Chiral azole derivatives. Part 5: Synthesis of enantiomerically pure 1-[α-(benzofuran-2-yl)arylmethyl]-1H-1,2,4-triazoles, antifungal and antiaromatase agents

Article abstract of DOI:10.1016/S0957-4166(00)00486-9

Racemic and enantiopure benzofuranmethanamines 5a-c have been reacted with N-Boc-3-(4-cyanophenyl)oxaziridine to give N-Boc-hydrazines 7a-c, which have in turn been transformed by deprotection and cyclisation into triazoles 4a-c, potent antiaromatase agen

Full text of DOI:10.1016/S0957-4166(00)00486-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 4895–4901
Chiral azole derivatives. Part 5:† Synthesis of enantiomerically
pure 1-[a-(benzofuran-2-yl)arylmethyl]-1H-1,2,4-triazoles,
antifungal and antiaromatase agents
Flavia Messina,‡ Maurizio Botta,* Federico Corelli* and Antonella Paladino
Dipartimento Farmaco Chimico Tecnologico, Universita` di Siena, Via A. Moro, 53100 Siena, Italy
Received 19 October 2000; accepted 5 December 2000
Abstract
Racemic and enantiopure benzofuranmethanamines 5a–c have been reacted with N-Boc-3-(4-
cyanophenyl)oxaziridine to give N-Boc-hydrazines 7a–c, which have in turn been transformed by
deprotection and cyclisation into triazoles 4a–c, potent antiaromatase agents, in good overall yield and
with high enantiomeric excess. © 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
Inhibition of the cytochrome P-450 enzyme aromatase has been recognized as a good
therapeutic strategy for the treatment of estrogen-dependent breast cancers.2 Efforts in this area
have resulted in the identification of structurally diverse aromatase inhibitors, among which
some 1-substituted azole (imidazole and 1,2,4-triazole) compounds proved to be potent, long-
acting, and selective inhibitors. In particular, fadrozole hydrochloride 13 and letrazole 24 have
been introduced into the clinical practice as antineoplastic drugs useful in the treatment of
advanced, post-menopausal breast cancer and are devoid of significant side effects (Fig. 1).
Among aromatase inhibitors under investigation, 1-[2-benzofuranyl(4-chlorophenyl)methyl]-
1H-imidazole (3, R=4-Cl) has been shown to display potent activity both in vitro and in vivo,5
with a 15-fold enantioselectivity (IC50 5.3 nM versus 65.0 nM) in favor of the (+)-enantiomer,6,7
whilst the racemic triazole derivative 4 (R=4-Cl) proved to be an even more potent aromatase
inhibitor.7
In connection with our investigations on chiral non-racemic azole compounds as antifungal
and antiaromatase agents,1,8 we have recently described the palladium-mediated heteroannula-
tion of homochiral a-arylpropargylamines9 to give enantiomerically pure or enriched a-aryl-2-
* Corresponding authors. E-mail: botta@unisi.it; corelli@unisi.it
†
For Part 4, see Ref. 1.
Present address: GlaxoWellcome, Medicines Research Centre, Verona, Italy.
‡
0957-4166/00/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00486-9

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Figure 1.
benzofuranmethanamines 5.10 Pursuing the same research line, herein the first synthesis of
homochiral 1-[a-(benzofuran-2-yl)arylmethyl]-1H-1,2,4-triazoles 4 is reported, according to the
retrosynthetic approach depicted in Scheme 1.
Scheme 1.
2. Results and discussion
Enantiomerically pure amines 5 were used as the starting materials for the synthesis of the
target compounds 4. First attempts to transform 5 into the corresponding hydrazino derivatives
via nitrosation (NaNO2, HCl, EtOH) followed by in situ reduction (SnCl2, MeOH) of the
intermediate N-nitroso compounds were unsuccessful, since only trace amounts of benzofuran-
methanehydrazines could be detected by GC/MS. Therefore, we turned our attention to a new
electrophilic aminating reagent recently developed by Vidal et al.,11 namely N-Boc-3-(4-
cyanophenyl)oxaziridine 6.12
Reaction of benzofuranmethanamine (R)-5a (Scheme 2) with a stoichiometric amount of 6 in
CHCl3 at room temperature afforded the Boc-protected hydrazine (R)-7a in a 60% yield after
chromatographic purification. Removal of the protecting group of 7a with HCl/Et2O gave the
hydrazine dihydrochloride (R)-8a in 27% overall yield (Table 1) and with an enantiomeric excess
]94% (vide infra). Based on the assumption that the stereogenic center in the starting amine is
not affected during this transformation, the absolute stereochemistry of (R)-8a can be assigned.
Other enantiopure benzofuranmethanamines have been subjected to the same amination reac-

F. Messina et al. / Tetrahedron: Asymmetry 11 (2000) 4895–4901
4897
Scheme 2.
Table 1
Preparation of compounds 7 and 8
Product
R
Time (h)
Yield (%)a
Mp (°C)
(R)-7a
(R)-7b
(S)-7b
(R)-7c
(R)-8a
(R)-8b
(S)-8b
(R)-8c
H
Cl
Cl
F
H
Cl
Cl
F
22
26
26
24
2
1.5
1.5
2
66
70
68
65
50
55
55
50
Oil
Oil
Oil
Oil
190–191
203–204
202–203
204–205
a Reaction yields refer to isolated and purified materials.
tion with 6, followed by deprotection of the hydrazine group, to give compounds 8 in reasonable
yield and with high enantiomeric excess.
Conversion of 8a–c into the final triazoles 4a–c was achieved using s-triazine as the cyclization
reagent.13 Thus, heating 8a–c with s-triazine in refluxing EtOH (Scheme 3, Table 2) provided
4a–c in 45–55% yield as yellowish oils.
Scheme 3.
Enantiomeric excesses were determined by enantioselective HPLC analyses (Fig. 2), while the
absolute configurations were assigned based on those of the corresponding hydrazines. It should
be pointed out that the enantiomeric excess of the resulting products 4 was always identical with
that of the corresponding starting amines 5, thus demonstrating the complete stereospecificity of
the reaction sequence.
In conclusion, the first synthesis of triazoles of general structure 4 in homochiral form has
been developed, thus allowing for the biological evaluation of single enantiomers of these
pharmacologically relevant compounds. The results of the biological studies will be reported in
due course.

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Table 2
Synthesis of 1,2,4-triazoles 4
Product
R
Time (h)
Yield (%)a
[h]2D3 b
Ee (%)c
(R)-4ad
(R)-4b
(S)-4b
(R)-4c
H
Cl
Cl
F
8
10
10
11
50
55
55
52
+8.2 (c 0.23)
+10.1 (c 0.97)
−13.8 (c 1.83)
+12.9 (c 0.16)
95
89
93
95
a Reaction yields refer to isolated and purified materials.
b Measured in chloroform solution.
c Enantiomeric excesses were determined by HPLC analyses on a Chiralcel OD column (Daicel Chemical Co., Ltd,
250×4.6 mm) eluting with n-hexane/isopropanol 90/10 (flow rate 1.0 ml/min).
d Absolute configurations were assigned based on those of the starting benzofuranmethanamines.
Figure 2. Chromatogram of (S)-4b: (a) in comparison with (RS)-4a, (b) (Chiralcel OD column, Daicel Chemical Co.,
Ltd, 250×4.6 mm, eluant: n-hexane/isopropanol 90/10, flow rate: 1.0 ml/min)
3. Experimental
3.1. General methods
Melting points were taken on a Gallenkamp apparatus and are uncorrected. Optical rotations
were measured on a Perkin–Elmer 241 polarimeter. IR spectra were recorded on a Perkin–Elmer
1
1600 spectrophotometer. H NMR and 13C NMR spectra were run on a Bruker AC 200
spectrometer at 200 MHz and 50 MHz, respectively. The chemical shifts are reported relative to
CDCl3 at l 7.24 ppm and tetramethylsilane at l 0.00 ppm. EI and FAB low-resolution mass
spectra were recorded on a Saturn 2 spectrometer with an electron beam of 70 eV. Elemental
analyses (C, H, N) were performed in house on a Perkin–Elmer 240C Analyzer. All reactions
were carried out under an argon atmosphere. Organic solutions were dried over anhydrous
sodium sulfate. Reagents were from commercial suppliers and used without further purification.
N-Boc-3-(4-cyanophenyl)oxaziridine was prepared according to the reported procedure.11
3.2. Experimental methods
3.2.1. General procedure for the synthesis of Boc-protected hydrazines 7
A solution of N-Boc-3-(4-cyanophenyl)oxaziridine 6 (1 mmol) in dry CHCl3 (4 ml) was added
dropwise to a solution of 5 (1 mmol) in dry CHCl3 (4 ml) at 0°C. After stirring for 2 h at 0°C,

F. Messina et al. / Tetrahedron: Asymmetry 11 (2000) 4895–4901
4899
the solution was slowly warmed up to rt and then stirred for 20–24 h (Table 1) until the reaction
was complete (TLC: silica gel, hexanes/ethyl acetate 4/3). Sodium borohydride (2 mmol) was
added to reduce the by-product 4-cyanobenzaldehyde and make the purification step easier.
Removal of the solvent under reduced pressure gave the crude product, which after purification
by flash chromatography on silica gel (hexanes/CHCl3/ethyl acetate=10/7/1) afforded the pure
product as a colorless oil. Selected data for these compounds are as follows.
3.2.1.1. (R)-1-(tert-Butoxycarbonyl)-2-[h-(benzofuran-2-yl)phenylmethyl]hydrazine 7a. IR
1
(CHCl3): 1706 cm−1. H NMR (CDCl3): l 1.44 (s, 9H), 4.70 (br s, 1H), 5.55 (s, 1H), 6.11 (br s,
1H), 6.62 (s, 1H), 7.16–7.58 (m, 9H). EIMS m/z: 338 [M+], 281 [M+−C4H9, 100%]. Anal. calcd
for C20H22N2O3: C, 70.99; H, 6.55; N, 8.28. Found: C, 71.29; H, 6.45; N, 8.05.
3.2.1.2. (R)-1-(tert-Butoxycarbonyl)-2-[h-(benzofuran-2-yl)-(4-chlorophenyl)methyl]hydrazine 7b.
1
IR (CHCl3): 1704 cm−1. H NMR (CDCl3): l 1.48 (s, 9H), 4.58 (br s, 1H), 5.47 (s, 1H), 6.28 (br
s, 1H), 6.58 (s, 1H), 7.14–7.49 (s, 8H). EIMS m/z: 375/373 [M++H]. Anal. calcd for
C20H21ClN2O3: C, 64.43; H, 5.68; N, 7.51. Found: C, 64.64; H, 5.55; N, 7.30.
3.2.1.3. (S)-1-(tert-Butoxycarbonyl)-2-[a-(benzofuran-2-yl)-(4-chlorophenyl)methyl]hydrazine 7b.
Same spectroscopic data as above. Anal. calcd for C20H21ClN2O3: C, 64.43; H, 5.68; N, 7.51.
Found: C, 64.55; H, 5.60; N, 7.33.
3.2.1.4. (R)-1-(tert-Butoxycarbonyl)-2-[h-(benzofuran-2-yl)-(4-fluorophenyl)methyl]hydrazine 7c.
1
IR (CHCl3): 1704 cm−1. H NMR (CDCl3): l 1.44 (s, 9H), 4.60 (br s, 1H), 5.45 (s, 1H), 6.33 (br
s, 1H), 6.97 (s, 1H), 6.98–7.22 (m, 4H), 7.44–7.63 (m, 4H). EIMS m/z: 355 [M+−H], 225
[M+−C4H9OCONHNH, 100%]. Anal. calcd for C20H21FN2O3: C, 67.40; H, 5.94; N, 7.86. Found:
C, 67.62; H, 6.11; N, 7.60.
3.2.2. General procedure for the synthesis of hydrazine dihydrochlorides 8
Dry HCl gas was bubbled into a solution of 7 (1 mmol) in dry diethyl ether (15 ml) at 0°C
for 30 min, then the reaction was stirred at rt for 1–1.5 h (Table 1). Removal of the solvent
under reduced pressure left a yellowish solid, which was triturated with diethyl ether to give 8
as colorless crystals, which were recrystallized from ethanol/water. Selected data for these
compounds are as follows.
1
3.2.2.1. (R)-[h-(Benzofuran-2-yl)phenylmethyl]hydrazine dihydrochloride 8a. H NMR (CD3OD):
l 5.31 (s, 1H), 6.45 (s, 1H), 7.14–7.60 (m, 9H). FABMS m/z: 239 [M++H], 207 [M+−N2H3,
100%]. Anal. calcd for C15H16Cl2N2O: C, 57.89; H, 5.18; N, 9.00. Found: C, 58.10; H, 5.23; N,
8.77.
1
3.2.2.2. (R)-[h-(Benzofuran-2-yl)-(4-chlorophenyl)methyl]hydrazine dihydrochloride 8b. H NMR
(CD3OD): l 5.72 (s, 1H), 6.67 (s, 1H), 7.32–7.49 (m, 8H). FABMS m/z: 275/273 [M+−H]. Anal.
calcd for C15H15Cl3N2O: C, 52.12; H, 4.37; N, 8.10. Found: C, 52.35; H, 4.43; N, 7.88.
3.2.2.3. (S)-[h(Benzofuran-2-yl)-(4-chlorophenyl)methyl]hydrazine dihydrochloride 8b. Same
spectroscopic data as above. Anal. calcd for C15H15Cl3N2O: C, 52.12; H, 4.37; N, 8.10. Found:
C, 51.92; H, 4.46; N, 7.90.

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3.2.2.4. (R)-[h-(Benzofuran-2-yl)-(4-fluorophenyl)methyl]hydrazine dihydrochloride 8c. H NMR
(CD3OD): l 5.54 (s, 1H), 6.62 (s, 1H), 6.96–7.43 (m, 8H). FABMS m/z: 256 [M+]. Anal. calcd
for C15H15Cl2FN2O: C, 54.73; H, 4.59; N, 8.51. Found: C, 54.53; H, 4.68; N, 8.68.
3.2.3. General procedure for the synthesis of 1,2,4-triazoles 4
A solution of 8 (1 mmol) and s-triazine (6 mmol) in absolute EtOH (50 ml) was refluxed for
8–11 h (Table 2), then evaporated under reduced pressure. The residue was taken up into diethyl
ether (50 ml) and this solution was washed with water (2×20 ml), brine (2×20 ml), then dried.
Removal of the solvent left an oily residue, which was purified by flash chromatography on
silica gel (hexanes/ethyl acetate=1/1) to yield compounds 4 as light yellow oils. Selected data for
these compounds are as follows.
1
3.2.3.1. (R)-(+)-1-[h-(Benzofuran-2-yl)phenylmethyl]-1H-1,2,4-triazole 4a. H NMR (CDCl3): l
6.49 (s, 1H), 6.53 (s, 1H), 6.58 (s, 1H), 7.24–7.42 (m, 9H), 8.34 (s, 1H). EIMS m/z: 275 [M+],
207 [M+−C2H2N3, 100%]. Anal. calcd for C17H13N3O: C, 74.17; H, 4.76; N, 15.26. Found: C,
74.43; H, 4.88; N, 15.00.
1
3.2.3.2. (R)-(+)-1-[a-(Benzofuran-2-yl)-(4-chlorophenyl)methyl]-1H-1,2,4-triazole 4b. H NMR
(CDCl3): l 6.38 (s, 1H), 6.44 (s, 1H), 6.52 (s, 1H), 7.18–7.30 (m, 4H), 7.32–7.52 (m, 4H), 8.35
(s, 1H). EIMS m/z: 312/310 [M++H]. Anal. calcd for C17H12ClN3O: C, 65.92; H, 3.90; N, 13.57.
Found: C, 66.19; H, 3.79; N, 13.84.
3.2.3.3. (S)-(+)-1-[h-(Benzofuran-2yl)-(4-chlorophenyl)methyl]-1H-1,2,4-triazole 4c. Same spec-
troscopic data as above. Anal. calcd for C17H12ClN3O: C, 65.92; H, 3.90; N, 13.57. Found: C,
65.72; H, 3.76; N, 13.69.
1
3.2.3.4. (R)-(+)-1-[h-(Benzofuran-2-yl)-(4-fluorophenyl)methyl]-1H-1,2,4-triazole 4c. H NMR
(CDCl3): l 6.42 (s, 1H), 6.50 (s, 1H), 6.58 (s, 1H), 7.14–7.51 (m, 8H), 8.35 (s, 1H). EIMS m/z:
292 [M+−H], 225 [M+−C2H2N3, 100%]. Anal. calcd for C17H12FN3O: C, 69.62; H, 4.12; N, 14.33.
Found: C, 69.48; H, 4.30; N, 14.45.
3.2.4. Enantioselective HPLC analysis
HPLC analysis was performed on Chiralcel OD column (4.6×250 mm), Daicel Chemical Co.,
Ltd, Japan. Mobile phase 10% isopropanol in hexane; flow rate 1 ml/min; T=25°C; detection
wavelength 250 nm. Retention times: (S)-4a 25.6; (R)-4a 46.5; (S)-4b 29.5; (R)-4b 46.6; (S)-4c
25.4; (R)-4c 41.7 min.
Acknowledgements
We thank Professor M. G. Quaglia Strano, University of Rome ‘La Sapienza’, for the
determination of enantiomeric excess. This work was supported by the University of Siena (60%
funds, 1999) and Italian CNR.

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