Synthesis of novel 3-amino-5-trifluoromethylazoles: A convenient method of obtaining N-(azol-3-yl)amines

Article abstract of DOI:10.1055/s-2006-926443

A convenient method to obtain 10 3-amino-5-trifluoromethyl-5-hydroxy-4,5- dihydroisoxazoles and 18 3-amino-5-trifluoromethyl-1H-pyrazoles by cyclocondensation reaction of 4-amino-4-ethoxy-1,1,1,-trifluorobut-3-en-2-ones [CF₃COCH=C(OEt)NHR, wher

Full text of DOI:10.1055/s-2006-926443

PAPER
1485
Synthesis of Novel 3-Amino-5-trifluoromethylazoles: A Convenient Method of
Obtaining N-(Azol-3-yl)amines
S
ynthesis of 3-Amino-
a
5-trifluorom
r
ethylaz
c
oles os A. P. Martins,* Wilson Cunico, Sergio Brondani, Rodrigo L. Peres, Nilo Zimmermann, Fernanda A. Rosa,
Gabriela F. Fiss, Nilo Zanatta, Helio G. Bonacorso
Núcleo de Química de Heterociclos (NUQUIMHE), Departamento de Química, Universidade Federal de Santa Maria, 97105-900 Santa
Maria, RS, Brazil
Fax +55(55)32208756; E-mail: mmartins@base.ufsm.br
Received 23 September 2005; revised 29 November 2005
The presence of a trifluoromethyl group into cyclic com-
Abstract: A convenient method to obtain 10 3-amino-5-trifluorom-
pounds especially at a strategic position of drug molecules
has become an important aspect of pharmaceutical re-
ethyl-5-hydroxy-4,5-dihydroisoxazoles and 18 3-amino-5-trifluo-
romethyl-1H-pyrazoles by cyclocondensation reaction of 4-amino-
4-ethoxy-1,1,1,-trifluorobut-3-en-2-ones [CF3COCH=C(OEt)NHR,
search owing to the unique physical and biological prop-
where R = H, Me, Et, CH2CH2OH, CMe2Et, CH2Ph, Ph, 4- erties of fluorine.7a The steric requirement of the fluorine
NH2C6H4, 4-AcC6H4, 4-NO2C6H4, 5-methylisoxazol-3-yl, thiazol-
2-yl, CH2CO2Et, CH(Ph)CO2Me, CH(i-Bu)CO2Et] with hydroxyl-
amine, hydrazine and phenylhydrazine is reported.
atom resembles that of hydrogen (van der Waals radii:
CF3 = 1.35 Å versus CH3 = 1.29 Å). Thus substitution of
a methyl by a trifluoromethyl group in a drug candidate
usually allows the trifluoromethylated analogue to be
Key words: isoxazoles, pyrazoles, enones, amines, azolylation
comparable in size and follow similar drug-protein inter-
actions of the parent methyl compound. However, the
There is an extensive range of methods used to prepare strong covalent bonding of C–F bond (116 kcal/mol) ver-
amines (alkylation, dealkylation and acylation of sus that of the C–H bond (100 kcal/mol)7b can often avoid
amines).1 One particularly convenient method for the syn- unwanted metabolic transformations. The high electro-
thesis of new amines could be the azolylation of primary negativity of fluorine enables a trifluoromethyl group to
amines. Amines and their derivatives have fundamental decrease the electron density and the basicity or enhance
importance as natural products, pharmacological agents, the electrophilicity of the neighboring functional groups
fine chemicals and dyes. We were mainly interested in ob- within a molecule. In many systems, the substitution of
taining amines containing azoles (Figure 1). Many of methyl group by a trifluoromethyl group results in added
these heterocyclic compounds have interesting biological lipophilicity [p (CF3) = 1.07 versus p (CH3) = 0.50],7c
activities. Pyrazoles and isoxazoles are heterocyclic com- which may lead to easier absorption and transportation of
pounds with extensive biological properties.2,3 Their im- the molecules within biological systems and thereby im-
portance as active drugs for medical applications can be prove the overall pharmacokinetic properties of drug can-
evaluated by the fact that they represent 3% of the com- didates. Our contribution to this library focuses on the
pounds in the MDL Drug Report (MDDR-3D, 99.2) and preparation of the aminoazoles depicted in Figure 1. The
1.6% of the entries in the Comprehensive Medicinal synthetic route leading to the new 3-aminopyrazoles and
Chemistry (CMC-3D 99.1).4 The search for new azole 3-isoxazoles is another result of our continuous study of
structures is a matter of great relevance, as a comprehen- the chemical properties of 1,1,1-trihalo-4-methoxyalk-3-
sive library of these compounds for biological studies is en-2-one compounds,8 which are important halogen-con-
very much desired. Pyrazoles and isoxazoles are of con- taining building blocks that can be employed in the prep-
siderable interest due to their herbicidal, fungicidal, insec- aration of many heterocyclic compounds, e.g., isoxazoles,
ticidal, analgesic, antipyretic and anti-inflammatory pyrazoles, pyrazolium chlorides, pyrrolidines, pyrim-
properties.5,6
idines, thiazines, diazepines, thiazoles, selenazoles and
quinolines.8 Some aminopyrazoles have been prepared
from b-ketonitrile,9 cyanoethylene compounds10 or by the
[4+1] cyclocondensation of a-haloketene hydrazones
with isocyanides.11 All these methods show only NH2 as a
substituent group on the heterocycle requiring an extra
step (N-alkylation or N-acylation) to obtain different
amines. Stachel12 has used benzoylketene O,N-acetal
blocks as a precursor to the synthesis of some non-trifluo-
romethyl substituted aminoazoles. The aim of this work is
to report an efficient method for the preparation of new
amines containing an N-(azol-3-yl) group (Scheme 1).
NH R
NH R
HO
CF3
N
N
CF3
N
O
R1
Figure 1 Aminoazoles
SYNTHESIS 2006, No. 9, pp 1485–1493
Advanced online publication: 11.04.2006
x
x
.
x
x
.2
0
0
6
1,1,1-Trihalo-4-methoxyalk-3-en-2-ones were easily
DOI: 10.1055/s-2006-926443; Art ID: M06605SS
© Georg Thieme Verlag Stuttgart · New York
transformed into b-enamino ketones upon reaction with

1486
M. A. P. Martins et al.
PAPER
NH
R
NH
R
HO
CF3
ii
O
OEt
OEt
N
N
58–86%
N
CF3
N
R1
3i, j
CF3
R1
O
NH
R
i
+
4a–l,5a,d,f,g,i,j
54–98%
CF3
OEt
R
NH2
1a–o
2a–o
NH
R
HO
CF3
iii
N
53–83%
O
6a,e–h,j,k,m–o
Scheme 1 Reagents and conditions: i: a) MeCN, 25 °C, 2 h (1a–g, R–NH2); b) MeCN, Et3N, 25 °C, 2 h (1h–l, R–NH2·HCl); c) EtOH, H2O,
pyridine, 40 °C, 48 h (1m–o, R–NH2·HCl); ii: NH2NHR1·HCl, Et3N, EtOH, reflux, 8 h; iii: NH2OH·HCl, pyridine, MeOH, reflux, 4 h
amines.13 The b-ethoxy-b-enamino ketones 2, the key pre- 4–8 hours. These reactions occur with exclusive displace-
cursors for the preparation of the new aminoazoles de- ment of the ethoxy substituent because of the primary
scribed in this work, were similarly prepared from 1,1,1- amino groups’ poor ability to act as leaving groups. The
trifluoro-4,4-dimethoxybut-3-en-2-one (Scheme 1 and correct regiochemistry of the cyclocondensation cannot
Table 1). We have found one report in the literature14 de- be distinguished using the non-labeled hydrazine reagent,
scribing a procedure to obtain compounds 2 by stirring but from reactions with phenylhydrazine, we have ob-
1,1,1-trifluoro-4,4-dimethoxy but-3-en-2-one and the cor- served an exclusive coupling of the N-phenylamino group
responding alkyl amine 1 at room temperature in acetoni- to the carbonyl carbon of the enaminone. This assignment
trile for 18 hours. We significantly improved the is based on the 1H NMR spectra of the products obtained
efficiency of this reaction in solvent-free conditions. from enaminones 2i and 2j, reactions which allowed the
Higher yields of 2 were obtained after two hours of con- intermediate 3-N-arylamino-5-hydroxy-5-trifluorometh-
tinuous stirring. In cases involving volatile amines 1a,b, yl-1-phenyl-4,5-dihydropyrazoles, 3i,j (not isolated, en-
aqueous solutions of the amines were used. The experi- tries 17 – 18, Table 1). The observance of two doublets in
ment leading to 2a was carried out using gaseous ammo- the 1H NMR of 3i,j [3i, d = 2.67 (J = 19 Hz); 2.39 (J = 19
nia, since it gave better yields when compared to the Hz); 3j, d = 3.43 (J = 17 Hz); 3.05 (J = 17 Hz)] is in per-
experiment involving an aqueous solution. Some amines fect agreement with values reported in the literature for
1h–l were liberated from the corresponding ammonium analogous 1,5-isomers of 4,5-dihydropyrazoles.15a,b The
salts, and this was accomplished by a reaction with pyri- regiochemistry of the cyclocondensation reaction can,
dine (or triethylamine). Compounds 2m–o were prepared therefore, be understood by the acid–base concept. In both
from the corresponding amino esters in reactions that re- cases, cyclization to pyrazoles and dihydroisoxazoles, we
quire long reaction times (48 h). In every case, the stereo- found the harder basic site of the dinucleophile, phenylhy-
chemistry of the enamino ketones 2 was assigned based drazine or hydroxylamine bonded to the harder carbonyl
on 1H NMR spectroscopy. The downfield peak of the ami- carbon acidic site of the enaminone 2. The 4,5-dihydropy-
no protons (10–12 ppm) suggests the existence of hydro- razole intermediates 3i,j were detected only in these cases.
gen bonding, and therefore a cis-relationship between NH Aromatic pyrazole products 5 were produced from reac-
and the C=O groups has been deduced (E-configuration). tions with all the other amines depicted in Table 1.
In a second step, this work involved the cyclocondensa- The cyclocondensation of the b-enamino ketones 2 with
tion reaction of enaminones 2 with the dinucleophile hy- hydroxylamine was examined (reaction iii, entries 21–30,
drazine and hydroxylamine. Considering that the main Scheme 1 and Table 1). The reaction was carried out at a
objectives of this work are: (i) to show the wide scope of molar ratio of 1.0:1.2 using pyridine and methanol as the
synthetic strategies used in the azolylation of amines; and solvent under reflux. Product formation was monitored by
(ii) to show the large number of compounds that can be TLC, and the optimal reaction time was 4 hours.
synthesized, we selected enaminones 2a–e,g,j,k,m–o to
react with hydroxylamine, enaminones 2a–l to react with
hydrazine, and enaminones 2a,d,f,g,i,j to react with phen-
ylhydrazine. The reagents, products and yields of isolated
The reactions regiospecifically produced the 3-amino-
4,5-dihydroisoxazole derivatives 6a,e–g,j,k,m–o, which
are derived from exclusive coupling (amino group to ole-
finic carbon and hydroxyl group to carbonyl carbon) be-
products are shown in Table 1.
tween the enaminone 2 and hydroxylamine. The pair of
The cyclocondensation of N-alkyl and N-aryl enaminones doublets (H-4) observed in the 1H NMR spectra centered
2 and hydrazine (reaction ii, entries 1–12, Table 1) and/or near 3.0 and 3.4 ppm, with J = 17 Hz and the quartet (C-
phenylhydrazine (reaction ii, entries 13–20, Table 1) were 5) observed in the 13C NMR near 100 ppm with 2JC,F = 33
carried out at a molar ratio of 1.0:1.2 using triethylamine Hz are typical spectroscopic data for 4,5-dihydroisox-
and ethanol as the solvent under reflux. Product formation azoles.15c,d
was monitored by TLC, and the optimal reaction time was
Synthesis 2006, No. 9, 1485–1493 © Thieme Stuttgart · New York

PAPER
Synthesis of 3-Amino-5-trifluoromethylazoles
1487
Table 1 Aminoazoles 3–6 Prepared
Entry
1
R
R1
H
H
H
H
H
H
H
H
H
H
H
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
–
Reagents
2a
2b
2c
Product
4a
4b
4c
4d
4e
4f
Yield (%)a
H
+ NH2NH2·HCl
+ NH2NH2·HCl
+ NH2NH2·HCl
+ NH2NH2·HCl
+ NH2NH2·HCl
+ NH2NH2·HCl
+ NH2NH2·HCl
+ NH2NH2·HCl
+ NH2NH2·HCl
+ NH2NH2·HCl
+ NH2NH2·HCl
+ NH2NH2·HCl
+ NH2NHPh·HCl
+ NH2NHPh·HCl
+ NH2NHPh·HCl
+ NH2NHPh·HCl
+ NH2NHPh·HCl
+ NH2NHPh·HCl
+ NH2NHPh·HCl
+ NH2NHPh·HCl
+ NH2OH·HCl
+ NH2OH·HCl
+ NH2OH·HCl
+ NH2OH·HCl
+ NH2OH·HCl
+ NH2OH·HCl
+ NH2OH·HCl
+ NH2OH·HCl
+ NH2OH·HCl
+ NH2OH·HCl
69
78
65
81
58
73
80
62
68
72
75
69
74
86
59
70
2
Me
3
Et
4
CH2CH2OH
CMe2Et
2d
2e
5
6
CH2Ph
2f
7
Ph
2g
2h
2i
4g
4h
4i
8
4-NH2C6H4
4-AcC6H4
4-NO2C6H4
5-methylisoxazol-3-yl
thiazol-2-yl
H
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
2j
4j
2k
2l
4k
4l
2a
2d
2f
5a
5d
5f
CH2CH2OH
CH2Ph
Ph
2g
2i
5g
3i
b
4-AcC6H4
4-NO2C6H4
4-AcC6H4
4-NO2C6H4
H
–
b
2j
3j
–
2i
5i
69
76
81
75
70
70
71
74
59
53
72
64
2j
5j
2a
2e
6a
6e
6f
CMe2Et
–
CH2Ph
–
2f
Ph
–
2g
2h
2j
6g
6h
6j
4-NH2C6H4
4-NO2C6H4
5-methylisoxazol-3-yl
CH2CO2Et
CH(Ph)CO2Me
CH(i-Bu)CO2Et
–
–
–
2k
2m
2n
2o
6k
6m
6n
6o
–
–
–
a Yields of isolated and purified products.
b Product not isolated.
The 3-amino-4,5-dihydroisoxazole products 6 are stable The dehydration reaction of both 4,5-dihydroazoles is an
compounds and they were not converted to the aromatic elimination reaction where the stability of its activated
isoxazoles. However, the aromatization of 6 can be ob- complex depends on the participation of the electron pair
tained easily by stirring these compounds in concentrated of the neighbor heteroatom atom present in the azole ring.
sulfuric acid for a few hours at room temperature.15c
Thus, based on the experimental data15 we believe that the
easier dehydration of 4,5-dihydropyrazoles compared to
Synthesis 2006, No. 9, 1485–1493 © Thieme Stuttgart · New York

1488
M. A. P. Martins et al.
PAPER
4,5-dihydroisoxazole is caused by the larger electron-do-
nating strength of the nitrogen atom (N-1) in the pyrazole
ring than the oxygen atom (O-1) in the oxazole ring.
R
NH R
3
4
7,
O
HN
N
R
7,
N
R
5
N
4
2
F3C
CF3
OCH2CH3
2
3
N1
6
5
6
1
The reactions of 2 with hydrazine and phenylhydrazine
show interesting additional details, depending on the hy-
drazine reagent used and the substitution pattern of the
amino substituent in the enaminone 2. The 4-(dialkylami-
no)-4-ethoxy-1,1,1-trifluorobut-3-en-2-ones 2p and 2q
obtained from 4,4-diethoxy-1,1,1-trifluorobut-3-en-2-one
and aqueous diethylamine and dimethylamine, react with
hydrazine hydrochloride in triethylamine to afford a mix-
ture of the 3-aminopyrazoles 4p,q and the 3-ethoxypyra-
zole 7 (Scheme 2). Competition between the ethoxy and
the N,N-dialkylamino groups to act as the actual leaving
group seems to determine the product.
H
4
2
NH R
3
4
7,
N
R
5
N
F3C
2
N 1
6
6
Figure 2 Atom numbering in compounds 2, 4 and 6 for NMR as-
signments
NR2
OEt
rated in vacuo. The residue was extracted with CHCl3 (2 × 20 mL),
washed with H2O (3 × 20 mL), dried (MgSO4) and filtered, and the
solvent was evaporated in vacuum. The crude compounds 2a–d,f,g
were obtained with good purity, and 2e was purified by chromatog-
raphy on a silica gel column with CHCl3 as an eluent.
OEt
NR2
i
N
N
F3C
F3C
N
H
N
O
CF3
H
2p R = Et
4p,q
7
2q R = Me
(minor)
(major)
(E)-4-Amino-4-ethoxy-1,1,1-trifluorobut-3-en-2-one (2a)
Yield: 4.35 mmol (87%); mp 76–77 °C.
Scheme 2 Reagents and conditions: i: NH2NH2·HCl, Et3N, EtOH,
1H NMR: see Ref. 14.
reflux, 8 h
13C NMR (100 MHz, CDCl3): d = 175.9 (q, JC,F = 32 Hz, C-2),
2
171.6 (C-4), 117.8 (q, 1JC,F = 286 Hz, C-1), 73.4 (C-3), 65.2 (C-5),
To summarize, we have achieved an efficient procedure to
synthesize 3-aminoazoles from b-ethoxy-b-enamino
ketones. Specifically, 3-amino-5-hydroxy-5-trifluoro-
methyl-4,5-dihydroisoxazoles and 3-amino-5-trifluoro-
methylpyrazoles were obtained in good yields. The
reaction is regiospecific, with the attachment of the harder
basic site of the dinucleophile to the carbonyl carbon atom
of the enaminone, and no signs of other isomers were de-
tected. Also, the reaction described in this paper is a very
practical and easy method for the preparation of second-
ary N-(azol-3-yl) amines.
14.0 (C-6).
MS: m/z (%) = 183 (M+, 100), 155 (77), 100 (99), 69 (61).
(E)-4-Ethoxy-1,1,1-trifluoro-4-(methylamino)but-3-en-2-one
(2b)
Yield: 4.30 mmol (86%); mp 95–96 °C.
1H NMR: see Ref. 14.
2
13C NMR (100 MHz, CDCl3): d = 173.1 (q, JC,F = 33 Hz, C-2),
169.8 (C-4), 117.7 (q, 1JC,F = 286 Hz, C-1), 71.9 (C-3), 65.2 (C-5),
29.9 (C-7), 13.3 (C-6).
MS: m/z (%) = 197 (M+, 69), 128 (66), 100 (100), 69 (61).
Unless otherwise indicated, all solvents were used as obtained from
commercial suppliers without further purification. All melting
points were measured using a Reichert-Thermovar melting-point
microscope and are uncorrected. Yields listed are of isolated and
purified compounds. 1H and 13C NMR spectra were recorded on a
Bruker DPX 400 spectrometer (1H at 400.13 MHz and 13C at 100.63
MHz, respectively) at 298 K with a digital resolution of 0.01 ppm.
CDCl3, acetone-d6 or DMSO-d6 (0.5 M) were used as solvents con-
taining TMS as in internal standard. All spectra were acquired in a
5 mm tube, at natural abundance. Atom numbering for NMR spec-
tral assignments is shown in Figure 2.
(E)-4-Ethoxy-4-(ethylamino)-1,1,1-trifluorobut-3-en-2-one (2c)
Yield: 4.00 mmol (80%); mp 84–86 °C.
1H NMR (400 MHz, CDCl3): d = 10.49 (br, 1 H, NH), 5.11 (s, 1 H,
H-3), 4.17 (q, 2 H, J = 7 Hz, H-5), 3.38 (quin, 2 H, J = 7 Hz, H-7),
1.42 (t, 3 H, J = 7 Hz, H-6), 1.23 (t, 3 H, J = 7 Hz, N–R).
2
13C NMR (100 MHz, CDCl3): d = 174.0 (q, JC,F = 32 Hz, C-2),
169.5 (C-4), 117.9 (q, 1JC,F = 286 Hz, C-1), 72.3 (C-3), 65.4 (C-5),
35.2 (C-7), 14.3 (N–R), 13.9 (C-6).
MS: m/z (%) = 211 (M+, 68), 69 (100).
Mass spectra were registered in a HP 5973 MSD connected to a HP
6890 GC and interfaced by a Pentium PC. The GC was equipped
with a split-splitless injector, autosampler, cross-linked HP-5 capil-
lary column (30 m, 0.32 mm of internal diameter), and He was used
as the carrier gas.
(E)-4-Ethoxy-1,1,1-trifluoro-4-(2-hydroxyethylamino)but-3-
en-2-one (2d)
Yield: 4.35 mmol (87%); mp 100–102 °C.
1H NMR (400 MHz, CDCl3): d = 10.48 (br, 1 H, NH), 5.01 (s, 1 H,
H-3), 4.16 (q, 2 H, J = 7 Hz, H-5), 3.68 (t, 2 H, J = 7 Hz, N–R), 3.45
(t, 2 H, J = 7 Hz, H7), 1.41 (t, 3 H, J = 7 Hz, H-6).
(E)-4-Amino-4-ethoxy-1,1,1-trifluorobut-3-en-2-ones 2a–g;
General Procedure
The appropriate amine (5 mmol, gaseous ammonia or aqueous so-
lution for volatile amines, Scheme 1), was added to 4,4-diethoxy-
1,1,1-trifluorobut-3-en-2-one (1.06 g, 5 mmol) in MeCN (20 mL) at
r.t. The mixture was stirred for 2 h and then the solvent was evapo-
2
13C NMR (100 MHz, CDCl3): d = 173.9 (q, JC,F = 32 Hz, C-2),
169.5 (C-4), 117.8 (q, 1JC-F = 286 Hz, C-1), 72.6 (C-3), 65.5 (C-5),
59.8 (N–R), 42.3 (C-7), 13.5 (C-6).
MS: m/z (%) = 227 (M+, 20), 69 (100).
Synthesis 2006, No. 9, 1485–1493 © Thieme Stuttgart · New York

PAPER
Synthesis of 3-Amino-5-trifluoromethylazoles
1489
1
(E)-4-Ethoxy-1,1,1-trifluoro-4-(tert-pentylamino)but-3-en-2-
one (2e)
Yield: 4.25 mmol (85%); oil.
13C NMR (100 MHz, CDCl3): d = 197.1 (N–R), 176.2 (q, J = 33
Hz, C-2), 167.9 (C-4), 151.4, 133.7, 130.8, 121.3 (C6H5), 120.7 (q,
1J = 289 Hz, C-1), 74.9 (C-3), 66.9 (C-5), 26.4 (N–R), 14.1 (C-6).
1H NMR (400 MHz, CDCl3): d = 10.67 (br, 1 H, NH), 5.07 (s, 1 H,
H-3), 4.18 (q, 2 H, J = 7 Hz, H-5), 1.72 (q, 2-H, J = 7 Hz, N–R),
1.44 (t, 3-H, J = 7 Hz, H-6), 1.36 (s, 6 H, N–R), 0.92 (t, 3 H, J = 7
Hz, N–R).
MS: m/z (%) = 301 (M+, 84), 258 (100), 189 (54), 110 (36), 69 (58).
(E)-4-Ethoxy-1,1,1-trifluoro-4-(4-nitroanilino)but-3-en-2-one
(2j)
Yield: 3.85 mmol (77%); mp 110–112 °C.
2
13C NMR (100 MHz, CDCl3): d = 173.7 (q, JC,F = 32 Hz, C-2),
169.7 (C-4), 118.1 (q, 1JC,F = 285 Hz, C-1), 72.7 (C-3), 65.4 (C-5),
55.6 (C-7), 34.1 (N–R), 26.7 (N–R), 13.9 (C-6), 8.1 (N–R).
MS: m/z (%) = 253 (M+, 44), 224 (69), 184 (49), 114 (100), 86 (75),
1H NMR (400 MHz, acetone-d6): d = 12.39 (br, 1 H, NH), 7.99–6.83
(m, 5 H, C6H5), 5.45 (s, 1 H, H-3), 4.30 (q, 2 H, J = 7 Hz, H-5), 1.54
(t, 3 H, J = 7 Hz, H-6).
13C NMR (100 MHz, acetone-d6): d = 175.3 (q, 2JC,F = 33 Hz, C-2),
167.2 (C-4), 141.3, 128.4, 125.1, 120.6 (C6H5) 118.1 (q, 1JC,F = 286
Hz, C-1), 73.8 (C-3), 66.7 (C-5), 12.7 (C-6).
58 (100).
(E)-4-(Benzylamino)-4-ethoxy-1,1,1-trifluorobut-3-en-2-one
(2f)
MS: m/z (%) = 304 (M+, 60), 276 (41), 235 (50), 207 (47), 108 (93),
69 (100).
Yield: 3.50 mmol (70%); mp 62–63 °C.
1H NMR (400 MHz, CDCl3): d = 10.83 (br, 1 H, NH), 7.23–7.39 (m,
5 H, C6H5), 5.13 (s, 1 H, H-3), 4.48 (d, 2 H, J = 7 Hz, H-7), 4.13 (q,
2 H, J = 7 Hz, H-5), 1.36 (t, 3 H, J = 7 Hz, H-6).
(E)-4-Ethoxy-1,1,1-trifluoro-4-[(5-methylisoxazol-3-yl)ami-
no]but-3-en-2-one (2k)
Yield: 3.50 mmol (70%); mp 118–120 °C.
2
13C NMR (100 MHz, CDCl3): d = 174.7 (q, JC,F = 33 Hz, C-2),
169.1 (C-4), 136.5, 128.6, 128.3, 127.5 (C6H5), 118.3 (q, 1JC,F = 286
Hz, C-1), 72.6 (C-3), 65.4 (C-5), 44.7 (C-7), 14.0 (C-6).
MS: m/z (%) = 273 (M+, 23), 244 (23), 204 (21), 106 (61), 91 (100).
1H NMR (400 MHz, acetone-d6): d = 12.54 (br, 1 H, NH), 6.45 (s,
1H, N–R), 5.49 (s, 1 H, H-3), 4.48 (q, 2 H, J = 7 Hz, H-5), 2.41 (s,
3 H, N–R), 1.52 (t, 3H, J = 7 Hz, H-6).
13C NMR (100 MHz, acetone-d6): d = 176.8 (q, 2JC,F = 33 Hz, C-2),
171.5 (C-4), 168.4, 156.9, 94.5, 12.1 (C, isoxazolyl), 118.1 (q,
1JC,F = 286 Hz, C-1), 74.4 (C-3), 68.3 (C-5), 13.8 (C-6).
(E)-4-Anilino-4-ethoxy-1,1,1-trifluorobut-3-en-2-one (2g)
Yield: 4.15 mmol (83%); oil.
1H NMR: see Ref. 14.
MS: m/z (%) = 264 (M+, 52), 195 (85), 167 (33), 125 (100).
13C NMR (100 MHz, CDCl3): d = 175.3 (q, JC,F = 33 Hz, C-2),
2
(E)-4-Ethoxy-1,1,1-trifluoro-4-(1,3-thiazol-2-ylamino)but-3-en-
2-one (2l)
Yield: 3.70 mmol (74%); mp 150–152 °C.
1H NMR (400 MHz, CDCl3): d = 12.88 (br, 1 H, NH), 7.32 (d, 1 H,
J = 4 Hz, N–R), 6.92 (d, 2 H, J = 4 Hz, N–R), 5.19 (s, 1 H, H-3),
4.25 (q, 2 H, J = 7 Hz, H-5), 1.47 (t, 3 H, J = 7 Hz, H-6).
13C NMR (100 MHz, CDCl3): d = 176.4 (q, 2J = 34 Hz, C-2), 164.8
(C-4), 155.8, 138.5, 114.8 (C, thiazolyl), 117.1 (q, 1J = 286 Hz, C-
1), 73.6 (C-3), 67.6 (C-5), 13.6 (C-6).
167.7 (C-4), 135.9, 129.3, 127.4, 122.1 (C6H5), 117.9 (q, 1JC,F = 286
Hz, C-1), 73.6 (C-3), 66.2 (C-5), 14.0 (C-6).
MS: m/z (%) = 259 (M+, 67), 231 (27), 162 (57), 144 (44), 93 (100).
(E)-4-Amino-4-ethoxy-1,1,1-trifluorobut-3-en-2-ones 2h–l;
General Procedure
The appropriate amine hydrochloride (5.2 mmol, Scheme 1) was
added to a solution of the 4,4-diethoxy-1,1,1-trifluorobut-3-en-2-
one (5 mmol) and Et3N (1.06 g, 5.2 mmol) in MeCN (10 mL). The
mixture was stirred at r.t. for 2 h and extracted with CH2Cl2 (2 × 20
mL). The combined CH2Cl2 extracts were washed with water (2 ×
20 mL) and evaporated. When necessary, the products were recrys-
tallized from n-hexane.
MS: m/z (%) = 266 (M+, 42), 197 (56), 127 (100), 101 (57), 69 (68).
(E)-4-Amino-4-ethoxy-1,1,1-trifluorobut-3-en-2-ones 2m–o;
General Procedure
The appropriate solution of amino ester hydrochloride (5.2 mmol)
in a mixture (20:1) of EtOH–H2O (5 mL) was added to a solution of
the 4,4-diethoxy-1,1,1-trifluorobut-3-en-2-one (1.06 g, 5 mmol)
and pyridine (410 mg, 5.2 mmol) in EtOH (20 mL). The mixture
was stirred at 40 °C for 48 h and extracted with CHCl3 (2 × 20 mL).
The combined CHCl3 extracts were washed with H2O (2 × 10 mL).
The residue obtained after evaporation of CHCl3 was recrystallized
from a mixture of n-hexane–EtOAc (4:1).
(E)-4-(4-Aminoanilino)-4-ethoxy-1,1,1-trifluorobut-3-en-2-one
(2h)
Yield: 2.75 mmol (55%); mp 120–121 °C.
1H NMR (400 MHz, CDCl3): d = 12.23 (br, 1 H, NH), 7.28–6.64 (m,
5 H, C6H5), 5.23 (s, 1 H, H-3), 4.23 (q, 2 H, J = 7 Hz, H-5), 3.66 (br,
2 H, NH2), 1.43 (t, 3 H, J = 7 Hz, H-6).
2
13C NMR (100 MHz, CDCl3): d = 174.6 (q, JC,F = 33 Hz, C-2),
167.4 (C-4), 144.5, 126.8, 123.9, 116.7 (C6H5), 118.5 (q, 1JC,F = 289
4-Ethoxy-4-[ethyl (L)-glycinate]-1,1,1-trifluorobut-3-en-2-one
(2m)
Yield: 3.75 mmol (75%); oil.
1H NMR (400 MHz, CDCl3): d = 10.66 (br, 1 H, NH), 5.15 (s, 1 H,
H-3), 4.27 (q, 2 H, J = 7 Hz, H-5), 4.14 (q, 2 H, J = 7 Hz, N–R), 4.09
(d, 2 H, J = 7 Hz, H-7), 1.41 (t, 3 H, J = 7 Hz, H-6), 1.29 (t, 3 H,
J = 7 Hz, N–R).
Hz, C-1), 73.4 (C-3), 66.0 (C-5), 14.1 (C-6).
MS: m/z (%) = 274 (M+, 100), 229 (18), 205 (74), 177 (36), 132
(63).
(E)-4-(4-Acetylanilino)-4-ethoxy-1,1,1-trifluorobut-3-en-2-one
(2i)
Yield: 3.95 mmol (79%); mp 132–133 °C.
1H NMR (400 MHz, CDCl3): d = 12.55 (br, 1 H, NH), 7.95–7.43 (m,
5 H, C6H5), 5.32 (s, 1 H, H-3), 4.33 (q, 2 H, J = 7 Hz, H-5), 2.59 (s,
3 H, H-12), 1.54 (t, 3 H, J = 7 Hz, H-6).
2
13C NMR (100 MHz, CDCl3): d = 175.3 (q, JC,F = 33 Hz, C-2),
169.7 (N–R), 168.0 (C-4), 117.8 (q, 1JC,F = 286 Hz, C-1), 72.6 (C-
3), 65.8 (C-7), 61.5 (C-5), 42.1 (N–R), 14.0 (N–R), 13.9 (C-6).
MS: m/z (%) = 269 (M+, 66), 200 (80), 168 (100), 139 (69).
Synthesis 2006, No. 9, 1485–1493 © Thieme Stuttgart · New York

1490
M. A. P. Martins et al.
PAPER
(E)-4-Ethoxy-1,1,1-trifluoro-4-[methyl (L)-phenylglyci-
nate]but-3-en-2-one (2n)
5-Trifluoromethyl-3-(2-hydroxyethylamino)-1H-pyrazole (4d)
Yield: 1.62 mmol (81%); mp 124–126 °C.
Yield: 3.55 mmol (71%); oil.
1H NMR (400 MHz, acetone-d6): d = 5.58 (s, 1 H, H-4), 3.59 (t, 2
H, J = 7 Hz, N–R), 3.12 (t, 2 H, J = 7 Hz, H-7).
13C NMR (100 MHz, acetone-d6): d = 152.3 (C-3), 142.5 (q,
2JC,F = 37 Hz, C-5), 123.0 (q, 1JC,F = 268 Hz, C-6), 85.0 (C-4), 61.4
(N–R), 48.2 (C-7).
1H NMR (400 MHz, CDCl3): d = 11.26 (br, 1 H, NH), 7.38 (s, 5 H,
C6H5), 5.40 (d, 2 H, J = 7 Hz, H-7), 5.28 (s, 1 H, H-3), 4.11 (q, 2 H,
J = 7 Hz, H-5), 3.69 (s, 3 H, N–R), 1.31 (t, 3 H, J = 7 Hz, H-6).
13C NMR (100 MHz, CDCl3): d = 175.6 (q, JC,F = 33 Hz, C-2),
2
169.8 (N–R), 169.0 (C-4), 136.2 (N–R), 129.1, 128.8, 127.1, 124.3
(C6H5) 118.9 (q, 1JC,F = 286 Hz, C-1), 73.2 (C-3), 66.2 (C-7), 62.6
(C-5), 58.6 (N–R), 14.3 (C-6).
MS: m/z (%) = 331 (M+, 5), 272 (100), 244 (5), 106 (63), 79 (15).
MS: m/z (%) = 195 (M+, 22), 164 (100), 144 (63), 66 (38).
5-Trifluoromethyl-3-(tert-pentylamino)-1H-pyrazole (4e)
Yield: 1.16 mmol (58%); oil.
1H NMR (400 MHz, CDCl3): d = 5.69 (s, 1 H, H-4), 1.48 (q, 2 H,
J = 7 Hz, N–R), 1.11 (s, 6 H, N–R), 0.86 (t, 3 H, J = 7 Hz, N–R).
(E)-4-Ethoxy-1,1,1-trifluoro-4-[ethyl (L)-leucinate]but-3-en-2-
one (2o)
Yield: 3.70 mmol (74%); oil.
1H NMR (400 MHz, CDCl3): d = 11.26 (br, 1 H, NH), 7.38 (s, 5 H,
C6H5), 5.40 (m, 1 H, H-7), 5.28 (s, 1 H, H-3), 4.11 (q, 2 H, J = 7 Hz,
H-5), 1.31 (t, 3 H, J = 7 Hz, H-6), 1.70 (m, 3 H, N–R), 0.96 (d, 6 H,
J = 7 Hz, N–R).
13C NMR (100 MHz, CDCl3): d = 148.2 (C-3), 142.3 (q, 2JC,F = 37
1
Hz, C-5), 122.2 (q, JC-F = 268 Hz, C-6), 88.2 (C-4), 54.1 (C-7),
33.4 (N–R), 26.6 (N–R), 8.2 (N–R).
MS: m/z (%) = 221 (M+, 28), 206 (30), 192 (100), 151 (71), 71 (72),
55 (51).
13C NMR (100 MHz, CDCl3): d = 175.6 (q, JC,F = 33 Hz, C-2),
2
3-(Benzylamino)-5-trifluoromethyl-1H-pyrazole (4f)
Yield: 1.46 mmol (73%); oil.
1H NMR (400 MHz, CDCl3): d = 7.29 (m, 5 H, C6H5), 5.63 (s, 1 H,
H-4), 4.24 (s, 2 H, H-7).
13C NMR (100 MHz, CDCl3): d = 151.0 (C-3), 141.9 (q, 2JC,F = 37
Hz, C-5), 137.9, 128.6, 127.5, 117.0 (C6H5), 121.9 (q, JC,F = 268
171.0 (N–R), 169.8 (C-4), 118.9 (q, 1JC,F = 286 Hz, C-1), 72.5 (C-
3), 65.8 (C-5), 62.3 (N–R), 52.1 (C-7), 40.9 (N–R), 22.4 (N–R),
21.5 (N–R), 21.3 (N–R), 13.7 (C-6), 13.5 (N–R).
MS: m/z (%) = 325 (M+, 17), 252 (100), 224 (19), 139 (23), 86 (73),
69 (28).
1
Hz, C-6), 85.6 (C-4), 49.2 (C-7).
MS: m/z (%) = 241 (M+, 86), 222 (16), 164 (22), 91 (100), 65 (60).
3-Amino-5-trifluoromethyl-1H-pyrazoles 4a–l; 5a,d,f,g,i,j;
General Procedure
Hydrazine hydrochloride (144 mg, 2.1 mmol) [or phenylhydrazine
hydrochloride (304 mg, 2.1 mmol)] and Et3N (212 mg, 2.1 mmol)
were added to a stirred solution of 2 (2 mmol) in EtOH (15 mL) at
r.t. The mixture was stirred under reflux for 8 h and then extracted
with CHCl3 (2 × 20 mL). The combined CHCl3 extracts were
washed with H2O (2 × 10 mL) and evaporated. The oily residue was
purified by chromatography (silica gel 230-400 mesh) with CHCl3
or CHCl3–MeOH (1%) as eluent.
3-Anilino-5-trifluoromethyl-1H-pyrazole (4g)
Yield: 1.60 mmol (80%); mp 81–82 °C.
1H NMR (400 MHz, CDCl3): d = 7.30–6.96 (m, 5 H, C6H5), 6.25 (s,
1 H, H-4).
2
13C NMR (100 MHz, CDCl3): d = 146.0 (q, JC,F = 37 Hz, C-5),
141.3 (C-3), 141.7, 129.6, 121.9, 116.5 (C6H5), 120.9 (q, 1JC,F = 267
Hz, C-6), 91.9 (C-4).
3-Amino-5-trifluoromethyl-1H-pyrazole (4a)
Yield: 1.38 mmol (69%); mp 82–84 °C.
MS: m/z (%) = 227 (M+, 100), 208 (10), 178 (8), 157 (10), 77 (23).
1H NMR (400 MHz, CDCl3): d = 5.78 (s, 1 H, H-4).
3-(4-Aminoanilino)-5-trifluoromethyl-1H-pyrazole (4h)
Yield: 1.24 mmol (62%); oil.
1H NMR (400 MHz, CDCl3): d = 6.87 – 6.64 (m, 5 H, C6H5), 5.98
(s, 1 H, H-4), 5.83 (br, 1 H, NH).
13C NMR (100 MHz, CDCl3): d = 148.3 (C-3), 141.9 (q, 2JC,F = 38
Hz, C-5), 121.8 (q, 1JC,F = 268 Hz, C-6), 88.3 (C-4).
MS: m/z (%) = 151 (M+, 100), 132 (49), 103 (49), 75 (36), 52 (47).
13C NMR (100 MHz, CDCl3): d = 147.8 (C-3), 141.3 (q, 2JC,F = 38
1
Hz, C-5), 142.0, 133.0, 127.7, 116.4 (C6H5), 121.0 (q, JC,F = 269
3-(Methylamino)-5-trifluoromethyl-1H-pyrazole (4b)
Yield: 1.56 mmol (78%); oil.
Hz, C-6), 89.1 (C-4).
MS: m/z (%) = 242 (M+, 100), 223 (12), 172 (10), 145 (19), 119
(39), 65 (36).
1H NMR (400 MHz, CDCl3): d = 5.55 (s, 1 H, H-4), 2.71 (s, 3 H, H-
7).
13C NMR (100 MHz, CDCl3): d = 152.2 (C-3), 142.2 (q, 2JC,F = 37
3-(4-Acetylanilino)-5-trifluoromethyl-1H-pyrazole (4i)
Yield: 1.36 mmol (68%); mp 123–125 °C.
1H NMR (400 MHz, acetone-d6): d = 7.90–7.17 (m, 5 H, C6H5), 6.47
(s, 1 H, H-4), 2.48 (s, 3 H, N–R).
Hz, C-5), 121.3 (q, 1JC,F = 268 Hz, C-6), 84.8 (C-4), 31.4 (C-7).
MS: m/z (%) = 165 (M+, 100), 144 (56), 102 (18), 75 (38), 67 (61),
52 (39).
13C NMR (100 MHz, acetone-d6): d = 197.7 (N–R), 149.3, 146.0 (C-
3), 141.8 (q, 2JC,F = 37 Hz, C-5), 149.3, 132.4, 130.8, 115.7 (C6H5),
123.1 (q, 1JC,F = 269 Hz, C-6), 94.9 (C-4), 27.2 (N–R).
3-(Ethylamino)-5-trifluoromethyl-1H-pyrazole (4c)
Yield: 1.30 mmol (65%); oil.
1H NMR (400 MHz, acetone-d6): d = 5.63 (s, 1 H, H-4), 3.17 (q, 2
H, J = 7 Hz, H-7), 1.22 (t, 3 H, J = 7 Hz, N–R).
MS: m/z (%) = 269 (M+, 53), 254 (100), 206 (9), 157 (20), 129 (9),
90 (11).
13C NMR (100 MHz, acetone-d6): d = 150.3 (C-3), 141.5 (q,
2JC,F = 37 Hz, C-5), 120.9 (q, 1JC,F = 268 Hz, C-6), 83.4 (C-4), 38.9
(C-7), 13.6 (N–R).
5-Trifluoromethyl-3-(4-nitroanilino)-1H-pyrazole (4j)
Yield: 1.44 mmol (72%); mp 133–135 °C.
MS: m/z (%) = 179 (M+, 61), 164 (100), 144 (77), 102 (12), 75 (29),
52 (40).
Synthesis 2006, No. 9, 1485–1493 © Thieme Stuttgart · New York

PAPER
Synthesis of 3-Amino-5-trifluoromethylazoles
1491
1H NMR (400 MHz, acetone-d6): d = 8.58–7.71 (m, 5 H, C6H5), 6.84
(s, 1 H, H-4).
13C NMR (100 MHz, CDCl3): d = 154.7 (C-3), 142.2 (q, 2JC,F = 39
1
Hz, C-5), 137.8, 132.4, 129.7, 116.6 (C6H5), 120.9 (q, JC,F = 267,
C-6), 92.8 (C-4).
MS: m/z (%) = 303 (M+, 100), 167 (9), 128 (9), 116 (9), 77 (78), 51
(35).
13C NMR (100 MHz, acetone-d6): d = 150.4 (C-3), 140.9 (q,
2JC,F = 38 Hz, C-5), 138.2, 126.9, 126.6, 114.9 (C6H5), 122.1 (q,
1JC,F = 268 Hz, C-6), 95.7 (C-4).
MS: m/z (%) = 272 (M+, 100), 242 (37), 157 (30), 90 (20), 75 (20).
3-(4-Acetylanilino)-5-trifluoromethyl-1-phenyl-1H-pyrazole
(5i)
5-Trifluoromethyl-3-[(5-methylisoxazol-3-yl)amino]-1H-pyra-
zole (4k)
Yield: 1.50 mmol (75%); mp 164–166 °C.
1H NMR (400 MHz, acetone-d6): d = 6.30 (s, 1 H, N–R), 5.91 (s, 1
H, H-4), 2.34 (s, 3 H, N–R).
Yield: 1.38 mmol (69%); oil.
1H NMR (400 MHz, CDCl3): d = 7.90–6.93 (m, 10 H, 2 C6H5), 6.54
(s, 1 H, H-4), 2.54 (s, 3 H, N–R).
13C NMR (100 MHz, CDCl3): d = 195.6 (N–R), 149.2 (C-3), 142.4
(q, 2JC,F = 38 Hz, C-5), 139.0, 131.5, 129.3, 114.9 (C6H5), 122.3 (q,
1JC,F = 268 Hz, C-6), 98.5 (C-4), 25.9 (N–R).
13C NMR (100 MHz, acetone-d6): d = 170.1, 160.6, 98.5, 12.0 (C,
2
isoxazolyl), 151.8 (C-3), 140.4 (q, JC,F = 37 Hz, C-5), 123.5 (q,
1JC,F = 269 Hz, C-6), 95.5 (C-4).
MS: m/z (%) = 345 (M+, 26), 330 (100), 232 (6), 205 (8), 77 (40).
MS: m/z (%) = 232 (M+, 100), 218 (21), 202 (39), 175 (51), 151
(37).
5-Trifluoromethyl-3-(4-nitroanilino)-1-phenyl-1H-pyrazole
(5j)
Yield: 1.52 mmol (76%); oil.
1H NMR (400 MHz, acetone-d6): d = 7.98–7.40 (m, 10 H, 2 C6H5),
6.60 (s, 1 H, H-4).
13C NMR (100 MHz, acetone-d6): d = 156.9 (C-3), 143.9 (q,
2JC,F = 38 Hz, C-5), 138.8, 131.2, 127.4, 113.6 (C6H5), 122.5 (q,
1JC,F = 267 Hz, C-6), 99.9 (C-4).
5-Trifluoromethyl-3-(thiazol-2-ylamino)-1H-pyrazole (4l)
Yield: 1.38 mmol (69%); mp 200 °C.
1H NMR (400 MHz, DMSO-d6): d = 7.24 (d, 1 H, J = 4 Hz, N–R),
6.87 (d, 1 H, J = 4 Hz, N–R), 6.38 (s, 1 H, H-4).
13C NMR (100 MHz, DMSO-d6): d = 162.9, 137.8, 109.1, (C, thia-
2
zolyl), 144.3 (C-3), 139.3 (q, JC,F = 37 Hz, C-5), 121.6 (q,
1JC,F = 266 Hz, C-6), 89.9 (C-4).
MS: m/z (%) = 348 (M+, 100), 318 (14), 205 (12), 77 (63), 51 (24).
MS: m/z (%) = 234 (M+, 100), 202 (43), 175 (62), 151 (40), 52 (25).
3-Amino-5-trifluoromethyl-5-hydroxy-4,5-dihydroisoxazoles
6a,e–h,j,k,m–o; General Procedure
3-Amino-5-trifluoromethyl-1-phenyl-1H-pyrazole (5a)
Yield: 1.48 mmol (74%); oil.
1H NMR (400 MHz, CDCl3): d = 7.65–7.28 (m, 5 H, C6H5), 5.75 (s,
1 H, H4), 2.82 (br, 2 H, NH2).
Hydroxylamine hydrochloride (144 mg, 2.1 mmol) and pyridine
(166 mg, 2.1 mmol) were added to a stirred solution of 2 (2 mmol)
in MeOH (15 mL) at r.t. The mixture was stirred at 40 °C for 4 h and
extracted with CH2Cl2 (2 × 20 mL). The combined CH2Cl2 extracts
were washed with H2O (2 × 10 mL). The crude product obtained by
removal of solvent was recrystallized from a mixture of n-hexane–
EtOAc (9:1).
13C NMR (100 MHz, CDCl3): d = 148.9 (C-3), 142.8 (q, 2JC,F = 37
1
Hz, C-5), 130.2, 129.5, 126.7, 124.6 (C6H5), 123.5 (q, JC,F = 268
Hz, C-6), 88.0 (C-4).
MS: m/z (%) = 227 (M+, 100), 208 (13), 131 (21), 92 (23), 77 (51).
3-Amino-5-trifluoromethyl-5-hydroxy-4,5-dihydroisoxazole
(6a)
5-Trifluoromethyl-3-[(2-hydroxyethyl)amino]-1-phenyl-1H-
pyrazole (5d)
Yield: 1.72 mmol (86%); oil.
1H NMR (400 MHz, CDCl3): d = 7.28–7.18 (m, 5 H, C6H5), 5.64 (s,
1 H, H-4), 3.64 (t, 2-H, J = 5 Hz, N–R), 3.18 (t, 2-H, J = 5 Hz, H-7).
Yield: 1.62 mmol (81%); mp 85–87 °C.
1H NMR (400 MHz, acetone-d6): d = 5.36 (br, 2 H, NH2), 3.44 (d, 1
H, J = 17 Hz, H-4a), 3.06 (d, 1 H, J = 17 Hz, H-4b).
13C NMR (100 MHz, acetone-d6): d = 158.2 (C-3), 123.1 (q,
1JC,F = 282 Hz, C-6), 102.6 (q, 2JC,F = 33 Hz, C-5), 43.2 (C-4).
13C NMR (100 MHz, CDCl3): d = 148.4 (C-3), 142.6 (q, 2JC,F = 37
MS: m/z (%) = 170 (M+, 66), 153 (9), 138 (13), 101 (100), 69 (52),
55 (33).
1
Hz, C-5), 129.6, 128.9, 128.6, 119.8 (C6H5), 120.1 (q, JC,F = 269
Hz, C-6), 84.9 (C-4), 60.2 (N–R), 47.5 (C-7).
MS: m/z (%) = 271 (M+, 66), 240 (100), 220 (46), 213 (78), 77 (94).
5-Trifluoromethyl-5-hydroxy-3-(tert-pentylamino)-4,5-dihy-
droisoxazole (6e)
Yield: 1.50 mmol (75%); mp 100–101 °C.
1H NMR (400 MHz, acetone-d6): d = 5.21 (s, 1 H, OH), 3.42 (d, 1
H, J = 17 Hz, H-4a), 3.05 (d, 1 H, J = 17 Hz, H-4b), 1.71 (q, 2 H,
J = 7 Hz, N–R), 1.31 (s, 6 H, N–R), 0.83 (t, 3 H, J = 7 Hz, N–R).
13C NMR (100 MHz, acetone d6): d = 156.0 (C-3), 123.8 (q,
1JC,F = 282 Hz, C-6), 101.3 (q, 2JC,F = 33 Hz, C-5), 54.7 (C-7), 45.1
(C-4), 32.3 (N–R), 26.3 (N–R), 8.5 (N–R).
3-(Benzylamino)-5-trifluoromethyl-1-phenyl-1H-pyrazole (5f)
Yield: 1.18 mmol (59%); oil.
1H NMR (400 MHz, CDCl3): d = 7.52 – 7.29 (m, 10 H, 2 C6H5), 5.74
(s, 1 H, H-4), 4.25 (s, 2 H, H-7).
13C NMR (100 MHz, CDCl3): d = 148.6 (C-3), 142.7 (q, 2JC,F = 38.1
Hz, C-5), 132.5, 129.0–124.6 (2 C6H5), 121.2 (q, 1JC,F = 269.1 Hz,
C-6), 85.7 (C-4), 49.7 (C-7).
MS: m/z (%) = 317 (M+, 25), 298 (3), 91 (100), 77 (21), 65 (14).
MS: m/z (%) = 240 (M+, 33), 211 (35), 170 (100), 101 (62), 71 (81),
55 (42).
3-Anilino-5-trifluoromethyl-1-phenyl-1H-pyrazole (5g)
Yield: 1.40 mmol (70%); oil.
1H NMR (400 MHz, CDCl3): d = 7.58–7.42 (m, 10 H, 2 C6H5), 6.38
(s, 1 H, H-4).
3-(Benzylamino)-5-trifluoromethyl-5-hydroxy-4,5-dihydro-
isoxazole (6f)
Yield: 1.40 mmol (70%); mp 88–90 °C.
Synthesis 2006, No. 9, 1485–1493 © Thieme Stuttgart · New York

1492
M. A. P. Martins et al.
PAPER
1H NMR (400 MHz, acetone-d6): d = 7.39–7.25 (m, 5 H, C6H5), 5.96
(s, 1 H, OH), 4.31 (d, 2 H, J = 6 Hz, H-7), 3.53 (d, 1 H, J = 18 Hz,
H-4a) 3.15 (d, 1 H, J = 18 Hz, H-4b).
1H NMR (400 MHz, acetone-d6): d = 4.14 (q, 2 H, J = 7 Hz, N–R),
3.87 (s, 2 H, H-7), 3.48 (d, 1 H, J = 17 Hz, H-4a), 3.12 (d, 1 H,
J = 17 Hz, H-4b), 1.22 (t, 3 H, J = 7 Hz, N–R).
13C NMR (100 MHz, acetone-d6): d = 158.3 (C-3), 139.7, 130.1,
127.4, 122.7, 118.3 (C6H5), 123.7 (q, 1JC,F = 282 Hz, C-6), 102.8 (q,
2JC,F = 33 Hz, C-5), 47.7 (C-7), 43.5 (C-4).
13C NMR (100 MHz, acetone-d6): d = 170.7 (N–R), 166.2 (C-3),
1
2
123.3 (q, JC,F = 282 Hz, C-6), 103.9 (q, JC,F = 33 Hz, C-5), 67.1
(N–R), 45.2 (C-4), 40.8 (C-7), 14.5 (N–R).
MS: m/z (%) = 260 (M+, 12), 106 (11), 91 (100), 77 (9), 65 (10).
MS: m/z (%) = 256 (M+, 30), 183 (100), 102 (25).
3-Anilino-5-trifluoromethyl-5-hydroxy-4,5-dihydroisoxazole
(6g)
5-Trifluoromethyl-5-hydroxy-3-[methyl (L)-phenylglycinate]-
4,5-dihydroisoxazole (6n)
Yield: 1.40 mmol (70%); mp 72–73 °C.
Yield: 1.44 mmol (72%); mp 64–67°C.
1H NMR (400 MHz, acetone-d6): d = 8.24 (br, 1 H, NH), 7.39–6.82
(m, 5 H, C6H5), 3.88 (d, 1 H, J = 17 Hz, H-4a), 3.26 (d, 1 H, J = 17
Hz, H-4b).
1H NMR (400 MHz, acetone-d6): d = 7.45–7.33 (m, 5 H, C6H5), 5.17
(s, 1 H, H-7), 3.67 (s, 3 H, N–R), 3.54 (d, 1 H, J = 18 Hz, H-4a),
3.22 (d, 1 H, J = 18 Hz, H-4b).
13C NMR (100 MHz, acetone-d6): d = 154.9 (C-3), 123.6 (q,
13C NMR (100 MHz, acetone-d6): d = 172.1 (N–R), 157.2 (C-3),
2
1
1JC,F = 282 Hz, C-6), 102.5 (q, JC,F = 33 Hz, C-5), 140.7, 129.5,
137.9, 129.7, 127.9, 117.3 (C6H5), 123.7 (q, JC,F = 283 Hz, C-6),
122.1 118.4 (C6H5), 44.4 (C-4).
MS: m/z (%) = 246 (M+, 100), 229 (6), 214 (22), 131 (71), 92 (33),
103.1 (q, 2JC,F = 31 Hz, C-5), 60.7 (N–R), 52.8 (C-7), 43.3 (C-4).
MS: m/z (%) = 259 (M+ – 59 [CO2Me], 100), 104 (21), 77 (13).
77 (54).
5-Trifluoromethyl-5-hydroxy-3-[ethyl (L)-leucinate]-4,5-dihy-
droisoxazole (6o)
Yield: 1.28 mmol (64%); mp 91–93 °C.
3-(4-Aminoanilino)-5-trifluoromethyl-5-hydroxy-4,5-dihydro-
isoxazole (6h)
Yield: 1.42 mmol (71%); mp 102–104 °C.
1H NMR (400 MHz, CDCl3): d = 7.32–6.62 (m, 4 H, C6H5), 3.57 (d,
1 H, J = 17 Hz, H-4a), 3.12 (d, 1 H, J = 17 Hz, H-4b).
1H NMR (400 MHz, CDCl3): d = 4.22 (q, 3 H, J = 7 Hz, N–R), 3.52
(t, 1 H, J = 7 Hz, H-7), 3.41 (d, 1 H, J = 17 Hz, H-4a), 3.16 (d, 1 H,
J = 17 Hz, H-4b), 1.70–1.30 (m, 3 H, N–R), 0.96 (d, 6 H, N–R).
13C NMR (100 MHz, CDCl3): d = 154.8 (C-3), 123.7 (q, 1JC,F = 282
Hz, C-6), 101.7 (q, 2JC,F = 33 Hz, C-5), 146.8, 136.9, 120.8, 115.5
(C6H5), 44.6 (C-4).
MS: m/z (%) = 261 (M+, 100), 243 (15), 229 (22), 146 (32), 107
(77).
13C NMR (100 MHz, CDCl3): d = 174.2 (N–R), 157.1 (C-3), 122.1
(q, 1JC,F = 285 Hz, C-6), 102.2 (q, 2JC,F = 33 Hz, C-5), 61.6 (N–R),
54.7 (C-7), 42.7 (C-4), 41.4 (N–R), 24.9 (N–R), 22.6 (N–R), 22.1
(N–R), 14.2 (N–R).
MS: m/z (%) = 312 (M+, 7), 280 (38), 256 (48), 239 (100), 210 (92),
197 (67), 183 (71), 171 (23), 69 (31).
5-Trifluoromethyl-5-hydroxy-3-(4-nitroanilino)-4,5-dihydro-
isoxazole (6j)
Yield: 1.48 mmol (74%); mp 141–142 °C.
Acknowledgment
1H NMR (400 MHz, acetone-d6): d = 9.10 (br, 1 H, NH), 8.21–7.68
(m, 4 H, C6H5), 3.81 (d, 1 H, J = 17 Hz, H-4a), 3.37 (d, 1 H, J = 17
Hz, H-4b).
The authors thank the Conselho Nacional de Desenvolvimento
Científico e Tecnológico (CNPq/PADCT) and the Fundação de
Amparo à pesquisa do Estado do Rio Grande do Sul (FAPERGS)
for financial support. The fellowships from CNPq, CAPES and FA-
PERGS are also acknowledged.
1
13C NMR (100 MHz, acetone-d6): d = 155.6 (C-3), 124.5 (q, JC-
F = 282 Hz, C-6), 103.2 (q, 2JC-F = 33 Hz, C-5), 143.3, 127.9, 127.4,
119.2 (C6H5), 45.1 (C-4).
MS: m/z (%) = 291 (M+, 100), 273 (22), 243 (11), 162 (14), 132
(42), 76 (33).
References
(1) Malpass, J. R.; Lindsey, R. J. In Comprehensive Organic
Chemistry, Vol. 2; Barton, D.; Ollis, W. D., Eds.; Pergamon:
Oxford, 1979, 1–143.
(2) (a) Elguero, J. In Comprehensive Heterocyclic Chemistry,
Vol. 5; Katritzky, A. R.; Rees, C. W., Eds.; Pergamon:
Oxford, 1984. (b) Elguero, J. In Comprehensive
Heterocyclic Chemistry, Vol. 2; Katritzky, A. R.; Rees, C.
W.; Scriven, E. F., Eds.; Pergamon: Oxford, 1996.
(3) (a) Novinson, T.; Robins, R. K.; Matthews, T. R. J. Med.
Chem. 1977, 20, 296. (b) Penning, T. D. J. Med. Chem.
1997, 40, 1347. (c) Hainzl, D.; Cole, L. M.; Casida, J. E.
Chem. Res. Toxicol. 1998, 11, 1529. (d) Unverferth, K.;
Engel, J.; Höfgen, N.; Rostock, A.; Günter, R.; Lankau, H.-
J. J. Med. Chem. 1998, 41, 63. (e) Talley, J. J. J. Med.
Chem. 2000, 43, 775. (f) Talley, J. J. J. Med. Chem. 2000,
43, 1661. (g) Kordik, C. P.; Luo, C.; Zanoni, B. C.; Dax, S.
L.; McNally, J. J.; Lovemberg, T. W.; Wilson, S. J.; Reitz,
A. B. Bioorg. Med. Chem. Lett. 2001, 11, 2283.
5-Trifluoromethyl-5-hydroxy-3-[(5-methylisoxazol-3-yl)ami-
no]-4,5-dihydroisoxazole (6k)
Yield: 1.18 mmol (59%); mp 87–89 °C.
1H NMR (400 MHz, CDCl3): d = 8.61 (br, 1 H, NH), 5.98 (s, 1 H,
N–R), 3.47 (d, 1 H, J = 18 Hz, H-4a), 3.06 (d, 1 H, J = 18 Hz, H-
4b), 2.41 (s, 3 H, N–R)
13C NMR (100 MHz, CDCl3): d = 170.7, 160.2, 96.6, 12.4 (C, isoxa-
1
zolyl), 154.3 (C-3), 123.6 (q, JC,F = 284 Hz, C-6), 103.1 (q,
2JC,F = 33 Hz, C-5), 43.7 (C-4).
MS: m/z (%) = 251 (M+, 91), 219 (23), 182 (100), 149 (24), 108
(47).
5-Trifluoromethyl-5-hydroxy-3-[ethyl (L)-glycinate)]-4,5-dihy-
droisoxazole (6m)
Yield: 1.06 mmol (53%); mp 98–100 °C.
(4) Both databases are from MDL Information System.
Synthesis 2006, No. 9, 1485–1493 © Thieme Stuttgart · New York

PAPER
(5) (a) Welch, J. T. Tetrahedron 1987, 43, 3123. (b) Gaeda, B.
Synthesis of 3-Amino-5-trifluoromethylazoles
1493
(9) (a) Watson, S. P.; Wilson, R. D.; Judd, D. B.; Richards, S. A.
Tetrahedron Lett. 1997, 38, 9065. (b) Mitsui Chemicals
Inc., Chiba-Ken. Japan, US Patent 6235911, 2001.
(10) (a) Tominaga, Y.; Yoshioka, N.; Kataoka, S.; Aoyama, N.;
Masuman, T.; Miike, A. Tetrahedron Lett. 1995, 36, 8641.
(b) Zaharan, M. A.; Sh. El-Sharief, A. M.; El-Gaby, M. S.
A.; Ammar, Y. A. Il Farmaco 2001, 56, 277.
(11) El Kaïm, L.; Atlan, V.; Buron, C. Synlett 2000, 489.
(12) Stachel, H. D. Chem. Ber. 1963, 96, 1088.
(13) Hojo, M.; Masuda, R.; Okada, E. Synthesis 1986, 1013.
(14) Hojo, M.; Masuda, R.; Okada, E.; Yamamoto, H.;
Morimoto, K.; Okada, K. Synthesis 1990, 195.
(15) (a) Bonacorso, H. G.; Lewandowski, H.; Drekener, R. L.;
Costa, M. B.; Pereira, C. M. P.; Wastowski, A. D.; Peppe, C.;
Martins, M. A. P.; Zanatta, N. J. Fluorine Chem. 2003, 122,
159. (b) Bonacorso, H. G.; Wastowski, A. D.; Muniz, M. N.;
Zanatta, N.; Martins, M. A. P. Synthesis 2002, 1079.
(c) Martins, M. A. P.; Siqueira, G. M.; Bastos, G. P.;
Bonacorso, H. G.; Zanatta, N. J. Heterocycl. Chem. 1996,
33, 1619. (d) Martins, M. A. P.; Pereira, C. M. P.; Cunico,
W.; Moura, S.; Rosa, F. A.; Peres, R. L.; Machado, P.;
Zanatta, N.; Bonacorso, H. G. Ultrason. Sonochem. 2005, in
press.
J.; McDermott, L. J. Heterocycl. Chem. 1993, 30, 49.
(c) Ishii, S.; Yagi, K.; Umehara, T.; Kudo, M.; Nawamaki,
T.; Watanabe, S. Japanese Patent 129171, 1990; Chem.
Abstr. 1990, 113, 172014. (d) Shimori, H.; Ishii, T.;
Yamazaki, H.; Yanasc, Y.; Tanaka, Y. German Patent 3713,
1987; Chem. Abstr. 1988, 108, 112445. (e) Buntaim, J. G.;
Hatton, L. R.; Hawkins, D.; Pearson, C. J.; Roberts, D. A.
Eur. Pat. Appl. 295,117, 1988; Chem. Abstr. 1990, 112,
35845. (f) Mcazza, G.; Zanardi, G. J. Heterocycl. Chem.
1993, 30, 365.
(6) (a) Gombos, Z.; Nyitrai, J.; Doleschall, G.; Kolonits, P.;
Párkányi, L.; Kálmán, A. J. Chem. Soc., Perkin Trans. 1
1993, 139. (b) Paravelo, P.; Varasi, M. Synth. Commun.
1992, 22, 1939. (c) Dannahardt, G.; Kiefer, W.; Lambrecht,
G. Eur. J. Med. Chem. 1995, 30, 839. (d) Bräuner-Osborne,
H.; Nielsen, B.; Krogsgaard-Larsen, P. J. Eur. Phamacol.
1998, 350, 311.
(7) (a) Lin, P.; Jiang, J. Tetrahedron 2000, 56, 3635.
(b) McAtee, J. J.; Schinazi, R. F.; Liotta, D. C. J. Org. Chem.
1998, 63, 2161. (c) Arnone, A.; Bernardi, R.; Blasco, F.;
Cardillo, R.; Resnati, G.; Gerus, I. I.; Kukhar, V. P.
Tetrahedron 1998, 54, 2809.
(8) Martins, M. A. P.; Cunico, W.; Pereira, C. M. P.; Flores, A.
F. C.; Bonacorso, H. G.; Zanatta, N. Curr. Org. Synth. 2004,
1, 391; and references cited therein.
Synthesis 2006, No. 9, 1485–1493 © Thieme Stuttgart · New York