, 1H, 6-CH), 7.23 (d,
Jꢂ8.35 Hz, 2H, Ph-H), 7.40 (m, 2H, Ph-H), 7.43 (m,
1H, 7-CH), 7.51 (s, 1H, 2-CH), 7.69 (d, Jꢂ7.60 Hz, 1H,
4-CH).
/
7.10 Hz, 2H, CH2), 4.95 (m, 1H, CH), 5.00
10.60 Hz, Jtrans 17.00 Hz, 2H,
4.75 Hz, 1H, OH), 5.40 (s, 2H,
7.05 Hz, 1H, 5-CH),
Jꢂ1.80 Hz, 1H, 4-CH).
/
ꢂ
/
ꢂ
/
/
4.2.6.9. 5-Bromo-1-(4-fluorobenzyl)-3-(1-
hydroxymethyl)-1H-indole (32a). Yellow powder (95%),
/
/
/
/
1
m.p. 70ꢀ
/
73 8C; IR nmax 3358 cmꢁ1. H-NMR (DMSO-
/
d6) d 4.62 (d, Jꢂ
/
5.40 Hz, 2H, CH2), 4.89 (t, Jꢂ5.40
/
/
Hz, 1H, OH), 5.45 (s, 2H, CH2), 7.21 (m, 2H, Ph-H),
7.33 (m, 1H, 6-CH), 7.40 (s, 1H, 2-CH), 7.41 (m, 2H, Ph-
H), 7.44 (m, 1H, 7-CH), 7.78 (d, Jꢂ
CH).
/
1.50 Hz, 1H, 4-
4.2.7.3. 1-(4-Fluorobenzyl)-3-(1-hydroxyethyl)-1H-
indole (24b). Yellow oil (79%); IR nmax 3369, 1286, 1154
cmꢁ1. 1H-NMR (DMSO-d6) d 1.52 (d, Jꢂ
/
6.30 Hz, 3H,
4.60 Hz, 1H, OH), 5.03 (dd, Jꢂ6.30
4.60 Hz, 1H, CH), 5.38 (s, 2H, CH2), 7.02 (dd,
7.70 Hz, J?ꢂ7.00 Hz, 1H, 5-CH), 7.13 (dd, Jꢂ8.20
Hz, J?ꢂ7.00 Hz, 1H, 6-CH), 7.19 (m, 2H, Ph-H), 7.30
(m, 2H, Ph-H), 7.38 (s, 1H, 2-CH), 7.68 (m, 1H, 7-CH),
7.69 (d, Jꢂ7.70 Hz, 1H, 4-CH).
4.2.6.10. 5-Bromo-1-(4-chlorobenzyl)-3-(1-
hydroxymethyl)-1H-indole (33a). Yellow oil (94%); IR
CH3), 4.95 (d, Jꢂ
Hz, J?ꢂ
Jꢂ
/
/
/
1
nmax 3356 cmꢁ1. H-NMR (DMSO-d6) d 4.65 (d, Jꢂ
/
/
/
/
5.40 Hz, 2H, CH2), 4.97 (t, Jꢂ
(s, 2H, CH2), 6.74 (dd, Jꢂ7.50 Hz, J?ꢂ
Ph-H), 7.25 (m, 2H, 6-CH and Ph-H), 7.35 (s, 1H, 2-
CH), 7.40 (m, 1H, Ph-H), 7.53 (dd, Jꢂ7.80 Hz, J?ꢂ
1.50 Hz, 1H, Ph-H), 7.86 (d, Jꢂ1.80 Hz, 1H, 4-CH).
/5.40 Hz, 1H, OH), 5.51
/
/
/
1.50 Hz, 1H,
/
/
/
/
4.2.7.4. 1-(2,4-Difluorobenzyl)-3-(1-hydroxyethyl)-1H-
indole (25b). Yellow oil (73%); IR nmax 3299, 1248, 1155
cmꢁ1. 1H-NMR (DMSO-d6) d 1.51 (d, Jꢂ
/
6.40 Hz, 3H,
4.60 Hz, 1H, OH), 5.03 (m, 1H, CH),
4.2.6.11. 5-Bromo-1-(4-chlorobenzyl)-3-(1-
hydroxymethyl)-1H-indole (34a). Yellow oil (95%); IR
CH3), 4.96 (d, Jꢂ
/
1
nmax 3267 cmꢁ1. H-NMR (DMSO-d6) d 4.64 (d, Jꢂ
5.40 Hz, 2H, CH2), 4.95 (t, Jꢂ5.40 Hz, 1H, OH), 5.41
(s, 2H, CH2), 7.24 (m, 1H, 6-CH), 7.25 (d, Jꢂ8.40 Hz,
2H, Ph-H), 7.41 (d, Jꢂ8.40 Hz, 2H, Ph-H), 7.44 (m,
1H, 7-CH), 7.49 (s, 1H, 2-CH), 7.83 (d, Jꢂ
4-CH).
/
5.42 (s, 2H, CH2), 7.02 (m, 1H, 5-CH), 7.05 (m, 1H, Ph-
H), 7.10 (m, 1H, 6-CH), 7.20 (m, 2H, Ph-H), 7.31 (s, 1H,
/
/
2-CH), 7.48 (d, Jꢂ
/
7.90 Hz, 1H, 7-CH), 7.68 (m, 1H, 4-
/
CH).
/1.75 Hz, 1H,
4.2.7.5. 1-(2,4-Dichlorobenzyl)-3-(1-hydroxyethyl)-1H-
indole (26b). Yellow oil (98%); IR nmax 3358, 1259, 1095
4.2.7. General procedure for alcohols 23ꢀ
11 to 15, 17 and 18
/
27, 29, 30 from
cmꢁ1. 1H-NMR (DMSO-d6) d 1.52 (d, Jꢂ
/
6.30 Hz, 3H,
4.60 Hz, 1H, OH), 5.02 (m, 1H, CH),
5.48 (s, 2H, CH2), 6.71 (d, Jꢂ8.35 Hz, 1H, Ph-H), 7.32
(m, 2H, 5,6-CH), 7.41 (m, 1H, Ph-H), 7.45 (m, 1H, 7-
CH), 7.75 (s, 1H, 2-CH), 7.77 (d, Jꢂ8.50 Hz, 1H, Ph-
H), 7.78 (m, 1H, 4-CH).
CH3), 4.98 (d, Jꢂ
/
A solution of 11ꢀ/15, 17 or 18 in tetrahydrofuran was
/
cooled at ꢁ40 8C and then appropriate alkylmagnesium
/
halogenide (1.2 equiv.) was added dropwise over a
period of 15 min to the solution. The whole was stirred
at the same temperature. A saturated aqueous solution
of NH4Cl (400 mL) and water was added and the
resulting mixture was extracted with ethyl acetate. The
extracts were combined, washed successively with water
and brine and dried over Na2SO4. The solvent was
/
4.2.7.6. 1-(4-Fluorobenzyl)-3-(1-hydroxyethyl)-2-
methyl-1H-indole (27b). Yellow oil (96%); IR nmax 3288,
1
1269, 1160 cmꢁ1. H-NMR (DMSO-d6) d 1.50 (d, Jꢂ
/
6.30 Hz, 3H, CH3), 2.36 (s, 3H, CH3), 4.87 (d, Jꢂ4.75
/

84
Y.-M. Na et al. / European Journal of Medicinal Chemistry 38 (2003) 75ꢀ87
/
Hz, 1H, OH), 5.12 (m, 1H, CH), 5.39 (s, 2H, CH2), 6.98
(dd, J,J?ꢂ7.00 Hz, 1H, 5-CH), 7.05 (m, 1H, 6-CH),
7.07 (m, 2H, Ph-H), 7.15 (m, 2H, Ph-H), 7.38 (d, Jꢂ
7.00 Hz, 1H, 7-CH), 7.75 (d, Jꢂ7.00 Hz, 1H, 4-CH).
Hz, 1H, CH), 6.88 (s, 1H, imidazole-H), 7.00 (dd, J,J?ꢂ
7.45 Hz, 1H, 5-CH), 7.13 (dd, J,J?ꢂ7.45 Hz, 1H, 6-
CH), 7.22 (s, 1H, imidazole-H), 7.25 (d, Jꢂ8.40 Hz,
2H, Ph-H), 7.42 (d, Jꢂ8.40 Hz, 2H, Ph-H), 7.41 (m,
/
/
/
/
/
/
/
1H, 7-CH), 7.44 (m, 1H, 4-CH), 7.73 (s, 1H, 2-CH), 7.85
(s, 1H, imidazole-H). Anal. C21H20ClN3 (C, H, N).
4.2.7.7. 1-(4-Bromobenzyl)-3-(1-hydroxyethyl)-2-
methyl-1H-indole (29b). Yellow oil (96%); IR nmax 3287,
1259, 1088 cmꢁ1. H-NMR (DMSO-d6) d 1.50 (d, Jꢂ
6.20 Hz, 3H, CH3), 2.35 (s, 3H, CH3), 4.88 (d, Jꢂ4.70
Hz, 1H, OH), 5.12 (m, 1H, CH), 5.56 (s, 2H, CH2), 6.99
(m, 2H, 5,6-CH), 7.01 (m, 2H, Ph-H), 7.35 (d, Jꢂ7.90
Hz, 1H, 7-CH), 7.52 (d, Jꢂ8.00 Hz, 1H, Ph-H), 7.75 (d,
Jꢂ7.00 Hz, 1H, 4-CH).
/
4.2.8.4. 1-(4-Chlorobenzyl)-3-[1-(1H-imidazol-1-
yl)butyl]-1H-indole (35d). IR nmax 1636, 1312 cmꢁ1
.
1
/
1H-NMR (DMSO-d6) d 0.98 (t, Jꢂ
1.27 (m, 2H, CH2), 2.28 (t, Jꢂ7.45 Hz, 2H, CH2), 5.47
(s, 2H, CH2), 5.68 (t, Jꢂ7.60 Hz, 1H, CH), 6.89 (s, 1H,
imidazole-H), 7.03 (dd, Jꢂ7.40 Hz, J?ꢂ7.35 Hz, 1H, 5-
CH), 7.14 (dd, J,J?ꢂ7.35 Hz, 1H, 6-CH), 7.24 (s, 1H,
imidazole-H), 7.27 (d, Jꢂ8.40 Hz, 2H, Ph-H), 7.43 (d,
Jꢂ8.40 Hz, 2H, Ph-H), 7.45 (m, 1H, 7-CH), 7.49 (m,
/7.25 Hz, 3H, CH3),
/
/
/
/
/
/
/
/
4.2.7.8. 1-(2,4-Dichlorobenzyl)-3-(1-hydroxyethyl)-2-
/
methyl-1H-indole (30b). White powder (84%), m.p.
/
107ꢀ
NMR (DMSO-d6) d 1.53 (d, Jꢂ
2.31 (s, 3H, CH3), 4.93 (d, Jꢂ4.65 Hz, 1H, OH), 5.15
/
108 8C; IR nmax 3179, 1237, 1094 cmꢁ1
.
1H-
1H, 4-CH), 7.76 (s, 1H, 2-CH), 7.88 (s, 1H, imidazole-
H). Anal. C22H22ClN3 (C, H, N).
/5.80 Hz, 3H, CH3),
/
(m, 1H, CH), 5.43 (s, 2H, CH2), 7.02 (m, 2H, 5,6-CH),
7.28 (m, 3H, Ph-H and 7-CH), 7.77 (m, 2H, Ph-H and 4-
CH).
4.2.8.5. 1-(4-Chlorobenzyl)-3-[1-(1H-imidazol-1-yl)-2-
methylpropyl]-1H-indole (35e). IR nmax 1653, 1305
1
cmꢁ1. H-NMR (DMSO-d6) d 0.80 and 0.99 (d, Jꢂ
/
6.10 Hz, 6H, CH3), 2.71 (m, 1H, CH), 5.45 (s, 2H, CH2),
6.29 (d, Jꢂ10.00 Hz, 1H, CH), 6.86 (s, 1H, imidazole-
H), 7.09 (m, 2H, 5,6-CH), 7.23 (d, Jꢂ8.20 Hz, 2H, Ph-
H), 7.28 (s, 1H, imidazole-H), 7.41 (d, Jꢂ8.20 Hz, 2H,
Ph-H), 7.43 (m, 1H, 7-CH), 7.67 (d, Jꢂ7.65 Hz, 1H, 4-
4.2.8. General procedure for the preparation of 3-
/
imidazolylmethylindole derivatives 35ꢀ
/
46
/
To a solution of 23ꢀ34 in anhydrous tetrahydrofuran
/
/
(20 mL), 1,1?-carbonydiimidazole (1.2 equiv.) was
added. The reaction mixture was refluxed with stirring
for 5 h. The mixture was extracted with CH2Cl2 and the
organic layer was washed with brine, dried over Na2SO4
and evaporated under vacuum. The residue was chro-
matographed with CH2Cl2: EtOH (20: 1).
/
CH), 7.83 (s, 1H, 2-CH), 7.86 (s, 1H, imidazole-H).
Anal. C22H22ClN3 (C, H, N).
4.2.8.6. 1-(4-Chlorobenzyl)-3-[1-(1H-imidazol-1-
yl)but-3-enyl]-1H-indole (35f). IR nmax 1643, 1303
.
cmꢁ1 1H-NMR (DMSO-d6) d 2.74 (m, 2H, CH2),
4.2.8.1. 1-(4-Chlorobenzyl)-3-(1H-imidazol-1-
ylmethyl)-1H-indole (35a). IR nmax 1621, 1297 cmꢁ1
3.04 (m, 1H, CH), 5.05 and 5.15 (d, Jcis
Jtrans 17.20 Hz, 2H, CH2), 5.45 (s, 2H, CH2), 5.74 (m,
1H, CH), 6.86 (s, 1H, imidazole-H), 7.01 (dd, J,J?ꢂ7.35
Hz, 1H, 5-CH), 7.15 (m, 1H, 6-CH), 7.24 (s, 1H,
imidazole-H), 7.26 (d, Jꢂ8.50 Hz, 2H, Ph-H), 7.42 (d,
Jꢂ8.50 Hz, 2H, Ph-H), 7.44 (m, 2H, 4,7-CH), 7.76 (s,
ꢂ
/
10.20 Hz,
.
ꢂ
/
1H-NMR (DMSO-d6) d 5.36 (s, 2H, CH2), 5.45 (s, 2H,
CH2), 6.88 (s, 1H, imidazole-H), 7.10 (m, 2H, 5,6-CH),
/
7.20 (s, 1H, imidazole-H), 7.25 (d, Jꢂ
H), 7.41 (m, Jꢂ8.30 Hz, 2H, Ph-H), 7.47 (m, 1H, 7-
CH), 7.59 (d, Jꢂ7.55 Hz, 1H, 4-CH), 7.63 (s, 1H, 2-
/8.30 Hz, 2H, Ph-
/
/
/
/
1H, 2-CH), 7.84 (s, 1H, imidazole-H). Anal.
C22H20ClN3 (C, H, N).
CH), 7.79 (s, 1H, imidazole-H). Anal. C19H16ClN3 (C,
H, N).
4.2.8.7. 1-(4-Chlorobenzyl)-3-[1-(1H-imidazol-1-
4.2.8.2. 1-(4-Chlorobenzyl)-3-[1-(1H-imidazol-1-
yl)ethyl]-1H-indole (35b). IR nmax 1631, 1326 cmꢁ1
yl)pentyl]-1H-indole (35g). IR nmax 1655, 1295 cmꢁ1
.
.
1H-NMR (DMSO-d6) d 0.89 (t, Jꢂ
1.22 (m, 4H, CH2), 2.28 (m, 2H, CH2), 5.45 (s, 2H,
CH2), 5.63 (t, Jꢂ7.35 Hz, 1H, CH), 6.87 (s, 1H,
imidazole-H), 7.00 (dd, J,J?ꢂ7.40 Hz, 1H, 5-CH),
7.12 (dd, J,J?ꢂ7.40 Hz, 1H, 6-CH), 7.22 (s, 1H,
imidazole-H), 7.25 (d, Jꢂ8.50 Hz, 2H, Ph-H), 7.40 (d,
Jꢂ7.40 Hz, 1H, 4-CH), 7.41 (d, Jꢂ8.50 Hz, 2H, Ph-
H), 7.43 (d, Jꢂ7.40 Hz, 1H, 7-CH), 7.74 (s, 1H, 2-CH),
/6.70 Hz, 3H, CH3),
1H-NMR (DMSO-d6) d 1.89 (d, Jꢂ
7.00 Hz, 3H, CH3),
/
5.44 (s, 2H, CH2), 5.88 (m, 1H, CH), 6.92 (s, 1H,
imidazole-H), 6.99 (m, 2H, 5,6-CH), 7.27 (s, 1H,
imidazole-H), 7.26 (m, 2H, Ph-H), 7.42 (m, 2H, Ph-H),
7.45 (m, 1H, 7-CH), 7.68 (m, 2H, 2,4-CH), 7.87 (s, 1H,
imidazole-H). Anal. C20H18ClN3 (C, H, N).
/
/
/
/
/
/
/
4.2.8.3. 1-(4-Chlorobenzyl)-3-[1-(1H-imidazol-1-
yl)propyl]-1H-indole (35c). IR nmax 1652, 1290 cmꢁ1
7.86 (s, 1H, imidazole-H). Anal. C23H24ClN3 (C, H, N).
.
7.20 Hz, 3H, CH3),
7.40
1H-NMR (DMSO-d6) d 0.88 (t, Jꢂ
2.32 (m, 2H, CH2), 5.45 (s, 2H, CH2), 5.55 (t, Jꢂ
/
4.2.8.8. 1-(4-Chlorobenzyl)-3-[1-(1H-imidazol-1-yl)-
2,2-dimethylpropyl]-1H-indole (35h). IR nmax 1636,
/

Y.-M. Na et al. / European Journal of Medicinal Chemistry 38 (2003) 75ꢀ
/87
85
1
1323 cmꢁ1. H-NMR (DMSO-d6) d 1.02 (s, 9H, CH3),
CH), 7.83 (s, 1H, imidazole-H). Anal. C19H15Cl2N3 (C,
H, N).
5.47 (s, 2H, CH2), 5.64 (s, 1H, CH), 6.88 (s, 1H,
imidazole-H), 7.09 (m, 2H, 5,6-CH), 7.10 (s, 1H,
imidazole-H), 7.26 (d, Jꢂ
Jꢂ8.25 Hz, 2H, Ph-H), 7.42 (m, 1H, 7-CH), 7.74 (d,
Jꢂ7.55 Hz, 1H, 4-CH), 7.88 (s, 1H, imidazole-H), 8.08
/
8.25 Hz, 2H, Ph-H), 7.41 (d,
4.2.8.14. 1-(2,4-Dichlorobenzyl)-3-[1-(1H-imidazol-1-
/
yl)ethyl]-1H-indole (38b). IR nmax 1663, 1368 cmꢁ1
.
/
1H-NMR (DMSO-d6) d 1.88 (d, Jꢂ
5.54 (s, 2H, CH2), 5.89 (q, Jꢂ6.70 Hz, 1H, CH), 6.37
(d, Jꢂ8.30 Hz, 1H, Ph-H), 6.88 (s, 1H, imidazole-H),
7.03 (dd, J,J?ꢂ7.70 Hz, 1H, 5-CH), 7.15 (dd, J,J?ꢂ
7.70 Hz, 1H, 6-CH), 7.22 (s, 1H, imidazole-H), 7.38 (m,
2H, 4,7-CH), 7.39 (d, Jꢂ8.30 Hz, 1H, Ph-H), 7.63 (s,
1H, 2-CH), 7.74 (d, Jꢂ2.10 Hz, 1H, Ph-H), 7.82 (s, 1H,
/6.70 Hz, 3H, CH3),
(s, 1H, 2-CH). Anal. C23H24ClN3 (C, H, N).
/
/
/
/
4.2.8.9. 1-(4-Fluorobenzyl)-3-(1H-imidazol-1-
ylmethyl)-1H-indole (36a). IR nmax 1646, 1362 cmꢁ1
.
1H-NMR (DMSO-d6) d 5.36 (s, 2H, CH2), 5.43 (s, 2H,
CH2), 6.88 (s, 1H, imidazole-H), 7.11 (m, 1H, 5-CH),
7.11 (m, 4H, 6-CH, Ph-H, imidazole-H), 7.30 (m, 2H,
/
/
imidazole-H). Anal. C20H17Cl2N3 (C, H, N).
Ph-H), 7.50 (d, Jꢂ
Hz, 1H, 4-CH), 7.63 (s, 1H, 2-CH), 7.82 (s, 1H,
imidazole-H). Anal. C19H16FN3 (C, H, N).
/
8.10 Hz, 1H, 7-CH), 7.59 (d, Jꢂ7.59
/
4.2.8.15. 1-(4-Fluorobenzyl)-3-(1H-imidazol-1-
ylmethyl)-2-methyl-1H-indole (39a). IR nmax 1662, 1290
1
cmꢁ1. H-NMR (DMSO-d6) d 2.48 (s, 3H, CH3), 5.36
(s, 2H, CH2), 5.45 (s, 1H, CH2), 6.85 (s, 1H, imidazole-
H), 7.05 (m, 2H, 5,6-CH), 7.15 (m, 4H, Ph-H), 7.12 (s,
4.2.8.10. 1-(4-Fluorobenzyl)-3-[1-(1H-imidazol-1-
1
yl)ethyl]-1H-indole (36b). IR nmax 1638, 1285mꢁ1. H-
1H, imidazole-H), 7.43 (d, Jꢂ
(d, Jꢂ7.30 Hz, 1H, 4-CH), 7.75 (s, 1H, imidazole-H).
Anal. C20H18FN3 (C, H, N).
/
7.63 Hz, 1H, 7-CH), 7.58
NMR (DMSO-d6) d 1.89 (d, Jꢂ
4.77 (m, 1H, CH), 5.43 (s, 2H, CH2), 6.89 (s, 1H,
imidazole-H), 6.99 (dd, J,J?ꢂ7.30 Hz, 1H, 5-CH), 7.13
(dd, Jꢂ7.80 Hz, J?ꢂ7.30 Hz, 1H, 6-CH), 7.14 (s, 1H,
imidazole-H), 7.20 (d, Jꢂ8.50 Hz, 2H, Ph-H), 7.32 (m,
/6.90 Hz, 3H, CH3),
/
/
/
/
4.2.8.16. 1-(4-Fluorobenzyl)-3-[1-(1H-imidazol-1-
yl)ethyl]-2-methyl-1H-indole (39b). IR nmax 1649, 1308
/
3H, Ph-H and 7-CH), 7.46 (m, 1H, 4-CH), 7.69 (s, 1H,
2-CH), 7.83 (s, 1H, imidazole-H). Anal. C20H18FN3 (C,
H, N).
cmꢁ1. 1H-NMR (DMSO-d6) d 1.98 (d, Jꢂ
/
7.30 Hz, 3H,
CH3), 2.42 (s, 3H, CH3), 5.44 (s, 2H, CH2), 5.78 (q, Jꢂ
7.30 Hz, 1H, CH), 6.89 (s, 1H, imidazole-H), 7.02 (m,
2H, 5,6-CH), 7.08 (m, 2H, Ph-H), 7.13 (d, Jꢂ8.60 Hz,
2H, Ph-H), 7.20 (s, 1H, imidazole-H), 7.42 (d, Jꢂ7.30
Hz, 1H, 7-CH), 7.46 (d, Jꢂ7.00 Hz, 1H, 4-CH), 7.76 (s,
/
/
4.2.8.11. 1-(2,4-Difluorobenzyl)-3-(1H-imidazol-1-
/
ylmethyl)-1H-indole (37a). IR nmax 1618, 1333 cmꢁ1
.
/
1H-NMR (DMSO-d6) d 5.36 (s, 2H, CH2), 5.47 (s, 2H,
CH2), 6.89 (s, 1H, imidazole-H), 7.08 (m, 2H, 5,6-CH),
7.19 (m, 2H, 7-CH, Ph-H), 7.20 (s, 1H, imidazole-H),
1H, imidazole-H). Anal. C21H20FN3 (C, H, N).
4.2.8.17. 1-(4-Chlorobenzyl)-3-(1H-imidazol-1-
ylmethyl)-2-methyl-1H-indole (40a). IR nmax 1649, 1334
7.32 (t, Jꢂ
/
9.00 Hz, 1H, Ph-H), 7.53 (d, Jꢂ/8.15 Hz,
1H, Ph-H), 7.58 (s, 1H, 2-CH), 7.60 (d, Jꢂ/7.35 Hz, 1H,
1
cmꢁ1. H-NMR (DMSO-d6) d 2.46 (s, 3H, CH3), 5.36
4-CH), 7.82 (s, 1H, imidazole-H). Anal. C19H15F2N3 (C,
H, N).
(s, 2H, CH2), 5.46 (s, 2H, CH2), 6.86 (s, 1H, imidazole-
H), 7.08 (m, 4H, 5,6-CH, Ph-H), 7.04 (s, 1H, imidazole-
H), 7.38 (d, Jꢂ
Ph-H), 7.58 (d, Jꢂ
imidazole-H). Anal. C20H18ClN3 (C, H, N).
/
8.00 Hz, 2H, Ph-H), 7.38 (m, 2H, 7-CH,
7.10 Hz, 1H, 4-CH), 7.75 (s, 1H,
4.2.8.12. 1-(2,4-Difluorobenzyl)-3-[1-(1H-imidazol-1-
yl)ethyl]-1H-indole (37b). IR nmax 1650, 1299 cmꢁ1
/
.
1H-NMR (DMSO-d6) d 1.88 (d, Jꢂ
5.48 (s, 2H, CH2), 5.84 (q, Jꢂ7.00 Hz, 1H, CH), 7.10
/
7.00 Hz, 3H, CH3),
/
4.2.8.18. 1-(4-Bromobenzyl)-3-[1-(1H-imidazol-1-
yl)ethyl]-2-methyl-1H-indole (41b). IR nmax 1628, 1352
cmꢁ1. 1H-NMR (DMSO-d6) d 1.97 (d, Jꢂ
7.00 Hz, 3H,
CH3), 2.40 (s, 3H, CH3), 5.43 (s, 2H, CH2), 5.76 (m, 1H,
CH), 6.88 (s, 1H, imidazole-H), 6.96 (m, 1H, 5-CH),
(m, 1H, Ph-H), 6.87 (s, 1H, imidazole-H), 7.00 (m, 1H,
5-CH), 7.18 (m, 1H, 6-CH), 7.19 (s, 1H, imidazole-H),
7.30 (m, 1H, Ph-H), 7.35 (m, 1H, Ph-H), 7.37 (m, 1H, 7-
/
CH), 7.49 (d, Jꢂ8.20 Hz, 1H, 4-CH), 7.62 (s, 1H, 2-
/
CH), 7.80 (s, 1H, imidazole-H). Anal. C20H17F2N3 (C,
H, N).
6.97 (d, Jꢂ
7.21 (s, 1H, imidazole-H), 7.41 (m, 1H, 7-CH), 7.44 (m,
1H, 4-CH), 7.53 (d, Jꢂ8.20 Hz, 2H, Ph-H), 7.76 (s, 1H,
/
8.20 Hz, 2H, Ph-H), 7.07 (m, 1H, 6-CH),
/
4.2.8.13. 1-(2,4-Dichlorobenzyl)-3-(1H-imidazol-1-
ylmethyl)-1H-indole (38a). IR nmax 1639, 1292 cmꢁ1
imidazole-H). Anal. C21H20BrN3 (C, H, N).
.
1H-NMR (DMSO-d6) d 5.38 (s, 2H, CH2), 5.52 (s, 2H,
CH2), 6.80 (s, 1H, imidazole-H), 6.90 (m, 1H, Ph-H),
7.16 (m, 2H, 5,6-CH), 7.20 (s, 1H, imidazole-H), 7.40
(m, 2H, Ph-H), 7.60 (m, 1H, 4,7-CH), 7.77 (s, 1H, 2-
4.2.8.19. 1-(2,4-Dichlorobenzyl)-3-(1H-imidazol-1-
ylmethyl)-2-methyl-1H-indole (42a). IR nmax 1660, 1320
1
cmꢁ1. H-NMR (DMSO-d6) d 2.43 (s, 3H, CH3), 5.39
(s, 2H, CH2), 5.49 (s, 2H, CH2), 6.18 (d, Jꢂ8.25 Hz,
/

86
Y.-M. Na et al. / European Journal of Medicinal Chemistry 38 (2003) 75ꢀ87
/
1H, Ph-H), 6.87 (s, 1H, imidazole-H), 7.08 (m, 2H, 5,6-
CH), 7.14 (s, 1H, imidazole-H), 7.31 (dd, Jꢂ8.25 Hz,
J?ꢂ2.00 Hz, 1H, 7-CH), 7.33 (dd, Jꢂ7.30 Hz, J?ꢂ
1.85 Hz, 1H, 4-CH), 7.61 (m, 1H, Ph-H), 7.76 (d, Jꢂ
4.2.8.25. 5-Bromo-1-(4-chlorobenzyl)-3-[1-(1H-
imidazol-1-yl)butyl]-1H-indole (46d). IR nmax 1644,
/
1
/
/
/
1329 cmꢁ1. H-NMR (DMSO-d6) d 0.95 (t, Jꢂ
/7.00
/
Hz, 3H, CH3), 1.22 (m, 2H, CH2), 2.22 (t, Jꢂ
/7.00 Hz,
2.15 Hz, 1H, Ph-H), 7.77 (s, 1H, imidazole-H). Anal.
C20H17Cl2N3 (C, H, N).
2H, CH2), 5.37 (m, 1H, CH), 5.45 (s, 2H, CH2), 6.89 (s,
1H, imidazole-H), 7.21 (m, 4H, Ph-H), 7.40 (s, 1H,
imidazole-H), 7.43 (m, 2H, 6,7-CH), 7.66 (s, 1H, 4-CH),
7.84 (s, 1H, 2-CH), 7.90 (s, 1H, imidazole-H). Anal.
C22H21BrClN3 (C, H, N).
4.2.8.20. 1-(2,4-Dichlorobenzyl)-3-[1-(1H-imidazol-1-
yl)ethyl]-2-methyl-1H-indole (42b). IR nmax 1646, 1291
cmꢁ1. 1H-NMR (DMSO-d6) d 2.00 (d, Jꢂ
/
7.00 Hz, 3H,
CH3), 2.86 (s, 3H, CH3), 5.48 (s, 2H, CH2), 5.80 (q, Jꢂ
7.00 Hz, 1H, CH), 6.19 (d, Jꢂ8.20 Hz, 1H, Ph-H), 6.90
(s, 1H, imidazole-H), 7.01 (dd, Jꢂ7.90 Hz, J?ꢂ7.00
Hz, 1H, 5-CH), 7.10 (dd, Jꢂ7.60 Hz, J?ꢂ7.00 Hz, 1H,
6-CH), 7.24 (s, 1H, imidazole-H), 7.33 (m, 1H, Ph-H),
7.47 (d, Jꢂ7.60 Hz, 1H, 7-CH), 7.77 (d, Jꢂ7.90 Hz,
1H, 4-CH), 7.75 (d, Jꢂ1.80 Hz, 1H, Ph-H), 7.78 (s, 1H,
/
4.2.8.26. 5-Bromo-1-(4-chlorobenzyl)-3-[1-(1H-
/
imidazol-1-yl)pentyl]-1H-indole (46g). IR nmax 1640,
1
7.00
/
/
1311 cmꢁ1. H-NMR (DMSO-d6) d 0.88 (t, Jꢂ
/
/
/
Hz, 3H, CH3), 1.31 (m, 4H, CH2), 2.25 (t, Jꢂ
/7.30 Hz,
2H, CH2), 5.45 (s, 2H, CH2), 5.48 (m, 1H, CH), 6.89 (s,
1H, imidazole-H), 7.25 (m, 4H, Ph-H), 7.40 (s, 1H,
imidazole-H), 7.43 (m, 2H, 6,7-CH), 7.66 (s, 1H, 4-CH),
7.84 (s, 1H, 2-CH), 7.90 (s, 1H, imidazole-H). Anal.
C23H23BrClN3 (C, H, N).
/
/
/
imidazole-H). Anal. C21H19Cl2N3 (C, H, N).
4.2.8.21. 5-Bromo-1-(2-fluorobenzyl)-3-(1H-imidazol-1-
ylmethyl]-1H-indole (43a). IR nmax 1599, 1324 cmꢁ1
1H-NMR (DMSO-d6) d 5.35 (s, 2H, CH2), 5.50 (s, 2H,
CH2), 6.88 (s, 1H, imidazole-H), 7.14 (s, 1H, imidazole-
.
4.2.9. General procedure for preparation of fumarate and
nitrate salts
Fumarate (35b, 35d, 35f, 35g, 36b, 38b, 46d, 46g): The
obtained 3-imidazolymethylindole derivative was dis-
solved in ethanol and a solution of fumaric acid (1
equiv.) in ethanol was added. The mixture was stirred
for 5 h. After removal of ethanol under reduced
pressure, a small amount of ether and then hexane
were added to afford white crystals which were collected
by filtration and recrystallised from ethyl acetate and
hexane mixture.
Nitrate (35c, 35f, 37b, 42b): The obtained 3-imidazo-
lymethylindole derivative was dissolved in ether and
nitric acid (1 equiv.) in ethanol was dropped slowly. The
mixture was stirred for 30 min. The crystals were
collected by filtration.
H), 7.22 (m, 5H, 6-CH, Ph-H), 7.50 (d, Jꢂ8.75 Hz, 1H,
/
7-CH), 7.65 (s, 1H, 2-CH), 7.81 (s, 1H, 4-CH), 7.81 (s,
1H, imidazole-H). Anal. C19H15BrFN3 (C, H, N).
4.2.8.22. 5-Bromo-1-(4-fluorobenzyl)-3-(1H-imidazol-1-
ylmethyl]-1H-indole (44a). IR nmax 1660, 1326 cmꢁ1
.
1H-NMR (DMSO-d6) d 5.34 (s, 2H, CH2), 5.43 (s, 2H,
CH2), 6.89 (s, 1H, imidazole-H), 7.17 (d, Jꢂ8.75 Hz,
1H, 6-CH), 7.20 (s, 1H, imidazole-H), 7.20 (m, 2H, Ph-
H), 7.28 (d, Jꢂ8.90, JHF 5.50 Hz, 2H, Ph-H), 7.49 (d,
Jꢂ8.75 Hz, 1H, 7-CH), 7.70 (s, 1H, 2-CH), 7.81 (s, 1H,
/
/
ꢂ
/
/
4-CH), 7.81 (s, 1H, imidazole-H). Anal. C19H15BrFN3
(C, H, N).
4.2.8.23. 5-Bromo-1-(2-chlorobenzyl)-3-(1H-imidazol-
1-ylmethyl]-1H-indole (45a). IR nmax 1623, 1353 cmꢁ1
4.3. Pharmacology
.
1H-NMR (DMSO-d6) d 5.36 (s, 2H, CH2), 5.54 (s, 2H,
CH2), 6.79 (d, Jꢂ7.60 Hz, Ph-H), 6.88 (s, 1H,
imidazole-H), 7.19 (s, 1H, imidazole-H), 7.30 (m, 3H,
6-CH, Ph-H), 7.34 (d, Jꢂ7.60, 1H, Ph-H), 7.43 (d, Jꢂ
8.75 Hz, 1H, 7-CH), 7.70 (s, 1H, 2-CH), 7.82 (s, 1H, 4-
CH), 7.82 (s, 1H, imidazole-H). Anal. C19H15BrClN3
(C, H, N).
4.3.1. Anti-Candida in vitro activity
/
C. albicans (CA980001) suspension was prepared in
RPMI 1640 medium supplemented with 0.165 M
morpholinopropanesulphonic acid (MOPS, Sigma), 2%
glucose and antibiotics (medium A) and adjusted to give
a final concentration of 103 cells mLꢁ1. A 96-well
microplate (Nunc, Polylabo, Strasbourg, France) was
seeded with 100 mL of Candida suspension. Molecules
were first dissolved in dimethylsulfoxide and then
diluted in medium A. Each concentration of molecule
(100 mL) to be tested was added (in triplicate) and plates
were incubated at 37 8C for 24 h. The cellular viability
was evaluated on the Fluorolite 1000 (Dynatech) with
an excitation at 550 nm and an emission at 590 nm after
a 4 h incubation with 10 mL of alamar Blue† (Interchim,
/
/
4.2.8.24. 5-Bromo-1-(4-chlorobenzyl)-3-(1H-imidazol-
1-ylmethyl)-1H-indole (46a). IR nmax 1639, 1295 cmꢁ1
.
1H-NMR (DMSO-d6) d 5.36 (s, 2H, CH2), 5.44 (s, 2H,
CH2), 6.91 (s, 1H, imidazole-H), 7.22 (s, 1H, imidazole-
H), 7.29 (d, Jꢂ
Hz, 1H, Ph-H), 7.41 (d, Jꢂ
Jꢂ8.80 Hz, 1H, 7-CH), 7.70 (s, 1H, 2-CH), 7.82 (s, 1H,
/
8.80 Hz, 1H, 6-CH), 7.33 (d, Jꢂ
/
8.55
/
8.55 Hz, 1H, Ph-H), 7.47 (d,
/
imidazole-H) 7.83 (s, 1H, 4-CH). Anal. C19H15BrClN3
(C, H, N).
Montlucon, France) [25]. The minimal inhibitory con-
¸
centration (MIC) is the concentration that inhibited 80

Y.-M. Na et al. / European Journal of Medicinal Chemistry 38 (2003) 75ꢀ
/87
87
[4] E.M. Johnson, J.O. Ojwang, A. Szekely, T.L. Wallace, D.W.
Warnock, Antimicrob. Agents Chemother. 42 (1998) 1412ꢀ
1416.
and 90% of the cell growth for azoles and amphotericin
B, respectively; MICs were determined by linear regres-
sion analysis and expressed as the mean of the triplicate
values.
/
[5] W.W. Turner, M.J. Rodriguez, Curr. Pharmaceut. Des. 2 (1996)
209ꢀ/224.
[6] G.P. Bodey, Clin. Infect. Dis. 14 (1992) S161ꢀ
/
S169.
[7] R. Grillot, Les Mycoses Humaines: De´marche Diagnostique,
Editions Scientifiques et Me´dicales Ed. Elsevier, Paris, 1996.
[8] J. Heeres, L.J.J. Backx, J.H. Mostmans, J.V. Cutsem, J. Med.
4.3.2. Anti-Aspergillus in vitro activity
Conidia of A. fumigatus (AF980003) were microsco-
pically counted and diluted in medium A. One hundred
microliters of a 104 cells mLꢁ1 suspension were
inoculated in a 96-well microplate (Nunc). In order to
use the hyphal forms of A. fumigatus, conidia were
incubated for 4 h at 37 8C. Drugs were diluted in the
same medium and 100 mL of the drug dilutions were
added to the cell suspension. After an incubation time of
48 h at 37 8C, the cellular viability was evaluated as in
Candida assay [25]. Activity of the studied and reference
molecules was expressed as the MIC.
Chem. 22 (1979) 1003ꢀ
[9] J.N. Galgiani, M.L. Lewis, Antimicrob. Agents Chemother. 41
(1997) 180ꢀ183.
/1005.
/
[10] J.H. Rex, P.W. Nelson, V.L. Paetznick, M. Lozano-Chiu, A.
Espinel-Ingroff, E.J. Anaissie, Antimicrob. Agents Chemother. 42
(1998) 129ꢀ134.
/
[11] A. Louie, G.L. Drusano, P. Banerjee, Q. Liu, W. Liu, P. Kaw, M.
Shayegani, H. Taber, M.H. Miller, Antimicrob. Agents Che-
mother. 42 (1998) 1105ꢀ
[12] R.A. Fromtling, J. Castaner, Drugs Fut. 22 (1997) 326ꢀ
[13] V. Cavrini, R. Gatti, P. Roveri, M.R. Cesaroni, Arch. Pharm. 317
(1984) 662ꢀ668.
[14] R. Gatti, V. Cavrini, P. Roveri, G. Luglio, Arch. Pharm. 318
(1985) 157ꢀ160.
[15] L.M. Levy, G.M. Cabrera, J.E. Wright, A.M. Seldes, Phytochem-
istry 54 (2000) 941ꢀ943.
[16] H. Sugiyama, F. Yokokawa, T. Aoyama, T. Shioiri, Tetrahedron
Lett. 42 (2001) 7277ꢀ7280.
[17] V.C.O. Njar, Synthesis (2000) 2019ꢀ
[18] J. Bergman, Acta Chem. Scand. 22 (1968) 1063ꢀ
[19] J. Bergman, J.E. Backvau, Tetrahedron 31 (1975) 2063ꢀ
/
1109.
/327.
/
/
Acknowledgements
/
This research was financially supported by YangJi
Chemical Company, Ansan, South of Korea.
/
/2028.
/1066.
/2073.
¨
References
[20] Y. Ito, K. Kobayashi, T. Saegosat, J. Org. Chem. 44 (1979) 2030ꢀ
/
2032.
[21] T. Sakamoto, T. Nagano, Y. Kondo, H. Yamanaka, Synthesis
[1] N.H. Georgopapadakou, T.J. Walsh, Antimicrob. Agents Che-
(1990) 215ꢀ
/
218.
mother. 40 (1996) 279ꢀ
/291.
[22] D.M. Ketcha, G.W. Gribble, J. Org. Chem. 50 (1985) 5451ꢀ
/
[2] E. Mutschler, H. Derendorf, Drug Actions*/Basic Principles and
5457.
[23] C.X. Yang, H.H. Patel, Y.Y. Ku, R. Shah, D. Savick, Synth.
Therapeutic Aspects, Medpharm Scientific Publishers, Stuttgart,
1995.
[3] J.E. Bennett, G.L. Mandell, R.G. Douglas, Principles and
Practice of Infections Diseases, vol. 1, third ed, Churchill
Livingstone, New York, 1990.
Commun. 27 (1997) 2125ꢀ
[24] P.N. James, H.R. Snyder, Org. Synth. 39 (1959) 30ꢀ
[25] F. Pagniez, P. Le Pape, J. Mycol. Med. 11 (2001) 73ꢀ
/
2132.
/
33.
78.
/