Synthesis and properties of β-cyanovinyl polyhaloalkyl ketones

Article abstract of DOI:10.1055/s-2002-19307

A number of β-cyanovinyl polyhaloalkyl ketones were prepared by the reaction of readily accessible 2-ethoxy-4-trimethylsiloxy-4-polyhaloalkylbut-3-ene nitriles with sulfuric acid. It was demonstrated, that β-cyanovinyl trifluoromethyl ketone, are useful fluorinated building blocks susceptible to 1,2- and 1,4-addition reactions.

Full text of DOI:10.1055/s-2002-19307

PAPER
71
Synthesis and Properties of -Cyanovinyl Polyhaloalkyl Ketones
S
ynthesi
g
s
of -Cyano
o
vinyl Polyha
r
loalkyl
K
etone
S
s
. Kruchok,* Igor I. Gerus, Valery P. Kukhar
Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine, Murmanskaya 1, 02094 Kiev, Ukraine
Fax +7(44)5732552; E-mail: kruchok@bpci.kiev.ua
Received 1 May 2001; revised 11 October 2001
der the conditions of the addition process at high temper-
Abstract: A number of -cyanovinyl polyhaloalkyl ketones were
ature or in the presence of Lewis acid catalysts and
prepared by the reaction of readily accessible 2-ethoxy-4-trimethyl-
undergoes elimination of TMSOMe to yield a -cyanovi-
siloxy-4-polyhaloalkylbut-3-ene nitriles with sulfuric acid. It was
nyl methyl ketone4 (cf. Scheme 1, R = Me). In contrast to
demonstrated, that -cyanovinyl trifluoromethyl ketone, are useful
fluorinated building blocks susceptible to 1,2- and 1,4-addition re- this compound, the adducts 1a–f with R = polyhaloalkyl
actions.
groups are stable under these reaction conditions. We as-
sumed that the use of Brönsted acids as catalysts allows
to realize the synthesis of -cyanovinyl polyhaloalkyl
ketones 2a–f from 1,4-adducts 1a–f by elimination of
TMSOEt at ambient temperature. The most readily avail-
able trifluoromethyl compound 1a was used as model sub-
stance to find optimal conditions for the synthesis of the
desired ketones 2.
Key words: eliminations
compounds, cycloadditions, heterocycles
, -unsaturated ketones, fluorinated
Fluorine containing organic compounds, in comparison to
non-fluorinated analogs, quite often exhibit a better set of
physical/chemical properties and a higher biological ac-
tivity. These reasons stimulated an increased interest in
the synthesis of fluorine-containing compounds in the last
few years.1 The most common and attractive synthetic
method for preparing fluorine-containing compounds, be-
sides direct fluorination, is using available fluorine-con-
taining building blocks as starting materials.2
We have found that the action of catalytic amounts of sul-
furic, trifluoroacetic, trifluoromethylsulfonic, or perchlo-
ric acid to 1,4-adduct 1a results in the formation of a
complex mixture of compounds, containing <15% -cy-
anovinyl ketone 2b at 70–100% conversion by 1H and 19F
NMR spectra. The highest yield of the ketone 2b was ob-
tained using 100% sulfuric acid. Variation of the H2SO4/
1b ratio showed that the yield of ketone 2b increases with
an increase in quantity of sulfuric acid, and with the use of
3–4 equivalents of H2SO4, ketone 2b was the major prod-
uct of the reaction. This ratio is optimal and was applied
by us to synthesize the other ketones 2a,c–f (Scheme 1).
Previously, we have shown that cyano(trimethyl)silane
(TMSCN) reacts with various -alkoxyvinyl polyha-
loalkyl ketones to give 1,4-adducts in high yields.3,4 The
obtained 1,4-adducts can be considered as trimethylsilyl
ethers of the enol form of corresponding -alkoxy ke-
tones. One of the inherent properties of -alkoxy ketones
is, they are known to undergo alcohol elimination with the
formation of , -unsaturated ketones. An application of
this reaction would allow the corresponding -cyanovinyl
haloalkyl ketones to be obtained in one step. They are at-
tractive polyfunctional electrophilic fluorine-containing
building blocks for further synthetic purposes. , -Unsat-
urated ketones with electron acceptor substituents in
-
position are well known to be widely applied in organic
synthesis, e.g. in cycloaddition reactions.5–7 The introduc-
tion of halogen atoms into the acyl residue of -cyano-
, -unsaturated ketones should increase the electrophilic-
ity of the conjugated system and the specific reactivity of
these compounds in reactions such as Diels–Alder addi-
tion and nucleophilic addition to the carbonyl group.
Scheme 1
The yields of ketones 2a–f were determined after extrac-
tion of the reaction mixture with CDCl3 by 1H NMR spec-
tra with a standard quantity of dibromomethane as
reference substance. According to these data the obtained
extracts of the products contain <3% of other products
In this paper we describe the synthesis of -cyanovinyl
polyfluoroalkyl ketones and some reactions of these pre-
viously unknown substances.
1
with a polyhaloalkyl group. In addition, in the H NMR
spectra of CDCl3 extracts there are signals of ethoxy (4.3
and 1.4 ppm) and trimethylsilyloxy (0.4 ppm) groups with
an integral intensity, which is in approximately equal ratio
As was shown earlier, the adduct of the reaction of
-
methoxyvinyl methyl ketone with TMSCN is unstable un- with the intensity of the signals of the ketones 2a–f. Com-
1
parison of these data with H NMR spectrum of the
TMSOEt allows to suppose that these signals are caused
Synthesis 2002, No. 1, 28 12 2001. Article Identifier:
by the formation of ethyl and trimethylsilyl sulfates dur-
1437-210X,E;2002,0,01,0071,0074,ftx,en;Z05901SS.pdf.
ing the reaction. 1H NMR spectrum of CDCl3 extract after
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

72
I. S. Kruchok et al.
PAPER
the model reaction between TMSOEt and H2SO4 was sim-
ilar to the above mentioned.
-Cyanovinyl polyhaloalkyl ketones 2a–f are formed as
single isomers with (E)-configuration as shown by the
coupling constants of vinyl protons JHH = 16.1–16.4 Hz
(Table 1) in the 1H NMR spectra. The ketones can be also
isolated by distillation, which was shown by isolation of
ketone 2b in the pure state. Liquid -cyanovinyl trifluo-
romethyl ketone 2b is stable for a long time at room tem-
perature in the absence of moisture and easily adds water
and methanol to yield adducts 3a,b, respectively
(Scheme 2). The high electrophilicity of the carbonyl
group in ketone 2b was also demonstrated by a fast 1,2-
addition reaction with cyano(trimethyl)silane, which pro-
ceeds in the absence of a catalyst, to give 1,3-dicyano-1-
trifluoromethyl-1-trimethylsiloxypentene (4) in high
Scheme 3
1
yield. According to the H and 19F NMR spectra, it was
shown that the C=C bond in compounds 3a and 4 retains
(E)-configuration.
With respect to the stereospecificity of the Diels–Alder re-
action, taking into account the (E)-configuration of the ke-
tone 2b and the 1H and 19F NMR spectra of the obtained
compounds, it is possible to prove that the CN and CF3CO
groups in adducts 5–7 are in a trans-configuration. Ad-
ducts 5 and 6 are formed as a single isomer, and adduct 7
is obtained as a mixture of endo- and exo-isomers in a 7:1
ratio.
We have also shown that the ketone 2b is active as diene
in hetero-Diels–Alder reaction with alkyl vinyl ethers.
Thus, interaction of the ketone 2b with ethyl vinyl ether
and 2,3-dihydrofuran results in the formation of adducts 8
and 9, respectively, in high yields (>97%) and with high
diastereoselectivity (de 88%) (Scheme 4).
Scheme 2
The ketone 2b was also introduced as dienophile into Di-
els–Alder reactions with 2,3-dimethylbuta-1,3-diene, an-
thracene, and cyclopentadiene. Whereas the non-
fluorinated trans- -cyanovinyl methyl ketone reacts with
2,3-dimethylbuta-1,3-diene only on heating,5 the ketone
2b gives the corresponding cycloaddition products 5,6,
and 7 in almost quantitative yields even at room tempera-
ture (Scheme 3).
All compounds 5, 7–9 are liquids stable for a long time at
room temperature in the absence of moisture.
In summary, we have developed a simple method to pre-
pare -cyanovinyl polyhaloalkyl ketones 2a–f. The high
reactivity of these compounds was demonstrated by 1,2-
addition reactions with the carbonyl group and [4+2] cy-
Table 1 Yield and NMR Spectra of Ketones 2a–f
Entry Product Yielda
(%)
1H NMR (CDCl3/TMS) , J (Hz)
CHCOR
19F NMR (CDCl3/CFCl3)
Others
CHCN
1
2
3
2a
2b
2c
44
7.27 (dt, J = 16.4, 1.0)
7.26 (dq, J = 16.3, 0.6)
7.33 (dt, J = 16.3, 1.2)
6.62 (d, J = 16.4)
6.71 (d, J = 16.3)
6.71 (d, J = 16.3)
5.98 (t, 1 H, J = 53.3)
–127.96 (br d, J = 53.3)
60b
52
-
-
–78.63 (br s)
–124.41 (br m, 2 F),
–82.23 (br s, 3 F)
4
2d
45
7.32 (d br t, J = 16.2, 1.0) 6.70 (d, J = 16.2)
-
–126.96 (s, 2 F), –122.53 (br q, 2
F, J = 8.5), –80.94 (t, 3 F, J = 8.5)
5
6
2e
2f
73
61
7.18 (d, J = 16.1)
7.61 (d, J = 16.1)
6.56 (d, J = 16.1)
6.77 (d, J = 16.1)
4.41 (hept, 1 H, J = 7.6) –63.34 (d, J = 7.6)
-
-
a NMR yield.
b Isolated yield: 53%.
Synthesis 2002, No. 1, 71–74 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of -Cyanovinyl Polyhaloalkyl Ketones
73
Ketones 2a–f from Adducts 1a-f; General Procedure
To 100% H2SO4 (0.196 g, 2 mmol) was added the adduct 1a–f (0.5
mmol) under stirring. After 30 min the product was extracted with
CDCl3 (3 0.5 mL). To the combined extracts were added CH2Br2
1
(0.045 g, 0.26 mmol) as standard. The yields were detected by H
NMR spectra as a ratio of the integrated intensity of vinyl protons
signals of ketones 2a–f and protons of CH2Br2 (Table 1).
(E)-5,5,5-Trifluoro-4-oxopent-2-enenitrile (2b)
To 100% H2SO4 (19.6 g, 200 mmol) was added the adduct 1b
(13.35 g, 50 mmol) under stirring. After 30 min the product was dis-
tilled from the reaction mixture in vacuo (0.5 mmHg) at a trap,
cooled by liquid nitrogen. At the end of the distillation the temper-
ature of the flask was raised up to 50–60 °C. Crude ketone 2b was
redistilled at atmospheric pressure, with careful protection from
Scheme 4
cloaddition reactions with dienes and vinyl ethers. The
high electrophilicity of the conjugated C=C–C=O system moisture; yield: 3.95 g (53%); bp 130–132 °C
13C NMR: = 115.14 (s), 115.70 (q, JCF = 289.3 Hz), 117.48 (s),
136.38 (s), 178.48 (q, JCF = 38.5 Hz). IR (CH2Cl2): 1744 (C=O),
1616 cm–1 (C=C).
opens a possibility to use these compounds as building
blocks containing polyfluoroalkyl units.
1H, 13C, and 19F NMR spectra were measured at 300, 75.43, and
282.24 MHz (Varian VXR-300), respectively, in CDCl3 solution
(unless otherwise noted) using TMS and CFCl3 as the internal stan-
dards. Adducts 1a–f were prepared according to the literature pro-
cedure.4 100% H2SO4 was obtained by mixing of 36 g of 95%
H2SO4 and 40 g of 20% oleum. Other reagents were purchased from
Aldrich. Satisfactory microanalyses were obtained for all new com-
pounds: C, 0.24; H, 0.19; N, 0.17.
(E)-5,5,5-Trifluoro-4,4-dihydroxypent-2-enenitrile (3a);
Typical Procedure
To a solution of the ketone 2b (0.45 g, 3.0 mmol) in Et2O (6 ml) was
added H2O (0.09 g, 5.0 mmol). Then the mixture was stirred for 30
min. The solvent and excess of H2O were removed in vacuo
(Table 2).
Table 2 Yield and NMR Spectra of Compounds 3a,b and 4–9
Product Yield (%) Mp (°C) or bp
(°C/mm Hg)
1H NMR (CDCl3/TMS)
19 F NMR (CDCl3/CFCl3)
, J (Hz)
3aa
3ba
4
>97
>97
112–113
97–99
6.25 (d, 1 H, J = 16.2), 6.91 (dq, 1 H, J = 16.2, 0.6), 6.91 (br s, 2 H)
3.23 (s, 3 H), 6.25 (d, 1 H, J = 16.2), 6.86 (d, 1 H, J = 16.2), 8.18 (s, 1 H) –84.96 (br s)
0.34 (s, 9 H), 6.08 (d, 1 H, J = 16.1), 6.67 (dq, 1 H, J = 16.1, 0.6) –79.49 (br s)
–83.86 (d, J = 0.6)
97
88–90/14
(85)b
5
98
oil
1.66 (br s, 6 H), 2.12 (m, 1 H), 2.32–2.54 (m, 3 H), 3.06 (ddd, 1 H, J = –78.02 (br s)
10.1, 10.1, 6.1), 3.37 (ddd, 1 H, J = 10.1, 10.1, 5.5)
6
97
152–153 (hex-
ane)
3.55 (dd, 1 H, J = 4.9, 2.5), 3.65 (dd, 1 H, J = 4.9, 2.3), 4.67 (br d, 1 H, –76.08 (s)
J = 2.5), 4.82 (br s, 1 H), 7.14–7.52 (m, 8 H)
7c
97
major: 1.79 (dm, 1 H, J = 9.5), 1.88 (br d, 1 H, J = 9.5), 2.85 (dd, 1 H, major: –77.47 (br s)
(84)b
96–98/7
J = 4.1, 1.8), 3.40 (br s, 1 H), 3.62 (br s, 1 H), 3.73 (dd, 1 H, J = 4.1,
4.0), 5.93 (dd, 1 H, J = 5.5, 2.8), 6.29 (dd, 1 H, J = 5.5, 3.2)
minor: –77.46 (br s)
minor:d 1.45 (dm, 1 H, J = 9.8), 1.58 (dm, 1 H, J = 9.8), 3.06 (br m, 1
H), 3.35 (br m, 1 H), 6.46 (br d, 1 H, J = 5.8), 6.59 (dd , 1 H, J = 5.8, 2.9)
8c
98
major: 1.27 (t, 3 H, J = 7.0), 2.08 (ddd, 1 H, J = 14.2, 7.3, 2.3), 2.35
(ddd, 1 H, J = 14.2, 3.8, 2.5), 3.44 (m, 1 H), 3.67 (dq, 1 H, J = 9.5, 7.0), minor: –73.68 (d, J = 2.4)
3.89 (dq, 1 H, J = 9.5, 7.0), 5.35 (dd, 1 H, J = 2.5, 2.3), 5.56 (br d, 1 H,
major: –73.76 (d, J = 1.6)
(82)b
123–125/17
106–108/0.5
J = 4.8)
minor:d 1.21 (t, 3 H, J = 7.0)
9c
97
major: 2.03 (m, 1 H), 2.37 (m d, 1 H, J = 2.7), 2.81 (m, 1 H), 3.94 (m, 1 major: –73.66 (d, J = 2.5)
H), 4.12 (ddd, 1 H, J = 9.0, 8.8, 7.6), 4.30 (ddd, 1 H, J = 9.2, 9.0, minor: –73.70
(79)b
2.7), 5.40 (br m, 1 H), 5.54 (d, 1 H, J = 3.6)
(d, J = 1.5)
minor:d 3.48 (m, 1 H), 5.44 (br d, 1 H, J = 5.3), 5.66 (br d, 1 H, J = 3.7)
a 1H and 19F NMR spectra were measured in acetone-d6 (3a) or DMSO-d6 (3b).
b Yield after distillation, ratio of isomers not changed.
c Mixture of isomers, ratio: 7:1 (for 7), 16:1 (for 8), 15:1 (for 9).
d The signals are not overlapped by signals of the major isomer.
Synthesis 2002, No. 1, 71–74 ISSN 0039-7881 © Thieme Stuttgart · New York

74
I. S. Kruchok et al.
PAPER
(E)-5,5,5-Trifluoro-4-hydroxy-4-methoxypent-2-enenitrile (3b)
Prepared from the ketone 2b (0.45 g, 3.0 mmol) and anhyd MeOH
(0.16 g, 5.0 mmol) following the typical procedure described for 3a
(Table 2).
r.t. and then the solvent was removed in vacuo. Additional purifica-
tion of 7 can be achieved by vacuum distillation (Table 2).
2-Ethoxy-6-trifluoromethyl-3,4-dihydro-2H-4-pyrancarbo-
nitrile (Mixture of Isomers) (8); Typical Procedure
(E)-4-Trifluoromethyl-4-trimethylsilyloxypent-2-enedinitrile
(4)
To TMSCN (0.69 g, 7 mmol) was added the ketone 2b (0.75 g, 5
mmol). The mixture was allowed to stand for 1 h. Excess of
TMSCN was removed in vacuo. Additional purification of 4 can be
achieved by vacuum distillation (Table 2).
To a solution of ethyl vinyl ether (0.50 g, 7 mmol) in CHCl3 (10 mL)
was added the ketone 2b (0.75 g, 5 mmol) under stirring, and then
the mixture was allowed to stand for 1 day at r.t. The solvent and
excess of vinyl ether were removed in vacuo. Additional purifica-
tion of 8 can be achieved by vacuum distillation (Table 2).
6-Trifluoromethyl-2,3,3a,7a-tetrahydro-4H-furo[2,3-b]pyran-
4-carbonitrile (Mixture of Isomers) (9)
Prepared from 2,3-dihydrofuran (0.49 g, 7.0 mmol) following the
typical procedure described for 8. (Table 2).
(E)-3,4-Dimethyl-6-trifluoroacetylcyclohex-3-ene-1-carbo-
nitrile (5)
To a solution of 2,3-dimethylbuta-1,3-diene (0.22 g, 2.6 mmol) in
CHCl3 (6 mL) was added the ketone 2b (0.30 g, 2.0 mmol) under
stirring and the mixture was allowed to stand for 12 h at r.t. The sol-
vent and excess of 2,3-dimethylbuta-1,3-diene were removed in
vacuo (Table 2).
References
(1) (a) Welch, J. T.; Eswarakrishnan, S. Fluorine in Bioorganic
Chemistry; Wiley: New York, 1991. (b) Filler, R.;
Kobayashi, Y.; Yagupolski, L. M. Organofluorine
Compounds in Medicinal Chemistry and Biomedical
Applications; Elsevier: Amsterdam, 1993.
(2) Percy, J. M. Top. Curr. Chem. 1997, 193, 131.
(3) Gerus, I. I.; Kruchok, I. S.; Kukhar, V. P. Tetrahedron Lett.
1999, 40, 5923.
(E)-16-(Trifluoroacetyl)tetracyclo[6.6.2.02,7.09,14]hexadeca-
2(7),3,5,9(14),10,12-hexaene-15-carbonitrile (6)
To a suspension of anthracene (0.54 g, 3 mmol) in CHCl3 (15 mL)
was added the ketone 2b (0.60 g, 4 mmol) with stirring and under
argon. Then the mixture was stirred for 3 d at 20 °C. The solvent and
excess 2b were removed in vacuo (Table 2).
(4) Kruchok, I. S.; Gerus, I. I.; Kukhar, V. P. Tetrahedron 2000,
56, 6533.
(5) Hosokawa, T.; Aoki, S.; Murahashi, S.-I. Synthesis 1992,
558.
(6) Nudelman, A.; Keinan, E. Synthesis 1982, 687.
(7) Franck-Neumann, M.; Miesch, M. Tetrahedron 1983, 39,
1247.
3-(Trifluoroacetyl)bicyclo[2.2.1]hept-5-ene-2-carbonitrile
(Mixture of Isomers) (7)
To a solution of the ketone 2b (0.75 g, 5 mmol) in CHCl3 (10 mL)
was added a solution of cyclopentadiene (0.33 g, 5 mmol) in CHCl3
(2 mL) under stirring. The mixture was allowed to stand for 12 h at
Synthesis 2002, No. 1, 71–74 ISSN 0039-7881 © Thieme Stuttgart · New York