Polyfluoro- and perfluoroalkoxyenaminones in syntheses of nitrogen containing heterocycles

Article abstract of DOI:10.1016/j.jfluchem.2013.11.007

2-Fluoroalkoxyenaminones were synthesized from α- fluoroalkoxyacetophenones and dimethylformamide dimethylacetal in almost quantitative yields. These compounds are promising aliphatic precursors for fluoroalkoxy containing heterocycles construction that w

Full text of DOI:10.1016/j.jfluchem.2013.11.007

Journal of Fluorine Chemistry 157 (2014) 58–62
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Polyfluoro- and perfluoroalkoxyenaminones in syntheses of nitrogen
containing heterocycles
*
Yulia A. Davydova, Taras M. Sokolenko, Yurii L. Yagupolskii
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmans0ka St. 5, Kyiv 02660, Ukraine
A R T I C L E I N F O
A B S T R A C T
Article history:
2-Fluoroalkoxyenaminones were synthesized from
a-fluoroalkoxyacetophenones and dimethylforma-
Received 14 October 2013
Received in revised form 5 November 2013
Accepted 7 November 2013
Available online 15 November 2013
mide dimethylacetal in almost quantitative yields. These compounds are promising aliphatic precursors
for fluoroalkoxy containing heterocycles construction that was proved by reactions with hydrazine,
hydroxylamine and amidines yielding corresponding pyrazoles, isoxazoles and pyrimidines.
ß 2013 Elsevier B.V. All rights reserved.
Keywords:
Enaminones
Fluoroalkoxy group
Pyrazoles
Isoxazoles
Pyrimidines
1. Introduction
electrophilic sites (C-1 and C-3) in the enaminone molecule [6],
thus these substances can be considered as synthetic equivalents
Among fluorine containing substituents polyfluoroalkoxy
groups gain considerable interest of modern synthetic audience
due to their high impact into biological and material science
of
of
b
b
-dicarbonyl compounds in heterocycles syntheses. Preparation
-enaminoketones bearing fluoroalkoxy groups provides
promising possibility for synthesis of wide range of heterocycles
with such groups.
applicable properties of organic molecules. a-Fluorinated ethers of
aromatic compounds since the first publication [1] in 1955 by
Yagupolskii were extensively investigated and widely used,
nevertheless, heterocycles bearing fluoroalkoxy groups remain
rare [2,3].
Previously it was shown that synthesis of heterocyclic
compounds from aliphatic fluoroalkoxy containing building blocks
is promising and useful strategy [3]. We have reported the
2. Results and discussion
Ketones with methylene group condense readily with
dimethylformamide dimethyl acetal (DMFDMA) to yield enam-
inones in refluxing toluene, DMF or by heating without solvent that
are common reaction conditions [5].
synthesis of
a-bromo-a-fluoroalkoxyacetophenones and recog-
We have tested all these conditions utilizing reaction of the
nized their ability to undergo Hantzsch-type cyclization yielding
thiazoles with fluoroalkoxy groups at the 50-position.
readily available [3]
a-tetrafluoroethoxyacetophenone 1a and
DMFDMA (Table 1). The best result was obtained, when reaction
was carried out without any solvent (entry 3, Table 1). Efficiency
and simplicity of reaction performance and isolation of product
make this condition the most favorable. We applied this method to
acetophenons with different fluoroalkoxy groups and prepared
enaminones 2a–d with similarly high yields (Scheme 1).
It is well known that enaminones readily react with hydrazine
hydrate yielding corresponding pyrazoles [7]. Nevertheless, we
detected no tetrafluoroethoxypyrazole formation reacting
In present paper we present our continuous investigation on
the search of novel aliphatic fluoroalkoxy containing building
blocks and their usage in heterocycles syntheses, that is focused on
previously unknown enaminones modified by –ORF moieties [4].
Enaminones are chemical compounds containing an amino
group linked through a C55C double bond to a carbonyl group. They
are versatile readily available reagents and their chemistry has
received considerable attention in recent years [5]. There are two
b-
enaminoketone 2a with hydrazine hydrate, and only signals of
tetrafluoroethoxy group destruction were observed in 19F NMR
spectra of reaction mixture. The largest peak was the signal of the
CHF2-group as a doublet (2JFH = 52.4 Hz) at ꢀ128.1 ppm, but the
*
Corresponding author. Tel.: +380 44 5590349; fax: +380 44 5732643.
E-mail address: Yagupolskii@ioch.kiev.ua (Y.L. Yagupolskii).
0022-1139/$ – see front matter ß 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jfluchem.2013.11.007

Y.A. Davydova et al. / Journal of Fluorine Chemistry 157 (2014) 58–62
59
O
O
ORF
Me
Me
O Me
O Me
ORF
+
N
Me
94 - 98%
N
Me
1a-d
2a-d
1a, 2a: RF = CF2CHF2; 1b, 2b: RF = CF2CHClF; 1c, 2c: RF = CF3; 1d, 2d: RF = C2F5.
Scheme 1. Synthesis of fluoroalkoxyenaminones.
Table 1
Thus, it became clear to us, that basic or strong acidic conditions
prevent the formation of key compounds and we decided to use
hydrazine salt with weak organic acid. Pyrazoles 2a and 2b were
prepared in 85% and 78%, respectively, when hydrazine acetate and
acetic acid were used (Method A) (Scheme 3). However, in cases of
Reaction conditions for synthesis of fluoroalkoxyenaminone 2a.
Entry
Solvent
Temp (@E)
Reaction time (h)
Yield by NMR 19F (%)
1
2
3
Toluene
DMF
–
90
90
90
8
8
8
ꢁ40
ꢁ60
100 (98)a
enaminones 2c and 2d elimination of
a-fluorine atoms occurred
a
under these conditions. The better results were obtained when
acetic acid was replaced with trifluoroacetic acid (Method B). In
this case all target pyrazoles, even 3c and 3d, were prepared in
almost quantitative yields (Scheme 3).
Isolated yield.
signal of corresponding CF2-moiety was absent. Probably, elimi-
nation of -fluorine atoms occurred due to basic reaction
a
As a rule, b-enaminoketones readily react with hydroxylamine
conditions. The same result was obtained when hydrazine acetate
in dioxane was used.
On the other hand, it is known that acidic media lead to
destruction of C55C double bond of enaminones by retro-Mannich
reaction [8], and we found out that treatment of b-enaminoketone
2a with hydrochloric acid in dioxane at room temperature results
in formation of acetophenone 1a (Scheme 2).
to yield isoxazoles [8,9]. However, refluxing of enaminones 2a–b in
ethanol with hydroxylamine hydrochloride led to formation of
oximes 4a–b. It was found out that dehydratation of compounds
4a–b in benzene in the presence of p-toluenesulphonic acid (PTSA)
results in isoxazoles 5a–b with high yields (Scheme 4).
Enaminones are also widely used for pyrimidines synthesis [7].
Taking into account abovementioned properties of fluoroalkox-
yenaminones we used benzamidine salt with weak organic acid.
Thus, 2,4-diphenylpyrimidine 6 was synthesized with high yield
by reaction of compound 2a with benzamidine acetate in dioxane
under reflux (Scheme 5).
O
O
OCF2CHF2
HClaq.
OCF2CHF2
Me
N
Me
Dioxane,
r.t., 24 h
74 %
Heating of
b-enaminoketones 2a–d with formamidine acetate
in the absence of any solvent results in desired fluoroalkoxypyr-
imidines 7a–d in yields up to 88% (Scheme 6).
2a
1a
The corresponding fluoroalkoxyacetophenones were identified
as byproducts in all cases. Their quantity varied from 10% for
Scheme 2. Retro-Mannich reaction of fluoroalkoxyenaminone 2a.
O
RF O
.
ORF
NH2NH2 AcOH
N
Ph
Dioxane,
N
H
Me
10-15oC, 10 h
N
2a-d
Me
3a-d
Method A (10 eq. CH3COOH): 3a, 3b; 78-85%.
Method B (10 eq. CF3COOH): 3a-3d; 92-98%.
2a, 3a: RF = CF2CHF2; 2b, 3b: RF = CF2CHClF; 2c, 3c: RF = CF3; 2d, 3d: RF = C2F5.
Scheme 3. Reaction of fluoroalkoxyenaminones with hydrazine acetate.
O
O
RFO
Ph
ORF
.
ORF
NH2OH HCl
PTSA
N
Benzene,
reflux, 15 h
EtOH, reflux,
10 h
Me
NOH
O
N
Me
2a-b
5a-b
overall yield 70-82%
4a-b
2a, 4a, 5a: RF = CF2CHF2; 2b, 4b, 5b: RF = CF2CHClF.
Scheme 4. Synthesis of isoxazoles with polyfluoroalkoxy groups.

60
Y.A. Davydova et al. / Journal of Fluorine Chemistry 157 (2014) 58–62
H2N
Ph
O
.
Ph AcOH
N
N
OCF2CHF2
HN
OCF2CHF2
75%
Ph
Me
N
Me
Dioxane,
reflux, 65 h
2a
6
Scheme 5. Reaction of fluoroalkoxyenaminone 2a with benzamidine acetate.
H2N
HN
O
Ph
.
H
AcOH
ORF
N
N
ORF
Me
115oC, 7 h
45-88%
N
Me
7a-d
2a-d
2a, 7a: RF = CF2CHF2; 2b, 7b: RF = CF2CHClF; 2c, 7c: RF = CF3; 2d, 7d: RF = C2F5.
Scheme 6. Reaction of fluoroalkoxyenaminones with formamidine acetate.
enaminones with polyfluoroalkoxy groups to 20% for perfluor-
oalkoxyenaminone derivatives, these byproducts were easily
removed by column chromatography.
of DMFDMA distilled off in vacuum (20 mbar), then in high vacuum
(0.3 mbar) at 40–45 8C. The residue was dissolved in dichlor-
omethane (50 mL), organic layer was washed with water (3ꢂ
25 mL) and dried with MgSO4. After removal of the solvent
enaminones 2a–d were obtained as reddish-brown low-melt solid.
3. Conclusions
We developed a simple and practical method for the synthesis
of enaminones with poly- and perfluoroalkoxy groups at the
second position. It was demonstrated that these compounds are
convenient and useful precursors for preparation of pyrazoles,
isoxazoles and pyrimidines with such a group. This methodology
might be promising to get other five- and six-membered nitrogen
containing heterocycles.
4.2.1. 3-Dimethylamino-2-(1,1,2,2-tetrafluoroethoxy)-1-
phenylpropenone (2a)
Yield 2.85 g (98%), mp 24–25 8C. 1H NMR:
d 3.07 (s, 6H, 2CH3),
2
6.01 (t, JHF = 52.4 Hz, 1H, CHF2), 6.97 (bs, 1H, CH), 7.33–7.45 (m,
3H, arom. H), 7.55 (d, 3JHH = 7.5 Hz, 2H, arom. H). 13C NMR:
d 43.3
(bs, 2CH3), 108.1 (tt, 1JCF = 251.4 Hz, 2JCF = 41.0 Hz, CHF2), 116.9 (tt,
2
1JCF = 272.9 Hz, JCF = 27.5 Hz, CF2), 121.7, 128.1, 128.2, 130.4,
139.5, 146.2, 189.1. 19F NMR:
d
ꢀ90.14 (s, 2F, CF2), ꢀ137.22 (d,
2JFH = 52.4 Hz, 2F, CHF2). GC–MS: m/z = 291 [M]+. Anal. calcd. for
13H13F4NO2: C, 53.61; H, 4.51; N, 4.81; found: C, 53.46; H, 4.35; N,
4. Experimental
4.1. General
C
4.93.
4.1.1. Materials
4.2.2. 3-Dimethylamino-2-(2-chloro-1,1,2-trifluoroethoxy)-1-
a
-Fluoroalkoxyacetophenones were prepared according to
phenylpropenone (2b)
literature procedures [3]. For -fluoroalkoxyacetophenones syn-
a
Yield 2.95 g (96%), mp 22–23 8C. 1H NMR:
d
3.09 (s, 6H, 2CH3),
6.40 (d, 2JHF = 48.3 Hz, 1H, CHClF), 6.97 (bs, 1H, CH), 7.34–7.45 (m,
3H, arom. H), 7.55 (d, 3JHH = 7.5 Hz, 2H, arom. H). 13C NMR:
43.8
(bs, 2CH3), 95.4 (dt, JCF = 251.5 Hz, JCF = 41.6 Hz, CHClF), 118.5
theses see also [10]. Solvents were dried before use by standard
methods. For column chromatography Merck Kieselgel silica gel 60
was used. Thin layer chromatography (TLC) was carried out on
aluminum-backed plates coated with silica gel (Merck Kieselgel 60
F254).
d
1
2
1
2
(td, JCF = 270.4 Hz, JCF = 25.3 Hz, CF2), 122.1, 128.1, 128.3, 130.4,
139.5, 146.0, 189.2. 19F NMR:
d
ꢀ85.40 (d, 2JFF = 139.8 Hz, 1F, CF),
2
2
ꢀ86.80 (d, JFF = 139.8 Hz, 1F, CF), ꢀ153.92 (d, JFH = 48.3 Hz, 1F,
CHClF). GC–MS: m/z = 309 [M (37Cl)]+, 307 [M (35Cl)]+. Anal. calcd.
for C13H13ClF3NO2: C, 50.74; H, 4.27; Cl, 11.52; N, 4.55; found: C,
50.60; H, 4.15; Cl, 11.51; N, 4.67.
4.1.2. Measurements
1H NMR spectra were recorded on a Varian VRX-300 instrument
(300 MHz). 13C NMR (proton decoupled) spectra were recorded on
a Bruker Avance DRX-500 instrument. The chemical shifts (
given relative to external TMS. 19F NMR spectra were recorded on a
Varian Gemini-200 instrument (188 MHz). The chemical shifts (
are given relative to internal CCl3F. Deuterated chloroform was the
solvent in all cases. Mass spectra were recorded on a Hewlett-
Packard HP GC/MS 5890/5972 (EI, 70 eV) or an Agilent 1100 LCMS
SL instrument. Melting points were measured on a Stuart Scientific
melting point apparatus SMP3.
d) are
4.2.3. 3-Dimethylamino-2-trifluoromethoxy-1-phenylpropenone
d
)
(2c)
Yield 2.48 g (96%), mp 32–33 8C. 1H NMR:
d
3.06 (s, 6H, 2CH3),
6.95 (bs, 1H, CH), 7.32–7.41 (m, 3H, arom. H), 7.55 (d, 3JHH = 7.5 Hz,
2H, arom. H). 13C NMR: 42.0 (bs, 2CH3), 121.2 (q, 1JCF = 259.4 Hz,
d
CF3), 122.8, 128.1, 128.3, 130.5, 139.3, 145.4, 188.4. 19F NMR:
d
ꢀ59.32 (s, CF3). GC–MS: m/z = 259 [M]+. Anal. calcd. for
C12H12F3NO2: C, 55.59; H, 4.68; N, 5.41; found: C, 55.46; H,
4.2. Typical procedure for synthesis of enaminones (2a–d) without
4.57; N, 5.50.
solvent
4.2.4. 3-Dimethylamino-2-pentafluoroethyloxy-1-phenylpropenone
The mixture of the corresponding acetophenones 1a–d
(10 mmol) and DMFDMA (1.45 mL, 11 mmol) was heated at
90 8C for 7 h. Methanol, that formed in the reaction, and the excess
(2d)
Yield 2.9 g (94%), mp 27–28 8C. 1H NMR:
d
3.07 (s, 6H, 2CH3),
7.11 (bs, 1H, CH), 7.34–7.45 (m, 3H, arom. H), 7.59 (d, 3JHH = 7.5 Hz,

Y.A. Davydova et al. / Journal of Fluorine Chemistry 157 (2014) 58–62
61
2
2H, arom. H). 13C NMR:
2JCF = 41.0 Hz, CF2), 116.8 (qt, JCF = 284.8 Hz, JCF = 44.6 Hz, CF3),
120.8, 128.0, 128.3, 130.6, 139.1, 145.3, 188.6. 19F NMR:
(s, 3F, CF3), ꢀ88.71 (s, 2F, CF2). GC–MS: m/z = 309 [M]+. Anal. calcd.
for C13H12F5NO2: C, 50.49; H, 3.92; N, 4.53; found: C, 50.41; H, 3.87;
N, 4.68.
d
41.9 (bs, 2CH3), 114.6 (tq, 1JCF = 276.7 Hz,
19F NMR:
d
ꢀ86.55 (s, 2F, CF2), ꢀ154.24 (d, JFH = 48.0 Hz, 1F,
CHClF). GC–MS: m/z = 278 [M (37Cl)]+, 276 [M (35Cl)]+. Anal. calcd.
for C11H8ClF3N2O: C, 47.76; H, 2.92; Cl, 12.81; N, 10.13; found: C,
47.73; H, 2.92; Cl, 12.90; N, 10.14.
1
2
d
ꢀ85.89
4.4.3. 4-Trifluoromethoxy-5-phenyl-1H-pyrazole (3c)
Yield: method B – 0.63 g (92%), white powder, mp 89–90 8C
4.3. Acidic hydrolysis of enaminone 2a
(after sublimation at 65–70 8C (0.5 mbar)). 1H NMR:
d
7.39–7.45
(m, 3H, arom. H), 7.59 (s, 1H, CH-pyrazole), 7.71 (d, 3JHH = 7.5 Hz, 2
H, arom. H), 11.00 (bs, 1H, NH). 13C NMR: 120.7 (q, 1JCF = 258.2 Hz,
The mixture of enaminone 2a (0.87 g, 3 mmol) and aqueous
hydrochloric acid (2 mL) in dioxane (10 mL) was stirred at room
temperature for 24 h. After removal of the solvent and hydro-
chloric acid in vacuum (20 mbar) the residue was quenched with
water (30 mL). The product was extracted with dichloromethane
(3ꢂ 50 mL). The organic layer was washed with saturated aqueous
solution of sodium bicarbonate (3ꢂ 20 mL) and then with water
(3ꢂ 25 mL) and dried with MgSO4. After removal of the solvent the
d
CF3), 126.7, 127.1, 128.5, 128.8, 128.9, 130.6, 138.0. 19F NMR:
d
ꢀ60.9 (s, CF3). GC–MS: m/z = 228 [M]+. Anal. calcd. for C10H7F3N2O:
C, 52.63; H, 3.10; N, 12.28; found: C, 52.71; H, 3.10; N, 12.24.
4.4.4. 4-Pentafluoroethoxy-5-phenyl-1H-pyrazole (3d)
Yield: method B – 0.78 g (94%), white powder, mp 93–94 8C
(after sublimation at 80–85 8C (0.3 mbar)). 1H NMR:
d
7.38–7.44
3
product was obtained as a white solid. Yield 0.52 g (74%), mp 29–
(m, 3H, arom.H), 7.60 (s, 1H, CH-pyrazole), 7.69 (d, JHH = 7.5 Hz,
31 8C [3]. 1H NMR:
d
5.18 (s, 2H, CH2), 5.86 (t, JHF = 52.4 Hz, 1H,
2H, arom. H), 10.56 (bs, 1H, NH). 13C NMR:
d 114.3 (tq,
2
3
3
2
1
CHF2), 7.49 (t, JHH = 7.5, 2H, arom. H), 7.62 (t, 2H, JHH = 7.5, 1H,
1JCF = 274.4 Hz, JCF = 42.0 Hz, CF2), 116.7 (qt, JCF = 284.4 Hz,
arom. H), 7.90 (d, JHH = 7.5, 2H, arom. H). 13C NMR:
d
65.8 (t,
2JCF = 43.4 Hz, CF3), 126.6, 127.4, 128.6, 128.8, 128.9, 129.2,
3
3JCF = 3.9 Hz, CH2), 107.7 (tt, JCF = 251.5 Hz, JCF = 40.2 Hz, CHF2),
138.4. 19F NMR:
d
ꢀ86.31 (s, 3F, CF3), ꢀ90.18 (s, 2F, CF2). GC–
1
2
1
2
117.4 (tt, JCF = 277.9 Hz, JCF = 21.4 Hz, CF2), 127.9, 129.0, 134.0,
134.2, 190.0. 19F NMR:
MS: m/z = 278 [M]+. C11H7F5N2O: C, 47.48; H, 2.54; N, 10.07; found:
d
ꢀ94.32 (s, 2F, CF2), ꢀ138.63 (d,
C, 47.61; H, 2.48; N, 9.98.
2JFH = 52.4 Hz, 2F, CHF2). GC–MS: m/z = 236 [M]+.
4.5. Typical procedure for isoxazoles (5a–b) synthesis
4.4. Typical procedures for pyrazoles (3a–d) syntheses
The mixture of the corresponding enaminones 2a–b (5 mmol)
and hydroxylamine hydrochloride (0.7 g, 10 mmol) in ethanol
(20 mL) was refluxed for 10 h. After removal of the solvent in
vacuum (20 mbar), the residue was dissolved in dichloromethane
(75 mL). Organic layer was washed with water (3ꢂ 15 mL) and
dried with MgSO4. Dichloromethane was evaporated in vacuum.
The residue (the corresponding oximes 4a–b) was dissolved in
benzene (60 mL), PTSA (0.86 g, 5 mmol) was added to the solution
and the mixture was refluxed with Dean-Stark apparatus until no
more water is distilled off (c.a. 15 h). The solvent was removed in
vacuum (20 mbar) and the residue was dissolved in t-butylmethyl
ether (150 mL). The organic layer was washed with saturated
aqueous solution of sodium bicarbonate (3ꢂ 10 mL) and then with
water (3ꢂ 25 mL) and dried with MgSO4. After removal of the
solvent the product was purified by distillation in vacuum.
Method A. The mixture of the corresponding enaminones 2a–b
(3 mmol), hydrazine acetate (0.3 g, 3.3 mmol) and acetic acid
(1.7 mL, 30 mmol) in 1,4-dioxane (5 mL) was stirred at 15 8C for
10 h. The solution was quenched with water (100 mL) and
neutralized with sodium bicarbonate. The product was extracted
with dichloromethane (3ꢂ 25 mL). Organic layer was washed with
water (3ꢂ 15 mL) and dried with MgSO4. After removal of the
solvent the residue was purified by sublimation in vacuum (3a) or
crystallization from hexane (3b).
Method B. The mixture of the corresponding enaminones 2a–d
(3 mmol), hydrazine acetate (0.3 g, 3.3 mmol) and trifluoroacetic
acid (2.3 mL, 30 mmol) in 1,4-dioxane (5 mL) was stirred at 15 8C
for 10 h. The solution was quenched with water (100 mL) and
neutralized with sodium bicarbonate. The product was extracted
with dichloromethane (3ꢂ 25 mL), organic layer was washed with
water (3ꢂ 15 mL) and dried with MgSO4. After removal of the
solvent the product was purified by sublimation in vacuum (3a, 3c,
3d) or crystallization from hexane (3b).
4.5.1. 3-Oxo-3-phenyl-2-(1,1,2,2-tetrafluoroethoxy)propionaldehyde
oxime (4a)
Yield 1.4 g (100%), brown oil, that contains 90% of main product.
1H NMR: 3.58 (bs, 1H, OH), 5.73 (t, 2JHF = 52.4 Hz, 1H, CHF2), 5.75
d
4.4.1. 4-(1,1,2,2-Tetrafluoroethoxy)-5-phenyl-1H-pyrazole (3a)
Yield: method A – 0.66 g (85%), method B – 0.76 g (98%), white
powder, mp 93–94 8C (after sublimation at 90–95 8C (0.3 mbar)).
(s, 1H, CH), 5.93 (s, 1H, CH), 7.38–7.43 (m, 3H, arom. H), 7.65–7.70
2
(m, 2H, arom. H). 19F NMR:
d
ꢀ89.03 (d, JFF = 146.8 Hz, 1F, CF),
2
2
ꢀ91.58 (d, JFF = 146.8 Hz, 1F, CF), ꢀ137.97 (d, JFH = 52.4 Hz, 2F,
2
1H NMR:
d
5.93 (t, JHF = 52.4, 1H, CHF2), 7.37–7.43 (m, 3H, arom.
CHF2). LC–MS: m/z = 280 [M+H]+.
3
H), 7.59 (s, 1H, CH-pyrazole), 7.70 (d, JHH = 7.5 Hz, 2H, arom. H),
11.16 (bs, 1H, NH). 13C NMR:
d
107.6 (tt, JCF = 252.0 Hz,
4.5.2. 3-Oxo-3-phenyl-2-(2-chloro-1,2,2-
1
2JCF = 41.2 Hz, CHF2), 116.5 (tt, JCF = 272.5 Hz, JCF = 28.7 Hz,
trifluoroethoxy)propionaldehyde oxime (4b)
1
2
CF2), 126.7, 127.4, 128.7, 128.8, 128.9, 129.7, 138.3. 19F NMR:
d
Yield 1.48 g (100%), that contains 90% of main product. 1H NMR:
2
ꢀ90.27 (s, 2F, CF2), ꢀ137.04 (d, JFH = 52.4 Hz, 2F, CHF2). GC–MS:
m/z = 260 [M]+. Anal. calcd. for C11H8F4N2O: C, 50.77; H, 3.11; N,
10.77; found: C, 50.69; H, 3.26; N, 10.60.
d
3.54 (bs, 1H, OH), 5.74 (s, 1H, CH), 5.96 (s, 1H, CH), 6.04 (d,
2JHF = 48.0 Hz, 1H, CHClF), 7.40–7.45 (m, 3H, arom. H), 7.68–7.73
(m, 2H, arom. H). 19F NMR:
ꢀ85.17 to ꢀ87.89 (m, 2F, CF2),
ꢀ154.28 to ꢀ154.36 (m, 1F, CHClF). LC–MS: m/z = 298 [M
37Cl)+H]+, 296 [M (35Cl)+H]+.
d
4.4.2. 4-(2-Chloro-1,1,2-trifluoroethoxy)-5-phenyl-1H-pyrazole (3b)
(
Yield: method A – 0.65 g (78%), method B – 0.79 g (95%), white
2
powder, mp 74–75 8C. 1H NMR:
d
6.29 (d, JHF = 48.0 Hz, 1H,
4.5.3. 4-(1,1,2,2-Tetrafluoroethoxy)-5-phenylisoxazole (5a)
CHClF), 7.36–7.43 (m, 3H, arom. H), 7.60 (s, 1H, CH-pyrazole), 7.73
Yield 0.91 g (70%), yellowish oil, bp 73–75 8C (0.4 mbar). 1H
(d, 3JHH = 7.5 Hz, 2H, arom. H), 10.80 (bs, 1H, NH). 13C NMR:
d
94.8
NMR:
d
5.97 (t, JHF = 52.4 Hz, 1H, CHF2), 7.48–7.50 (m, 3H, arom.
2
(dt, 1JCF = 251.8 Hz, 2JCF = 41.2 Hz, CHClF), 118.3 (td, 1JCF = 271.6 Hz,
2JCF = 26.0 Hz, CF2), 126.8, 127.4, 128.7, 128.8, 128.9, 129.0, 130.0.
H), 7.83–7.86 (m, 2H, arom. H), 8.56 (s, 1H, CH-isoxazole). 13C
1
2
NMR:
d 107.3 (tt, JCF = 252.5 Hz, JCF = 40.6 Hz, CHF2), 116.4

62
Y.A. Davydova et al. / Journal of Fluorine Chemistry 157 (2014) 58–62
1
2
(tt, JCF = 275.3 Hz, JCF = 29.2 Hz, CF2), 126.5, 127.5, 128.9, 129.6,
130.5, 149.1, 155.2. 19F NMR:
ꢀ91.13 (s, 2F, CF2), ꢀ137.17 (d,
2JFH = 52.4 Hz, 2F, CHF2). GC–MS: m/z = 261 [M]+. Anal. calcd. for
11H7F4NO2: C, 50.57; H, 2.71; N, 5.36; found: C, 50.69; H, 2.70; N,
4.7.2. 5-(2-Chloro-1,1,2-trifluoroethoxy)-4-phenylpyrimidine (7b)
d
Yield 1.2 g (85%), yellowish oil, Rf = 0.1 (hexane/CH2Cl2 = 1/1).
2
1H NMR:
d
6.21 (d, JHF = 48.3 Hz, 1H, CHClF), 7.49–7.51 (m, 3H,
C
arom. H), 7.92–7.95 (m, 2H, arom. H), 8.77 (s, 1H, 60CH-
5.20.
pyrimidine), 9.17 (s, 1H, 20CH-pyrimidine). 13C NMR:
d 94.6 (dt,
1JCF = 252.5 Hz, JCF = 40.7 Hz, CHClF), 118.4 (td, JCF = 275.1 Hz,
2
1
4.5.4. 5-(2-Chloro-1,1,2-trifluoroethoxy)-4-phenylisoxazole (5b)
Yield 1.14 g (82%), yellowish oil, bp 78–80 8C (0.4 mbar). 1H
2JCF = 26.5 Hz, CF2), 128.5, 129.5, 130.8, 133.8, 142.1, 151.3, 156.3,
158.7. 19F NMR:
d
ꢀ83.68 (s, 2F, CF2), ꢀ154.01 (d, 2JFH = 48.0 Hz, 1F,
NMR:
d
6.31 (d, 2JHF = 48.0 Hz, 1H, CHClF), 7.47–7.49 (m, 3H, arom.
CHClF). GC–MS: m/z = 290 [M (37Cl)]+, 288 [M (35Cl)]+. Anal. calcd.
for C12H8ClF3N2O: C, 49.93; H, 2.80; Cl, 12.28; N, 9.71; found: C,
50.04; H, 2.85; Cl, 12.37; N, 9.59.
H), 7.85–7.87 (m, 2H, arom. H), 8.58 (s, 1H, CH-isoxazole). 13C
1
2
NMR:
1JCF = 274.3 Hz, JCF = 26.4 Hz, CF2), 126.5, 127.6, 128.9, 129.9,
130.5, 149.0, 155.2. 19F NMR:
ꢀ87.20 (s, 2F, CF), ꢀ154.55 (d,
2JFH = 48.0 Hz, 1F, CHClF). GC–MS: m/z = 279 [M (37Cl)]+, 277 [M
35Cl)]+. Anal. calcd. for C11H7ClF3NO2: C, 47.59; H, 2.55; Cl, 12.77;
d 94.4 (dt, JCF = 252.1 Hz, JCF = 40.5 Hz, CHClF), 118.2 (td,
2
d
4.7.3. 5-Trifluoromethoxy-4-phenylpyrimidine (7c)
Yield 0.62 g (52%) yellowish oil, Rf = 0.1 (hexane/CH2Cl2 = 1/1).
(
1H NMR:
d 7.49–7.53 (m, 3H, arom. H), 7.97–8.00 (m, 2H, arom. H),
N, 5.05; found: C, 47.68; H, 2.61; Cl, 12.72; N, 4.93.
8.74 (s, 1H, 60CH-pyrimidine), 9.19 (s, 1H, 20CH-pyrimidine). 13C
1
NMR:
d
120.3 (q, JCF = 259.6 Hz, CF3), 128.7, 129.4, 131.1, 133.6,
4.6. 5-(1,1,2,2-Tetrafluoroethoxy)-2,4-diphenylpyrimidine (6)
142.0, 150.7, 156.7, 158.2. 19F NMR:
z = 240 [M]+. Anal. calcd. for C11H7F3N2O: C, 55.00; H, 2.94; N,
d
ꢀ59.78 (s, CF3). GC–MS: m/
The mixture of benzamidine (0.9 g, 7.5 mmol), enaminone 2a
(1.45 g, 5 mmol) and glacial acetic acid (0.43 mL, 7.5 mmol) in 1,4-
dioxane (5 mL) was refluxed for 65 h. After cooling to room
temperature the mixture was quenched with water (50 mL) and
extracted with dichloromethane (3ꢂ 50 mL). The organic layer was
washed with 5% sodium bicarbonate aqueous solution (15 mL) and
then with water (3ꢂ 25 mL) and dried with MgSO4. After removal
of the solvent in vacuum the residue was purified by silica gel
column chromatography. Yield 1.3 g (75%), white solid, Rf = 0.3
11.67; found: C, 55.12; H, 3.10; N, 11.61.
4.7.4. 5-Pentafluoroethyloxy-4-phenylpyrimidine (7d)
Yield 0.65 g (45%), yellowish oil, Rf = 0.1 (hexane/CH2Cl2 = 1/1).
1H NMR:
d
7.45–7.53 (m, 3H, arom. H), 7.92–7.94 (m, 2H, arom. H),
8.75 (s, 1H, 60CH-pyrimidine), 9.20 (s, 1H, 20CH-pyrimidine). 13C
1
2
NMR:
d 114.3 (tq, JCF = 278.4 Hz, JCF = 42.8 Hz, CF2), 116.4 (qt,
1JCF = 284.9 Hz, JCF = 42.9 Hz, CF3), 128.5, 129.4, 131.0, 133.5,
2
141.4, 151.4, 156.9, 158.9. 19F NMR:
d
ꢀ86.23 (s, 3F, CF3), ꢀ87.76 (s,
(hexane/EtOAc = 50/1), mp 64–65 8C. 1H NMR:
d
5.89 (t,
2F, CF2). GC–MS: m/z = 290 [M]+. Anal. calcd. for C12H7F5N2O: C,
2JHF = 52.4 Hz, 1H, CHF2), 7.50–7.54 (m, 6H, arom. H), 8.05–8.08
49.66; H, 2.44; N, 9.66; found: C, 49.74; H, 2.45; N, 9.51.
(m, 2H, arom. H), 8.51–8.54 (m, 2H, arom. H), 8.80 (s, 1H, CH-
1
2
pyrimidine). 13C NMR:
d 107.4 (tt, JCF = 252.5 Hz, JCF = 40.9 Hz,
References
1
2
CHF2), 116.6 (tt, JCF = 275.1 Hz, JCF = 29.3 Hz, CF2), 128.4, 128.5,
[1] L.M. Yagupolskii, Dokl. Akad. Nauk SSSR 105 (1955) 100–103;
Chem. Abstr. 50 (1955) 11270b.
[2] (a) F. Leroux, P. Jeschke, M. Schlosser, Chem. Rev. 105 (2005) 827–856;
(b) F. Leroux, B. Manteau, J.-P. Vors, S. Pazenok, Beilstein J. Org. Chem. 4 (2008),
http://dx.doi.org/10.3762/bjoc.4.13;
128.7, 129.6, 130.8, 131.0, 134.5, 136.7, 140.2, 151.8, 158.4, 162.4.
19F NMR:
d
ꢀ89.28 (s, 2F, CF2), ꢀ138.55 (d, 2JFH = 52.4 Hz, 2F, CHF2).
GC–MS: m/z = 348 [M]+. Anal. calcd. for E18H12F4N2O: C, 62.07; H,
3.48; N, 8.05; found: C, 62.25; H, 3.56; N, 8.13.
(c) M.V. Vovk, O.M. Pinchuk, V.A. Sukach, A.O. Tolmachov, A.A. Gakh, in: A.A.
Gakh, K.L. Kirk (Eds.), ACS Symposium Series, Vol. 1003 (Fluorinated Hetero-
cycles), American Chemical Society, Washington, DC, 2009, pp. 307–345;
(d) D. O’Hagan, J. Fluorine Chem. 131 (2010) 1008–1071.
4.7. Typical procedure for pyrimidines (7a–d) synthesis
[3] T.M. Sokolenko, Yu.A. Davydova, Yu.L. Yagupolskii, J. Fluorine Chem. 136 (2012) 20–25.
[4] General results of our investigation have been presented at 17th European
Symposium on Fluorine Chemistry, Paris, July 21–25, 2013:
(a) Yu. Davydova, T. Sokolenko, Yu. Yagupolskii, Book of Abstracts of 17th
European Symposium on Fluorine Chemistry, Paris, July, 2013 (Paper P1.27);
While preparing current paper, we became aware of a closely related work
devoted to syntheses of OCF3-containing enaminoketones and their transforma-
tion into trifluoromethoxy pyrazoles. See:
The mixture of the corresponding enaminones 2a–d (5 mmol)
and formamidine acetate (0.78 g, 7.5 mmol) was heated at 115 8C
for 7 h. After cooling to room temperature the mixture was
quenched with water (50 mL) and extracted with dichloro-
methane (3ꢂ 50 mL). The organic layer was washed with
saturated aqueous sodium bicarbonate solution (2ꢂ 20 mL) and
then with water (3ꢂ 25 mL) and dried with MgSO4. After removal
of the solvent the residue was purified by silica gel column
chromatography.
(b) B.R. Langlois, Abstracts of Papers, 245th ACS National Meeting & Exposition,
New Orleans, LA, United States, April 7–11, 2013 (Paper FLUO 8);
(c) J. Barbion, B. Thierry, B. Langlois, O. Marrec, S. Pazenok, J.-P. Vors, EP Patent
2628722 (August 21, 2013).
[5] A.-Z.A. Elassar, A.A. El-Khair, Tetrahedron 59 (2003) 8463–8480.
[6] C.M. Kascheres, J. Braz. Chem. Soc. 14 (2003) 945–969.
[7] H. Bredereck, R. Sell, F. Effenberger, Chem. Ber. (1964) 3407–3417.
[8] R. Olivera, R. SanMartin, E. Dominguez, X. Solans, M.K. Urtiaga, M.I. Arriortua, J.
Org. Chem. 65 (2000) 6398–6411.
[9] F.A. Rosa, P. Machado, H.G. Bonacorso, N. Zanatta, M.A.P. Martins, J. Heterocycl.
Chem. 45 (2008) 879–885.
[10] (a) C. Wakselman, J. Leroy, J. Fluorine Chem. 12 (1978) 101–109;
(b) W.B. Farnham, W.J. Middleton, US Patent 4,628,094 (1986).
Chem. Abstr. 105 (1986) 114600n;
4.7.1. 5-(1,1,2,2-Tetrafluoroethoxy)-4-phenylpyrimidine (7a)
Yield 1.2 g (88%), yellowish oil, Rf = 0.2 (hexane/CH2Cl2 = 1/1).
2
1H NMR:
d
5.87 (t, JHF = 52.4 Hz, 1H, CHF2), 7.48–7.51 (m, 3H,
arom. H), 7.92–7.95 (m, 2H, arom. H), 8.76 (s, 1H, 60CH-
pyrimidine), 9.17 (s, 1H, 20CH-pyrimidine). 13C NMR:
d 107.3 (tt,
1JCF = 252.6 Hz, JCF = 40.9 Hz, CHF2), 116.5 (tt, JCF = 276.0 Hz,
2
1
2JCF = 29.4 Hz, CF2), 128.5, 129.4, 130.9, 133.8, 141.8, 151.3,
(c) A.A.Kolomeitsev,M.Vorobyev,H. Gillandt,TetrahedronLett. 49 (2008)449–454;
(d) R. Zriba, E. Magnier, J.-C. Blazejewski, Synlett 7 (2009) 1131–1135;
(e) O. Marrec, T. Billard, J.-P. Vors, S. Pazenok, B.R. Langlois, J. Fluorine Chem. 131
(2010) 200–207;
(f) O. Marrec, T. Billard, J.-P. Vors, S. Pazenok, B.R. Langlois, Adv. Synth. Catal. 352
(2010) 2831–2837.
156.4, 158.7. 19F NMR:
d
ꢀ87.84 (s, 2F, CF2), ꢀ137.03 (d,
2JFH = 52.4 Hz, 2F, CHF2). GC–MS: m/z = 272 [M]+. Anal. calcd. for
12H8F4N2O: C, 52.94; H, 2.97; N, 10.29; found: C, 52.86; H, 3.06; N,
10.23.
C