Synthesis and properties of α-bromomethyl-substituted β-ethoxyvinyl polyfluoroalkyl ketones

Article abstract of DOI:10.1055/s-0033-1339668

An efficient and practical method for the synthesis of α-bromomethyl- substituted β-alkoxyvinyl polyfluoroalkyl ketones is reported. These highly functionalized α-bromomethyl enones easily react with various nucleophiles and binucleophiles affording a wide variety of new functionalized enones and heterocyclic systems that are perspective starting materials for the synthesis of compounds with potentially high biological and pharmacological activity. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1339668

PAPER
▌3157
paper
Synthesis and Properties of α-Bromomethyl-Substituted β-Ethoxyvinyl
Polyfluoroalkyl Ketones
1-(Bromomethyl)-2-ethoxyvinyl Polyfluoroalkyl Ketones
Maksym Ya. Bugera,a Karen V. Tarasenko,a Valery P. Kukhar,a Gerd-Volker Röschenthaler,b Igor I. Gerus*a
a
Department of Fine Organic Synthesis, Institute of Bioorganic Chemistry and Petrochemistry, National Ukrainian Academy of Science,
Murmanska Str. 1, Kiev 02094, Ukraine
b
Jacobs University Bremen gGmbH, School of Engineering and Science, Campus Ring 1, 28759 Bremen, Germany
Received: 14.05.2013; Accepted after revision: 02.08.2013
pounds 1a gives α-bromo-substituted enones 2 by an
addition–dehydrohalogenation mechanism.9a It is a good
starting material for numerous heterocyclic syntheses.9b,10
The products of allylic bromination, compounds 3, were
Abstract: An efficient and practical method for the synthesis of α-
bromomethyl-substituted β-alkoxyvinyl polyfluoroalkyl ketones is
reported. These highly functionalized α-bromomethyl enones easily
react with various nucleophiles and binucleophiles affording a wide
variety of new functionalized enones and heterocyclic systems that formed by the reaction of 1b with bromine. Brominated
are perspective starting materials for the synthesis of compounds
with potentially high biological and pharmacological activity.
enones 2 and 3 can be easily transformed into various flu-
orinated heterocycles, phosphonates, phosphates, etc.11
Key words: enones, fluorine, halogenation, radical reaction, nu-
cleophilic reaction, heterocycles
Also the complex behavior of cyclic and linear fluorinated
1,3-dicarbonyls and their boron and metal derivatives to-
wards such halogenating agents as bromine, N-bromosuc-
cinimide, and sulfuryl chloride was recently studied and
The introduction of fluorine atoms and fluorinated groups products with various structures were characterized.5c
into organic molecules often confers significant and use-
ful changes to their chemical and physical properties1 that
O
R2
O
O
are actively used by medicinal and agricultural chemists.
As a result, the occurrence of fluorine-substituted com-
pounds in new commercial pharmaceutical substances has
increased from 2% in 1970 to about 20% today. The mar-
ket share of fluoro-containing compounds as new agro-
chemicals is higher, above 28%.2 Methods for the
synthesis of fluorinated compounds have received consid-
erable interest in recent years.3 Although direct fluorinat-
ing or polyfluoroalkylating methods are the most
attractive and powerful new tools for constructing fluori-
nated compounds,4 fluoro-containing building blocks are
often more convenient starting reagents.5 Fluorinated car-
bonyl and dicarbonyl compounds are often used as start-
ing materials to obtain the desired fluoro-containing
substances.6 Particularly, (E)-β-alkoxyvinyl polyfluoroal-
kyl ketones 1 are versatile polyfluoroalkylated building
blocks for the synthesis of various fluoro-containing het-
erocycles, enaminones, dyes, drugs, and protective re-
agents for amino group protection in peptide synthesis.7
Enones 1 may be considered as synthetic equivalents of
1,3-ketoaldehydes or 1,3-diketones, and they are readily
available by the reaction of polyfluoroacylation reagents
with alkyl vinyl ethers (Figure 1). Whereas the nucleo-
philic reactions of enones 1 have been studied in detail,8
there only a few reports on the reactions of fluorinated
enones 1 with electrophiles such as halogens.9
RF
RF
OAlk
R2
R1
R1
1
R1, R2 = H, Alk, Ar
Figure 1 Enones 1 as synthetic equivalent of 1,3-ketoaldehydes or
1,3-diketones
O
RF
OEt
0 o
C
Br
2
Br2, Py
CH2Cl2
O
R1
RF
OAlk
1a,b
Br
O
0–25 °C
RF
OMe
3
1a; 2: Alk = Et; RF = CF3, CHF2, CCl3, CH(CF3)2; R1 = H
1b; 3: Alk = Me; RF = CF3, C2F5, C3F7, CF2Cl;
R1 = Me
Scheme 1 Reactions of enones 1 with bromine
At that time, the bromination of α-methyl-substituted
enones had not been reported. Taking into account the in-
terest in halogen-substituted fluoro-containing enones, we
have now developed a simple and effective synthesis of α-
bromomethyl-containing fluorinated enones. The synthet-
ic potential of this class of compounds has been investi-
gated for the example of a trifluoromethyl-containing
enone.
Earlier we showed that the structure of starting fluorinated
enones 1 plays a key role in the pathway of the bromina-
tion reaction (Scheme 1).9a The bromination of com-
SYNTHESIS 2013, 45, 3157–3163
Advanced online publication: 29.08.2013
DOI: 10.1055/s-0033-1339668; Art ID: SS-2013-T0354-OP
© Georg Thieme Verlag Stuttgart · New York
A series of α-methyl-substituted enones 4a–e was synthe-
sized by the reaction of an E,Z-mixture of 1-ethoxyprop-
1-ene with the corresponding acyl chloride or anhydride
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

3158
M. Ya. Bugera et al.
PAPER
in high yields by a general method (Scheme 2).5i,12 The enones 6a,b, reacted with N-bromosuccinimide to form
1
structure of obtained enones 4a–e was confirmed by H, complex mixtures of products (Scheme 3).
19F, and 13C NMR analysis.
O
NBS
CCl4, reflux
O
complex mixture
RFCOX, Py
F3C
O
OEt
RF
OEt
CH2Cl2, 0–10 °C
n
6a,b
n = 1 (a), 2 (b)
4a–e
58–78%
RF = CF3 (a), C2F5 (b), C3F7 (c), CF2H (d), CF2Cl (e)
X = OC(O)CF3 (a), Cl (b–e)
Scheme 3 Reaction of 6a,b and N-bromosuccinimide
Scheme 2 Synthesis of enones 4a–e
Synthesized enones 5 are highly functionalized substanc-
es that have several potential reactive centers in their
structure for nucleophilic attack: carbon atoms in the car-
bonyl group, at the β-position of the carbon–carbon dou-
ble bond, and at the bromomethyl group. We used
trifluoromethyl-containing enone 5a as a model com-
pound to investigate reactions of enones 5 with nucleo-
philes of various natures. We found that 5a readily reacts
with typical nucleophiles: sodium iodide, sodium azide,
potassium thiocyanate, sodium nitrite, 4-methylbenzene-
thiol, and the corresponding products 7–11 were formed
in 41–91% yields (Scheme 4).
First, we checked the reaction of enone 4a with bromine
and observed neither the addition of bromine to the car-
bon–carbon double bond nor the bromination of the meth-
yl group in compound 4a in a reaction mixture containing
an excess of bromine in dichloromethane or deuterochlo-
roform at room temperature. This was clearly proved by
19
1H and F NMR spectroscopy: only a small shift in the
signals of the trifluoromethyl and methyl groups and the
olefinic proton was observed. Moreover, after workup we
recovered 80–90% of enone 4a.
It was found that compounds 4a–e readily react with N-
bromosuccinimide in boiling tetrachloromethane in the
presence of benzoyl peroxide, and α-bromomethyl-substi-
tuted enones 5a–e were formed in high yields (Table 1).
All obtained compounds were purified by vacuum distil-
O
O
O
F3C
OEt
F3C
OEt
F3C
OEt
NCS
9 (88%)
N3
I
7 (89%)
8 (91%)
1
lation and fully characterized by H, 19F, and 13C NMR
spectroscopy and elemental analysis. It is worth to men-
tion that enones 5a–e possess Z-configuration (trans-
position of alkoxy and acyl groups), a property being
characteristic for β-alkoxyvinyl polyfluoroalkyl ketones.12a
a
a
b
O
F3C
OEt
Table 1 Synthesis of 5a–e
Br
5a
O
O
NBS
a
a
RF
OEt
O
CCl4 , reflux
RF
OEt
O
Br
F3C
OEt
F3C
OEt
5a–e
4a–e
RF = CF3 (a), C2F5 (b), C3F7 (c), CF2H (d), CF2Cl (e)
S
NO2
10 (89%)
RF
Starting
Product
Bp
Yielda
(%)
11 (41%)
compound
(°C/Torr)
Scheme 4 Reactions of 5a with nucleophiles. Reagents and condi-
tions: (a) corresponding nucleophilic reagent (NaN3, KSCN, NaI, or
NaNO2), acetone, r.t.; (b) 4-methylbenzenethiol, K2CO3, acetone, r.t.
CF3
4a
4b
4c
4d
4e
5a
5b
5c
5d
5e
115–118/10
120–125/10
130–135/10
131–134/10
128–132/10
70
69
69
64
71
C2F5
C3F7
CF2H
CF2Cl
It is worthy to note that the reaction of the 5a with the am-
bident nucleophile sodium thiocyanate led to isothiocya-
nate 9, in contrast to previously published results for β-
bromomethyl trichloromethyl enone that gave the corre-
sponding thiocyanate.13 The proposed isothiocyanate
group containing structure of compound 9 is based on the
analysis of 13C NMR spectroscopic data: the characteristic
signal of the isothiocyanate function at δ =133.3 was ob-
served, and, moreover, the characteristic absorption band
for the isothiocyanate group at 2061 cm–1 (N=C=S) is
present in the IR spectra.
a Yield of isolated product.
It should be noted that N-chlorosuccinimide did not react
with enone 4a under the same conditions (boiling CCl4,
benzoyl peroxide). Structural analogues of 4a, cyclic
Synthesis 2013, 45, 3157–3163
© Georg Thieme Verlag Stuttgart · New York

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1-(Bromomethyl)-2-ethoxyvinyl Polyfluoroalkyl Ketones
3159
Earlier it was shown that enones 1 react with aliphatic
amines under mild conditions leading to the correspond-
ing enaminones.9a,14 We found that the addition of one
equivalent of a secondary aliphatic amine to a solution of
enone 5a leads to a complex unidentifiable mixture of
products. However we could synthesize and fully charac-
terize by NMR spectroscopy the products 12a–f from the
reaction of one molecule of enone 5a and two molecules
of amine by changing the order of the addition of the re-
agents and using a large excess of amine (Table 2).
O
NH2OH•HCl, Py
HO
F3C
OEt
N
reflux, EtOH (20% yield)
or
MeCN (57% yield)
F3C
O
13
Br
5a
Scheme 5 Reaction of 5a with hydroxylamine
S
Ph
O
O
NH2
K2CO3
F3C
N
F3C
OEt
Table 2 Reaction of 5a with Secondary Amines
acetone, r.t.
O
O
S
Ph
Br
5a
HNR1R2
14 (21%)
F3C
OEt
F3C
NR1R2
CH2Cl2, r.t.
Scheme 6 Synthesis of 14
R2R1N
12a–f
Br
5a
Amine
Product
Mpa (°C)
Yieldb (%)
Me2NH
12a
12b
12c
12d
12e
12f
wax
40
65
50
48
46
79
Et2NH
oil
i-Pr2NH
pyrrolidine
piperidine
oil
78–79
87–89
93–95
Figure 2 Single crystal X-ray structure of 1416
morpholine
a From hexane.
est as a possible starting material for the synthesis of new
trifluoromethyl-containing cephem analogues.15
b Yield of isolated product.
In conclusion, we have studied the bromination reaction
of α-methyl-substituted trifluoroacetyl-containing enones
with elemental bromine and N-bromosuccinimide. The
method allows new polyfunctional α-bromomethyl-con-
taining fluorinated enones 5 to be obtained in preparative
quantities. Using trifluoromethyl-containing enone 5a,
the reactivity of this class of compounds with various nu-
cleophiles and binucleophiles was investigated. Similari-
ties and differences of chemical properties between
enones 5 and previously published β-bromomethyl-con-
taining analogues were shown. New perspective synthons
for the synthesis of polyfluoroalkylated, potentially bioac-
tive, heterocycles, trifluoromethyl-bearing dihydroisoxa-
zolinol 13 and trifluoroacetyl-containing 6H-1,3-thiazine
14, were synthesized and characterized.
Enones 5 are promising compounds as starting materials
for heterocyclization reactions with binucleophiles, but all
our attempts to involve enone 5a in reactions with hydra-
zine hydrate, amidines, urea, and thiourea led to the for-
mation of complex mixtures of unidentified products
under various reaction conditions (solvent: EtOH,
CH2Cl2, AcOH; base: pyridine, K2CO3; r.t. and boiling
EtOH). Unfortunately, these mixtures could not be sepa-
rated by column chromatography to yield pure com-
pounds. We suppose the formation of the mixtures of
products occurs as a result of unselective reaction of vari-
ous reactive centers in enone 5a and the above-mentioned
binucleophiles. Apart from these negative results, the re-
action between enone 5a and hydroxylamine in boiling
ethanol led to the formation of an unexpected five-mem-
bered heterocyclic compound 13 in 20% yield (Scheme
5). The replacement of ethanol by acetonitrile increased
the yield of compound 13 up to 57%. The heterocycle 13
was purified by column chromatography and fully charac-
1
Solvents were purified according to standard procedures. H, 13C,
and 19F NMR spectra were recorded on a Bruker Avance DRX 500
(500 MHz) and Varian Unity plus 400 (400 MHz) spectrometers
referenced to TMS (1H, 13C) or CFCl3 (19F) as internal standards. IR
spectra were recorded on Bruker Vertex 70. Agilent 1200 Series
LC/MSD system with DAD\ELSD and Agilent LC\MSD SL
(G6130A), SL (G6140A) mass spectrometer, all the LC/MS data
were obtained using positive/negative mode switching. The prog-
ress of reactions was monitored by TLC (silica gel 60 F254, Merck).
Column chromatography was carried out on silica gel 60 (Merck
No. 109385, particle size 0.040–0.063). All starting materials were
of the highest commercial quality and were used without further pu-
rification. The synthesis of starting enones 4 was recently pub-
lished.5i
1
19
13
terized by H, F, and C NMR spectroscopy and mass
spectrometry.
The reaction of 5a with thiobenzamide gave 2-phenyl-5-
trifluoroacetyl-6H-1,3-thiazine (14) in 21% yield
1
(Scheme 6). The structure of 14 was proved by H, 19F,
and 13C NMR spectroscopy and confirmed by X-ray crys-
tal structure analysis (Figure 2). Compound 14 is of inter-
© Georg Thieme Verlag Stuttgart · New York
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M. Ya. Bugera et al.
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α-Bromomethyl Enones 5a–e; General Procedure
13C NMR (126 MHz, CDCl3): δ = 179.0 (t, J = 29.0 Hz), 166.6 (t,
J = 6.0 Hz), 120.4 (t, J = 304.1 Hz), 112.4, 73.4, 21.5, 15.4.
19F NMR (376 MHz, CDCl3): δ = –59.23 (s).
A solution of α-methyl enone 4 (100 mmol), NBS (35.6 g, 200
mmol), and (BzO)2 (2.4 g, 10 mmol) in anhydrous CCl4 (300 mL)
was stirred at reflux for 2 h. The end of the reaction was determined
by TLC (EtOAc–hexane, 1:4). The cold mixture was filtered, and
the solvent was removed under vacuum. The residue was distilled
under vacuum to give α-bromomethyl enones with 90–95% purity
as white or yellow low-melting crystals or an oil.
Anal. Calcd for C7H8BrClF2O2: C, 30.30; H, 2.91. Found: C, 30.18;
H, 2.73.
Reaction of α-Bromomethyl Enone 5a with Nucleophiles To
Give Сompounds 7–10; General Procedure
A solution of 5a (2.61 g, 10 mmol) and the corresponding nucleo-
philic reagent (NaI, NaN3, KSCN, or NaNO2) (30 mmol) in acetone
(20 mL) was stirred at r.t. for 12 h. The end of the reaction was de-
termined by TLC (EtOAc–hexane, 1:4). The mixture was filtered
and the solvent was removed under vacuum. The residue was a
crude product with high purity (93–96% by NMR spectroscopy da-
ta).
(Z)-3-(Bromomethyl)-4-ethoxy-1,1,1-trifluorobut-3-en-2-one
(5a)
White low-melting crystals; yield: 18.3 g (70%); bp 115–118
°C/10–12 Torr.
1H NMR (500 MHz, CDCl3): δ = 7.65 (s, 1 H), 4.36 (q, J = 7.1 Hz,
2 H), 4.22 (s, 2 H), 1.45 (t, J = 7.1 Hz, 3 H).
13C NMR (126 MHz, CDCl3): δ = 177.8 (q, J = 35.0 Hz), 166.7 (q,
J = 4.5 Hz), 116.7 (q, J = 290.7 Hz), 113.9, 73.5, 20.7, 15.3.
19F NMR (376 MHz, CDCl3): δ = –70.40 (s).
(Z)-4-Ethoxy-1,1,1-trifluoro-3-(iodomethyl)but-3-en-2-one (7)
Pale yellow oil; yield: 2.75 g (89%).
1H NMR (500 MHz, CDCl3): δ = 7.63 (s, 1 H), 4.36 (q, J = 7.1 Hz,
2 H), 4.09 (s, 2 H), 1.47 (t, J = 7.1 Hz, 3 H).
13C NMR (126 MHz, CDCl3): δ = 177.5 (q, J = 35.0 Hz), 165.6–
165.4 (br m), 116.8 (q, J = 290.7 Hz), 115.2, 73.4, 15.6, –8.6.
Anal. Calcd for C7H8BrF3O2: C, 32.21; H, 3.09. Found: C, 32.34; H,
3.20.
(Z)-2-(Bromomethyl)-1-ethoxy-4,4,5,5,5-pentafluoropent-1-en-
3-one (5b)
Yellow low-melting crystals; yield: 21.5 g (69%); bp 120–125
°C/10–12 Torr.
1H NMR (500 MHz, CDCl3): δ = 7.77 (s, 1 H), 4.36 (q, J = 7.1 Hz,
2 H), 4.21 (s, 2 H), 1.44 (t, J = 7.1 Hz, 3 H).
13C NMR (126 MHz, CDCl3): δ = 179.9 (t, J = 26.0 Hz), 167.2 (t,
J = 8.6 Hz), 118.0 (qt, J = 286.6, 34.3 Hz), 115.6, 108.8 (tq, J =
267.8, 37.1 Hz), 76.6, 20.8, 15.3.
19F NMR (376 MHz, CDCl3): δ = –82.36 (br s, 3 F), –114.86 (br s,
2 F).
19F NMR (376 MHz, CDCl3): δ = –70.22 (s).
Anal. Calcd for C7H8F3IO2: C, 27.29; H, 2.62. Found: C, 27.12; H,
2.43.
(E)-3-(Azidomethyl)-4-ethoxy-1,1,1-trifluorobut-3-en-2-one (8)
Pale yellow oil; yield: 2.04 g (91%).
1H NMR (500 MHz, CDCl3): δ = 7.75 (s, 1 H), 4.30 (q, J = 7.1 Hz,
2 H), 4.08 (s, 2 H), 1.41 (t, J = 7.1 Hz, 3 H).
13C NMR (126 MHz, CDCl3): δ = 178.9 (q, J = 34.8 Hz), 167.4 (q,
J = 4.4 Hz), 116.8 (q, J = 290.9 Hz), 111.3, 73.3, 42.7, 15.2.
19F NMR (376 MHz, CDCl3): δ = –70.36 (s).
Anal. Calcd for C8H8BrF5O2: C, 30.89; H, 2.59. Found: C, 30.98; H,
2.64.
Anal. Calcd for C7H8F3N3O2: C, 37.68; H, 3.61; N, 18.83. Found:
C, 37.73; H, 3.51; N, 18.96.
(Z)-2-(Bromomethyl)-1-ethoxy-4,4,5,5,6,6,6-heptafluorohex-1-
en-3-one (5c)
Yellow low-melting crystals; yield: 25.0 g (69%); bp 130–135
°C/10–12 Torr.
1H NMR (500 MHz, CDCl3): δ = 7.73 (s, 1 H), 4.35 (q, J = 7.1 Hz,
2 H), 4.22 (s, 2 H), 1.44 (t, J = 7.1 Hz, 3 H).
13C NMR (126 MHz, CDCl3): δ = 179.5 (t, J = 25.4 Hz), 167.3 (t,
J = 9.1 Hz), 121.3–106.0 (m), 116.4, 73.6, 21.0, 15.3.
(E)-4-Ethoxy-1,1,1-trifluoro-3-(isothiocyanatomethyl)but-3-en-
2-one (9)
Pale yellow oil; yield: 2.10 g (88%).
IR (CCl4): 1695 (C=O), 2061 cm–1 (N=C=S).
1H NMR (500 MHz, CDCl3): δ = 7.73 (s, 1 H), 4.40–4.27 (m, 4 H),
1.46 (t, J = 7.1 Hz, 3 H).
13C NMR (126 MHz, CDCl3): δ = 177.0 (q, J = 35.1 Hz), 167.2 (q,
J = 4.5 Hz), 133.3, 116.7 (q, J = 290.9 Hz), 110.5, 73.7, 37.4, 15.4.
19F NMR (471 MHz, CDCl3): δ = –70.43 (s).
19F NMR (376 MHz, CDCl3): δ = –80.70 (t, J = 9.1 Hz, 3 F),
–113.25 (q, J = 9.1 Hz, 2 F), –126.35 (br s, 2 F).
Anal. Calcd for C9H8BrF7O2: C, 29.94; H, 2.23. Found: C, 30.03; H,
2.34.
Anal. Calcd for C8H8F3NO2S: C, 40.17; H, 3.37; N, 5.86. Found: C,
40.29; H, 3.21; N, 5.67.
(Z)-3-(Bromomethyl)-4-ethoxy-1,1-difluorobut-3-en-2-one (5d)
Yellow oil; yield: 15.6 g (64%); bp 131–134 °C/10–12 Torr.
1H NMR (500 MHz, CDCl3): δ = 7.74 (s, 1 H), 5.99 (t, J = 53.9 Hz,
1 H), 4.31 (q, J = 7.1 Hz, 2 H), 4.20 (s, 2 H), 1.42 (t, J = 7.1 Hz, 3 H).
13C NMR (126 MHz, CDCl3): δ = 185.3 (t, J = 25.7 Hz), 166.0 (t,
J = 6.1 Hz), 114.6, 112.0 (t, J = 254.7 Hz), 73.0, 21.1, 15.4.
(E)-4-Ethoxy-1,1,1-trifluoro-3-(nitromethyl)but-3-en-2-one
(10)
Pale yellow oil; yield: 2.03 g (89%).
1H NMR (500 MHz, CDCl3): δ = 7.87 (s, 1 H), 5.24 (s, 2 H), 4.37
(q, J = 7.1 Hz, 2 H), 1.44 (t, J = 7.1 Hz, 3 H).
13C NMR (126 MHz, CDCl3): δ = 178.2 (q, J = 35.6 Hz), 168.8 (d,
J = 4.2 Hz), 116.7 (q, J = 290.1 Hz), 107.1, 74.0, 67.1, 15.4.
19F NMR (376 MHz, CDCl3): δ = –119.95 (d, J = 53.8 Hz).
Anal. Calcd for C7H9BrF2O2: C, 34.59; H, 3.73. Found: C, 34.63; H,
3.64.
19F NMR (376 MHz, CDCl3): δ = –70.77 (s).
Anal. Calcd for C7H8F3NO4: C, 37.02; H, 3.55; N, 6.17. Found: C,
37.13; H, 3.51; N, 6.06.
(Z)-3-(Bromomethyl)-1-chloro-4-ethoxy-1,1-difluorobut-3-en-
2-one (5e)
Yellow low-melting crystals; yield: 19.7 g (71%); bp 128–132
°C/10–12 Torr.
(Z)-4-Ethoxy-1,1,1-trifluoro-3-[(p-tolylthio)methyl]but-3-en-2-
one (11)
To a stirred solution of 5a (0.50 g, 1.92 mmol) and 4-methylbenze-
nethiol (0.24 g, 1.92 mmol) in acetone (20 mL), K2CO3 (0.29 g, 2.11
mmol) was added. The mixture was stirred at r.t. for 4 h to complete
1H NMR (500 MHz, CDCl3): δ = 7.76 (s, 1 H), 4.34 (q, J = 7.1 Hz,
2 H), 4.23 (s, 2 H), 1.43 (t, J = 7.1 Hz, 3 H).
Synthesis 2013, 45, 3157–3163
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PAPER
1-(Bromomethyl)-2-ethoxyvinyl Polyfluoroalkyl Ketones
3161
the reaction. The end of the reaction was determined by TLC
(EtOAc–hexane, 2:1). The mixture was filtered, the solvent was re-
moved under vacuum and the residue was purified by column chro-
matography (EtOAc–hexane, 2:1). The product 11 (0.24 g, 41%)
was obtained as a pale yellow oil.
1H NMR (500 MHz, CDCl3): δ = 7.49 (s, 1 H), 7.34 (d, J = 7.9 Hz,
2 H), 7.08 (d, J = 7.9 Hz, 2 H), 4.04 (q, J = 7.1 Hz, 2 H), 3.77 (s, 2
H), 2.31 (s, 3 H), 1.24 (t, J = 7.1 Hz, 3 H).
1H NMR (500 MHz, CDCl3): δ = 7.57 (s, 1 H), 3.93 (br s, 2 H), 3.63
(br m, 2 H), 3.35 (s, 2 H), 2.45 (br m, 4 H), 1.95 (br m, 4 H), 1.68
(br m, 4 H).
13C NMR (126 MHz, CDCl3): δ = 177.1 (q, J = 30.2 Hz), 152.8,
118.8 (q, J = 292.6 Hz), 103.0, 52.0, 47.8, 23.6.
19F NMR (376 MHz, CDCl3): δ = –66.06 (s).
Anal. Calcd for C13H19F3N2O: C, 56.51; H, 6.93; N, 10.14. Found:
C, 56.47; H, 6.75; N, 10.26.
13C NMR (126 MHz, CDCl3): δ = 178.6 (q, J = 34.3 Hz), 164.0 (q,
J = 4.3 Hz), 137.4, 132.0, 132.1, 129.5, 116.9 (q, J = 291.3 Hz),
114.1, 72.3, 28.5, 21.2, 15.1.
(E)-1,1,1-Trifluoro-4-(piperidin-1-yl)-3-(piperidin-1-ylmeth-
yl)but-3-en-2-one (12e)
White solid; yield: 0.70 g (46%); mp 87–89 °C (hexane).
1H NMR (500 MHz, CDCl3): δ = 7.35 (s, 1 H), 3.67 (br s, 4 H), 3.17
(s, 2 H), 2.29 (br m, 4 H), 1.68 (br m, 6 H), 1.45 (br m, 4 H), 1.38
(br m, 2 H).
19F NMR (471 MHz, CDCl3): δ = –69.82 (s).
Anal. Calcd for C14H15F3O2S: C, 55.25; H, 4.97. Found: C, 55.44;
H, 5.08.
13C NMR (126 MHz, CDCl3): δ = 177.9 (q, J = 30.2 Hz), 154.0,
118.8 (q, J = 292.5 Hz), 100.3, 53.1, 51.7, 26.0, 26.4, 24.7, 24.0.
19F NMR (376 MHz, CDCl3): δ = –65.88 (s).
α-Aminomethyl Enaminones 12a–f; General Procedure
A solution of 5a (1.3 g, 5 mmol) in CH2Cl2 (20 mL) was added
dropwise to a solution of the respective secondary amine (25 mmol)
in CH2Cl2 (30 mL) under stirring. The mixture was stirred at r.t. for
1 h. The mixture was filtered, and the organic phase was washed
with H2O and dried (Na2SO4). After evaporation of the solvent, the
residue was crystallized (if necessary) from hexane to afford pure
products.
Anal. Calcd for C15H23F3N2O: C, 59.20; H, 7.62; N, 9.20. Found: C,
59.35; H, 7.54; N, 9.39.
(E)-1,1,1-Trifluoro-4-morpholino-3-(morpholinomethyl)but-3-
en-2-one (12f)
Grey solid; yield: 1.21 g (79%); mp 93–95 °C (hexane).
1H NMR (500 MHz, CDCl3): δ = 7.33 (s, 1 H), 3.76 (br m, 8 H), 3.58
(br m, 4 H), 3.24 (s, 2 H), 2.37 (br m, 4 H).
13C NMR (126 MHz, CDCl3): δ = 178.2 (q, J = 30.4 Hz), 154.0–
154.7 (m), 118.4 (q, J = 292.8 Hz), 100.0, 67.2, 67.0, 52.2, 51.1.
19F NMR (376 MHz, CDCl3): δ = –66.48 (s).
(E)-4-(Dimethylamino)-3-[(dimethylamino)methyl]-1,1,1-tri-
fluorobut-3-en-2-one (12a)
Grey-brown wax; yield: 0.44 g (40%).
1H NMR (500 MHz, CDCl3): δ = 7.30 (s, 1 H), 3.23 (s, 6 H), 3.08
(s, 2 H), 2.06 (s, 6 H).
13C NMR (126 MHz, CDCl3): δ = 177.4 (q, J = 29.9 Hz), 156.8,
118.6 (q, J = 292.6 Hz), 101.5, 51.1, 43.8.
Anal. Calcd for C13H19F3N2O3: C, 50.65; H, 6.21; N, 9.09. Found:
C, 50.78; H, 6.20; N, 9.23.
19F NMR (376 MHz, CDCl3): δ = –66.25 (s).
Anal. Calcd for C9H15F3N2O: C, 48.21; H, 6.74; N, 12.49. Found:
C, 48.35; H, 6.88; N, 12.40.
4-Methylene-5-(trifluoromethyl)-4,5-dihydroisoxazol-5-ol (13)
To a solution of NH2OH·HCl (0.11 g, 1.59 mmol) in MeCN (10 mL)
was added pyridine (0.25 g, 3.17 mmol) and 5a (0.41 g, 1.59 mmol).
The mixture was stirred for 10 h at reflux. After cooling, the solvent
was evaporated and the residue was column chromatographed (sili-
ca gel, EtOAc–hexane, 2:1) to give product 13 (0.15 g, 57%) as a
pale yellow oil.
(E)-4-(Diethylamino)-3-[(diethylamino)methyl]-1,1,1-trifluoro-
but-3-en-2-one (12b)
Brown oil; yield: 0.91 g (65%).
1H NMR (500 MHz, CDCl3): δ = 7.42 (s, 1 H), 3.62 (br m, 4 H), 3.31
(s, 2 H), 2.46 (q, J = 7.1 Hz, 4 H), 1.26 (t, J = 7.1 Hz, 6 H), 0.97 (t,
J = 7.1 Hz, 6 H).
1H NMR (500 MHz, CDCl3): δ = 7.64 (s, 1 H), 5.93 (s, 1 H), 5.90
13C NMR (126 MHz, CDCl3): δ = 177.9 (q, J = 29.8 Hz), 155.0 (q,
J = 4.3 Hz), 118.8 (q, J = 292.6 Hz), 101.3, 46.9, 45.1, 14.9, 11.5.
19F NMR (376 MHz, CDCl3): δ = –65.73 (s).
(s, 1 H), 4.56 (s, 1 H).
13C NMR (126 MHz, CDCl3): δ = 148.1, 142.8, 121.9, 121.3 (q, J =
284.4 Hz), 99.7 (q, J = 34.8 Hz).
19F NMR (376 MHz, CDCl3): δ = –84.57 (s).
MS (CI): m/z (%) = 168 (100) [M + 1]+.
Anal. Calcd for C13H23F3N2O: C, 55.70; H, 8.27; N, 9.99. Found: C,
55.56; H, 8.13; N, 10.15.
Anal. Calcd for C5H4F3NO2: C, 35.94; H, 2.41; N, 8.38. Found: C,
36.15; H, 2.54; N, 8.36.
(E)-4-(Diisopropylamino)-3-[(diisopropylamino)methyl]-1,1,1-
trifluorobut-3-en-2-one (12c)
Brown oil; yield: 0.84 g (50%).
2,2,2-Trifluoro-1-(2-phenyl-6H-1,3-thiazin-5-yl)ethanone (14)
A solution of 5a (1.00 g, 3.93 mmol), benzothioamide (0.53, 3.93
mmol), and K2CO3 (0.58 g, 0.42 mmol) in acetone (25 mL) was
stirred at r.t. for 4 h. The mixture was filtered, the solvent was re-
moved, and the residue was chromatographed (EtOAc–hexane
1:15) to give product 14 (0.25 g, 21%) as yellow crystals; mp 74–
76 °C.
1H NMR (500 MHz, CDCl3): δ = 8.25 (s, 1 H), 8.10 (d, J = 7.7 Hz,
2 H), 7.62 (t, J = 6.8 Hz, 1 H), 7.51 (br dd, both J ~ 7.0 Hz, 2 H),
3.75 (s, 2 H).
1H NMR (500 MHz, CDCl3): δ = 7.47 (s, 1 H), 5.47 (br s, 1 H), 3.67
(br s, 1 H), 3.47 (s, 2 H), 3.00 (br s, 2 H), 1.23 (br s, 12 H), 1.00 (br
s, 12 H).
13C NMR (126 MHz, CDCl3): δ = 178.1 (q, J = 28.5 Hz), 151.4,
119.1 (q, J = 293.6 Hz), 101.0, 50.2, 47.8, 46.3, 20.7, 20.9.
19F NMR (376 MHz, CDCl3): δ = –65.22 (s).
Anal. Calcd for C17H31F3N2O: C, 60.69; H, 9.29; N, 8.33. Found: C,
60.90; H, 9.31; N, 8.42.
13C NMR (126 MHz, CDCl3): δ = 179.4 (q, J = 35.8 Hz), 172.6,
152.3 (q, J = 4.7 Hz), 136.8, 133.8, 129.5, 129.0, 116.7 (q, J = 290.6
Hz), 110.3, 21.1.
(E)-1,1,1-Trifluoro-4-(pyrrolidin-1-yl)-3-(pyrrolidin-1-ylmeth-
yl)but-3-en-2-one (12d)
White solid; yield: 0.66 g (48%), mp 78–79 °C (hexane).
19F NMR (376 MHz, CDCl3): δ = –70.72 (s).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3157–3163

3162
M. Ya. Bugera et al.
PAPER
Anal. Calcd for C12H8F3NOS: C, 53.13; H, 2.97; N, 5.16. Found: C,
53.27; H, 2.79; N, 5.04.
(7) Reviews on fluorinated enones and enaminones:
(a) Nenajdenko, V. G.; Sanin, A. V.; Balenkova, E. S. Russ.
Chem. Rev. 1999, 68, 483. (b) Druzhinin, S. V.; Balenkova,
E. S.; Nenajdenko, V. G. Tetrahedron 2007, 63, 7753.
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Zhu, S.; Liu, L.; Xu, L. Tetrahedron 2012, 68, 5677.
(b) Chopin, N.; Decamps, S.; Gouger, A.; Medebielle, M.;
Picot, S.; Bienvenu, A.-L.; Pilet, G. J. Fluorine Chem. 2011,
132, 850. (c) Xin, Y.; Zhao, J.; Zhu, S. J. Fluorine Chem.
2012, 133, 98. (d) Kim, M. S.; Ryu, H.; Kang, D. W.; Cho,
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S.; Bhondwe, R. S.; Kim, H. S.; Lee, J.; Park, S.-G.; Son, K.;
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B. Y.; Schiene, K.; Christoph, T. J. Med. Chem. 2012, 55,
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J. Inorg. Chem. 2012, 1093. (g) Baharfar, R.; Azimi, R.
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Gerus, I. I.; Vdovenko, S. I.; Haufe, G.; Kirzhner, Y. A.
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Acknowledgment
Financial support was provided by grant from DFG 436 UKR
113/101/0-1. We express our gratitude to Alexander N. Chernega
(Institute of Organic Chemistry, Kiev, Ukraine) for performing the
X-ray diffraction study.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
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© Georg Thieme Verlag Stuttgart · New York

PAPER
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1-(Bromomethyl)-2-ethoxyvinyl Polyfluoroalkyl Ketones
3163
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3157–3163