Design of new antifungal agents: synthesis and evaluation of 1-[(1H-indol-5-ylmethyl)amino]-2-phenyl-3-(1H-1,2,4-triazol-1-yl)propan- 2-ols

Article abstract of DOI:10.1016/j.bmcl.2009.08.089

We previously reported on the design and synthesis of 1-[((hetero)aryl- or piperidinylmethyl)amino]-2-phenyl-3-(1H-1,2,4-triazol-1-yl)propan-2-ols showing various degrees of antifungal activity against Candida albicans and Aspergillus fumigatus strains. N

Full text of DOI:10.1016/j.bmcl.2009.08.089

Bioorganic & Medicinal Chemistry Letters 19 (2009) 5833–5836
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design of new antifungal agents: synthesis and evaluation of
1-[(1H-indol-5-ylmethyl)amino]-2-phenyl-3-(1H-1,2,4-triazol-1-yl)propan-2-ols
a
b
Rémi Guillon a, Francis Giraud a, Cédric Logé a, , Marc Le Borgne , Carine Picot ,
*
Fabrice Pagniez b, Patrice Le Pape b
a Université de Nantes, Nantes Atlantique Universités, Département de Pharmacochimie, Cibles et Médicaments des Infections, de l’Immunité et du Cancer, IICIMED-EA 1155,
UFR Sciences Pharmaceutiques, 1 rue Gaston Veil, Nantes F-44035 Cedex 1, France
b Université de Nantes, Nantes Atlantique Universités, Département de Parasitologie et Mycologie Médicale, Cibles et Médicaments des Infections, de l’Immunité et du Cancer,
IICIMED-EA 1155, UFR Sciences Pharmaceutiques, 1 rue Gaston Veil, Nantes F-44035 Cedex 1, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 July 2009
Revised 26 August 2009
Accepted 26 August 2009
Available online 31 August 2009
We previously reported on the design and synthesis of 1-[((hetero)aryl- or piperidinylmethyl)amino]-2-
phenyl-3-(1H-1,2,4-triazol-1-yl)propan-2-ols showing various degrees of antifungal activity against
Candida albicans and Aspergillus fumigatus strains. Now we have identified a series of 1-[(1H-indol-5-
ylmethyl)amino] derivatives which exhibited potent MICs (<65 ng mLꢀ1) against C. albicans strain. The
synthesis and SAR behind the indole scaffold will be discussed.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Azoles
Candida albicans
CYP51 inhibitors
Antifungal agents
SAR studies
The growing population of immunocompromised hosts
(patients suffering from AIDS or chemotherapy-induced neutrope-
nia or transplant recipients receiving immunosuppressive therapy)
has led to an increased incidence of invasive and systemic fungal
infections due mainly to Candida and Aspergillus species which
are the most common pathogens.1 Among the current therapies
used in clinics, azoles (the most widely studied class of antifungal
agents) target the biosynthesis of ergosterol, a major component of
fungal membranes (thereby preventing fungal growth), by inhibit-
active compounds with MIC80 values of 0.6 and 0.37 ng mLꢀ1 on
C. albicans, respectively. These results confirmed several molecular
modeling studies highlighting the importance of hydrogen bond-
ing,
p–p stacking and hydrophobic interactions between azole
inhibitors and the active site of CYP51-C. albicans.3–6 Compared
to their pyridinyl- and piperidinylmethylamine analogues, these
compounds also exhibited an emergence of activity on A. fumigatus
strain with MIC80 of 1.96 and 2.41 l
g mLꢀ1, respectively.2
In this Letter, we describe the design, synthesis and evaluation
of 1-[(1H-indol-5-ylmethyl)amino] derivatives (I, Fig. 1). From a
synthetic point of view, these indole-based structures are easily
prepared and should keep integrality of the above characteristics
depending upon appropriate substituents.
ing mainly the cytochrome P450-dependent lanosterol 14a-
demethylase (CYP51), encoded by the ERG11 gene. Most azoles
are orally active, show a broad-spectrum against most yeasts and
filamentous fungi, and are relatively nontoxic. However, increased
use of these compounds has likely led to the emergence of resis-
tance showing the need to develop more effective new agents.
We recently reported on the design and synthesis of 1-[((het-
ero)aryl- or piperidinylmethyl)amino]-2-phenyl-3-(1H-1,2,4-tria-
zol-1-yl)propan-2-ols showing various degrees of antifungal
activity against Candida albicans and Aspergillus fumigatus strains.2
SAR studies demonstrated that the benzylamine series bearing
H-bond acceptors entities such as NO2 or CN in para position of
the benzyl group and a N-methyl group in the linker gave the most
N
N
R3
N
OH
X = Cl or F
R = H or CH3
N
*
R1 = H, Boc or Benzoyl
X
R
N
R3 = H or COCF3
R1
I
X
* Corresponding author. Tel.: +33 0 240411108; fax: +33 0 240412876.
E-mail address: cedric.loge@univ-nantes.fr (C. Logé).
Figure 1. General structures of synthesized compounds.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.08.089

5834
R. Guillon et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5833–5836
O
O
Br
H
H
(ii) or (iii)
(i)
N
H
N
N
H
R1
3 (93%)
R1 = Benzoyl 4 (100%)
1
2 (68%)
R1 = Boc
N
N
N
N
N
N
N
N
N
OH
OH
OH
N
H
NH2
N
3 or 4
(iv)
*
*
*
X
X
X
H
(v)
N
H
N
R1
X
X
X
X = Cl R1 = Boc
R1 = Benzoyl 7a (76%)
R1 = Boc
6b (87%)
6a (44%)
X = Cl 5a
X = F 5b
X = Cl 8a (97%)
X = F 8b (97%)
X = F
R1 = Benzoyl 7b (70%)
N
N
N
N
N
N
N
N
O
N
N
N
N
CF3
OH
OH
O
OH
N
N
NH
CH3
2, 3 or 4
(iv)
*
*
*
F
F
CH3
CH3
F
F
N
(vi)
N
(vii)
H
R1
R1 = H
R1 = Boc
R1 = Benzoyl 13 (59%)
11 (62%)
12 (37%)
F
F
F
F
14 (56%)
10 (82%)
9
Scheme 1. Preparation of targeted compounds 6a,b, 7a,b, 8a,b and 11–14. Reagents and conditions: (i) KH, t-BuLi, DMF, THF, ꢀ78 °C to rt, 16 h; (ii) NaH, Boc2O, DMF, rt, 1 h
30 min; (iii) benzoyl chloride, DMAP, Et3N, CH2Cl2, rt, 2 h; (iv) 2, 3 or 4, NaBH3CN, AcOH/MeOH 2% v/v, rt; (v) from compounds 7a,b: NaOH 2 M, MeOH, 60 °C, 4 h; (vi)
methylamine (33% in EtOH), EtOH, reflux, 2 h; (vii) from compound 11: trifluoroacetic anhydride, 1,2-dichloroethane, rt, 3 h.
Scheme 1 outlines the synthesis of compounds 6a,b, 7a,b, 8a,b
and 11–14. Treatment of the commercially available 5-bromo-
1H-indole 1 with KH, tBuLi and DMF in THF afforded 1H-indole-
5-carbaldehyde 2 in a 68% yield.7 Carbamate 3 was prepared from
compound 2 using a standard procedure with sodium hydride and
di-tert-butyl dicarbonate.8 On the other hand, treatment of 2 with
benzoyl chloride in methylene chloride and in the presence of tri-
ethylamine and 4-dimethylaminopyridine (DMAP) gave the N-ben-
zoylated indole 4.9,10 Derivatives 6a,b and 7a,b were synthesized
from previously described key intermediates 5a and 5b2 by reduc-
tive amination with 3 or 4.11,12 Removal of the Boc protective
group under acidic condition (HCl 3 M/AcOEt)13 or with tetra-n-
butylammonium fluoride in THF14 failed. Thus, targeted com-
pounds 8a,b were obtained by basic hydrolysis of N-benzoylated
derivatives 7a,b.15
N-methylated analogues 11–13 could be obtained from the pre-
viously described epoxide 916 which can be opened by methylamine
in ethanol to afford 2-(2,4-difluorophenyl)-1-methylamino-3-(1H-
1,2,4-triazol-1-yl)propan-2-ol 10 in a 82% yield,17 following a reduc-
tive amination with compounds 2–4.18 Finally, acylationof indole 11
using trifluoroacetic anhydride in 1,2-dichloroethane gave product
14.19
On C. albicans strain, our compounds displayed a high level of
activity with MIC values 3- to 60-fold lower than that of fluconaz-
ole. Interestingly, the best result is obtained with fluorinated com-
pound 6b bearing a N-Boc protective group on the indole moiety
and a N–H linker (MIC80 = 3.0 ng mLꢀ1). In contrast, neither the
N-benzoyl 7b nor the unsubstituted 8b derivatives improved the
inhibitory potency (MIC80 of 27.0 and 34.0 ng mLꢀ1, respectively),
suggesting that an appropriate substitution at position 1 of the
indole ring should be important for potent antifungal activity.
Moreover, introduction of a N-methyl group in the linker (11–
13) would not play a major role on the two tested strains (C. albi-
cans and A. fumigatus), even causing a significant decline in activity
for compound 12 (MIC80 = 60.0 ng mLꢀ1) compared to compound
6b (MIC80 = 3.0 ng mLꢀ1).
The supposed binding mode of the docked molecule 6b (GOLD
version 4.0; CCDC, Cambridge, UK) in our homology model of
CYP51-C. albicans2b suggests a key hydrogen bonding interaction
between the carbonyl group and the protonated imidazole side
chain of His377 (Fig. 2). The (S)-configuration was retained since
in a precedented series, these isomers were much more active than
(R)-enantiomers.21 In addition, the pyrrolo portion of indole may
be involved in
p–p interactions with the phenyl ring of residue
All these compounds were screened for their antifungal activity
against C. albicans CA98001 and A. fumigatus AF98003 strains. Inhi-
bition growth was measured as previously described.20 Fluconaz-
ole and itraconazole were used as positive controls. The
Phe380, but not with the phenol group of Tyr118, a highly con-
served residue in CYP51 family.
Even if the key elements of this new scaffold were conserved (a
H-bond acceptor positioned on an aromatic moiety), the lack of
activity on A. fumigatus strain could be explained either by a steric
hindrance within the active site induced by the bulky indole ring
minimum inhibitory concentration (MIC80) values (in ng mLꢀ1
are presented in Table 1.
)

R. Guillon et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5833–5836
5835
Table 1
In vitro antifungal activities of indol-5-ylmethylamino derivatives
N
N
R3
R1
N
OH
N
R
*
X
N
X
Compd
R
R1
R3
X
MIC80 valuesa (ng mLꢀ1
)
Candida albicans CA98001
Aspergillus fumigatus AF98003
6a
6b
7a
7b
8a
8b
11
12
H
H
H
H
H
H
CH3
CH3
CH3
CH3
Boc
Boc
Benzoyl
Benzoyl
H
H
H
H
H
H
H
H
H
H
Cl
F
Cl
F
Cl
F
F
F
F
F
39.0 ( 8.00)
3.0 ( 0.50)
31.0 ( 15.0)
27.0 ( 2.00)
31.0 ( 0.80)
34.0 ( 4.00)
35.0 ( 0.40)
60.0 ( 10.0)
32.0 ( 0.50)
64.0 ( 15.0)
190.0 ( 6.0)
—
na
na
na
na
na
na
na
na
H
H
Boc
Benzoyl
H
13
14
na
na
—
COCF3
Fluconazole
Itraconazole
420.0 ( 40.0)
a
Values are means of triplicate, standard deviation is given in parentheses (na = not active, MIC80 >30,000.0 ng mLꢀ1).
Table 2
In vitro antifungal activities on Candida species of compound 6b
Compd
MIC80 valuesa
CA424 CA284 CK506 CK8 CG468 CP-
Houdeau Rolland
(l )
g mLꢀ1
CP-
6b
33.0
32.0
27.0
3.8
12.0
24.0
19.0
Fluconazole >64.0
>64.0
>64.0
19.0 >64.0
>64.0
>64.0
a
CA = Candida albicans, CK = Candida krusei, CG = Candida glabrata, CP = Candida
parapsilosis.
Therefore, although these indol-5-ylmethylamino compounds
are more active than fluconazole on the Candida species, further
investigations are needed to design broad-spectrum antifungal
agents and to pinpoint the exact molecular mechanism of this inhi-
bition. From a purely chemical point of view, the role of H-bond
acceptors at position 2 of the indole or modification of the aromatic
heterocycle could be explored, since preliminary work at position 3
(compound 14) gave the same results. In addition, due to the lim-
ited range of variations at the indole moiety, the synthesis of indol-
3-ylmethylamino derivatives could also be explored to check the
utility of this scaffold for further optimization.
Figure 2. Docking solution of compound (S)-6b in the supposed active site pocket
(channel 2) of CYP51-Candida albicans. Hip377 is the protonated form of histidine
residue.
and/or an inappropriate position of the electron-withdrawing sub-
stituents compared to our previous more flexible and linear ben-
zylamine series.2a Of course, azoles are known to inhibit mainly
CYP51 enzymes but we can not exclude other factors such as lipo-
philicity parameters, differences in the membrane structures
between the two fungi or in molecular mechanisms and only
results on the isolated CYP51 could confirm our hypotheses.
To determine the potential of the indole moiety on various
Candida species, our best compound 6b was evaluated against
fluconazole-resistant (CA424, CA284, CK506, CG468, CP-Houdeau
and CP-Rolland) and fluconazole low-sensitive (CK8) species (Table
References and notes
1. Farowski, F.; Vehreschild, J. J.; Cornely, O. A. Future Microbiol. 2007, 2(3), 231.
2. (a) Giraud, F.; Logé, C.; Pagniez, F.; Crepin, D.; Le Pape, P.; Le Borgne, M. Bioorg.
Med. Chem. Lett. 2008, 18, 1820; (b) Giraud, F.; Guillon, R.; Logé, C.; Pagniez, F.;
Picot, C.; Le Borgne, M.; Le Pape, P. Bioorg. Med. Chem. Lett. 2009, 19, 301.
3. Sheng, C.; Zhang, W.; Ji, H.; Zhang, M.; Song, Y.; Xu, H.; Zhu, J.; Miao, Z.; Jiang,
Q.; Yao, J.; Zhou, Y.; Zhu, J.; Lu, J. J. Med. Chem. 2006, 49, 2512.
4. Fukuoka, T.; Johnston, D. A.; Winslow, C. A.; De Groot, M. J.; Burt, C.; Hitchcock,
C. A.; Filler, S. G. Antimicrob. Agents Chemother. 2003, 47, 1213.
5. Chen, S. H.; Sheng, C. Q.; Xu, X. H.; Zhang, W. N.; He, C. Biol. Pharm. Bull. 2007,
30, 1246.
2).20 The MIC80 values (in
are given.
l
g mLꢀ1) in comparison with fluconazole
6. Xiao, L.; Madison, V.; Chau, A. S.; Loebenberg, D.; Palermo, R. E.; McNicholas, P.
M. Antimicrob. Agents Chemother. 2004, 48, 568.
7. Yang, Y.; Martin, A. R.; Nelson, D. L.; Regan, J. Heterocycles 1992, 34(6), 1169.
8. Synthesis of 1-(tert-butoxycarbonyl)-1H-indole-5-carbaldehyde (3). To a solution
Compound 6b exhibited moderate antifungal activities against
all fungi tested with MIC values ranging from 3.8 to 33.0
lower than those of fluconazole.
l ,
g mLꢀ1
of
2 (415 mg, 2.86 mmol) in 8 mL of N,N-dimethylformamide at room

5836
R. Guillon et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5833–5836
temperature under argon was added sodium hydride (60% in mineral oil)
diethyl ether. Organic layers were dried over anhydrous Na2SO4 and
concentrated in vacuo. The residue was triturated in isopropyl ether and
compound 8b was obtained in a 97% yield as a green powder. Mp 53–54 °C; 1H
NMR (DMSO-d6): d 2.96 (s 2H), 3.73 (s, 2H), 4.57 (d, 1H, 2J = 14.3 Hz), 4.63 (d,
(165 mg, 4.29 mmol). The solution was stirred at room temperature for 1 h.
Then di-tert-butyl dicarbonate (936 mg, 4.29 mmol) was added and the
mixture was stirred for 30 min. Mixture was diluted with water and product
was extracted with diethyl ether. Organic layers were washed with water,
dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was
purified on silica gel column chromatography (dichloromethane) and
compound 3 was obtained in a 93% yield as a yellow oil. 1H NMR (DMSO-d6):
d 1.68 (s, 9H), 6.94 (d, 1H, 3J = 3.6 Hz), 7.85 (d, 1H, 3J = 3.6 Hz), 7.90 (dd, 1H,
1H, 2J = 14.3 Hz), 5.80 (s, 1H, OH), 6.38 (s, 1H), 6.93–7.03 (m, 2H), 7.16 (ddd, 1H,
3JH–F
=
3J0H—F = 9.2 Hz, JH–H = 2.4 Hz), 7.31–7.45 (m, 4H), 7.74 (s, 1H), 8.30 (s,
4
1H), 11.01 (s, 1H). IR (KBr cmꢀ1): 1128 (
C@C and C@N), 2927 ( CHaliph.), 3100–3560 (
384.3 (M+H).
m
C–F), 1272 (
m
C–N), 1420, 1503, 1616
N–H). MS m/z
(
m
m
m
m
O–H and m
3J = 8.8 Hz, 4J = 1.5 Hz), 8.25–8.28 (m, 2H), 10.09 (s, 1H). IR (NaCl cmꢀ1): 1215 (
C–N), 1461, 1533 ( C@C), 1687 ( C@O), 1740 ( C@O), 2957 ( C–Haliph.).
m
16. Lebouvier, N.; Giraud, F.; Corbin, T.; Na, Y. M.; Le Baut, G.; Marchand, P.; Le
Borgne, M. Tetrahedron Lett. 2006, 47, 6479.
m
m
m
m
9. Dhanoa, D. S.; Bagley, S. W.; Chang, R. S. L.; Lotti, V. J.; Bau Chen, T.; Kivlighn, S.
D.; Zingaro, G. J.; Siegl, P. K. S.; Patchett, A. A.; Greenlee, W. J. J. Med. Chem. 1993,
36, 4230.
17. Synthesis of 2-(2,4-difluorophenyl)-1-methylamino-3-(1H-1,2,4-triazol-1-yl)pro-
pan-2-ol (10). To a solution of 9 (200 mg, 0.84 mmol) in 0.75 mL of ethanol was
added methylamine (33% in ethanol) (3.65 mL, 29.51 mmol) and the solution
was refluxed for 2 h. Solvent was removed under reduced pressure and residue
was partitioned between dichloromethane and water. Product was extracted
with dichloromethane and organic layers were dried over anhydrous Na2SO4
then concentrated in vacuo. The residue was purified on silica gel column
chromatography (dichloromethane and dichloromethane /ethanol, 90:10) and
compound 10 was obtained in a 82% yield as a brown oil. 1H NMR (DMSO-d6): d
2.26 (s, 3H), 2.85 (d, 1H, 2J = 12.5 Hz), 2.96 (d, 1H, 2J = 12.5 Hz), 4.58 (s, 2H),
10. Synthesis of 1-benzoyl-1H-indole-5-carbaldehyde (4). To a solution of 2 (2.68 g,
18.48 mmol) in 30 mL of dichloromethane at room temperature under argon
was added 4-dimethylaminopyridine (452 mg, 3.70 mmol) and triethylamine
(5.15 mL, 69.96 mmol). Then benzoyl chloride was added and the solution was
stirred for 2 h. Mixture was diluted with water and product was extracted with
dichloromethane. Organic layers were washed with water, dried over
anhydrous Na2SO4 and concentrated in vacuo. The residue was purified on
silica gel column chromatography (dichloromethane) and compound 4 was
obtained in quantitative yield as a white powder. Mp 124–125 °C; 1H NMR
(DMSO-d6): d 6.98 (d, 1H, 3J = 3.7 Hz), 7.60 (d, 1H, 3J = 3.7 Hz), 7.66–7.69 (m,
2H), 7.74–7.77 (m, 1H), 7.82–7.89 (m, 2H), 7.96 (dd, 1H, 3J = 8.5 Hz, 4J = 1.2 Hz),
8.33 (d, 1H, 4J = 1.2 Hz), 8.46 (d, 1H, 3J = 8.5 Hz), 10.13 (s, 1H). IR (KBr cmꢀ1):
5.95 (s, 1H, OH), 6.98 (ddd, 1H, 3JH–F
=
3JH–H = 8.4 Hz, 4JH–H = 2.4 Hz), 7.18 (ddd,
3 4
1H, JH–F
=
3J0H—F = 9.2 Hz, JH–H = 2.4 Hz), 7.40 (ddd, 1H, JH–H = 8.4 Hz, JH–
3
4
=
4J0H—F = 6.8 Hz), 7.77 (s, 1H), 8.31 (s, 1H). IR (NaCl cmꢀ1): 1131 (
m
C–F), 1276
F
(
m
C–N), 1420, 1499, 1612 (m C@C and m C@N), 3300 (m O–H and m N–H).
18. Synthesis of 2-(2,4-difluorophenyl)-1-[(1H-indol-5-ylmethyl)methylamino]-3-(1H-
1,2,4-triazol-1-yl)propan-2-ol (11). To a solution of 10 (813 mg, 3.03 mmol) in
17 mL of methanol and 0.34 mL of acetic acid was added at room temperature
under argon 2 (440 mg, 3.03 mmol). Then sodium cyanoborohydride (229 mg,
3.64 mmol) was added and the mixture was stirred for 24 h. Mixture was
diluted with water and product was extracted with dichloromethane. Organic
layers were washed with saturated sodium bicarbonate, dried over anhydrous
Na2SO4 and concentrated in vacuo. The residue was purified on silica gel
column chromatography (dichloromethane and dichloromethane/ethanol,
98:2) and compound 11 was obtained in a 62% yield as a white powder. Mp
130–131 °C; 1H NMR (DMSO-d6): d 2.11 (s, 3H), 2.85 (d, 1H, 2J = 13.6 Hz), 3.03
(d, 1H, 2J = 13.6 Hz), 3.51 (d, 1H, 2J = 12.8 Hz), 3.60 (d, 1H, 2J = 12.8 Hz), 4.53 (d,
1274 (m C–N), 1461, 1535 (m C@C), 1688 (m C@O).
11. Synthesis of 1-{[(1-tert-butoxycarbonylindol-5-yl)methyl]amino}-2-(2,4-difluoro-
phenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (6b). To a solution of 5b (415 mg,
1.63 mmol) in 8 mL of methanol and 0.16 mL of acetic acid was added 3
(200 mg, 0.82 mmol) in 8 mL of dichloromethane at room temperature under
argon. The solution was stirred at room temperature for 48 h. Then sodium
cyanoborohydride (61 mg, 0.98 mmol) was added and the mixture was stirred
for 16 h. Mixture was diluted with water and product was extracted with
diethyl ether. Organic layers were washed with satd sodium bicarbonate, dried
over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified on
silica gel column chromatography (dichloromethane and dichloromethane/
ethanol, 98:2) and compound 6b was obtained in a 87% yield as a green oil. 1H
1H, 2J = 14.0 Hz), 4.59 (d, 1H, 2J = 14.0 Hz), 5.76 (s, 1H, OH), 6.34 (s, 1H),
3
NMR (DMSO-d6):
d
1.66 (s, 9H), 2.93 (s, 2H), 3.77 (s, 2H), 4.56 (d, 1H,
6.87 (dd, 1H, 3J = 8.0 Hz, 4J = 1.2 Hz), 0 7.00 (ddd, 1H, JH–F
=
3JH–H = 8.4 Hz,
2J = 14.0 Hz), 4.63 (d, 1H, 2J = 14.0 Hz), 5.82 (s, 1H, OH), 6.68 (d, 1H, 3J = 3.6 Hz),
4JH–H = 2.4 Hz), 7.18 (ddd, 1H, JH–F 3JH—F = 9.2 Hz, JH–H = 2.4 Hz), 7.27–7.33
=
3
4
6.98 0 (ddd, 1H, JH–F
=
3JH–H = 8.8 Hz, JH–H = 2.4 Hz), 7.15 (ddd, 1H, JH–
(m, 3H), 7.46 (ddd, 1H, 3JH–H = 8.4 Hz, 4JH–F
1H), 11.02 (s, 1H). IR (KBr cmꢀ1): 1133 (
C–F), 1274 (
C@C and C@N), 3234 ( O–H and N–H). MS m/z 398.0 (M+H).
19. Synthesis of 1-(5-{[(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)-
propyl)methylamino]methyl}-1H-indol-3-yl)-2,2,2-trifluoroethanone (14). To
solution of 11 (100 mg, 0.25 mmol) in 2 mL of 1,2-dichloroethane was added
at 0 °C trifluoroacetic anhydride (70 L, 0,50 mmol). The solution was stirred at
=
4J0H—F = 6.8 Hz), 7.76 (s, 1H), 8.33 (s,
C–N), 1421, 1499, 1614
3
4
3
4
=
3JH—F = 9.2 Hz, JH–H = 2.4 Hz), 7.23 (dd, 1H, 3J = 8.2 Hz, 4J = 3.7 Hz), 7.39
m
m
F
(ddd, 1H, JH–H = 8.4 Hz, JH–F
4J = 3.7 Hz), 7.74 (s, 1H), 7.97 (d, 1H, 3J = 8.2 Hz), 8.30 (s, 1H). IR (NaCl cmꢀ1):
1136 ( C–F), 1270 ( C–N), 1482, 1501, 1585 ( C@C), 1732 ( C@O), 2956 (
CHaliph.), 3250–3600 ( O–H and N–H). MS m/z 483.9 (M).
=
4J0H—F = 6.8 Hz), 7.48 (s, 1H), 7.67 (d, 1H,
(m
m
m
m
3
4
m
m
m
m
m
a
m
m
12. Synthesis of 1-{[(1-benzoylindol-5-yl)methyl]amino}-2-(2,4-difluorophenyl)-3-(1H-
1,2,4-triazol-1-yl)propan-2-ol (7b). Compound 7b was prepared from 5b and 4
according to the protocol described for 6b. Yield: 70%, yellow powder. Mp 70–
71 °C. 1H NMR (DMSO-d6): d 3.06 (d, 1H, 2J = 12.2 Hz), 3.28 (d, 1H, 2J = 12.2 Hz),
3.78 (s, 2H), 4.68 (d, 1H, 2J = 14.3 Hz), 4.92 (d, 1H, 2J = 14.3 Hz), 5.96 (s, 1H, OH),
6.74 (d, 1H, 3J = 3.6 Hz), 7.27–7.80 (m, 12H), 8.19 (d, 1H, 3J = 8.2 Hz), 8.32 (s, 1H).
l
room temperature for 3 h. Mixture was diluted with saturated sodium
bicarbonate and product was extracted with dichloromethane. Organic layers
were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was
triturated in isopropyl ether/dichloromethane and compound 14 was obtained
in a 56% yield as a white powder. Mp 178–179 °C; 1H NMR (DMSO-d6): d 2.13
(s, 3H), 2.81 (d, 1H, 2J = 13.6 Hz), 3.07 (d, 1H, 2J = 13.6 Hz), 3.55 (d, 1H,
2J = 13.0 Hz), 3.69 (d, 1H, 2J = 13.0 Hz), 4.52 (d, 1H, 2J = 14.2 Hz), 4.59 (d, 1H,
IR (KBr cmꢀ1): 809 (
1685 ( C@O), 2927 (
520.2 (M).
m
C–Cl), 1273 (
m
C–N), 1464, 1508, 1585 ( C@C and
m
m C@N),
m
m
CHaliph.), 3122–3525 (
m
O–H and m N–H). MS m/z
3
4
2J = 14.2 Hz), 5.78 (s, 1H, OH), 6.98 (ddd, 1H, JH–F
=
3JH–H = 8.4 Hz, JH–
13. Hiroya, K.; Itoh, S.; Sakamoto, T. J. Org. Chem. 2004, 69(4), 1126.
14. Jacquemard, U.; Bénéteau, V.; Lefoix, M.; Routier, S.; Merour, J. Y.; Coudert, G.
Tetrahedron 2004, 60(44), 10039.
15. Synthesis of 2-(2,4-difluorophenyl)-1-[(1H-indol-5-ylmethyl)amino]-3-(1H-1,2,4-
triazol-1-yl)propan-2-ol (8b). To a solution of 7b (671 mg, 1.38 mmol) in 15 mL
H = 2.4 Hz), 7.09–7.13 (m, 2H), 7.42–7.49 (m, 2H), 7.76 (s, 1H), 7.97 (s, 1H),
8.33 (s, 1H), 8.47 (s, 1H), 12.67 (s, 1H). IR (KBr cmꢀ1): 1135 (
N), 1446, 1497, 1615 ( C@C and C@N), 1667 ( C@O), 3451 (
H). MS m/z 494.0 (M+H).
20. Pagniez, F.; Le Pape, P. J. Mycol. Med. 2001, 11, 73.
m
C–F), 1276 (
O–H and
m
m
C–
N–
m
m
m
m
of methanol was added
23.00 mmol) under argon at room temperature. The solution was stirred at
a
solution of sodium hydroxide 2 M (12 mL,
21. Lebouvier, N. Ph.D. Thesis, Université de Nantes, Nantes Atlantique Universités,
October 2004.
60 °C for 4 h. Mixture was diluted with water and product was extracted with