A facile synthesis of 4-aryl-1,1,1-trifluorobut-3-en-2-ones via 4-aryl substituted CF3 - containing dihydropyran derivatives: A versatile method for the introduction of fluorine-containing C4- and C6- unit to aromatic compounds

Article abstract of DOI:10.3987/COM-09-S(S)60

The CF₃ - containing dihydropyran derivative (2) reacted easily with various aromatic compounds in trifluoroacetic acid to give novel 4-aryl substituted dihydropyran derivatives (7) in moderate to high yields. Retro hetero Diels-Alder reaction of thus obtained 7 proceeded readily by heating at 300 °C to afford the corresponding 4-aryl-1,1,1-trifluorobut-3-en-2-ones (12) in good to excellent yields. With the use of p-toluenesulfonic acid instead of trifluoroacetic acid together with dihydropyran (2) in acetonitrile, 4-trifluoroacetyl-1,3-butadienylation of 1,3-dimethoxybenzene occurred successfully. The bimolecular reaction of dihydropyran (2) in the presence of p-toluenesulfonic acid was also examined.

Full text of DOI:10.3987/COM-09-S(S)60

HETEROCYCLES, Vol. 80, No. 1, 2010
515
HETEROCYCLES, Vol. 80, No. 1, 2010, pp. 515 - 525. © The Japan Institute of Heterocyclic Chemistry
Received, 19th July, 2009, Accepted, 31st August, 2009, Published online, 1st September, 2009
DOI: 10.3987/COM-09-S(S)60
A
FACILE
SYNTHESIS
OF
4-ARYL-1,1,1-TRIFLUOROBUT-
3-EN-2-ONES VIA 4-ARYL SUBSTITUTED CF3 - CONTAINING
DIHYDROPYRAN DERIVATIVES: A VERSATILE METHOD FOR
THE INTRODUCTION OF FLUORINE-CONTAINING C4- AND C6- UNIT
TO AROMATIC COMPOUNDS
Norio Ota, Etsuji Okada,* Dai Shibata, Satoru Adachi, and Shohei Saikawa
Department of Chemical Science and Engineering, Graduate School of
Engineering, Kobe University, Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan
Fax: +81(78)8036194; E-mail: okaetsu@kobe-u.ac.jp
Abstract – The CF3 - containing dihydropyran derivative (2) reacted easily with
various aromatic compounds in trifluoroacetic acid to give novel 4-aryl
substituted dihydropyran derivatives (7) in moderate to high yields. Retro
hetero Diels-Alder reaction of thus obtained 7 proceeded readily by heating at
300 °C to afford the corresponding 4-aryl-1,1,1-trifluorobut-3-en-2-ones (12) in
good to excellent yields. With the use of p-toluenesulfonic acid instead of
trifluoroacetic acid together with dihydropyran (2) in acetonitrile,
4-trifluoroacetyl-1,3-butadienylation
of
1,3-dimethoxybenzene
occurred
successfully. The bimolecular reaction of dihydropyran (2) in the presence of
p-toluenesulfonic acid was also examined.
INTRODUCTION
Many new methodologies for carbon-carbon bond formation are developed in the field of organic
synthesis since the carbon-carbon bond formation has been one of the most interesting challenges in
organic chemistry.1-3 On the other hand, 6-arylhexa-3,5-dien-2-one systems are useful building blocks
for the synthesis of various heterocycles. For instance, it has been reported that the reaction of
6-arylhexa-3,5-dien-2-ones with N-tosyliminophenyliodinane give aziridine derivatives.4 Moreover, the
syntheses of 1,2-dihydropyridines,5 2-pyridones,6 and 2-aminopyrimidines7 from various
6-arylhexa-3,5-dien-2-one derivatives have been reported.
6-Arylhexa-3,5-dien-2-ones and
1,2,4-triazole-3,5-dione are also known to undergo Diels-Alder reaction to give the corresponding

516
HETEROCYCLES, Vol. 80, No. 1, 2010
[1,2,4]triazolo[1,2-a]pyridazines.8 In our previous papers, we reported that the ring-opening reactions of
fluorine-containing dihydropyran derivative (2), which was easily prepared by the hetero Diels-Alder
reaction of trifluoroacetylvinyl ether (1) with ethyl vinyl ether,9 with mercaptans in the presence of
p-toluenesulfonic acid afforded the corresponding 4-trifluoroacetyl-1,3-butadienyl sulfides (3).10 These
butadienyl sulfides (3) are easily converted to 4-trifluoroacetyl-1,3-butadienylamines (4) by S-N exchange
reactions11 as depicted in Scheme 1. Very recently, we have reported a facile and convenient synthetic
method for 4,4-bis(trifluoroacetyl)-1,3-butadienylated aromatic compounds (6) by the one step C8-unit
introduction to aromatic rings by making use of fluorine-containing dihydropyran derivative (5)12 in
trifluoroacetic acid.13 These findings prompted us to research on the new carbon-carbon bond formation
through the acid-catalyzed reaction of dihydropyran derivative (2).
OEt
EtO
Hetero Diels-Alder Reaction
EtO
COCF3
EtO
O
CF3
1
2
i) R1SH, TsOH
CH2Cl2
ii) CF3CO2H
R2
N
R2R3NH, MeCN
R1S
R3
COCF3
COCF3
4
3
6
OBu-i
COCF3
COCF3
COCF3
ArH, CF3CO2H
reflux
Ar
EtO
O
CF3
5
ArH = substituted benzenes, 1-methoxynaphthalenene and thiophene
Scheme 1
We here wish to present a synthesis of novel 4-aryl substituted dihydropyrans (7) which obtained
unexpectedly by the reaction of fluorine-containing dihydropyran (2) with various aromatic compounds in
trifluoroacetic acid. The synthesis of 4-aryl-1,1,1-trifluorobut-3-en-2-ones (12) from dihydropyrans (7)
by retro hetero Diels-Alder reactions is also described. In addition, a new synthetic method for
6-(2,4-dimethoxyphenyl)-1,1,1-trifluorohexa-3,5-dien-2-one (8), by making use of fluorine-containing
dihydropyran derivative (2), is briefly discussed in this report. Possibly, these aromatic compounds

HETEROCYCLES, Vol. 80, No. 1, 2010
517
having fluorine-containing ethene and butadiene fragments prepared by our novel C4- and C6-unit
introduction method can serve as versatile building blocks for the construction of CF3 -containing
heterocycles, which may be expected to show interesting biological activities.14-17
RESULTS AND DISCUSSION
The results of the reaction of dihydropyran derivative (2) with various aromatic compounds in
trifluoroacetic acid are shown in Scheme 2 and summarized in Table 1. The O-C exchange reaction of 2
with anisole easily proceeded at -15 °C for 18 h to give the corresponding 4-(4- and 2-methoxyphenyl)
substituted dihydropyran derivatives as a mixture of two regioisomers, 7a and 7a’, in 26% and 23%
yields, respectively (entry 1). m-Xylene also exhibited almost the same reactivity with anisole to afford
the dihydropyran (7b) in 53% yield (entry 2). The reaction of 2 with 1-methoxy-3-methylbenzene
occurred at ambient temperature within 15 min to provided a mixture of two kinds of regioisomers, 7c
and 7c’, in 72% as a combined yield (entry 3). Separation of the mixtures into 7c and 7c’ was hardly
performed by column chromatography. The reaction with 1,3-dimethoxybenzene proceeded quite
rapidly to afford 7d in 60% yield, selectively (entry 4). It was, moreover, found that this type of O-C
exchange reaction at 4-C of dihydropyran (2) had application to other aromatic compounds, as
1-methylnaphthalene and 1-methoxynaphthalene (naphthalenes) and thiophene (heteroaromatics), to
provide 7e-g in high yields (entries 5-7). The reactions of 2 with benzene, naphthalene, and aromatic
Ar
OEt
ArH, CF3CO2H
EtO
O
CF3
EtO
O
CF3
7a-g
2
R1
7a-d:
R2
7e,f:
R2
Ar =
Ar =
CF3
F3C
S
7g:
Ar =
S
O
O
OEt
EtO
7g'
Scheme 2
compounds having electron-withdrawing group were unsuccessful to give decomposed products.
In all cases in Table 1, 4-aryl substituted dihydropyrans (7) were obtained selectively under very mild
conditions without any products of ring-opening reaction of dihydropyran system, types of 3 and 6.

518
HETEROCYCLES, Vol. 80, No. 1, 2010
Table 1. Synthesis of 4-aryl-2-ethoxy-6-trifluoromethyl-3,4-dihydro-2H-pyrans (7a-g’).
ArH
(equiv.) (°C)
Temp. Time
Entry
1
R1
R2
Product
Yield (%)a
(min)
H
OMe
Me
Me
OMe
OMe
-
-
-
-
OMe
H
5
-15
18 h
7a
26b
23b
53
7a’
7b
7cc
7c’c
7d
7e
7f
7g
7g’
2
3
Me
OMe
Me
OMe
Me
OMe
-
5
1
-15
rt
24 h
15
72d
4
5
6
7
1
1
1
5
0
rt
rt
rt
5
15
15
15
60
74
88
73
17
-
a Isolated yield after column chromatography.
b The fraction of a mixture of 7a and 7a’ (combined yield: 8%) was accompanied.
c The regiochemistry and the ratio were not determined yet due to the impossibility of the
separation of the two regioisomers, 7c and 7c’.
d Combined yield (NMR yield) of two regioisomers.
These results of our approaches on the reactions of 2 with various aromatic compounds show sharp
contrast to the reaction of 5 with aromatic compounds in refluxing trifluoroacetic acid (see Scheme 1).13
Also, we tried the reactions of 2 with various aromatic compounds in trifluoroacetic acid under reflux in
stead of at -15 °C to room temperatures, which resulted in failure to give complex mixtures without any
formation of 1,3-butadinene derivatives. So, we attempted the acid-catalyzed reaction of 2 with
p-toluenesulfonic acid in place of trifluoroacetic acid in acetonitrile under reflux.
MeO
OMe
CF3
MeO
(1 equiv.)
O
OEt
OMe
p-TsOH (0.3 equiv.), MeCN
+
MeO
reflux, 15 min
EtO
O
CF3
COCF3
OMe
2
8 37%
9 36%
CF3
F3C
O
O
p-TsOH (0.3 equiv.), MeCN
OEt
+
reflux, 1 h
EtO
O
COCF3
CF3
10 57%
11 10%
Scheme 3

HETEROCYCLES, Vol. 80, No. 1, 2010
519
As shown in Scheme 3, the reaction of 2 with 1,3-dimethoxybenzene in the presence of p-toluenesulfonic
acid was found to occur in refluxing acetonitrile to afford a mixture of 4-trifluoroacetyl-1,3-butadiene
derivative (8) and 2-trifluoromethyl-4H-pyran derivative (9) in almost same yields, respectively.
Contrary to our expectation, the similar 4-trifluoroacetyl-1,3-butadienylation of the other aromatic
compounds by the p-toluenesulfonic acid catalyzed reaction of 2 was unsuccessful to give decomposed
products. Next, we tried the reaction of 2 without aromatic compounds in the presence of
p-toluenesulfonic acid in refluxing acetonitrile to afford the bimolecular reaction products, 2H-pyran (10)
and 4H-pyran (11).
OEt
p-TsOH
O
CF3
EtO
O
CF3
EtO
O
CF3
-
EtOH
EtO
2
I
II
F3C
CF3
F3C
O
O
O
O
OEt
OEt
+
EtO
O
COCF3
F3C
CF3
11
10
III
Scheme 4
A possible pathway for the formation of 10 and 11 is depicted in Scheme 4. Elimination of alcohols
from 2 by p-toluenesulfonic acid occurs first to form 2H-pyran (I) and pyrylium (II) at equilibrium,
electrophilic substitution on 3-C of I by 6-C of II gives 2H-pyran (III), and finally III undergoes
electrocyclic ring-opening reaction to afford 10. Meanwhile, electrophilic substitution on 3-C of I by
4-C of II simply gives 4H-pyran (11).
Lastly, we tried to carry out the retro hetero Diels-Alder reaction of 4-aryl substituted dihydropyrans (7)
at 300 °C under atmospheric pressure, as depicted in Scheme 5 and summarized in Table 2. The desired
retro hetero Diels-Alder reactions of 7a-f were thoroughly proceeded at 300 °C within 30-60 min to

520
HETEROCYCLES, Vol. 80, No. 1, 2010
provide the corresponding 4-aryl-1,1,1-trifluorobut-3-en-2-ones (12a-f) in medium to excellent yields.
Thus, we achieved a new method for the synthesis of trifluoroacetylvinylated aromatics (12) which were
easily obtained in two steps from dihydropyran (2) via the novel 4-arylated dihydropyrans (7). The
present C4-unit introduction method is one of the versatile and unique methods for the synthesis of
various trifluoroacetylvinylated aromatic compounds.18,19
Ar
300 oC
Ar
COCF3
EtO
O
CF3
Retro Hetero Diels-Alder Reaction
12a-f
7a-f
R1
R2
Ar =
7a-d:
7e,f:
R2
Ar =
Scheme 5
Table 2. Synthesis of (E)-4-aryl-1,1,1-trifluorobut-3-en-2-one (12a-f).
Time
(min)
Entry
Substrate
R1
R2
Product
Yield (%)a
1
2
3
4
5
6
7
7a
7a’
H
OMe
Me
Me / OMe
OMe
-
-
OMe
H
Me
OMe / Me
OMe
Me
60
60
60
60
30
30
30
12a
12a’
12b
79
78
68
7b
7c and 7c’b,c
12c and 12c’c 79d
7d
7e
7f
12d
12e
12f
83
96
87
OMe
a Isolated yield after column chromatography.
b A mixture of two regioisomers (7c and 7c’) was used as a starting material.
c The regiochemistry and the ratio were not determined yet.
d Combined yield of two regioisomers.
In conclusion, we succeeded in the synthesis of novel 4-aryl substituted dihydropyran derivatives (7),
which were successfully converted to 4-aryl-1,1,1-trifluorobut-3-en-2-ones (12). So we have developed
a simple method for the introduction of fluorine-containing C4-unit, 2-trifluoracetylvinyl system, to
various aromatic rings in two steps. The first step is the O-C exchange at 4-C of CF3-containing
dihydropyran derivative (2), and the following step is retro hetero Diels-Alder reactions of 4-aryl
substituted dihydropyran (7). We also found a novel method for the introduction of fluorine-containing
C6-unit, 4-trifluoroacetyl-1,3-butadienyl system, to 1,3-dimethoxybenzene using 2. Moreover, by a

HETEROCYCLES, Vol. 80, No. 1, 2010
521
bimolecular reaction of dihydropyran (2) in the presence of p-toluenesulfonic acid, novel 2H-pyran (10)
and 4H-pyran (11), which are not easily accessible by other methods, were synthesized. Further work is
under progress in our laboratory on the synthetic application of 7, 8, and 10 to the fluorine-containing
heterocycles of potentially biological importance.
EXPERIMENTAL
All melting points were determined on an electrothermal digital melting point apparatus and are
uncorrected. 1H NMR spectra were obtained with JEOL PMX60SI and Bruker AVANCE500
instruments. All chemical shifts are reported in ppm downfield from internal tetramethylsilane.
IR spectra were recorded on Hitachi EPI-G3 and PerkinElmer Spectrum ONE spectrophotometers.
Elemental analyses were performed by the Microanalyses Center of Kyoto University or taken with a
YANACO CHN-Corder MT-5 analyzer. Chromatographic separations were carried out on a silica gel
column (Fuji Silysia Chemical BW-127ZH; 100-270 mesh). All reagents were obtained commercially
and used without further purification. Final purification of products for elemental analyses was done by
recrystallization or Kugelrohr distillation.
Synthesis of 4-aryl-2-ethoxy-6-(trifluoromethyl)-3,4-dihydro-2H-pyrans (7).
To a mixture of 2 (661 mg, 2.75 mmol) and substituted benzenes (13.75 mmol or 2.75 mmol),
naphthalenes (2.75 mmol) and thiophene (13.75 mmol) was added dropwise trifluoroacetic acid (3.8 mL)
and this solution was stirred under the conditions as shown in Table 1. The reaction mixture was
washed with 10% aq. Na2CO3 (30 mL) and H2O (30 mL), extracted with CH2Cl2 (30 mL) and dried
(Na2SO4).
The solvent was removed under reduced pressure and the crude mixture was
chromatographed on silica gel column using n-hexane/benzene (1:1) as eluent to give 7a-g’.
2-Ethoxy-4-(4-methoxyphenyl)-6-trifluoromethyl-3,4-dihydro-2H-pyran (7a): bp 110 °C / 1 mmHg
(oven temperature); 1H NMR (CDCl3):  7.04 (d, 2H, J = 10.0 Hz, H-2’, H-6’), 6.72 (d, 2H, J = 10.0 Hz,
H-3’, H-5’), 5.42 (br s, 1H, H-5), 5.22 (t, 1H, J = 3.0 Hz, H-2), 4.26-3.30 (m, 3H, H-4, OCH2CH3), 3.71
(s, 3H, OCH3), 2.81-2.49 (m, 2H, H-3), 1.23 (t, 3H, J = 6.6 Hz, OCH2CH3); IR (neat): 1684, 1608 cm-1.
Anal. Calcd for C15H17O3F3: C, 59.60; H, 5.67; F, 18.85. Found: C, 59.75; H, 5.59; F, 19.06.
2-Ethoxy-4-(2-methoxyphenyl)-6-trifluoromethyl-3,4-dihydro-2H-pyran (7a’): bp 125 °C / 2 mmHg
1
(oven temperature); H NMR (CDCl3):  7.07 (d, 1H, J = 8.0 Hz, H-6’), 6.97 (dd, 1H, J = 8.0, 6.0 Hz,
H-4’), 6.86 (dd, 1H, J = 8.0, 6.0 Hz, H-5’), 6.74 (d, 1H, J = 8.0 Hz, H-3’), 5.46 (br s, 1H, H-5), 5.10 (t,
1H, J = 3.0 Hz, H-2), 4.31-3.42 (m, 3H, H-4, OCH2CH3), 3.73 (s, 3H, OCH3), 2.39-1.55 (m, 2H, H-3),
1.23 (t, 3H, J = 6.8 Hz, OCH2CH3); IR (neat): 1680, 1582 cm-1. Anal. Calcd for C15H17O3F3: C, 59.60;
H, 5.67; F, 18.85. Found: C, 59.67; H, 5.65; F, 19.25.
4-(2,4-Dimethylphenyl)-2-ethoxy-6-trifluoromethyl-3,4-dihydro-2H-pyran (7b): bp 100 °C / 1 mmHg

522
HETEROCYCLES, Vol. 80, No. 1, 2010
(oven temperature); 1H NMR (CDCl3):  6.89 (s, 3H, H-3’, H-5’, H-6’), 5.50 (br s, 1H, H-5), 5.15 (t, 1H,
J = 3.0 Hz, H-2), 4.01-3.45 (m, 3H, H-4, OCH2CH3), 2.28 (s, 3H, CH3), 2.25 (s, 3H, CH3), 2.22-1.46 (m,
2H, H-3), 1.23 (t, 3H, J = 6.8 Hz, OCH2CH3); IR (neat): 1680, 1610 cm-1. Anal. Calcd for C16H19O2F3:
C, 63.99; H, 6.38; F, 18.98. Found: C, 64.27; H, 6.53; F, 19.20.
A mixture of 2-ethoxy-4-(4-methoxy-2-methylphenyl)-6-trifluoromethyl-3,4-dihydro-2H-pyran (7c)
and 2-ethoxy-4-(2-methoxy-4-methylphenyl)-6-trifluoromethyl-3,4-dihydro-2H-pyran (7c’): bp
130 °C / 2 mmHg (oven temperature); 1H NMR (CDCl3):  7.16-6.67 (m, 3H, H-3’, H-5’, H-6’), 5.60 (br
s, 1H, H-5), 5.23 (t, 1H, J = 3.0 Hz, H-2), 4.40-3.50 (m, 3H, H-4, OCH2CH3), 3.83, 3.77 (s, 3H, OCH3),
2.50-1.55 (m, 2H, H-3), 2.33 (s, 3H, CH3), 1.27, 1.23 (t, 3H, J = 7.0 Hz, OCH2CH3); IR (neat): 1675,
1605 cm-1. Anal. Calcd for C16H19O3F3: C, 60.75; H, 6.05; F, 18.02. Found: C, 60.54; H, 6.01; F,
18.29.
4-(2,4-Dimethoxyphenyl)-2-ethoxy-6-trifluoromethyl-3,4-dihydro-2H-pyran (7d): bp 140 °C / 2 mmHg
1
(oven temperature); H NMR (CDCl3):  6.92 (d, 1H, J = 8.4 Hz, H-6’), 6.43 (d, 1H, J = 8.4 Hz, H-5’),
6.39 (s, 1H, H-3’), 5.46 (br s, 1H, H-5), 5.11 (t, 1H, J = 3.0 Hz, H-2), 4.13-3.44 (m, 3H, H-4, OCH2CH3),
3.72 (s, 3H, OCH3), 3.69 (s, 3H, OCH3), 2.47-1.52 (m, 2H, H-3), 1.23 (t, 3H, J = 7.0 Hz, OCH2CH3); IR
(neat): 1682, 1610 cm-1. Anal. Calcd for C16H19O4F3: C, 57.83; H, 5.76; F, 17.15. Found: C, 57.59; H,
5.89; F, 17.30.
2-Ethoxy-4-(4-methylnaphthalen-1-yl)-6-trifluoromethyl-3,4-dihydro-2H-pyran (7e): bp 150 °C / 3
mmHg (oven temperature); 1H NMR (CDCl3):  8.02-7.75 (m, 2H, Harom), 7.52-7.29 (m, 2H, Harom), 7.10
(s, 2H, H-2’, H-3’), 5.65 (br s, 1H, H-5), 5.15 (t, 1H, J = 3.0 Hz, H-2), 4.68-4.16 (m, 1H, H-4), 4.05-3.78
(m, 2H, OCH2CH3), 2.65 (s, 3H, CH3), 2.30-1.56 (m, 2H, H-3), 1.26 (t, 3H, J = 8.0 Hz, OCH2CH3); IR
(neat): 1680, 1596 cm-1. Anal. Calcd for C19H19O2F3: C, 67.85; H, 5.69; F, 16.95. Found: C, 68.06; H,
5.72; F, 17.11.
2-Ethoxy-4-(4-methoxynaphthalen-1-yl)-6-trifluoromethyl-3,4-dihydro-2H-pyran (7f): bp 190 °C / 2
mmHg (oven temperature); 1H NMR (CDCl3):  8.30-7.81 (m, 2H, Harom), 7.55-7.33 (m, 2H, Harom), 7.14
(d, 1H, J = 8.0 Hz, H-2’), 6.65 (d, 1H, J = 8.0 Hz, H-3’), 5.66 (br s, 1H, H-5), 5.16 (t, 1H, J = 3.0 Hz,
H-2), 4.60-4.15 (m, 1H, H-4), 3.90 (s, 3H, OCH3), 4.06-3.47 (m, 2H, OCH2CH3), 2.53-1.63 (m, 2H, H-3),
1.27 (t, 3H, J = 7.0 Hz, OCH2CH3); IR (neat): 1680, 1590 cm-1. Anal. Calcd for C19H19O3F3: C, 64.77;
H, 5.44; F, 16.18. Found: C, 65.03; H, 5.38; F, 16.44.
2-Ethoxy-4-(thiophen-2-yl)-6-trifluoromethyl-3,4-dihydro-2H-pyran (7g): bp 85 °C / 1 mmHg (oven
1
temperature); H NMR (CDCl3):  6.95 (d, 1H, J = 5.4 Hz, H-5’), 6.71 (dd, 1H, J = 5.4, 4.0 Hz, H-4’),
6.70 (d, J = 4.0 Hz, H-3’), 5.56 (br s, 1H, H-5), 5.19 (t, 1H, J = 3.0 Hz, H-2), 4.19-3.66 (m, 1H, H-4),
3.68 (q, 2H, J = 7.0 Hz, OCH2CH3), 2.47-1.67 (m, 2H, H-3), 1.22 (t, 3H, J = 7.0 Hz, OCH2CH3); IR
(neat): 1680, 1578 cm-1. Anal. Calcd for C12H13O2F3S: C, 51.79; H, 4.71; F, 20.48. Found: C, 51.86;

HETEROCYCLES, Vol. 80, No. 1, 2010
523
H, 4.68; F, 20.65.
1
2,5-Bis(2-ethoxy-6-trifluoromethyl-3,4-dihydro-2H-pyran-4-yl)thiophene (7g’): H NMR (CDCl3): 
6.62 (s, 2H, Hthienyl), 5.56 (br s, 2H, H-5), 5.19 (t, 2H, J = 2.8 Hz, H-2), 4.20-3.56 (m, 2H, H-4), 3.67 (q,
4H, J = 7.6 Hz, OCH2CH3), 2.46-1.66 (m, 4H, H-3), 1.22 (t, 6H, J = 7.6 Hz, OCH2CH3); IR (neat): 1680,
1582 cm-1.
Reaction of 2 with 1,3-dimethoxybenzene in the presence of p-toluenesulfonic acid.
To a stirred solution of 2 (697 mg, 2.90 mmol) and 1,3-dimethoxybenzene (401 mg, 2.90 mmol) in
MeCN (7 mL) was added p-toluenesulfonic acid (150 mg, 0.87 mmol) and the mixture was refluxed for
15 min. The reaction mixture was washed with 10% aq. Na2CO3 (30 mL) and H2O (30 mL), extracted
with CH2Cl2 (30 mL) and dried (Na2SO4). The solvent was removed under reduced pressure and the
crude mixture was chromatographed on silica gel column using n-hexane/benzene (4:1) as eluent to give
8 (307 mg, 37 %) and 9 (299 mg, 36 %).
(E,E)-6-(2,4-Dimethoxyphenyl)-1,1,1-trifluorohexa-3,5-dien-2-one (8): bp 150 °C / 2 mmHg (oven
temperature); 1H NMR (CDCl3):  7.61 (dd, 1H, J = 14.4, 10.4 Hz, H-4), 7.28 (d, 1H, J = 14.4 Hz, H-3),
7.10 (d, 1H, J = 15.2 Hz, H-6), 6.77 (dd, 1H, J = 15.2, 10.4 Hz, H-5), 6.41 (d, 1H, J = 7.8 Hz, H-6’), 6.37
(d, 1H, J = 7.8 Hz, H-5’), 6.31 (s, 1H, H-3’), 3.77 (s, 3H, OCH3), 3.75 (s, 3H, OCH3); IR (neat): 1680
cm-1. Anal. Calcd for C14H13O3F3: C, 58.74; H, 4.58; F, 19.91. Found: C, 58.91; H, 4.63; F, 20.17.
4-(2,4-Dimethoxyphenyl)-2-trifluoromethyl-4H-pyran (9): bp 170 °C / 2 mmHg (oven temperature);
1H NMR (CDCl3):  7.02 (d, 1H, J = 9.0 Hz, H-6), 6.42 (d, 1H, J = 7.2 Hz, H-6’), 6.39 (d, 1H, J = 7.2 Hz,
H-5’), 6.28 (s, 1H, H-3’), 5.47-5.37 (m, 1H, H-3), 5.93-5.69 (m, 1H, H-5), 4.54-4.30 (m, 1H, H-4), 3.69
(s, 6H, OCH3); IR (neat): 1600, 1582 cm-1. Anal. Calcd for C14H13O3F3: C, 58.74; H, 4.58; F, 19.91.
Found: C, 58.59; H, 4.52; F, 19.58.
Reaction of 2 in the presence of p-toluenesulfonic acid.
To a stirred solution of 2 (2964 mg, 12.34 mmol) in MeCN (30 mL) was added p-toluenesulfonic acid
(637 mg, 3.70 mmol) and the mixture was refluxed for 1 h. The reaction mixture was washed with 10%
aq. Na2CO3 (120 mL) and H2O (120 mL), extracted with CH2Cl2 (100 mL) and dried (Na2SO4). The
solvent was removed under reduced pressure and the crude mixture was chromatographed on silica gel
column using n-hexane/benzene (4:1) as eluent to give 10 (1204 mg, 57 %) and 11 (211 mg, 10 %).
(E,E)-6-(2-Ethoxy-6-trifluoromethyl-2H-pyran-3-yl)-1,1,1-trifluorohexa-3,5-dien-2-one (10): mp
110-112 °C (n-hexane); 1H NMR (CDCl3):  7.55 (dd, 1H, J = 14.2, 10.0 Hz, H-4), 6.87-5.95 (m, 5H, H-3,
13
H-5, H-6, H-4’, H-5’), 4.10-3.50 (m, 2H, OCH2CH3), 1.26 (t, 3H, J = 7.0 Hz, OCH2CH3); C NMR
(CDCl3):  179.9 (q, JCF = 35.4 Hz), 149.2, 142.2, 142.2 (q, JCF = 37.8 Hz), 128.1, 126.6, 126.4, 120.8,
119.8 (q, JCF = 272.2 Hz), 116.5 (q, JCF = 291.8 Hz), 103.2 (q, JCF = 3.7 Hz), 96.4, 64.4, 15.1; IR (KBr):
1702 cm-1. Anal. Calcd for C14H12O3F6: C, 49.13; H, 3.53; F, 33.31. Found: C, 48.85; H, 3.48; F,

524
HETEROCYCLES, Vol. 80, No. 1, 2010
33.22.
2-Ethoxy-6-trifluoromethyl-3-(2-trifluoromethyl-4H-pyran-4-yl)-2H-pyran (11): bp 90 °C / 1 mmHg
1
(oven temperature); H NMR (CDCl3): 6.46 (d, 1H, J = 6.0 Hz, H-6’), 6.00 (s, 2H, H-4, H-5), 5.56 (s,
1H, H-2), 5.43-5.35 (m, 1H, H-3’), 4.90-4.65 (m, 1H, H-5’), 4.03-3.43 (m, 3H, H-4’, OCH2CH3), 1.21 (t,
3H, J = 7.0 Hz, OCH2CH3); IR (KBr): 1645 cm-1. Anal. Calcd for C14H12O3F6: C, 49.13; H, 3.53; F,
33.31. Found: C, 48.99; H, 3.48; F, 33.71.
Synthesis of (E)-4-aryl-1,1,1-trifluorobut-3-en-2-one (12a-f).
The retro hetero Diels-Alder reaction of 7 was successfully carried out at 300 °C without solvent. The
reaction times were as shown in Table 2. The crude mixture was chromatographed on silica gel column
using n-hexane/EtOAc (100:1) as eluent to give products (12a, 12a’, and 12d) and n-hexane as eluent to
give 12b. For products (12c, 12c’, 12e, and 12f), n-hexane/benzene (1:1) was used as eluent.
1
(E)-1,1,1-Trifluoro-4-(4-methoxyphenyl)but-3-en-2-one (12a): mp 35-37 °C (n-hexane/benzene); H
NMR (CDCl3): 8.00 (d, 1H, J = 16.0 Hz, H-4), 7.67 (d, 2H, J = 9.0 Hz, H-2’, H-6’), 7.00 (d, 2H, J = 9.0
Hz, H-3’, H-5’), 6.92 (d, 1H, J = 16.0 Hz, H-3), 3.88 (s, 3H, OCH3); IR (KBr): 1713 cm-1. Anal. Calcd
for C11H9O2F3: C, 57.40; H, 3.94. Found: C, 57.23; H, 4.03.
(E)-1,1,1-Trifluoro-4-(2-methoxyphenyl)but-3-en-2-one (12a’): bp 190 °C / 5 mmHg (oven temperature);
1H NMR (CDCl3): 8.37 (d, 1H, J = 16.0 Hz, H-4), 7.70-6.90 (m, 5H, H-3, Harom), 3.93 (s, 3H, OCH3);
IR (KBr): 1712 cm-1. Anal. Calcd for C11H9O2F3: C, 57.40; H, 3.94. Found: C, 57.57; H, 4.18.
(E)-4-(2,4-Dimethylphenyl)-1,1,1-trifluorobut-3-en-2-one (12b): bp 200 °C / 5 mmHg (oven temperature);
1H NMR (CDCl3): 8.35 (d, 1H, J = 16.0 Hz, H-4), 7.63 (d, 1H, J = 8.0 Hz, H-6’), 7.30-6.77 (m, 3H, H-3,
H-3’, H-5’), 2.40 (s, 3H, CH3), 2.33 (s, 3H, CH3); IR (KBr): 1698 cm-1. Anal. Calcd for C12H11OF3: C,
63.16; H, 4.86. Found: C, 63.12; H, 4.50.
A mixture of (E)-1,1,1-trifluoro-4-(4-methoxy-2-methylphenyl)but-3-en-2-one (12c) and (E)-1,1,1-
trifluoro-4-(2-methoxy-4-methylphenyl)but-3-en-2-one (12c’): bp 95 °C / 2 mmHg (oven temperature);
1H NMR (CDCl3):  8.26-8.00 (m, 1H, H-4), 7.63-7.50 (m, 1H, H-6’), 6.83-6.60 (m, 3H, H-3, H-3’, H-5’),
3.87, 3.80 (s, 3H, OCH3), 2.47, 2.37 (s, 3H, CH3); IR (KBr): 1697 cm-1. Anal. Calcd for C12H11O2F3: C,
59.02; H, 4.54; F, 23.34. Found: C, 59.39; H, 4.54; F, 23.46.
(E)-4-(2,4-Dimethoxyphenyl)-1,1,1-trifluorobut-3-en-2-one (12d): mp 65-66 °C (n-hexane/benzene);
1H NMR (CDCl3): 8.04 (d, 1H, J = 15.0 Hz, H-4), 7.37 (d, 1H, J = 9.2 Hz, H-6’), 6.87 (d, 1H, J = 15.0
Hz, H-3), 6.41 (d, 1H, J = 9.2 Hz, H-5’), 6.32 (s, 1H, H-3’), 3.78 (s, 3H, OCH3), 3.76 (s, 3H, OCH3); IR
(KBr): 1697 cm-1. Anal. Calcd for C12H11O3F3: C, 55.39; H, 4.26; F, 21.90. Found: C, 55.11; H, 4.13;
F, 21.77.
(E)-1,1,1-Trifluoro-4-(4-methylnaphthalen-1-yl)but-3-en-2-one (12e): mp 68-69 °C (n-hexane/benzene);

HETEROCYCLES, Vol. 80, No. 1, 2010
525
1H NMR (CDCl3): 8.38 (d, 1H, J = 13.4 Hz, H-4), 7.81-7.56 (m, 2H, Harom), 7.33 (d, 1H, J = 8.0 Hz,
H-2’), 7.36-7.13 (m, 2H, Harom), 6.89 (d, 1H, J = 8.0 Hz, H-3’), 6.76 (d, 1H, J = 13.4 Hz, H-3), 2.43 (s,
3H, CH3); IR (KBr): 1708 cm-1. Anal. Calcd for C15H11OF3: C, 68.18; H, 4.20; F, 21.57. Found: C,
67.89; H, 4.06; F, 21.37.
(E)-1,1,1-Trifluoro-4-(4-methoxynaphthalen-1-yl)but-3-en-2-one (12f): mp 88-89 °C (n-hexane/benzene);
1H NMR (CDCl3): 8.06 (d, 1H, J = 15.0 Hz, H-4), 8.24-7.91 (m, 2H, Harom), 7.75 (d, 1H, J = 8.2 Hz,
H-2’), 7.35-7.20 (m, 2H, Harom), 6.88 (d, 1H, J = 15.0 Hz, H-3), 6.70 (d, 1H, J = 8.2 Hz, H-3’), 3.96 (s,
3H, OCH3); IR (KBr): 1694 cm-1. Anal. Calcd for C15H11O2F3: C, 64.29; H, 3.96. Found: C, 64.58; H,
4.09.
REFERENCES
1. B. M. Trost, Angew. Chem., Int. Ed. Engl., 1995, 34, 259.
2. B. M. Trost, F. D. Toste, and A. B. Pinkerton, Chem. Rev., 2001, 101, 2067.
3. V. Ritleng, V. C. Sirlin, and M. Pfeffer, Chem. Rev., 2002, 102, 1731.
4. L. Ma, D. Du, and J. Xu, Chirality, 2006, 18, 575.
5. F. Palacios, J. Vicario, and D. Aparicio, Eur. J. Org. Chem., 2006, 2843.
6. W. L. Singh, H. Ila, and H. Junjappa, Indian J. Chem., Section B: Organic Chemistry Including
Medicinal Chemistry, 1987, 26B, 607.
7. W. Wendelin, W. H. Schramm, and A. Blasi-Rabassa, Monatsh. Chem., 1985, 116, 385.
8. W. Bethaeuser, M. Regitz, and W. Theis, Tetrahedron Lett., 1981, 22, 2535.
9. M. Hojo, R. Masuda, and E. Okada, Synthesis, 1989, 215.
10. M. Hojo, R. Masuda, and E. Okada, Chem. Lett., 1990, 113.
11. M. Hojo, R. Masuda, and E. Okada, Chem. Lett., 1990, 2095.
12. M. Hojo, R. Masuda, and E. Okada, Synthesis, 1990, 347.
13. N. Ota, E. Okada, A. Sonoda, N. Muro, D. Shibata, and M. Médebielle, Heterocycles, 2008, 76, 215.
14. R. Filler and Y. Kobayashi, ‘Biomedicinal Aspects of Fluorine Chemistry,’ Kodansha & Elsevier
Biomedical, Tokyo, 1982.
15. R. Filler, ‘Organofluorine Chemicals and Their Industrial Applications,’ Ellis Horwood, London,
1979.
16. J. T. Welch, Tetrahedron, 1987, 43, 3123.
17. R. Filler, Y. Kobayashi, and L. M. Yagupolskii, ‘Organofluorine Compounds in Medicinal
Chemistry and Biomedical Applications,’ Elsevier, Amsterdam, 1993.
18. D. V. Sergey, B. S. Elizabeth, and N. G. Valentine, Tetrahedron, 2007, 63, 7753.
19. V. G. Nenajdenko, A. V. Sanin, and E. S. Balenkova, Molecules, 1997, 2, 186.