Trifluoroacetylation of unsymmetrical ketone acetals. A convenient route to obtain alkyl side chain trifluoromethylated heterocycles

Article abstract of DOI:10.1016/S0022-1139(99)00146-3

A convenient method to obtain β-alkyl-β-methoxyvinyl trifluoromethyl ketones [CF₃COCHC(OMe)R, where R = Et, n-Pr, i-Pr, i-Bu, t-Bu, -(CH₂)₂OMe] from the regiospecific acylation of kinetic enol ether generated in situ is reported. The unsymmetrical ketone dimethyl acetals react with trifluoroacetic anhydride in the presence of pyridine using dry chloroform as solvent with a temperature range of 25-60°C. These acetals [R-C(OMe)₂Me] are obtained from the reaction of alkyl methyl ketones with trimethyl orthoformate in the presence of p-toluenesulfonic acid as catalyst in pure methanol as solvent. The new acetylated enol ethers proved to be versatile building blocks for the construction of interesting alkyl trifluoromethyl substituted heterocycles. Thus, examples of isoxazoline, pyrazoline, pyrazole and pyrimidinone have been obtained in good yields (62-79%).

Full text of DOI:10.1016/S0022-1139(99)00146-3

Journal of Fluorine Chemistry 99 (1999) 177±182
Tri¯uoroacetylation of unsymmetrical ketone acetals.
A convenient route to obtain alkyl side chain
tri¯uoromethylated heterocycles
*
Helio G. Bonacorso , Marcos A.P. Martins , Sandra R.T. Bittencourt,
1
Rog e rio V. Lourega, Nilo Zanatta, Alex F.C. Flores
Departamento de Qu Âõ mica, Universidade Federal de Santa Maria, 97.105-900 Santa Maria, RS, Brazil
Received 22 April 1999; accepted 2 July 1999
Abstract
A convenient method to obtain b-alkyl-b-methoxyvinyl tri¯uoromethyl ketones [CF
t-Bu, ±(CH OMe] from the regiospeci®c acylation of kinetic enol ether generated in situ is reported. The unsymmetrical ketone dimethyl
acetals react with tri¯uoroacetic anhydride in the presence of pyridine using dry chloroform as solvent with a temperature range of 25±
08C. These acetals [R±C(OMe) Me] are obtained from the reaction of alkyl methyl ketones with trimethyl orthoformate in the presence of
3
COCH==C(OMe)R, where R = Et, n-Pr, i-Pr, i-Bu,
2 2
)
6
2
p-toluenesulfonic acid as catalyst in pure methanol as solvent. The new acetylated enol ethers proved to be versatile building blocks for the
construction of interesting alkyl tri¯uoromethyl substituted heterocycles. Thus, examples of isoxazoline, pyrazoline, pyrazole and
pyrimidinone have been obtained in good yields (62±79%). # 1999 Elsevier Science S.A. All rights reserved.
Keywords: b-Alkoxyvinyl tri¯uoromethyl ketones; Unsymmetrical ketone dimethyl acetals; Tri¯uoromethylated heterocycles
1
. Introduction
obtained. Moreover, the presence of trace acids in the
acylation reaction leads to the polymerization or hydrolysis
of enol ethers. Recently, an alternative one-pot procedure
with advantages over the direct acylation of enol ethers was
reported. In this procedure, enol ethers, generated in situ
from the respective ketone acetal are acylated to obtain b-
alkoxyvinyl halomethyl ketones [6±8,10±11,38]. This reac-
tion was carried out using the ketone dimethyl acetal and the
acylating reagent in a molar ratio of 1 : 2, respectively in
order to generate the enol ether in situ following by its
acetylation.
On the other hand, we have observed in the literature
many methods to put a desired alkyl side chain in hetero-
cyclic compounds. The great majority of these methods
introduce the alkyl side chain after the isolation of the
heterocyclic structure [28].
The introduction of alkyl chain plays a very important role
in many heterocycles with respect to their biological activity.
For example, pyroctone a pyrimidone described as an anti-
seborrheic agent, nabilone a 9-ketocannabinoid with anti-
emetic properties and nabitran that in addition of being
hypotensive and sedative-hypnotic has more potent analge-
sic effect than codeine [29]. Also, the increase of the
herbicidal activity has been investigated in 3-tri¯uoro-
Several methods for the synthesis of tri¯uoromethyl
enones have been reported [1,2] because the attempts to
perform the synthesis of a very simple tri¯uoromethyl
containing vinyl ketones, by conventional procedures, are
not yet successful. A route to obtain these compounds
has been the direct haloacetylation of acyclic enol
ethers described elsewhere [3±8] and by our research group
[
9±11], which has afforded b-alkoxyvinyl halomethyl
ketones or b-diketones. These haloacetylated enol ethers
have been used as a 3-atom synthetic precursor for the
synthesis of 5-, 6- and 7-membered trihalomethylated
heterocycles [12±23]. Conventionally, enol ethers have
been prepared from symmetrical ketone or aldehyde
acetals [24±26]. However, the isolation of these enol
ethers involves a tedious distillation process and in some
cases (e.g. those derived from unsymmetrical ketones) a
mixture of kinetic and thermodynamic enol ethers are
*
Corresponding author.
E-mail addresses: heliogb@base.ufsm.br (H.G. Bonacorso),
mmartins@base.ufsm.br (M.A.P. Martins)
1
Co-corresponding author.
0022-1139/99/$ ± see front matter # 1999 Elsevier Science S.A. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 9 9 ) 0 0 1 4 6 - 3

1
78
H.G. Bonacorso et al. / Journal of Fluorine Chemistry 99 (1999) 177±182
Scheme 1.
methyl- and 3-t-butyl-pyrazole and pyridin±carboxamide
derivatives [30]. Morever, a review of the literature showed
that the synthesis of important compounds, as pirimidin-2-
ones, from direct cyclization of 1,3-diketones with urea has
not been reported. For example, the synthesis of uracils,
involves the condensation of thiourea or alkylisothioureas
with b-ketoesters [31±33]. The subsequent removal of the S
atom, in order to obtain uracil, involves usually severe
conditions [34,35]. Another indirect method to obtain
tion of acetals derived from alkyl-methyl-dimethylacetals
was not known.
This situation prompted us to investigate the development
of a general method to obtain functionalized precursors for
heterocycles which contain in their structure both an alkyl
side chain and a tri¯uoromethyl group.
The aim of this work is (i) to use the methodology of
acylation of enol ethers, generated in situ from unsymme-
trical ketone dimethyl acetals (2a±f), as a general procedure
to synthesize regiospeci®cally b-alkyl-b-metoxyvinyl tri-
¯uoromethyl ketones (3a±f) derived from unsymmetrical
ketones (1a±f) that contain in their structure both an alkyl
side chain and a tri¯uoromethyl group (Scheme 1); and (ii)
to use one precursor (3d) to obtain interesting tri¯uoro-
methyl alkyl side chain heterocycles (4a±e) from the cyclo-
condensation reactions with hydroxylamine, semicarbazide,
thiosemicarbazide, phenylhydrazine and urea (Scheme 2).
2
-pyrimidin-ones is the condensation of b-ketoesters and
O-methylisourea bisulfate in a slightly basic medium. The
-methoxy-pyrimidin-4-one is then hydrolyzed to the cor-
2
responding uracils [36]. Speci®c and facile synthesis of
tri¯uoromethylated pyrimidin-2-one was developed by our
research group [37]. However, the introduction of an alkyl
side chain has not yet been studied, because the synthesis of
b-alkoxyvyniltri¯uoromethyl ketones from tri¯uoracetyla-
Scheme 2.

H.G. Bonacorso et al. / Journal of Fluorine Chemistry 99 (1999) 177±182
179
2
. Results and discussion
3. Conclusion
The alkyl methyl ketone dimethyl acetals 2a±f were
The regiospeci®city of the reaction on the methyl carbon
of 2a±f is achieved under kinetic control. For the conditions
used, the kinetic enol ether is generated and reacts with the
strong acylating agent [(CF CO) O] present in the medium.
This study affords a methodology to obtain regiospeci®cally
a series of b-methoxyvinyl tri¯uoromethyl ketones (3a±f),
in regular to good yield (see Table 1). This series can be
employed as a tri¯uoromethylated 3-atom block precursor
on organic synthesis, especially to obtain new alkyl side
chain substituted tri¯uoromethylated heterocycles 4a±e (see
Table 2), which often shown biological activity [27].
synthesized from the reaction of the respective unsymme-
trical methyl ketones 1a±f with trimethyl orthoformate
in molar ratio 1 : 1.5 and in the presence of p-toluenesul-
fonic acid [7,10±11,38] as catalyst and using pure
methanol as solvent. The acylation of 2a±f with tri¯uor-
oacetic anhydride in pyridine, in molar ratio 1 : 2 : 2, was
carried out in dry chloroform as solvent. Two equivalents
of the acylating reagent per dimethyl acetal was necessary
to obtain the b-methoxyvinyl tri¯uoromethyl ketones
3
2
3
a±f since one molecule of the acylating promotes the
acylation and a second traps the methoxy group liberated
by the ketone dimethyl acetal and to give methyl tri¯uor-
oacetate.
4. Experimental
A mixture of distilled ketone dimethyl acetals, pyridine
and dry chloroform is added to pure tri¯uoroacetic anhy-
dride at 08C or, with cooling in an ice/salt bath. After the
addition, the optimal reaction time and reaction temperature
for tri¯uoroacetylation were found to be 16 h at 25±308C for
Unless otherwise indicated all common reagents and
solvents were used as obtained from commercial suppliers
without further puri®cation. All boiling and melting points
1
13
are uncorrected. H and C NMR spectra were recorded on
a Bruker DPX-200 spectrometer ( H at 200.13 MHz and 13C
1
3
a±b, 3f and 24 h at 60±658C for 3c±e. It was observed that
the compounds (2a±b, 2f) derived from alkyl methyl
ketones with small substituents (R) could be readily con-
verted into b-methoxyvinyl tri¯uoromethyl ketones 3a±b,
at 50.32 MHz), 298 K and 0.5 M in chloroform-d /TMS
1
(3a±f) or in DMSO-d /TMS (4a±e). The mass spectra were
6
performed on a GC/MS spectrometric system (HP 6890 GC
coupling to HP 5973 mass selective detector).
3
f at ambient temperature. The same reaction must be
carried out for compounds (2c±e), derived from alkyl
methyl ketones with bulky substituent (R), at temperatures
above 608C. As expected, the Michael addition occurred
at the vinyl bond of the compound 1f and the saturated
ketone dimethyl acetal 2f was isolated in good yield.
Under the conditions employed, alkyl methyl ketone
dimethyl acetals react with tri¯uoroacetic anhydride to give
tri¯uoroacetyl vinyl enones (3a±f) in good yields. The
geometrical isomerism (E/Z) for compounds 3a±f have
not yet been determined. In all reactions we have not found
polymerization products and all crude products were pur-
i®ed by distillation. The compounds 3a±f are highly volatile
at room temperature and because of this property the
elemental analysis of 3a±f could not be performed.The
more satisfactory results of these reactions, selected phy-
sical (b.p.), NMR and mass spectral data of 3a±f are
presented in Table 1.
The cyclization reactions for compounds 4a±e were
carried out under similar conditions or with any modi®ca-
tions, as described in the literature [9,17,18,23,37] and are
presented in the experimental part. An important modi®ca-
tion was performed in the synthesis of 4b. This compound
was only obtained where previously the semicarbazide
hydrochloride was treated with sodium methoxide in metha-
nolic medium. On the other hand, the use of the procedure
described in the literature [17] to obtain 4d give a mixture of
4.1. Preparation of unsymmetrical ketone dimethyl acetals
(2a±f)
The ketone dimethyl acetals were synthesized according
with the literature [7,10±11,38] and puri®ed by distillation
process.
4.2. Preparation of b-methoxyvinyl trifluoromethyl ketones
(3a±f)
4.2.1. General procedure
A solution of ketone dimethyl acetals 2a±f (30 mmol) and
pyridine (60 mmol) in 30 ml of chloroform was added
dropwise to stirred pure tri¯uoroacetic anhydride (60 mmol)
kept at 08C. The mixture was stirred for 16 h at room
temperature (25±308C) for 3a±b, 3f or for 24 h at 60±
658C for 3c±e. The mixture was washed with a solution
of hydrochloric acid 0.1 M (once) and water (three times).
The organic layer was dried with magnesium sulfate, the
solvent was removed by rotatory evaporation and the pro-
ducts (3a±f) were puri®ed by distillation under reduced
pressure.
4.3. Preparation of 5-hydroxy-3-iso-butyl-5-
trifluoromethyl-4,5-dihydro-isoxazole (4a)
2
: 1 of 4d and the respective 4,5-dihydro-pyrazoline. This
problem was overcome by addition of sulfuric acid in a
second reaction step, where only 4d was obtained in 75%
yield.
Hydroxylamine hydrochloride (10 mmol) was added to a
stirred solution of 4-methoxy-4-iso-butyl-1,1,1-tri¯uoro-3-

1
80
H.G. Bonacorso et al. / Journal of Fluorine Chemistry 99 (1999) 177±182
Table 1
Selected physical properties and spectral data of compounds 3a-f
a
1H-NMR [ꢀ (ppm)]
13C-NMR [ꢀ
(ppm), JCF (Hz)]
Compound
Yield (%)
Boiling.point
8C) /mBar
Molecular formula
(weight)
MS [m/z (%)]
(
+
182 (M , 77), 165 (1),
3
a
90
49/9.0
C
7
H
H
9
O
2
F
3
(182.14)
5.63 (s, 1H, H-3), 3.81
186.2 (C-4), 188.4
(
(
(
s, 3H, OCH ), 2.83
3
(q, J = 33, C-2), 116.7
150 (3), 113
q, 2H, H-5), 1.14
t, 3H, H-6)
(q, CF
(C-3), 56.5 (OCH
7.4 (C-5), 10.7 C-6)
3
, J = 292), 90.5
(100), 85 (23), 69 (77)
3
),
2
+
196 (M , 50), 181 (33),
3
b
68
37/3.5
C
8
11
O
2
F
3
(196.16)
5.64 (s, 1H, H-3), 3.80
185.2 (C-4), 177.8
(
(
(
(
s, 2H, OCH ), 2.78
3
(q, J = 33, C-2), 116.7
164 (3), 127 (100), 99
(22), 69 (66)
t, 2H, H-5), 1.56
sext, 2H, H-6), 0.97
t, 3H, H-7)
3
(q, J = 292,CF ), 91.0
(C-3), 56.4 (OCH
3
),
35.6 (C-5), 20.3
(
C-6), 13.6 (C-7)
189.2 (C-4), 178.3
(q, J = 33, C-2,), 116.8
(q, J = 292, CF ), 89.7
(C-3), 56.5 (OCH ),
1.2 (C-5), 10.2 (2CH
184.6 (C-4), 178.4
(q, J = 33, C-2), 116.8
(q, J = 292, CF ), 91.5
),
+
196 (M , 95), 181 (17),
3
3
c
50
86
70/16
C
8
H
H
11
O
2
F
3
(196.16)
(210.19)
5.55 (s, 1H, H-3),
3
3
1
.94 (sept, 1H, H-5),
.79 (s, 3H, OCH ),
.11 (d, 6H, 2CH
164 (13), 127 (100), 99
(23), 69(81)
3
3
3
)
3
3
3
)
+
210 (M , 8),195 (81), 141
d
67/9.5
C
9
13
O
2
F
3
5.66 (s, 1H, H-3), 3.79
(
(
(
(
s, 3H, OCH ), 2.71
3
(100), 113 (32), 69 (58)
d, 2H, H-5), 2.01
m, 1H, H-6), 0.95
3
(C-3), 56.5 (OCH
46.0 (C-5), 27.8
3
3
d, 6H, 2CH )
(
3
C-6), 22.0 (2CH )
b
+
210 (M , 6), 195 (48),
3
e
45
51/7.0
C
9
H
13
O
2
F
3
(210.19)
6.05/5.78 (2s, 1H, H-3),
190.9/190.2 (2C-4),
), 176.5/175.2
4
.03/3.80 (2s, 3H, OCH
.23/1.19 (2s, 9H, 3CH
3
141 (100), 113 (35), 69
(58)
1
3
)
(2q, J = 33/42, 2C-2),
17.2/116.7
3
2q, J = 282/291, 2CF ),
1
(
9
6
3
2
1.6/90.1 (2C-3),
3.7/56.7 (2-OCH
9.8/39.5 (2C-5),
3
),
7.7/26.6 [2(3CH
3
)]
+
212 (M , 19), 197 (54),
3
f
62
87/15
C
8
H
11
O
3
F
3
(212.16)
5.70 (s, 1H, H-3), 3.82
181.9 (C-4), 178.1
(q, J = 33, C-2), 116.4
(q, J = 292, CF ), 91.6
(
(
(
(
s, 3H, OCH ), 3.63
3
181 (100), 143 (36), 115
(12), 69(19)
t, 2H, H-6), 3.34
s, 3H, H-7), 3.11
t, 2H, H-5)
3
(C-3), 68.7 (C-7),
57.78 (C-6), 56.3
(
3
OCH ), 33.8 (C-5)
a
Yields of isolated compounds; volatile compounds.
b
Mixture of E/Z isomers.
buten-2-one (5 mmol) and pyridine (10 mmol) in 15 ml of
methanol at room temperature. The mixture was stirred
and heated for 16 h at 45±508C. To this mixture is
added dichloromethane at room temperature. The new
mixture was washed with a solution of hydrochloric
acid 0.5 N (three times) and water (once). The organic
layer was dried with magnesium sulfate, the solvent was
removed by rotatory evaporation and the pure product was
isolated.
was stirred for 24 h at 558C. The product precipitated by
addition of 15 ml of cool water to the reaction. The crystal-
line solid were ®ltered off and recrystallized from hexane-
chloroform 3 : 1.
4.5. Preparation of 5-hydroxy-3-iso-butyl-5-
trifluoromethyl-4,5-dihydro-1H-1-pyrazolethio-
carboxyamide (4c)
To stirred solution of semicarbazide (5 mmol) in 25 m1 of
methanol, kept at 20±258C, pure 4-methoxy-4-iso-butyl-
1,1,1-tri¯uoro-3-buten-2-one (5 mmol) was added and the
mixture was stirred for 24 h at 20±258C.The solvent was
evaporated and hot chloroform was added to the solid
residue. The insoluble thiosecarbazide was ®ltered off.
The product was crystallized by addition of hexane to the
chloroform solution (1 : 2).
4
.4. Preparation of 5-hydroxy-3-iso-butyl-5-
trifluoromethyl-4,5-dihydro-1H-1-pyrazole-
carboxyamide (4b)
To a stirred solution of semicarbazide (10 mmol) in 10 ml
of methanol, 4-methoxy-4-iso-butyl-1,1,1-tri¯uoro-3-
buten-2-one (5 mmol) was added at 20±258C. The mixture

H.G. Bonacorso et al. / Journal of Fluorine Chemistry 99 (1999) 177±182
181
Table 2
Selected physical and spectral data of compounds 4a-e
a
Yield (%)
b
1H-NMR [ꢀ (ppm),
J (Hz)]
13C-NMR [ꢀ (ppm),
CF (Hz)]
Compound
Melting
point (8C)
Molecular formula
(weight)
J
4
a
65
99±100
C
8
H
12
F
3
NO
2
8.20 (s, 1H, OH), 3.35
159.0 (C3), 122.7 (q, J = 284,
CF ), 102.6 (q, J = 33, C5),
(211.18)
(d, 1H, J = 19, H4a), 3.02
3
(d, 1H, J = 19, H4b), 2.19
(d, 2H, H3'1, 1.88
(m, 1H, H3'2), 0.90
(d, 3H, H3'3), 0.87
(d, 3H, H3'3)
44.56 (C4), 35.6 (C3'1), 25.5
(C3'2), 22.1 (1C, C3'3), 21.9
(1C, C3'3)
4
b
67
100±101
C
9
H
14
F
3
N
3
O
2
7.30 (s, 1H, OH), 6.54
(s, 2H, NH ), 3.30
d, 1H, J = 19, H4a), 3.01
155.1 (C = 0),154.1 (C3), 123.6
(q, J = 286, CF ), 90.1 (q, J = 33,
(253.22)
2
3
(
(
(
(
(
(
C5), 46.7 (C4), 38.0 (C3'1), 25.6
(C3'2), 22.3 (1C, C3'3), 22.1
(1C, C3'3)
d, 1H, J = 19, H4b), 2.18
d, 2H, H3'1), 1.93
m, 1H, H3'2), 0.91
d, 3H, H3'3), 0.88
d, 3H, H3'3)
4
c
79
106±107
C
9
H
14
F
3
N
3
OS
9.15 (s, 1H, NHa), 9.02
(s,1H, OH), 8.55
176.1 (C5), 158.4 (C3), 123.7 (q,
(269.28)
3
J = 290, CF ), 91.9 (q, J = 33,
(s, 1H, NHb), 4.00
(d, 1H, J = 19, H4a), 3.83
(d, 1H, J = 19, H4b), 2.70
(d, 2H, H3'1), 2.49
(m, 1H, H3'2), 1.42
(d, 3H, H3'3), 1.37
(d, 3H, H3'3)
C5), 46.4 (C4), 38.0 (C3'1), 25.4
(C3'2), 22.4 (1C, C3'3), 22.0
(1C, C3'3)
4
d
75
Oil
C
14
H
15
F
3
N
2
8.10±7.98 (m, 5H, Ar±H),
7.40 (s, 1H, H4), 3.05
152.1, 129.1, 128.8, 125.5
(Ar±C), 138.7 (C3) 131.4
(q, J = 39, C5), 120.1
(268.28)
(
(
(
d, 2H, H3'1), 2.49
m, 1H, H3'2), 1.45
d, 6H, H3'3)
(q, J = 268, CF
36.3 (C3'1), 28.0 (C3'2), 22.0
C3'3)
3
),108.5 (C4),
(
4
e
62
123±124
C
9
H
11
F
3
N
2
O
12.77 (s, 1H, NH), 6.78
(s, 1H, H5), 2.56
168.0 (C = O),161.0
(220.19)
(q, J = 35, C4), 157.5
3
(C6), 120.0 (q, J = 277, CF ),
(
(
(
d, 2H, H6'1), 2.07
m, 1H, H6'2), 0.92
d, 6H, H6'3)
99.7 (C5), 48.6 (C6'1), 29.2
(C6'2), 22.3 (2C, C6'3)
a
Yields of isolated compounds.
b
Sactisfactory microanalyses obtained: C Æ 0.15, H Æ 0.11 N Æ 0 33.
4
.6. Preparation of 3-iso-butyl-5-trifluoromethyl-1H-1-
phenylpyrazol (4d)
4.7. Preparation of 6-iso-butyl-4-trifluoromethyl-
pyrimidin-2-one (4e)
Phenyl hydrazine (6.5 mmol) was added dropwise at
room temperature to a stirred solution of the 4-methoxy-
-iso-butyl-1,1,1-tri¯uoro-3-buten-2-one (5 mmol) in abso-
Compound 3d (5 mmol) and urea (10 mmol), were dis-
solved in 10 ml of methanol. To the mixture was added 1 ml
of concentrated HC1 and re¯uxed for 20 h. The solvent was
partially evaporated and the product was allowed to crystal-
ize by cooling the solution. The solid was ®ltered, washed
with cold water, and recrystalized from methanol.
4
lute ethanol (10 ml). The mixture was stirred and heated
under re¯ux for 3 h, then the solvent was evaporated in
vacuo. To this mixture was added 5 ml of dichloromethane
and 1 ml sulfuric acid 96% and heated at 408C for 2 h. After,
was added 10 ml of water and extracted with dichloro-
methane. The organic layer was dried with magnesium
sulfate and the solvent was removed by rotatory evapora-
tion. The crude product was passed through a column of
silica gel 60, eluent dichloromethane. After evaporation of
the solvent in vacuo a yellow oil was isolated, as pure
product.
Acknowledgements
The authors thank the ®nancial support from the Con-
selho Nacional de Desenvolvimento Cienti®co e Tecnol o -
gico (CNPq/PADCT III-Proj. 62.0228/97-0-QEQ).
Fellowship from CNPq (R.V.L.) and CAPES (S.R.T.B.),
are also acknowledged.

1
82
H.G. Bonacorso et al. / Journal of Fluorine Chemistry 99 (1999) 177±182
[
[
20] N. Zanatta, M.F.M. Cortelini, M.J.S. Carpes, H.G. Bonacorso,
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