Synthesis and structure of new trichloromethyl-β-diketones - 5-Trichloromethylisoxazole and 5-isoxazolecarboxylic acid derivatives

Article abstract of DOI:10.1139/v05-130

An improved method for the synthesis of a new series of trichloromethyl-β-diketones including 1,1,1-trichloropentan-2,4-dione (2a), 1,1,1-trichloro-3-methylhexan-2,4-dione (2b), 4,4,4-trichloro-1-phenylbutan-1, 3-dione (2c), 4,4,4-trichloro-2-methyl-1-phenylbutan-1,3-dione (2d), 2-trichloroacetylcyclohexanone (2e), 4-tert-butylcyclohexanone (2f), 4-tert-butylcycloheptanone (2g), and 4-tert-butylcyclooctanone (2h) is reported. A multinuclear NMR study showed that β-dicarbonyl compounds 2b and 2d-2h are predominantly in the keto form and 2a and 2c are in the enol form. The trichloromethyl-β-diketones react with hydroxylamine hydrochloride leading to three sets of isoxazole derivatives.

Full text of DOI:10.1139/v05-130

1171
Synthesis and structure of new trichloromethyl-␤-
diketones — 5-Trichloromethylisoxazole and 5-
isoxazolecarboxylic acid derivatives
Marcos A.P. Martins, Sergio Brondani, Victor L. Leidens, Darlene C. Flores,
Sidnei Moura, Nilo Zanatta, Manfredo Hörner, and Alex F.C. Flores
Abstract: An improved method for the synthesis of a new series of trichloromethyl-β-diketones including 1,1,1-
trichloropentan-2,4-dione (2a), 1,1,1-trichloro-3-methylhexan-2,4-dione (2b), 4,4,4-trichloro-1-phenylbutan-1,3-dione
(2c), 4,4,4-trichloro-2-methyl-1-phenylbutan-1,3-dione (2d), 2-trichloroacetylcyclohexanone (2e), 4-tert-butylcyclohexanone
(2f), 4-tert-butylcycloheptanone (2g), and 4-tert-butylcyclooctanone (2h) is reported. A multinuclear NMR study
showed that β-dicarbonyl compounds 2b and 2d–2h are predominantly in the keto form and 2a and 2c are in the enol
form. The trichloromethyl-β-diketones react with hydroxylamine hydrochloride leading to three sets of isoxazole deriva-
tives.
Key words: acetals, acylation, trichloromethyl-1,3-diketones, 2-trichloroacetylcycloalkanones, isoxazoles,
cyclocondensation.
Résumé : On rapporte la mise au point d’une méthode améliorée de synthèse d’une nouvelle série de trichlorométhyl-
β-dicétones, dont la 1,1,1-trichloropentan-2,4-dione (2a), la 1,1,1-trichloro-3-méthylhexan-2,4-dione (2b), la 4,4,4-
trichloro-1-phénylbutan-1,3-dione (2c), la 4,4,4-trichloro-2-méthyl-1-phénylbutan-1,3-dione (2d) et les 2-trichloroacétyl-
cyclohexanone (2e), 4-tert-butylcyclohexanone (2f), 4-tert-butylcycloheptanone (2g) et 4-tert-butylcyclooctanone (2h).
Une étude de RMN multinucléaire a permis de montrer que les composés β-dicarbonylés 2b et 2d–2h existent princi-
palement sous la forme dicétonique alors que les produits 2a et 2c existent sous la forme énolique. Les trichloromé-
thyl-β-dicétones réagissent avec le chlorhydrate d’hydroxylamine pour conduire à trois ensembles de dérivés isoxazoles.
Mots clés : acétals, acylation, trichlorométhyl-1,3-dicétones, 2-trichloroacétylcycloalkanones, isoxazoles, cyclocondensation.
[Traduit par la Rédaction] Martins et al. 1177
Introduction
is a result of the lability of the perchloroalkyl groups in
basic medium (21, 22).
An ongoing research program enabled the development of
a general acetal acylation method for the synthesis of
trihalomethyl-1,3-dielectrophiles and demonstrated their
usefulness for the preparation of heterocycles (1–4). The
easy transformation of the trichloromethyl group attached to
azoles into carboxyl groups led to devoting special attention
to trichloromethyl-1,3-dielectrophiles (5–7).
Although trifluoromethyl-1,3-dicarbonyl compounds are
well-known (8–16), the studies on trichloromethyl-1,3-
dicarbonyl analogs are scarce (17–20). The most employed
method to obtain trifluoromethyl-β-diketones is acylation of
enol and enolates with perfluoralkanoates (8, 11, 16). The
lack of literature and data on trichloromethyl-β-diketones is
due to the acylation of enolates by Claisen condensation be-
ing limited in use to obtain perchloroalkyl-β-diketones. This
Continuing research focus in trichloromethyl substituted
1,3-dielectrophiles and their cyclocondensations with
hydroxylamine hydrochloride prompted us to perform a sys-
tematic study of the dimethoxyacetals acylation with tri-
chloroacetyl chloride. The aim of this investigation is to
report the results of the synthesis of a series of the
trichloromethyl-β-diketones prepared from the reaction of
dimethoxy acetals with trichloroacetyl chloride. Also
1
discussed are H, 13C, and 17O NMR data for isolated β-
dicarbonyl compounds and the influence of the trichloro-
methyl group on the keto–enol equilibrium. In addition, we
report the cyclocondensation reactions of trichloromethyl-β-
dicarbonyl compounds with hydroxylamine hydrochloride
for the synthesis of isoxazole derivatives and the structural
1
study of 4-alkyl substituted 4,5-dihydroisoxazoles. H and
13C NMR and X-ray data showed that cyclocondensation
was enantioselective, only one pair of enantiomers was ob-
tained for 4-alkyl substituted 4,5-dihydroisoxazoles.
Received 27 October 2004. Published on the NRC Research
Press Web site at http://canjchem.nrc.ca on 23 September 2005.
M.A.P. Martins, S. Brondani, V.L. Leidens, D.C. Flores,
S. Moura, N. Zanatta, M. Hörner, and A.F.C. Flores.1
NUQUIMHE, Departamento de Química, Universidade
Federal de Santa Maria, 97.105-900 - Santa Maria, RS,
Brazil.
Results and discussion
Synthesis
Trichloromethyl-␤-diketones
Dimethoxy ketals 1a–1h were synthesized from the
1Corresponding author (e-mail: alexflores@smail.ufsm.br).
Can. J. Chem. 83: 1171–1177 (2005)
doi: 10.1139/V05-130
© 2005 NRC Canada

1172
Can. J. Chem. Vol. 83, 2005
Table 1. Yields, melting points, elemental analysis, and IR stretching frequencies of the β-diketones 2a–2h.
Elemental analysisc
(calcd.)
Elemental analysisc
(found)
IRd νC=O
Molecular
formula
Yield
(%)a
Melting
Compound
point (°C)b
C
H
C
H
C=O
Cl3CC=O
1600
2a
2b
2c
2d
2e
2f
C5H5Cl3O2
C7H9Cl3O2
C10H7Cl3O2
C11H9Cl3O2
C8H9Cl3O2
C12H17Cl3O2
C9H11Cl3O2
C10H13Cl3O2
90
85
95
80
95
80
92
95
Oil
29.50
36.32
45.24
47.26
39.46
48.10
41.97
44.23
2.48
3.92
2.66
3.25
3.73
5.72
4.31
4.82
29.50
36.50
45.50
47.30
39.50
48.00
42.00
44.40
2.50
4.00
2.70
3.30
3.80
5.70
4.30
4.80
1595
1700
1568
1670
1709
1713
1697
1695
Oil
1765
Oil
1593
65–68
88–90
91–93
54–56
44–46
1760
1750
1760
2g
1752
2h
1755
aYields of isolated compounds.
bThe melting points are uncorrected.
cElemental analyses were performed on a CHNS-Vario El Elementar Analysensysteme.
dFilm for 2a–2c and KBr pellets for 2d–2h.
Scheme 1.
Scheme 2.
acetalization reaction of the respective ketones with
trimethyl orthoformate in the presence of p-toluenesulfonic
acid (23). The acylation of compounds 1a–1h was carried
out with trichloroacetyl chloride in chloroform in the pres-
ence of pyridine. The reaction was monitored by HPLC and
the most satisfactory reaction time was found to be 12 h at
25–30 °C for 2a and 2c and 10 h at 50 °C for 2b and 2d–2g.
After the acylation time had elapsed, 2 mol/L sulfuric acid
was added and the mixture was stirred at 50 °C for 2 h. The
trichloromethyl-β-diketones 2a–2h were obtained with good
yields (75%–95%) (Scheme 1). Compounds 2a–2c are liquid
and were purified by column chromatography with silica gel
and hexane–chloroform (9:1) as the eluent. The crystalline
2d–2h compounds were purified by crystallization from
hexane. The yields and selected physical and spectral data
for compounds 2a–2h are reported in Table 1. We have the
acetal acylation method as routine work for 1,1,1-trihalo-4-
alkoxyalk-3-en-2-one synthesis (1–4), however, the posterior
hydrolysis to the respective trichloromethyl-1,3-diketones
closely with structural studies was the new contribution.
good yields (Scheme 2). However, when compounds 3a and
3b and 3e–3h were heated at 75–100 °C for 12 h in an 85%
sulfuric acid solution, respective 5-isoxazole carboxylic ac-
ids 5a and 5b and 5e–5h were obtained with good yields.
Under the same reaction conditions, compounds 3c and 3d
were not converted to the respective carboxylic acids (6).
We are able to demonstrate the effect of the substituents in
the trichloromethyl hydrolysis to the carboxyl group. The 3-
alkyl or 3,4-dialkyl substituted isoxazoles were suitable for
conversion of the 5-trichloromethyl group to a carboxyl,
however, the 3-phenyl substituted isoxazoles did not hydro-
lyse the 5-trichloromethyl group to a carboxyl even if a se-
verely acidic medium was used.
Molecular structure
Trichloromethyl-β-diketones
For compounds 2a and 2c only one set of signals in the
1H, 13C, and 17O NMR spectra was observed, which was as-
1
signed to an enol form (Tables 2 and 3). H NMR spectra
showed the signal of the enolic hydrogen at δ 13.0–14.0, and
the chemical shifts for H-2 and C-2 are typical of vinyl moi-
eties (δ 6.10–6.70 and δ 96.5–97.8, respectively) (see Ta-
bles 2 and 4). The IR spectra have a band at 1568–1595 cm–1
assigned to the absorption of the HO-C= group along with
the band at 1593–1600 cm–1 attributed to the vibration of the
C=O fragment from the trichloroacetyl group. 17O NMR
spectra for 2a and 2c showed two signals at δ 170 and δ 360,
Isoxazole derivatives
The cyclization of 2a–2h with hydroxylamine hydrochlo-
ride was carried out in methanol at 40 °C for 5–8 h. The
products (5-hydroxy-5-trichloromethyl-4,5-dihydroisoxazoles,
3a–3h) were obtained in good yields and they were dehy-
drated with concentrated sulfuric acid at 35 °C for 5 h to af-
ford the corresponding 5-trichloromethylisoxazoles 4a–4h in
© 2005 NRC Canada

Martins et al.
1173
1
Table 2. H NMRa data for 2-trichloroacetylcycloalkanones 2a–2h.
2
Compound
H-2 (mult., JHH Hz)
R1 and R2 (mult.)
2a
2b
2c
2d
2e
2f
6.10 (s)
4.50 (qu, 8.0)
6.70 (s)
5.4 (qu, 8.0)
4.35 (dd)
4.38 (dd, 12.6, 5.2)
2.2 (s) Me, 13.9 enolic hydrogen
2.65 (q) -CH2-, 1.55 (d) Me, 1.08 (t) Me
7.5–7.8 (m) Ar 5H, 12.5 enolic hydrogen
7.93 (m) Ar 2H, 7.45 (m) Ar 3H, 1.45 (d) Me
2.28 (m) H-3, 1.81 (m) H-4, 2.03 (m) H-5, 2.13 (m) H-5, 2.44 (ddd) H-6a, 2.58 (ddd) H-6e
1.93 (dt) H-3a, 2.31 (dm) H-3e (12.6, 12.6, 12.8), 1.71 (tt) H-4a (12.6, 2.8), 1.61 (tdd) H-5a,
2.19 (dm) H-5e (12.8), 2.51 (ddd) H-6a, 2.55 (ddd) H-6e, 0.95 (s) t-Bu
1.41 (m) H-3, 1.98 (m) H-3, 1.57 (m) H-4, 1.98 (m) H-4, 2.14 (m), 1.98 (m) H-5, 1.71 (m),
1.98 (m) H-6, 2.65 (m), 2.75 (m) H-7
2g
2h
4.55 (dd, 10.0, 3.6)
4.70 (dd, 11.4, 3.4)
2.27 (m) H-3e, 2.08 (m) H-3, 1.58 (m) H-4, 1.80 (m), 1.65 (m) H-5, 1.65 (m), 1.30 (m) H-6,
2.07 (m), 1.92 (m) H-7, 2.54 (m), 2.75 (m) H-8
a1H NMR spectra measured at 400 MHz in 0.01 mol/L CDCl3–TMS solutions, in a Bruker DPX 400 spectrometer.
1
Table 3. Selected H and 13C NMRa data for 2e in different solvents.
13C NMR δ
Solvent
δ H-2
2JH-2H-ax (Hz)
2JH-2H-eq (Hz)
C-1
C-2
COCCl3
CCl3
CDCl3
4.35
4.50
4.00
4.60
4.60
11.4
5.6
8.5
5.5
5.4
5.5
204.6
202.2
203.3
205.2
205.0
56.8
57.0
56.8
57.1
57.0
186.2
185.4
186.4
187.4
96.3
97.0
97.0
96.6
97.0
CCl4
8.90
C6D6
12.10
12.40
12.30
(CD3)2CO
(CD3)2SO
187.0
1
a0.01 mol/L solutions with internal TMS, in a Bruker DPX 400 spectrometer with SF 400.13 MHz for H and 100.62 MHz
for 13C.
the range of δ 52–58 for C-2 confirmed the keto structure for
compounds 2b and 2d–2h (Table 4). The IR spectra have a
band at 1670–1713 cm–1 assigned to the absorption of the
aromatic C=O (2d) and aliphatic C=O (2b, 2e–2h) groups,
along with the band at 1750–1765 cm–1 attributed to the vi-
bration of the C=O fragment from the trichloroacetyl group.
The 17O NMR spectra for 2b and 2d–2h showed two near
signals between δ 500–600, typical for nonconjugated car-
bonyl groups (29, 30). Therefore, the trichloroacetyl group
in 2e–2h strongly prefers a pseudo-equatorial position with-
out conjugation.
Table 4. MO calculation data for 2-trichloroacetylcyclohexanone.
The trichloromethyl-β-diketones with substituents at C-α
(between the two carbonyls) prefer the keto form probably
because of thermodynamic factors. Endocyclic or exocyclic
enol forms increase molecular strain by planar placement of
the bulky trichloroacetyl group. For these β-diketones, the
keto–enol equilibrium on the NMR timescale is unlikely.
Commonly simple 1,3-dicarbonyl compounds exhibit high
concentrations of enol forms in solution, except if prohibi-
tive structural factors are present. NMR data showed that 2-
acetylcycloalkanones and 2-trifluoroacetylcycloalkanones
are preferentially enol forms (31). These results showed that
the trichloromethyl group on compounds 2b and 2d–2h
(R2 = alkyl) act like an anchor for the keto form. The 1H and
(or) 13C NMR spectra of 2-trichloroacetylcyclohexanone
(2e) were performed in different deuterated solvents (Ta-
ble 3) without significant change to the spectral and (or)
structural characteristics. The AM1 calculations performed
showed that tautomer III of 2e presents the lowest minimum
energy. The calculated minimum energy values and relative
% values for tautomer and (or) conformer concentrations are
listed in the Table 4.
Note: The MO calculations were carried out by the AM1 semiempirical
method (see Experimental).
aCalculated for the equilibrium at 298 K, as described in the
Experimental.
characteristics for the push–pull conjugated keto–enol sys-
tem (24, 25). Compounds 1,1,1-trichloropentan-2,4-dione
(2a) and 4,4,4-trichloro-1-phenyl-butan-1,3-dione (2c) ex-
hibited the same enolic trend as the fluorinated analogs
1,1,1-trifluoropentan-2,4-dione and 4,4,4-trifluoro-1-phenyl-
butan-1,3-dione, respectively (26, 27) (Table 5).
1
The H, 13C, and 17O NMR spectra for trichloromethyl-β-
diketones 2b and 2d–2h showed that these compounds have
an overall preference for the keto form. The chemical shift
of H-2 is typical of the keto form for compounds 2b and 2d–
2h at δ 4.35–5.48 (Table 2). For compounds 2e–2h, the clear
doublet of doublets signal and the coupling constants (3JHH
)
are consistent with pseudo-axial placement of H-2 (28). The
13C{1H} NMR spectrum for compounds 2b and 2d–2h
showed only one set of peaks for each carbon. The signals in
© 2005 NRC Canada

1174
Can. J. Chem. Vol. 83, 2005
Table 5. 13C and 17O NMR data for trichloromethyl-β-diketones 2a–2h.
13C NMRa
17O NMRb δ (w1/2)
Compound
C-1
C-2
COCCl3
CCl3
R1/R2
C=O
C13CC=O
2a
2b
2c
2d
2e
198.7
204.1
181.5
188.4
204.6
97.8
52.1
96.5
52.0
175.9
186.7
175.5
187.2
186.2
96.8
96.0
95.9
94.3
96.3
26.9 (Me)
176 (170)
553 (410)
165 (170)
550 (750)
557 (470)
370 (230)
538 (480)
360 (400)
540 (750)
538 (470)
34.0 (CH2), 16.5 (Me-3), 7.55 (Me)
136.9, 130.7, 128.1, 127.7 (Ar)
143.9, 132.5, 130.6, 128.0 (Ar), 115 (Me)
23.9, 27.2, 32.7, 41.8
56.8, JCH = 132
2f
205.1
206.1
207.7
56.3, JCH = 132
57.6, JCH = 133
55.0, JCH = 130
186.5
186.6
184.4
96.3
96.2
96.3
28.1, 33.8, 41.3, 46.1
570 (600)
564 (470)
571 (450)
540 (650)
538 (470)
540 (510)
2g
2h
23.9, 28.5, 28.7, 30.3, 43.0
23.8, 24.2, 24.6, 27.5, 33.4, 42.1
a0.01 mol/L CDCl3–TMS solutions in a Bruker DPX 400 spectrometer with SF 100.62 MHz for 13C.
b1.5 mol/L CHCl3 solution, external coaxial reference capillary with H2O in a Bruker DPX 400 spectrometer with SF 54.23 MHz for 17O (locked with
C6D6 in a 5 mm coaxial tube). For details on 17O NMR see ref. 10.
5-Hydroxy-5-trichloromethyl-4,5-dihydroisoxazoles
Fig. 1. ORTEP plot with atom-labeling scheme of the structure
of: (a) 5-trichloromethyl-3-ethyl-5-hydroxy-4-methyl-4,5-
dihydroisoxazol (3b); and (b) 5-trichloromethyl-5-hydroxy-3,4-
hexamethylene-4,5-dihydroisoxazole (3h). Displacement ellip-
soids at the 30% level (see Experimental).
The nonequivalence for the diastereotopic hydrogens H-4a
and H-4b is well-known for 5-hydroxy-5-trichloromethyl-
4,5-dihydroisoxazoles 3a and 3c (19, 20). The 4,5-
dihydroisoxazoles substituted on position 4 have two chiral
centers, the C-4 and the C-5 of the isoxazole ring. However,
the 1H NMR spectra for 3b and 3d showed the signal of H-4
at δ 3.70–3.73 as quartets (3J = 8.0 Hz), and for compounds
1
3e–3h the H NMR spectra showed the H-4 signals at δ
3.15–3.77 as a doublet of doublets; the coupling constant
data is consistent with the pseudo-axial position of H-4 (28).
The 13C{1H} NMR spectra for compound 3 also showed one
set of signals for each carbon atom (see Experimental). The
presence of one set of signals indicates only one pair of en-
antiomers (4R,5R/4S,5S or 4R,5S/4S,5R). The X-ray diffrac-
tion for the monocrystals showed the 4S,5S configuration for
3b and 3h. In these compounds, the alkyl group is cis to the
OH group and the bulky CCl3 group is cis to H-4. The crystal
structures of 3-ethyl-4-methyl-5-hydroxy-5-trichloromethyl-
4,5-dihydroisoxazole (3b) and 5-trichloromethyl-3,4-
hexamethylene-5-hydroxy-4,5-dihydroisoxazole (3h) with
the atomic numbering are displayed in Fig. 1. Previous
structural analyses for X-ray diffraction performed on 3e
showed the 4R,5R configuration (32). X-ray diffraction en-
abled us to conclude that the synthetic procedure used al-
ways furnished a pair of diastereoisomers 4R,5R/4S,5S for
compounds 3b and 3d–3h. The regiochemistry of these
cyclocondensation reactions was discussed in ref. 32. The
NMR and selected physical data from aromatic isoxazole de-
rivatives 4 and 5 are shown in the Experimental.
Conclusion
In summary, this work has presented a convenient one-pot
method to obtain unusual trichloromethyl-β-diketones and
we have demonstrated some important features of their mo-
lecular structure. This series of trichloromethyl-β-diketones
were successfully used as precursors to obtain regiospeci-
fically new 5-trichloromethylisoxazoles and 5-isoxazole
carboxylic acids.
without further purification. All melting points were taken
on a Reichert-Thermovar melting point microscope and are
Experimental
1
uncorrected. The H and 13C NMR spectra were recorded on
Unless otherwise indicated, all common reagents and sol-
vents were used as obtained from commercial suppliers
a Bruker DPX 400 (1H at 400.13 MHz, 13C at 100.62 MHz)
with 5 mm sample tubes, at 300 K, in 0.02 mol/L in CDCl3–
© 2005 NRC Canada

Martins et al.
1175
Table 6. Crystallographic data2 for compounds 3b and 3h.
Crystal data
3b
3h
C7H10Cl3NO2
C10H14Cl3NO2
Molecular formula
Molecular mass
246.51
286.57
Crystal color
Colorless
0.55 × 0.25 × 0.05
Monoclinic
Colorless
0.15 × 0.20 × 0.28
Monoclinic
Crystal size (mm3)
Crystal class
Parameters of the unit cell
a (Å)
b (Å)
9.9547(5)
9.1478(5)
11.8058(6)
1062.12(10)
P21/c
24.667(2)
7.227(4)
18.767(3)
2536.9(15)
C2/c
c (Å)
Volume of the unit cell (V, Å3)
Space group
Number of molecules per unit cell (Z)
Density (d, g/cm3)
4
8
1.543
1.501
Absorption coefficient (µ, mm–1)
Number of independent reflexions
Number of reflexions with I > 2σ(I)
Number of parameters refined
Final residual factor (R)
0.831
2201
2092
119
0.707
2552
2488
150
0.0492
0.0542
TMS, with a digital resolution of 0.01 ppm. The 17O NMR
spectra were recorded at 54.26 MHz in 10 mm tubes, at
323 K, in 2 mol/L CHCl3 solutions, with chemical shifts ref-
erenced to external H2O (capillary coaxial tube). The spectra
were recorded at natural abundance with a ring down elimi-
nate (RIDE) sequence for suppression of acoustic ringing
(31, 32). 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 capillary column (30 m,
0.32 mm i.d.), and helium was used as the carrier gas. The
dimethoxy ketals 1a–1h were synthesized according to the
literature (23) and purified by distillation.
from the minimum energy associated with each compound
employing the relationships: (1) ∆E = –RT ln K (where ∆E
stands for the standard energy difference between two given
species, R is the molar gas constant expressed in units of
kcal mol–1 K–1, T is the absolute temperature in K, K is the
corresponding equilibrium constant) and (2) [I] + [II] + [III] +
[IV] = 100, where [I], [II], [III], and [IV] represent the per-
centage molar ratio of each tautomer and (or) conformer in
equilibrium (Table 4). The calculations were performed us-
ing a Dell Precision 330 Pentium IV 1.4 GHz computer.
Trichloroacetylation of acetals 1a–1h
General procedure
Monocrystals of compounds 3b and 3h were grown from
hexane. Diffraction data were collected at 293(2) K on an
Enraf-Nonius CAD4 automatic four-circle diffractometer
(MoKα, 2θmax = (3b), 2θmax = (3h)) (33). The structures were
solved by direct methods and refined by full-matrix least-
squares in anisotropic approximation. The basic crystallo-
graphic characteristics and the parameters of the refined
crystal structures are cited in Table 6. Calculations were car-
ried out using the programs ZORTEP and SHELXS-93 (34,
35).
To a stirred solution of dimethoxy acetal derivatives 1a–
1h (30 mmol) and pyridine (5.2 mL, 60 mmol) in chloro-
form (30 mL) kept at 0 °C, a solution of trichloroacetyl
chloride (7.0 mL, 60 mmol) in chloroform (20 mL) was
added dropwise. The mixture was stirred for 10–12 h at 25–
50 °C. The mixture was quenched with a 2 mol/L sulfuric
acid solution (30 mL) and stirred for 2 h at 80 °C. The or-
ganic layer was dried with sodium sulfate, the solvent was
evaporated, and the products were obtained with high purity
(see Table 1). The liquid compounds 2a–2c were purified by
column chromatography with Kieselgel 60 and hexane–chlo-
roform (9:1) as the eluent. The crystalline compounds 2d–2h
were purified by recrystallization from hexane.
MO calculations were performed using the Austin Model
(AM1) semiempirical method, implemented in the
1
HyperChem 4.5 package (1995) (36). Geometries were com-
pletely optimized without fixing any parameter, thus bring-
ing all geometric variables to their equilibrium values. The
energy minimization protocol employs the Polak–Ribiere al-
gorithm, which is a conjugated gradient method. Conver-
gence to a local minimum was achieved when the energy
gradient was <0.01 kcal mol–1 (1 cal = 4.184 J). The relative
abundance of each species in equilibrium was calculated
Synthesis of 5-trichloromethyl-4,5-dihydroisoxazoles 3a–3h
General procedure
To a stirred solution of trichloromethyl-β-diketones 2a–2h
(15 mmol) in methanol (5 mL), kept at 40 °C, was added
2 Supplementary data for this article are available on the Web site or may be purchased from the Depository of Unpublished Data, Document
Delivery, CISTI, National Research Council Canada, Ottawa, ON K1A 0S2, Canada. DUD 4012. For more information on obtaining mate-
rial refer to http://cisti-icist.nrc-cnrc.gc.ca/irm/unpub_e.shtml. CCDC 241207 and 241208 contain the crystallographic data for this manu-
script. These data can be obtained, free of charge, via www.ccdc.cam.ac.uk/conts/retrieving.html (Or from the Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax +44 1223 336033; or deposit@ccdc.cam.ac.uk).
© 2005 NRC Canada

1176
Can. J. Chem. Vol. 83, 2005
hydroxylamine hydrochloride (1.2 g, 16.5 mmol) in metha-
nol (10 mL). The mixture was stirred for 10 h at 40 °C. The
solvent was evaporated and the solid residue was dried un-
der vacuum. The 3-alkyl-5-trichloromethyl-4,5-dihydroiso-
xazoles 3a and 3b and 3e–3h were recrystallized from
hexane. The 3-phenyl-5-trichloromethyl-4,5-dihydroisoxazoles
3c and 3d were recrystallized from methanol. The overall
yields were higher than 90% (see Scheme 2). 5-
Trichloromethyl-4,5-dihydroisoxazole compounds were
fully characterized by spectroscopic methods. Data for 3a:
characterized by spectroscopic methods. Data for 4a:
C5H4Cl3NO, oil. 1H NMR δ (mult., J Hz): 7.25 (H-4, s), 2.04
(Me-3, s). 13C NMR δ: 160.0 (C-3), 168.5 (C-5), 104.4 (C-
4), 84.8 (CCl3). Anal. calcd.: C 29.96, H 2.01; found: C
1
30.0, H 2.00. 4b: C7H8Cl3NO, oil. H NMR δ (mult., J Hz):
2.60 (CH2, q, 7.4), 2.30 (Me-4, s), 1.1 (Me, t, 7.4). 13C NMR
δ: 160.8 (C-3), 159.3 (C-5), 105.1 (C-4), 84.0 (CCl3). Anal.
calcd.: C 36.79, H 3.53; found: C 37.0, H 3.50. 4c:
C10H6Cl3NO, mp 80–84 °C, lit. value (37) mp 80 to 81 °C.
1H NMR δ (mult., J Hz): 7.41 (H-4, s), 7.20–7.85 (Ph, m).
13C NMR δ: 163.5 (C-3), 169.6 (C-5), 103.2 (C-4), 85.0
(CCl3). Anal. calcd.: C 45.75, H 2.30; found: C 46.0, H
1
C5H6Cl3NO2, mp 125–127 °C, lit. value (19) mp 127 °C. H
NMR δ (mult., J Hz): 3.7 (Ha-4, d, 18.8), 3.25 (Hb-4, d,
18.8), 2.04 (Me-3, s). 13C NMR δ: 156.7 (C-3), 111.0 (C-5),
101.9 (CCl3), 47.9 (C-4). Anal. calcd.: C 27.49, H 2.77;
found: C 27.30, H 2.75. 3b: C7H10Cl3NO2, mp 140–142 °C.
1H NMR δ (mult., J Hz): 3.73 (H-4, q, 7.6), 2.45 (CH2, dq,
J2 = 16, J3 = 7.6), 2.25 (CH2, dq, J2 = 16, J3 = 7.6), 1.35
(Me-4, d, 7.6), 1.20 (Me, t, 7.6). 13C NMR δ: 164.7 (C-3),
109.4 (C-5), 102.3 (CCl3), 49.0 (C-4), 20.0 (CH2), 11.45
(Me-4), 10.2 (Me). Anal. calcd.: C 34.11, H 4.10; found: C
34.00, H 4.20. 3c: C10H8Cl3NO2, mp 155–158 °C, lit. value
1
2.50. 4d: C11H8Cl3NO, oil. H NMR δ (mult., J Hz): 2.40
(Me-4, s), 7.2–7.8 (Ph, m). 13C NMR δ: 162.8 (C-3), 160.2
(C-5), 105.4 (C-4), 83.6 (CCl3). Anal. calcd.: C 47.78, H
2.92; found: C 48.0, H 3.0. 4e: C8H8Cl3NO, mp 174–
1
177 °C. H NMR δ (mult., J Hz): 1.7–2.0 ((CH2)2, m), 2.6–
3.0 ((CH2)3, m). 13C NMR δ: 161.8 (C-3), 159.9 (C-5),
112.8 (C-4), 85.9 (CCl3). Anal. calcd.: C 39.95, H 3.35;
1
found: C 40.4, H 3.5. 4f: C12H16Cl3NO, mp 79–82 °C. H
NMR δ (mult., J Hz): 1.3–3.1 (CH2, m). 13C NMR δ: 162.4
(C-3), 160.4 (C-5), 114.0 (C-4), 86.3 (CCl3). Anal. calcd.: C
48.59, H 5.44; found: C 49.00, H 5.5. 4g: C9H10Cl3NO, mp
1
(38) mp 156 °C. H NMR δ (mult., J Hz): 4.15 (Ha-4, d,
18.8), 3.73 (Hb-4, d, 18.8), 7.1–7.8 (Ph, m). 13C NMR δ:
157.5 (C-3), 112.8 (C-5), 102.5 (CCl3), 45.3 (C-4). Anal.
calcd.: C 42.80, H 2.87; found: C 42.60, H 2.85. 3d:
1
34–37 °C. H NMR δ (mult., J Hz): 1.5–1.9 ((CH2)3, m),
2.7–2.95 ((CH2)2, m). 13C NMR δ: 167.7 (C-3), 161.2 (C-5),
1
C11H10Cl3NO2, mp 170–172 °C. H NMR δ (mult., J Hz):
118.2 (C-4), 86.4 (CCl3). Anal. calcd.: C 42.47, H 3.96;
3.7 (H-4, q, 7.8), 2.2 (Me-4, d, 7.8), 7.0–8.0 (Ph, m). 13C
NMR δ: 156.7 (C-3), 111.0 (C-5), 101.9 (CCl3), 47.9 (C-4).
Anal. calcd.: C 44.85, H 3.42; found: C 45.0, H 3.5. 3e:
C8H10Cl3NO2, mp 148–150 °C, lit. value (38) mp 148–
found: C 42.3, H 3.90. 4h: C10H12Cl3NO, oil, n20 1.5675. H
1
NMR δ (mult., J Hz): 1.0–5.4 (-CH2-, m). 13C NMR δ: 166.4
(C-3), 161.1 (C-5), 116.0 (C-4), 86.4 (CCl3). Anal. calcd.: C
44.72, H 4.50; found: C 44.50, H 4.50.
1
151 °C. H NMR δ (mult., J Hz): 3.15 (H-4, dd, 12.6, 6.0).
13C NMR δ: 161.6 (C-3), 109.0 (C-5), 102.12 (CCl3), 52.8
(C-4). Anal. calcd.: C 37.17, H 3.90; found: C 37.2, H 3.85.
3f: C12H18Cl3NO2, mp 183–186 °C. 1H NMR δ (mult.,
J Hz): 3.52 (H-4, dd, 12.6, 6.0). 13C NMR δ: 161.9 (C-3),
109.2 (C-5), 102.1 (CCl3), 53.4 (C-4). Anal. calcd.: C 45.81,
H 5.77; found: C 46.0, H 5.9. 3g: C9H12Cl3NO2, mp 123–
Synthesis of 5-carboxyisoxazoles 5a and 5b and 5e–5h
General procedure
A mixture of 5-trichloromethyl-4,5-dihydroisoxazoles 3a–
3h (5 mmol) and a solution of 85% sulfuric acid (5–10 mL)
was stirred at 75–100 °C for 5–10 h. The mixture was
slowly poured into 20 mL of ice water; the product 5 was
obtained in high purity by filtration from the cold aqueous
solution and washed with water. The crystalline compounds
5a and 5b and 5e–5h were purified by recrystallization from
hexane–chloroform or hexane. 5-Carboxyisoxazole com-
pounds were fully characterized by spectroscopic methods.
1
125 °C. H NMR δ (mult., J Hz): 3.8 (H-4, ddt, 8.6, 4.8,
1.2). 13C NMR δ: 164.8 (C-3), 109.6 (C-5), 102.2 (CCl3),
55.9 (C-4). Anal. calcd.: C 39.66, H 4.44; found: C 40.0, H
1
4.5. 3h: C10H14Cl3NO2, mp 118–120 °C. H NMR δ (mult.,
J Hz): 3.7 (H-4, dd, 7.2, 4.0). 13C NMR δ: 164.2 (C-3),
110.2 (C-5), 102.5 (CCl3), 54.1 (C-4). Anal. calcd.: C 41.49,
H 4.92; found: C 41.80, H 5.00.
1
5a: C5H5NO3, mp 210 °C, lit. value (6) mp 208–210 °C. H
NMR δ: 7.0 (H-4), 2.3 (Me-3). 13C NMR δ: 158.7 (COOH),
161.5 (C-3), 161.3 (C-5), 110.3 (C-4). Anal. calcd.: C 42.23,
H 3.97; found: C 42.32, H 4.02. 5b: C7H9NO3, mp 210 °C.
1H NMR δ: 7.0 (CH2), 2.3 (Me-4), 1.0 (Me). 13C NMR δ:
158.7 (COOH), 161.5 (C-3), 161.3 (C-5), 110.3 (C-4). Anal.
calcd.: C 54.19, H 5.85; found: C 54.0, H 6.0. 5e: C8H9NO3,
Synthesis of 5-trichloromethylisoxazoles 4a–4h
General procedure
A mixture of 5-trichloromethyl-4,5-dihydroisoxazoles 3a–
3h (5 mmol) and concentrated sulfuric acid (5–10 mL) was
stirred at 25–30 °C for 5 h. The mixture was slowly poured
into 50 mL of ice water and the solution was extracted with
chloroform (3 × 30 mL). The combined organic fractions
were washed with water, dried under anhydrous sodium sul-
fate, and the solvent removed under vacuum. The liquid
compound 4a was purified by distillation and the liquid 4b
was purified by column chromatography with Kieselgel 60
and hexane–chloroform (9:1) as the eluent. The crystalline
compounds 4c and 4d were purified by crystallization from
methanol and crystalline 4e–4h were recrystallized from
hexane. 5-Trichloromethylisoxazole compounds were fully
1
mp 128–130 °C, lit. value (38) mp 128–130 °C. H NMR δ:
1.5–1.9 (CH2)2, 2.6–2.9 (CH2)2. 13C NMR δ: 152.9 (COOH),
162.1 (C-3), 160.8 (C-5), 123.2 (C-4). Anal. calcd.: C 57.48,
H 5.43; found: C 57.60, H 5.5. 5f: C12H17NO3, mp 191–
1
196 °C. H NMR δ: 1.35–3.2 (CH2)2. 13C NMR δ: 152.9
(COOH), 162.5 (C-3), 161.6 (C-5), 124.8 (C-4). Anal.
calcd.: C 64.55, H 7.67; found: C 64.5, H 7.8. 5g:
1
C9H11NO3, mp 132–134 °C. H NMR δ: 1.65–1.8 (CH2)2,
1.85 (CH2), 2.8–3.0 (CH2)2. 13C NMR δ: 152.8 (COOH),
167.2 (C-3), 161.6 (C-5), 128.5 (C-4). Anal. calcd.: C 57.48,
H 5.43; found: C 57.60, H 5.5. 5h: C10H13NO3, mp 130–
© 2005 NRC Canada

Martins et al.
1177
1
132 °C. H NMR δ: 1.5–1.9 (CH2)2, 2.6–2.9 (CH2)2. 13C
14. K.C. Joshi and V.N. Pathak. Coord. Chem. Rev. 22, 37 (1977).
15. J.T. Welch. Tetrahedron, 43, 3123 (1987).
16. J.D. Park, H.A. Brown, and J.R. Lacher. J. Am. Chem. Soc.
75, 4753 (1953).
NMR δ: 153.3 (COOH), 165.7 (C-3), 161.34 (C-5), 126.6
(C-4). Anal. calcd.: C 61.53, H 6.71; found: C 61.5, H 6.70.
17. F. Effenberger, R. Maier, K.-H. Schönwälder, and T. Ziegler.
Acknowledgements
Chem. Ber. 115, 2766 (1982).
18. W. Spiegler and N. Götz. Synthesis, 69 (1986).
19. A. Colla, M.A.P. Martins, G. Clar, S. Krimmer, and P. Fischer.
Synthesis, 483 (1991).
20. M. Hojo, R. Masuda, S. Sakaguchi, and M. Takagawa. Synthe-
sis, 1016 (1986).
The authors are thankful for the financial support from
Fundação de Apoio à Pesquisa do Estado do Rio Grande do
Sul (FAPERGS) and Conselho Nacional de Desenvolvimento
Científico e Tecnológico (CNPq/PADCT III, Proj.62.0228/
97-0–QEQ). Fellowships from CNPq (D.C. Flores, S. Brondani,
S. Moura, V.L. Leidens, and W. Cunico) are also acknowl-
edged.
21. C. Zucco, C.F. Lima, M.C. Rezende, and R.A. Rebelo. J. Org.
Chem. 52, 5356 (1987).
22. C. Zucco, F. Nome, M.C. Rezende, and R.A. Rebelo. Synth.
Commun. 17, 1741 (1987).
23. R.A. Wohl. Synthesis, 38 (1974).
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© 2005 NRC Canada