Efficient synthesis of trifluoromethylated dihydrochalcones, aryl vinyl ketones and indanones by superelectrophilic activation of 4,4,4-trifluoro/3- (trifluoromethyl)crotonic acids

Article abstract of DOI:10.1016/j.jfluchem.2012.07.008

Superacid catalyzed electrophilic substitution of arenes using 4,4,4,-trifluoro/3-trifluoromethylcrotonic acids has been investigated. The direct synthesis of various trifluoromethylated dihydrochalcones, aryl vinyl ketones and indanones has been achieved by this methodology. It has been found that the position of the trifluoromethyl group has a profound effect on the nature of the reaction and the products. In the pharmaceutical industry, many fluoroorganics are shown to possess significant biological and therapeutic activities. Therefore, these novel compounds can be considered key intermediates for the preparation of potential biologically active molecules.

Full text of DOI:10.1016/j.jfluchem.2012.07.008

Journal of Fluorine Chemistry 143 (2012) 292–302
Contents lists available at SciVerse ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Efficient synthesis of trifluoromethylated dihydrochalcones,
aryl vinyl ketones and indanones by superelectrophilic activation
of 4,4,4-trifluoro/3-(trifluoromethyl)crotonic acids
*
G.K. Surya Prakash , Farzaneh Paknia, Arjun Narayanan, Golam Rasul,
*
Thomas Mathew , George A. Olah
Loker Hydrocarbon Research Institute, Department of Chemistry, University of Southern California, Los Angeles, CA 90089-1661, United States
A R T I C L E I N F O
A B S T R A C T
Article history:
Superacid catalyzed electrophilic substitution of arenes using 4,4,4,-trifluoro/3-trifluoromethylcrotonic
acids has been investigated. The direct synthesis of various trifluoromethylated dihydrochalcones, aryl
vinyl ketones and indanones has been achieved by this methodology. It has been found that the position
of the trifluoromethyl group has a profound effect on the nature of the reaction and the products. In the
pharmaceutical industry, many fluoroorganics are shown to possess significant biological and
therapeutic activities. Therefore, these novel compounds can be considered key intermediates for the
preparation of potential biologically active molecules.
Received 17 May 2012
Received in revised form 12 July 2012
Accepted 16 July 2012
Available online 28 July 2012
Dedicated to Professor David O’Hagan on
the occasion of receiving the 2012 American
Chemical Society Award for Creative Work
in Fluorine Chemistry.
ß 2012 Elsevier B.V. All rights reserved.
Keywords:
Crotonic acid
Friedel–Crafts reaction
Trifluoromethyl dihydrochalcones
Trifluoromethylindanones
Acylation/cyclialkylation
Ab initio theory
1. Introduction
trifluoromethylated compounds have been often achieved by two
different strategies, direct introduction of CF3 group by substitu-
The formation of a carbon–carbon bond (C–C) is the funda-
mental process for the construction of a molecular framework in
organic synthesis. Friedel–Crafts reactions are the most widely
used procedure for (C–C) bond formation by directly introducing
carbon substituent into an aromatic ring [1]. The two major
aromatic electrophilic substitution reactions – alkylation and
acylation, often provide a variety of highly important aromatic
substances under mild conditions [2]. On the other hand, synthesis
of the compounds containing trifluoromethyl group continues to
be an important area in the fields of agricultural, medicinal and
synthetic organic chemistry due to the unique properties
incurred by the presence of fluorine atom [3]. Preparation of
tion of hydrogen or functional groups or using CF3-containing
building blocks [4]. Prakash and Yudin have carried out significant
work in this area by developing novel fluorinating and fluor-
omethylating agents [5]. Introduction of trifluoromethyl group
through building block strategy also represents an attractive
method for the synthesis of trifluoromethylated compounds [6].
Flavonoids continue to attract the interest of scientists in many
different aspects due to their structural diversity and biological
activities [7]. Among them, dihydrochalcones that are widely
present in nature display a broad spectrum of bioactivities such as
anticancer, antifungal, antibacterial, antiviral, antioxidant and
anti-inflammatory properties [9]. Phloretin 1 and phloridzin 2 are
dihydrochalcone flavonoids having potent antioxidant activities
[8]. Phloretin and phloridzin are abundantly found in apples [9].
Cytotoxic dihydrochalcones uvaretin 3, isouvaretin 4 and diuvar-
etin 5 isolated from Uvaria acuminate, displayed growth inhibitory
effects against human promyelotic leukemia HL-60 cells [10].
Davidigenin 6 and DHC 7 isolated from Artemisia dracunculus have
antidiabetic activity [11]. The DHC 8 as a main metabolite
* Corresponding authors at: 837 Bloom Walk, Loker Hydrocarbon Research
Institute, Department of Chemistry, University of Southern California, Los Angeles,
CA 90089-1661, United States. Tel.: +1 213 740 5984.
E-mail addresses: gprakash@usc.edu (G.K. Surya Prakash), tmathew@usc.edu
(T. Mathew).
0022-1139/$ – see front matter ß 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jfluchem.2012.07.008

G.K. Surya Prakash et al. / Journal of Fluorine Chemistry 143 (2012) 292–302
293
extracted from a traditional Amazonian medicinal plant Iryanthera
juruensis shows cytotoxic activity against a panel of cancer cell
lines as well as significant anti-Trypanosoma cruzi activity in vitro
[12]. Chromeno dihydrochalcones 9–11 from Crotalaria ramosis-
sima, which are very rare as plant secondary metabolites, exhibit a
variety of biological activities [13]. Dihydrochalcones have also
received considerable attention as food sweeteners (neohesper-
idine) etc. [14,15] (see Fig. 1).
dihydrochalcones and aryl vinyl ketones carrying ‘‘CF3’’ group
would be highly desirable. However, synthetic methodologies
reported for the synthesis of trifluoromethyl containing dihy-
drochalcones [24] aryl vinyl ketones [25] are quite limited. Herein,
we report an efficient synthesis of trifluoromethylated dihydro-
chalcones and aryl vinyl ketones through superacid catalyzed
Friedel–Crafts alkylation/acylation reactions of trifluoromethy-
lated crotonic acids with arenes.
DHCs are also key intermediates for the synthesis of flavones,
anthocyanin-type dyes [8b,16], quinoline derivatives as antibac-
terial agents [17], and phenyl indoles as plasminogen activator
inhibitors [18]. The general synthesis of dihydrochalcones involves
the Claisen–Schmidt condensation of acetophenone with appro-
priate aldehyde and subsequent reduction of the chalcone double
bond [11,19]. Other methods include palladium catalyzed aryla-
tion of allyl alcohol, based on Heck coupling reaction [8b,16],
transition metal catalyzed reaction of benzyl alcohol with
acetophenone [20a–d], phenylacetylene [20e], 1-phenylethanol
[20f], and decarboxylative coupling reaction of benzylic chlor-
oformate with silyl enol ether [20g]. Chalcone 12 demonstrated
significant chemopreventive activities against lung, breast, pros-
tate and colorectal cancers [21]. Since aryl vinyl ketones have been
widely used for the synthesis of chalcones [22a], various
2. Results and discussion
Recently, we have carried out one-pot synthesis of trifluor-
omethylated arylpropanoic acids (16), indanones (17), and
dihydrocoumarins (18) using Friedel–Crafts alkylation and cyclia-
cylation of arenes/phenols with 2-(trifluoromethyl)acrylic acid
(15) under superacidic conditions using trifluoromethanesulfonic
acid (Scheme 1) [26]. It is important to notice that the selective
preparation of trifluoromethylated propanoic acid (16) or inda-
nones (17) has been achieved from the same arene substrate by
properly tuning and optimizing the reaction conditions. The
formation of propanoic acid (16) occurs by intermolecular Friedel–
Crafts alkylation while the indanones (17) are formed by
subsequent Friedel–Crafts intramolecular cycliacylation at
higher temperature.
a
heterocycles [22b–i],
b-amino ketones [22j], polymers [22k],
and for cycloaddition reactions [22l,m], methodologies for their
synthesis are of great interest. The main methods to prepare such
compounds are the 1,3-rearrangement of propargyl alcohols
(Meyer–Schuster rearrangement) [23a,b], palladium-catalyzed
coupling reactions, reaction of alkynes with aldehydes [23c–e],
and allylation of ketones [23f].
1-Indanone ring system constitutes the core structures of many
biologically important compounds. 1-Indanones are present in
many cytotoxic natural compounds. 1-Indanones have also been
used as intermediates in the synthesis of Sulindac, a non-steroidal
anti-inflammatory drug (NSAID) and other novel biologically
important compounds [23g]. Knowing the importance of
dihydrochalcones and aryl vinyl ketones as potential drug
candidates, the economical, facile and rapid one pot synthesis of
Intrigued by these results, we have now probed to carry out the
condensation of 4,4,4-trifluorocrotonic acid (19a) and 3-(trifluor-
omethyl)crotonic acid (19b) with arenes under similar conditions
as a one-pot protocol toward the direct access of trifluoromethy-
lated dihydrochalcones (20), aryl vinyl ketones (21) and indanones
(22). To our delight, it has been found that 4,4,4-trifluorocrotonic
acid (19a) undergoes intermolecular Friedel–Crafts acylation and
alkylation to afford trifluoromethylated dihydrochalcones (DHCs,
20) as the main product in a single step whereas 3-(trifluor-
omethyl)crotonic acid gives aryl vinyl ketones (21) and indanones
(22) in most cases (Scheme 2). Nucleophilic attack occurs at the
less substituted position of the olefinic group, leading to anti-
Markovnikov addition giving the favored conjugate addition
product. 4,4,4-Trifluorocrotonic acid (19a) with benzene at 55 8C
OH
O
OR
O
R2
HO
OH
OH
HO
OCH3
R1
1
Phloretin , R = H
Uvaretin 3, R1 = H, R2 = 2-hydroxybenzyl
Phloridzin 2, R = D-glucose
4
Isouvaretin , R1 = 2-hydroxybenzyl, R2 = H
Diuvaretin 5, R1 = R2 = 2-hydroxybenzyl
R2
O
OH
O
R2
R1
R3
R4
R1
O
9
, R1 = OCH3, R2 = H
6
7
, R1 = OH, R2 = R3 = OH, R4 = H
, R1 = OMe, R2 = R3 = OH, R4 = H
10
, R1 = OH, R2 = H
, R1 = OH, R2 = OH
11
8,
R1 = OMe, R2 = R3 = OH, R4 = OMe
Cl
O
O
Cl
O
OMe O
C2H5
CH3
O
N
MeO
OMe
N
12 (chalcone)
14
13
H3C
Fig. 1. Biologically active dihydrochalcones and aryl vinyl ketones.

294
G.K. Surya Prakash et al. / Journal of Fluorine Chemistry 143 (2012) 292–302
Scheme 1. Triflic acid catalyzed Friedel–Crafts alkylation and alkylation/cycliacylation of arenes with 2-(trifluoromethyl)acrylic acid (15).
afforded trifluoromethylated dihydrochalcone (20a) as the only
product in 80% yield. Interestingly, no desired product has been
isolated using less acidic sulfuric acid or trifluoroacetic acid as
catalysts implying the higher acidity requirement for this reaction.
Condensation of toluene with 4,4,4-trifluorocrotonic acid at 45 8C
gives p,p0-substituted DHC (20b) exclusively in 75% yield. In the
case of benzene, increase in temperature (75 8C) has resulted in a
mixture of trifluoromethylated DHC (20a), indanone (22a0) and
indene (23) in the ratio 6:1:2 (vide infra) whereas toluene gives a
mixture of unidentified products (not easily separable) possibly
due to transalkylation and isomerization followed by Friedel–
Crafts acylation and alkylation. Reaction with trifluoromethox-
ybenzene yields the p,p0-substituted DHC (20c) with high
regioselectivity. No product has been observed with p-xylene
possibly due to the presence of two methyl groups and the
enhanced steric effect at the ortho position to the four equivalent
reaction centers. Condensation of halobenzenes with 4,4,4-
trifluorocrotonic acid also yield the corresponding trifluoromethy-
lated DHCs (20d–f) in good yields. Unlike as reported earlier in the
case of 2-(trifluoromethyl)acrylic acid [26], phenols undergo
condensation reaction with 4,4,4-trifluorocrotonic acid to afford
the corresponding DHCs as the only product rather than 3,4-
dihydrocoumarin derivatives (18, Scheme 1). Therefore, the
position of trifluoromethyl group is powerful handle having a
dramatic effect on the direction of the reaction and nature of the
products.
In the presence of excess triflic acid, reaction of 3-(trifluor-
omethyl)crotonic acid (19b) with arenes gives trifluoromethylated
aryl vinyl ketones and indanones in a single step (Table 2)
depending on the reaction conditions. At room temperature,
Scheme 2. Triflic acid catalyzed Friedel–Crafts alkylation/acylation/cyclialkylation of arenes with 4,4,4-trifluorocrotonic acid (19a) and 3-(trifluoromethyl)crotonic acid
(19b).

G.K. Surya Prakash et al. / Journal of Fluorine Chemistry 143 (2012) 292–302
295
Table 1
Triflic acid catalyzed synthesis of trifluoromethylated dihydrochalcones (20a–h) from 4,4,4-trifluorocrotonic acid (19a).a
Entry
ab
Arene
Temp (8C)
Products
Yield (%)
55
80
b
c
45
55
(p,p0-):other regioisomers
75
92:8
66
d
e
60
70
70
65
(p,p0-):other regioisomers
78:22
f
80
50
(p,p0-):other regioisomers
85
85
73:27
g
h
55
85
a
Reaction time – 24 h.
b
With excess of benzene.
intermolecular Friedel–Crafts acylation of benzene occurs with
19b giving (E, Z)-4,4,4-trifluoro-3-methyl-1-phenyl-2-buten-1-
one (21a) as the only product. When the temperature is increased
to 120 8C indanone is formed through intramolecular Friedel–
Crafts alkylation. In contrast, reaction of 2-(trifluoromethyl)acrylic
acid (15) with arenes gives 2-trifluoromethyl-3-phenyl propanoic
acids (16) followed by intramolecular acylation to form indanone
2.1. Comparative study of structures and energies of protonated 4,4,4-
trifluorocrotonic acid, protonated 3-(trifluoromethyl)crotonic acid,
and their acyl cations (oxocarbenium ions) by ab initio methods
To rationalize the formation of the products, calculations of
possible protonated/protosolvated 4,4,4-trifluorocrotonic acid
species were performed using the Gaussian 09 program [27].
The geometry optimizations were performed at the MP2/6-31G**
level. Vibrational frequencies at the MP2/6-31G**//MP2/6-31G**
level were used to characterize stationary points as minima
(number of imaginary frequency (NIMAG) = 0)) and to evaluate
zero point vibrational energies (ZPE) which were scaled by a factor
of 0.95 [28]. For MP2/6-31G** structures further geometry
optimizations were carried out at the MP2/cc-pVTZ level. Final
energies were computed at the MP2/cc-pVTZ//MP2/cc-pVTZ + ZPE
level.
products 17 [26]. Again, this is
a clear manifestation of
trifluoromethyl group acting as a control group depending on its
position in propenoic acids 15 and 19 (acrylic or crotonic acids),
leading the reaction regioselectively. With toluene, o-xylene as
well as fluorobenzene and chlorobenzene 3-(trifluoromethyl)cro-
tonic acid 19b has yielded the corresponding aryl vinyl ketones,
with only the para-derivatives. However, the indanone products 22
are achieved by increasing the temperature as required (Table 2).
Interestingly, the reaction of phenol with 3-(trifluoromethyl)cro-
tonic acid at 50 8C yields the corresponding aryl vinyl ketone
product unlike the formation of 3,4-dihydrocoumarins with
2-(trifluoromethyl)acrylic acid (15) as reported before [26].
Two structures of protonated 4,4,4-trifluorocrotonic acid,
oxygen protonated 24, C55C protonated 25, were found to be
minima on the potential energy surface at the MP2/6-31G** and

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Table 2
Synthesis of 4,4,4-trifluoro-3-methyl-1-aryl-2-buten-one (22) and 3-methyl-3-(trifluoromethyl)indanone (23) from 3-(trifluoromethyl)crotonic acid.
Entry
a
Arene
Temp (8C)
Time (h)
24
Products
Yielda (%)
80
RT
120
RT
24
6
50
85
b
c
RT
5
90
d
RT
10
24
75
60
130
e
60
24
24
69
55
150
f
50
24
36, 7
a
Only para-products are formed in the case of toluene, fluorobenzene and chlorobenzene.
˚
MP2/cc-pVTZ levels (Fig. 2). The C
does not correspond to a minimum and converted into 25 upon
optimization without any activation barrier. Similarly, the C
a
carbon protonated structure
bond length of 1.362 A in 26 is slightly shorter than the C
a
–C(CO)
˚
bond length of 1 by about 0.04 A. This is due to extended
conjugation between C 55C double bond, C –C(CO) bond and the
b
a
b
a
carbon protonated structure also does not correspond to a
minimum and converted into same 25 upon optimization. The
structure 24 is 42.3 kcal/mol more stable than structure 25
C55O bond in 26. Thus, both dications 26 and 27 can be considered
as superelectrophiles [29] with greatly increased electrophilic
reactivity compared to their parent monoprotonated monocation.
Structures of oxocarbenium ion of 4,4,4-trifluorocrotonic acid 28
and its oxygen protonated superelectrophilic 29 were also found to
be minima at the MP2/cc-pVTZ level (Fig. 2).
(Table 3). The calculated C
a
55C
b and Ca–C(CO) distances of 25
˚
˚
are 1.339 A and 1.441 A, respectively. The structure 25 is a
hydrogen-bridged structure involving
carbon atoms.
a hydrogen and two
For comparison we have also calculated the structures of
protonated 3-(trifluoromethyl)crotonic acid at the same level. Two
Two isomeric structures, 26 and 27 were located as minima for
diprotonated 4,4,4-trifluorocrotonic acid dications (Fig. 2). The
structure 26 was characterized as O,O-diprotonated dication. The
structure 27 contains a difluorocarbenium unit and a carboxono-
nium unit separated by two carbon atoms and can be characterized
as carbenium–carboxononium dication. However, the structure 27
structures, O-protonated 30 and Ca carbon protonated structure
31 were found to be viable minima on the potential energy surface
(Fig. 2). No hydrogen-bridged structure could be located as a
minimum. The structure 30 is 33.8 kcal/mol more stable than 31
(Table 3). The structure 31 is in fact a carboxyl, trifluoromethyl
substituted tertiary cation.
is 34.9 kcal/mol more stable than 26 (Table 2). The central Ca55Cb

G.K. Surya Prakash et al. / Journal of Fluorine Chemistry 143 (2012) 292–302
297
Fig. 2. MP2/cc-pVTZ calculated structure of 24–29.
Two isomeric diprotonated dications, O,O-diprotonated 32 and
2.2. Plausible mechanism
O-protonated 33 containing a hydrogen-bridged unit were located
as minima (Fig. 2). The structure 32 is substantially less stable than
the structure 33 by 20.5 kcal/mol (Table 3). The structure 33
contains a protonated ethyl cation unit and a carboxonium ion unit
separated by a CH2 unit. Thus, the structure can be considered as a
carbonium–carboxonium dication.
Structures of oxocarbenium ion of 3-(trifluoromethyl)crotonic
acid 34 and its oxygen protonated superelectrophilic 35 were also
found to be minima at the MP2/cc-pVTZ level (Fig. 3).
The nature of the products and the results from calculational
studies clearly indicate that the possible mechanistic pathway
involves protosolvation of crotonic acids leading to superelec-
trophilic dications 38 through protonation, subsequent dehydra-
tion and further protosolvation. Intermolecular Friedel–Crafts
acylation leads to the formation of aryl vinyl ketone 21. Further
protosolvation of 21 leads to the superelectrophile 40, which can
either initiate intermolecular Friedel–Crafts alkylation with arene

298
G.K. Surya Prakash et al. / Journal of Fluorine Chemistry 143 (2012) 292–302
Table 3
mixture was poured over ice/water (ꢀ25 g) and extracted with
CH2Cl2 (3ꢁ 15 mL). The organic extracts were combined, washed
with water and dried over anhydrous Mg2SO4. The solvent was
removed by vacuum evaporation. The products were characterized
by spectral analysis (NMR, GC–MS and HRMS).
Total energies (-au), ZPEa and relative energies (kcal/mol).b
MP2/6-31G**
ZPE (kcal/mol)
MP2/cc-pvtz
Rel. energy
24
25
602.96737
51.9
49.4
603.63974
603.56839
0.0
602.89842
42.3
26
27
603.01423
603.07050
57.5
59.2
603.68228
603.74065
34.9
0.0
4,4,4-Trifluoro-1,3-diphenyl-1-butanone (20a)
28
29
526.68989
526.67468
33.7
39.1
527.26596
527.24772
0.0
1H NMR (400 MHz, CDCl3):
3.68 (dd, J = 17.76, 9.16 Hz, 1H), 4.23 (pd, J = 9.52, 4.03 Hz, 1H),
d 3.58 (dd, J = 17.76, 4.03 Hz, 1H),
16.9
30
31
642.16300
642.10732
69.0
66.3
642.87484
642.81671
0.0
7.27–7.35 (m, 3H), 7.39–7.47 (m, 4H), 7.54–7.59 (m, 1H), 7.91–7.94
33.8
(m, 2H); 13C NMR (100.5 MHz, CDCl3):
d
38.24 (q, 3J(C–F) = 1.2 Hz),
2
1
32
33
642.22422
642.25828
74.3
74.1
642.93263
642.96505
20.5
0.0
44.76 (q, J(C–F) = 27.47 Hz),126.94 (q, J(C–F) = 279.62 Hz), 127.70,
128.01, 128.27, 128.67, 128.70, 129.00, 133.54, 136.25, 195.25; 19
NMR (376 MHz, CDCl3):
F
d
ꢂ70.14 (d, J(H–F) = 9.15 Hz); HRMS (EI) m/
34
35
565.89358
565.90488
50.8
55.4
566.51242
566.51907
0.0
0.4
z calcd. for C16H13F3O 278.0918, found 278.0913.
a
Zero point vibrational energies (ZPE) at MP2/6-31G**//MP2/6-31G** scaled by a
factor of 0.95.
4,4,4-Trifluoro-1,3-bis(p-tolyl)butan-1-one (20b)
b
Relative energy at MP2/cc-pVTZ//MP2/cc-pVTZ +ZPE level.
1H NMR (400 MHz, CDCl3):
d 2.30 (s, 3H), 2.39 (s, 3H), 3.53 (dd,
J = 17.70, 4.1 Hz, 1H), 3.65 (dd, J = 17.70, 9.3 Hz, 1H), 4.20 (pd,
J = 9.60, 4.06 Hz, 1H), 7.13 (d, J = 7.8, 2H), 7.22–7.28 (m, 4H), 7.82
toward the formation of dihydrochalcones 20 or undergo
intramolecular cycli-alkylation (Nazarov cyclization) leading to
indanones 22 depending on the crotonic acid substrate 19a or 19b
(Scheme 3). Formation of indene 23, isolated in the case of
benzene, can be rationalized by further protonation/protosolvation
of the dihydrochalcone 20a followed by intramolecular cyclode-
hydration [30].
(dt, J = 8.2, 1.73 Hz, 2H); 13C NMR (100.5 MHz, CDCl3):
d
21.034,
21.61, 38.02 (q, 3J(C–F) = 1.0 Hz), 44.40 (q, 2J(C–F) = 27.47 Hz),126.94
1
3
(q, J(C–F) = 279.8 Hz), 128.13, 128.82, 129.34, 131.57 (q, J(C–
F) = 1.4 Hz), 133.85, 137.96, 144.40, 194.98; 19F NMR (376 MHz,
CDCl3):
d
ꢂ70.27 (d, J(H–F) = 9.7 Hz); HRMS (EI) m/z calcd. for
C18H17F3O 306.1232, found 306.1220.
3. Conclusion
4,4,4-Trifluoro-1,3-bis(4-trifluoromethoxyphenyl)butan-1-one (20c)
1H NMR (400 MHz, CDCl3)
= 3.56–3.70 (m, 2H), 4.26 (pd,
J = 9.4, 4.6 Hz, 1H), 7.19 (d, J = 8.1 Hz, 2H), 7.28 (d, J = 8.1 Hz,
2H), 7.43 (d, J = 8.7 Hz, 2H), 7.95–8.00 (m, 2H); 13C NMR
In summary, we have developed a novel and highly efficient
direct synthetic route to trifluoromethylated dihydrochalcones,
aryl vinyl ketones and indanones based on Friedel–Crafts reaction
of 4,4,4-trifluorocrotonic acid 19a and 3-(trifluoromethyl)cro-
tonic acid 19b with arenes in superacidic conditions. 4,4,4-
Trifluorocrotonic acid and 3-(trifluoromethyl)crotonic acid are
found to be highly useful synthetic precursors for the synthesis of
a variety of new potent biologically active trifluoromethylated
compounds.
d
3
2
(100.5 MHz, CDCl3)
d = 38.30 (d, J(C–F) = 1.6 Hz), 44.17 (q, JC–
1
1
F = 27.9 Hz), 120.21 (q, J(C–F) = 259.1 Hz), 120.35 (q, J(C–
F) = 257.5 Hz), 120.46 (d, J = 1.0 Hz), 121.07 (s), 126.59 (q, J(C–
1
F) = 279.4 Hz), 130.06 (s), 130.45 (s), 133.00 (d, J = 1.8 Hz),
134.19 (s), 149.15 (d, J = 1.8 Hz), 153.03 (q, J = 1.7 Hz), 193.42
(s); 19F NMR (376 MHz, CDCl3)
d
= ꢂ57.80 (s), ꢂ58.00 (s), ꢂ69.83
(d, 3J(H–F) = 9.5 Hz). HRMS calcd. for C18H11F9O3 446.0564, found
4. Experimental
446.0561.
4.1. General
4,4,4-Trifluoro-1,3-bis(4-fluorophenyl)butan-1-one (20d)
Unless otherwise mentioned, all chemicals were purchased
from commercial sources. 1H, 13C, and 19F NMR spectra were
recorded on Varian NMR at 400 MHz. 1H NMR chemical shifts were
determined relative to internal tetramethylsilane at 0.0 ppm, 13C
NMR chemical shifts were determined relative to 13C signal of
CDCl3 at 77.0 ppm. 19F NMR chemical shifts were determined
relative to internal CFCl3 at 0.0 ppm. HRMS data were obtained
from a high resolution Micromass GCT (GC–MS TOF) spectrometer
at the Mass Spectrometry Facility, Department of Chemistry,
University of Arizona.
1H NMR (400 MHz, CDCl3)
d = 3.37–3.54 (m, 2H), 4.09 (pd,
J = 9.5, 4.2 Hz, 1H), 6.83 (t, J = 8.7 Hz, 2H), 6.92 (t, J = 8.6 Hz, 2H),
7.21 (dd, J = 8.6, 5.3 Hz, 2H), 7.77 (dd, J = 8.9, 5.3 Hz, 2H); 13C NMR
3
2
(100.5 MHz, CDCl3)
d = 38.12 (d, J(C–F) = 1.3 Hz), 44.18 (q, J(C–
F) = 27.7 Hz), 115.61 (d, 2JC–F = 21.6 Hz), 115.78 (d, 2J(C–
F) = 22.0 Hz), 122.70 (d, J = 1.0 Hz), 124.34 (d, J = 3.7 Hz), 126.86
1
3
3
(q, J(C–F) = 279.3 Hz), 130.06 (d, J(C–F) = 8.6 Hz), 130.66 (d, J(C–
1
1
F) = 9.5 Hz), 162.59 (d, J(C–F) = 247.2 Hz), 165.99 (d, J(C–
F) = 255.6 Hz), 193.48 (s); 19F NMR (376 MHz, CDCl3)
= ꢂ69.96
(dd, J = 9.5, 1.5 Hz), ꢂ104.15 (m), ꢂ113.69 (m). HRMS calcd. for
16H11F5O 314.0730, found 314.0740.
d
C
4.2. General procedure for the synthesis of trifluoromethylated
dihydrochalcones, aryl vinyl ketones and indanones
4,4,4-Trifluoro-1,3-bis(4-chlorophenyl)butan-1-one (20e)
4,4,4-Trifluorocrotonic acid or 3-(trifluoromethyl)-crotonic
acid (2 mmol) was mixed with excess of arene (10 mmol) in a
pressure tube. The mixture was cooled to 0 8C and TfOH (3 mL,
34 mmol) was added slowly. The mixture was stirred for the
required period of time and temperature (Tables 1 and 2). Progress
of the reaction was monitored by TLC (4:1 hexane/ethyl acetate)
and 19F NMR spectroscopy. After the reaction was complete the
1H NMR (400 MHz, CDCl3)
d = 3.59 (qd, J = 17.9, 6.7 Hz, 2H), 4.20
(m, 1H), 7.32 (s, 4H), 7.46–7.41 (m, 2H), 7.83–7.88 (m, 2H); 13C
2
NMR (100.5 MHz, CDCl3)
d
= 38.11 (s), 44.23 (q, JC–F = 27.7 Hz),
1
126.56 (q, J(C–F) = 279.4 Hz), 128.94 (s), 129.08 (s), 129.38 (s),
130.28 (s), 132.81 (d, J(C–F) = 1.9 Hz), 140.23 (s), 193.78 (s); 19F
3
NMR (376 MHz, CDCl3)
d
= ꢂ70.21 (d, 3J(H–F) = 9.5 Hz). HRMS calcd.
for C16H11Cl2F3O 346.0139, found 346.0123.

G.K. Surya Prakash et al. / Journal of Fluorine Chemistry 143 (2012) 292–302
299
Fig. 3. MP2/cc-pVTZ calculated structure of 30–35.
4,4,4-Trifluoro-1,3-bis(4-bromophenyl)butan-1-one (20f)
4,4,4-Trifluoro-1,3-bis(3-hydroxy-4-methylphenyl)butan-1-one
(20g)
1H NMR (400 MHz, CDCl3)
J = 9.4, 4.4 Hz, 1H), 7.23–7.29 (m, 2H), 7.44–7.49 (m, 2H), 7.57–7.62
(m, 2H), 7.74–7.79 (m, 2H); 13C NMR (100.5 MHz, CDCl3)
= 38.05
d = 3.51–3.65 (m, 2H), 4.18 (pd,
1H NMR (399 MHz, acetone-d6)
d
= 2.01 (s, 3H), 2.06 (s, 3H),
d
3.35 (dd, J = 17.5, 4.0 Hz, 1H), 3.64 (dd, J = 17.5, 9.4 Hz, 1H), 3.95–
4.08 (m, 1H), 6.63 (d, J = 8.3 Hz, 1H), 6.74 (d, J = 8.4 Hz, 1H), 6.96
(dd, J = 8.2, 1.7 Hz, 1H), 7.05 (s, 1H), 7.60 (dd, J = 8.4, 2.2 Hz, 1H),
7.68 (d, J = 1.6 Hz, 1H), 8.16 (s, 1H), 9.05 (s, 1H); 13C NMR
(d, J = 1.5 Hz), 44.31 (q, J = 27.8 Hz), 122.58 (s), 122.94–129.21 (q,
1J(C–F) = 281 Hz), 129.02 (s), 129.50 (d, J = 2.5 Hz), 130.63 (s),
131.92 (s), 132.10 (s), 133.34 (d, J = 1.8 Hz), 134.73 (s), 193.98 (s);
3
19F NMR (376 MHz, CDCl3)
d
= ꢂ70.17 (d, J(H–F) = 9.5 Hz). HRMS
(100.5 MHz, acetone-d6)
d = 15.32 (s), 15.45 (s), 37.15 (s), 44.10 (q,
calcd. for C16H11Br2F3O 433.9129, found 433.9150.
2J(C–F) = 26.9 Hz), 114.46 (s), 114.64 (s), 124.33 (s), 124.62 (s),

300
G.K. Surya Prakash et al. / Journal of Fluorine Chemistry 143 (2012) 292–302
O
HO
O
O
R
R
OH
H
OH
R
R
-H2O
CF
37
CF3
F3C
F3C
36
19a R = H, 19b R = CH3
H
R1
O
H
R
OH
R
O
CF3
CF3
H
R
CF3
38
intermolecular
F-C acylation
39
21 R = CH3
R1
R1
O
H
R2
OH
R1
CF3
H3C
22
H
CF3
O
CF3
R
R1
40
R1
R1
20
R1 = H
H
OH
CF3
HO
Ph
CF3
CF3
Ph
-H2O
H
41
42
23
Scheme 3. Suggested mechanism for the formation of dihydrochalcones 20, aryl vinyl ketones 21, indanones 22, and indene 23.
3
1
125.63 (d, 3J(C–F) = 1.8 Hz), 127.54 (s), 127.68 (q, 1J(C–
(100.5 MHz, CDCl3):
d
12.50 (q, J(C–F) = 1.5 Hz), 123.60 (q, J(C–
3
F) = 278.9 Hz), 128.16 (s), 128.74 (s), 131.49 (s), 131.75 (s),
F) = 273.9 Hz), 126.0 (q, J(C–F) = 5.1 Hz), 128.70, 129.10, 134.05,
137.40, 139.40 (q, J(C–F) = 30.2 Hz), 191.81; 19F NMR (376 MHz,
155.23 (s), 160.34 (s), 193.93 (s); 19F NMR (376 MHz, acetone-
2
3
d6)
d
= ꢂ70.23 (d, J(H–F) = 10.1 Hz). HRMS calcd. for C18H17F3O3
CDCl3):
d
ꢂ71.33; HRMS (ESI), m/z calcd. for C11H9F3O 214.0605,
338.1101, found 337.10570 (M+ꢂH)
found 214.0600.
4,4,4-Trifluoro-1,3-bis(2-hydroxy-5-methylphenyl)butan-1-one
4,4,4-Trifluoro-3-methyl-1-p-tolyl-2-buten-1-one (21b)
(20h)
1H NMR (400 MHz, CDCl3):
d 2.13 (d, J = 1.2 Hz, 3H), 2.42 (s, 3H),
7.20 (Hept, J = 1.40 Hz, 1H), 7.29 (d, J = 8.2 Hz, 2H), 7.83 (d,
1H NMR (400 MHz, acetone-d6)
d
= 2.17 (s, 3H), 2.26 (s, 3H), 3.76
3
(dd, J = 17.8, 4.9 Hz, 1H), 3.97 (dd, J = 17.8, 8.9 Hz, 1H), 4.89 (pd,
J = 9.8, 4.9 Hz, 1H), 6.76–6.83 (m, 2H), 6.92 (ddd, J = 8.2, 2.2, 0.6 Hz,
1H), 7.25 (s, 1H), 7.29 (ddd, J = 8.5, 2.1, 0.4 Hz, 1H), 7.89 (d,
J = 1.3 Hz, 1H), 8.58 (s, 1H), 11.82 (s, 1H); 13C NMR (100 MHz,
J = 8.2 Hz, 2H); 13C NMR (100.5 MHz, CDCl3):
d
12.54 (q, J(C–
1
3
F) = 1.4 Hz), 21.50 123.42 (q, J(C–F) = 273.9 Hz), 125.89 (q, J(C–
2
F) = 5.1 Hz), 128.60, 129.45, 134.62, 138.48 (q, J(C–F) = 30.2 Hz),
144.77, 190.51; 19F NMR (376 MHz, CDCl3):
d
ꢂ70.91; HRMS (EI)
acetone-d6)
d
= 19.50 (s), 19.71 (s), 36.60 (dd, J = 54.2, 26.5 Hz),
m/z calcd. for C12H11F3O 228.0762, found 228.0757.
37.00 (d, J = 1.9 Hz), 115.36 (s), 117.71 (s), 118.91 (s), 120.70 (d,
1
J = 1.8 Hz), 127.55 (q, J(C–F) = 279.5 Hz), 128.17–128.28 (m),
4,4,4-Trifluoro-1-(3,4-dimethylphenyl)-3-methyl-2-buten-1-one
128.54 (s), 129.04 (s), 129.54 (s), 130.18 (s), 137.58 (s), 153.47
(21c)
(s), 160.18 (s), 202.49 (s); 19F NMR (376 MHz, acetone-d6)
3
d
= ꢂ69.98 (d, J(H–F) = 9.9 Hz). HRMS calcd. for C18H17F3O3
1H NMR (400 MHz, CDCl3):
7.20 (Hept, J = 1.40 Hz, 1H), 7.25 (d, J = 8.1 Hz, 1H), 7.66 (dd, J = 7.7,
d 2.13 (d, J = 1.4 Hz, 3H), 2.33 (s, 6H),
338.1101, found 337.1057 (M+ꢂH).
1.9 Hz, 1H), 7.71 (d, J = 1.4 Hz, 1H); 13C NMR (100.5 MHz, CDCl3):
d
4,4,4-Trifluoro-3-methyl-1-phenyl-2-buten-1-one (21a)
12.56 (q, 3J(C–F) = 1.5 Hz), 19.57, 19.94, 123.43 (q, 1J(C–
3
F) = 273.9 Hz), 126.08 (q, J(C–F) = 5.2 Hz), 126.33, 129.49, 129.97,
134.94, 137.28, 138.26 (q, J(C–F) = 30.2 Hz), 143.63, 190.89; 19F
1H NMR (400 MHz, CDCl3):
d
2.15 (d, J = 1.46 Hz, 3H), 7.23
2
(Hept, J = 1.46 Hz, 1H), 7.17–7.20 (m, 2H), 7.47–7.52 (m, 2H), 7.60
(tt, J = 7.32, 1.55 Hz, 1H), 7.92–7.95 (m, 2H); 13C NMR
NMR (376 MHz, CDCl3):
C13H13F3O 242.0918, found 242.0920.
d
ꢂ71.26; HRMS (EI) m/z calcd. for

G.K. Surya Prakash et al. / Journal of Fluorine Chemistry 143 (2012) 292–302
301
4,4,4-Trifluoro-1-(4-fluorophenyl)-3-methyl-2-buten-1-one (21d)
1-(Trifluoromethyl)-3-phenyl-1H-indene (23)
1H NMR (400 MHz, CDCl3):
4.24 (qd, J = 9.4, 2.15 Hz, 1H), 6.42
(d, J = 2.3 Hz, 1H), 7.32 (td, J = 7.5, 0.8 Hz, 1H), 7.36–7.50 (m, 4H),
7.55–7.60 (m, 3H), 7.66 (d, J = 7.4 Hz, 1H); 13C NMR (100.5 MHz,
1H NMR (400 MHz, CDCl3):
7.21 (m, 3H), 7.95–7.99 (m, 2H); 13C NMR (100.5 MHz, CDCl3):
12.77 (q, 3J(C–F) = 1.5 Hz), 116.06 (d, 2J(C–F) = 22.1 Hz), 123.31 (q,
d
2.16 (d, J = 1.3 Hz, 3H), 7.15–
d
d
3
3
2
3
1J(C–F) = 273.9 Hz), 125.36 (q, J(C–F) = 5.2 Hz), 131.27 (d, J(C–
F) = 9.5 Hz), 133.55 (d, 4J(C–F) = 2.9 Hz), 139.37 (q, 2J(C–
F) = 30.2 Hz), 166.10 (d, 1J(C–F) = 256.2 Hz), 189.42; 19F
CDCl3): d 52.59 (q, J(C–F) = 29.4 Hz), 121.16, 124.72 (q, J(C–
1
F) = 5.1 Hz), 124.80, 126.10 (q, J(C–F) = 278.3 Hz), 126.32, 127.72,
128.41, 128.51, 128.73, 134.50, 138.66 (q, 3J(C–F) = 2.3 Hz), 144.10,
149.28; 19F NMR (376 MHz, CDCl3):
NMR (376 MHz, CDCl3):
(m); HRMS (ESI), m/z calcd. for C11H8F4O 232.0511, found
d
ꢂ71.37 (d, J(H–F) = 1.4 Hz), ꢂ103.96
d
ꢂ67.78 (d, J(H–F) = 9.15 Hz);
HRMS (EI) m/z calcd. for C16H11F3 260.0813, found 260.0814.
232.0512.
References
4,4,4-Trifluoro-1-(4-chlorophenyl)-3-methyl-2-buten-1-one
(21e)
[1] G.A. Olah, Friedel–Crafts and Related Reactions, vol. 2, part I, Wiley-Interscience,
New York, 1964.
[2] (a) G.A. Olah, Friedel–Crafts Chemistry, Wiley-Interscience, New York, 1973;
(b) H. Heaney, in: B.M. Trost (Ed.), Comprehensive Organic Synthesis, vol. 2,
Pergamon, Oxford, 1991, pp. 733–752;
1H NMR (400 MHz, CDCl3):
d 2.16 (d, J = 1.6 Hz, 3H), 7.19 (Hept,
J = 1.50 Hz, 1H), 7.46 (dt, J = 8.8, 2.2 Hz, 2H), 7.87 (dt, J = 8.8, 2.2 Hz,
2H); 13C NMR (100.5 MHz, CDCl3):
123.28 (q, J(C–F) = 274.13 Hz), 125.04 (q, J(C–F) = 5.4 Hz), 129.15,
129.87, 135.47, 139.95 (q, J(C–F) = 30.2 Hz), 140.30, 189.59; 19F
NMR (376 MHz, CDCl3):
3
d 12.75 (q, J(C–F) = 1.5 Hz),
(c) G.A. Olah, R. Krishnamurti, G.K.S. Prakash, in: B.M. Trost (Ed.), Comprehensive
Organic Synthesis, vol. 3, Pergamon, Oxford, 1991, pp. 293–339;
(d) R.P. Singh, R.M. Kamble, K.L. Chandra, P.S. Singh, V.K. Singh, Tetrahedron 57
(2001) 241–247.
1
3
2
d
ꢂ71.34; HRMS (ESI), m/z calcd. for
[3] (a) H.-J. Bo¨hm, D. Banner, S. Bendels, M. Kansy, B. Kuhn, K. Mu¨ller, U. Obst-Sander,
M. Stahl, ChemBioChem 5 (2004) 637–643;
C11H8ClF3O 248.0216, found 248.0205.
(b) J.P. Begue, D. Bonnet-Delpon, Journal of Fluorine Chemistry 127 (2006)
992–1012;
(c) D. O’Hagan, D.B. Harper, Journal of Fluorine Chemistry 100 (1999) 127–133;
(d) Y.C. Wu, Y.J. Chen, H.J. Li, X.M. Zou, F.Z. Hu, H.Z. Yang, Journal of Fluorine
Chemistry 127 (2006) 409–416;
4,4,4-Trifluoro-1-(4-hydroxyphenyl)-3-methyl-2-buten-1-one (21f)
1H NMR (400 MHz, CDCl3):
2.12 (d, J = 1.5 Hz, 3H), 6.41 (br,
d
(e) M.A. McClinton, D.A. McClinton, Tetrahedron 48 (1992) 6555–6666;
(f) S. Purser, P.R. Moore, S. Swallow, V. Gouverneur, Chemical Society Reviews 37
(2008) 320–330;
1H), 7.46 (dt, J = 8.8, 2.4 Hz, 2H), 7.18 (Hept, J = 1.4 Hz, 1H), 7.89
(dt, J = 8.9, 2.4 Hz, 2H); 13C NMR (100.5 MHz, CDCl3):
d 12.75 (q,
1
3J(C–F) = 1.5 Hz), 115.78, 123.39 (q, J(C–F) = 273.8 Hz), 126.21 (q,
(g) W.K. Hagmann, Journal of Medicinal Chemistry 51 (2008) 4359–4369;
(h) L. Hunter, Beilstein Journal of Organic Chemistry 6 (2010) 38.
[4] (a) K. Burger, L. Hennig, J. Spengler, F. Albericio, Heterocycles 69 (2006) 569–592;
(b) T. Billard, B.R. Langlois, European Journal of Organic Chemistry (2007)
891–897.
3J(C–F) = 5.2 Hz), 130.05, 131.52, 138.30 (q, J(C–F) = 30.2 Hz),
2
161.13, 190.35; 19F NMR (376 MHz, CDCl3):
d
ꢂ71.27; HRMS
(ESI), m/z calcd. for C11H9F3O2 230.0555, found 230.0566.
[5] G.K.S. Prakash, A.K. Yudin, Chemical Reviews 97 (1997) 757–786.
[6] (a) J. Wu, S. Cao, Current Organic Chemistry 13 (2009) 1791–1804;
(b) J.P. Begue, D. Bonnet-Delpon, Chemical Society Reviews 34 (2005) 562–572.
[7] C.A. Williams, R.J. Grayer, Natural Products Reports 21 (2004) 539–573.
[8] (a) B.M. Rezk, G.R.M.M. Haenen, W.J.F. Vijgh, A. Bast, Biochemical and Biophysical
Research Communications 295 (2002) 9–13;
3-Methyl-3-(trifluoromethyl)-2,3-dihydro-1H-inden-1-one (22a)
1H NMR (400 MHz, CDCl3):
1H), 3.10 (d, J = 19.1 Hz, 1H), 7.51–7.55 (m, 1H), 7.67–7.72 (m, 2H),
7.60 (d, J = 7.8, 1H); 13C NMR (100.5 MHz, CDCl3): 21.62 (q, 3J(C–
d 1.67 (s, 3H), 2.56 (d, J = 18.9 Hz,
(b) E. Alacid, C. Na´jera, Advanced Synthesis and Catalysis 349 (2007) 2572–2584;
(c) Z. Nowakowska, European Journal of Medical Chemistry 42 (2007) 125–137;
(d) J.R. Dimmock, D.W. Elias, M.A. Beazely, N.M. Kandepu, Current Medicinal
Chemistry 6 (1999) 1125–1149.
d
F) = 2.20 Hz), 45.47 (q, 3J(C–F) = 1.4 Hz), 47.12 (q, 2J(C–
F) = 27.3 Hz),123.92, 125.50, 127.58 (q, 1J(C–F) = 281.33 Hz),
129.56, 135.39, 136.67, 152.64, 202.03; 19F NMR (376 MHz,
´
´
[9] (a) F.A. Tomas-Barberan, M.N. Clifford, Journal of the Science of Food and Agri-
culture 80 (2000) 1073–1080;
CDCl3):
found 214.0596.
d
ꢂ76.03; HRMS (EI) m/z calcd. for C11H9F3O 214.0605,
(b) H.P.V. Rupasinghe, A. Yasmin, Molecules 15 (2010) 251–257.
[10] N. Nakatani, M. Ichimaru, M. Moriyasu, A. Kato, Biological and Pharmaceutical
Bulletin 28 (2005) 83–86.
[11] S. Logendra, D.M. Ribnicky, H. Yang, A. Poulev, J. Ma, E.J. Kennelly, I. Raskin,
Phytochemistry 67 (2006) 1539–1546.
6-Chloro-3-methyl-3-(trifluoromethyl)-2,3-dihydro-1H-inden-1-one
(22e)
´
[12] (a) J.C. Aponte, M. Verastegui, E. Malaga, M. Zimic, M. Quiliano, A.J. Vaisberg, R.H.
Gilman, G.B. Hammond, Journal of Medicinal Chemistry 51 (2008) 6230–6234;
(b) J.C. Aponte, A.J. Vaisberg, R. Rojas, L. Caviedes, W.H. Lewis, G. Lamas, S. Ce´sar,
R.H. Gilman, G.B. Hammond, Journal of Natural Products 71 (2008) 102–105.
[13] T. Narender, S. Gupta, S. Gupta, Bioorganic and Medicinal Chemistry Letters 14
(2004) 3913–3916.
1H NMR (400 MHz, CDCl3):
J = 19.1 Hz,1H), 3.10 (d, J = 19.1 Hz, 1H), 7.41 (dd, J = 8.2, 1.7 Hz,
1H), 7.62 (s, 1H), 7.66 (d, J = 8.2, 1H); 13C NMR (100.5 MHz, CDCl3):
22.02 (q, 3J(C–F) = 2.20 Hz), 45.77 (q, 3J(C–F) = 1.5 Hz), 47.28 (q, 2J(C–
F) = 27.46 Hz),125.04, 125.88, 127.21 (q, J(C–F) = 281.20 Hz),
130.35, 135.03, 141.94, 153.92 (q, J(C–F) = 1.5 Hz), 202.32; 19F
d 1.65 (s, 3H), 2.57 (d,
[14] (a) V. Siddaiah, C.V. Rao, S. Venkateswarlu, G.V. Subbaraju, Tetrahedron 62 (2006)
841–846;
d
1
(b) Z. Jia, X. Yang, C.A. Hansen, C.B. Naman, C.T. Simons, J.P. Slack, K. Gray, PCT Int.
Appl., WO 2008148239 (2008).
(c) L. Krbechek, G.E. Inglett, M. Holik, B. Dowling, R. Wagner, R. Riter, Journal of
Agricultural and Food Chemistry 16 (1968) 108–112.
3
NMR (376 MHz, CDCl3):
11H8ClF3O 248.0216, found 248.0205.
d
ꢂ76.01; HRMS (ESI), m/z calcd. for
C
[15] (a) P.Z. Sanoner, S. Guyot, C. Leguerneve, J.M. Lequere, J.F. Drilleau, C. Renard, FR
2862303 2005 (2005).;
(b) F. Bruno, D. Wilfried, PCT Int. Appl., WO 2009052895 (2009).
[16] A. Briot, C. Baehr, R. Brouillard, A. Wagner, C. Mioskowski, Journal of Organic
Chemistry 69 (2004) 1374–1377.
[17] (a) J.E.G. Guillemont, D.F.A. Lancois, E.T.J. Pasquier, K.J.L.M. Andries, A. Koul, PCT
Int. Appl., WO 2007014885 (2007).
3-(Trifluoromethyl)-2,3-dihydro-1H-inden-1-one (22a0)
1H NMR (400 MHz, CDCl3):
2.78 (dd, J = 19.23, 3.66 Hz, 1H),
d
2.91 (dd, J = 19.23, 8.42 Hz, 1H), 4.08 (qd, J = 8.79, 3.66 Hz, 1H),
(b) C.S. Cho, W.X. Ren, N.S. Yoon, Journal of Molecular Catalysis A: Chemical 299
(2009) 117–120;
7.49–7.53 (m, 1H), 7.64–7.68 (m, 2H), 7.80 (d, J = 7.69 Hz, 1H); 13
C
3
(c) C.S. Cho, W.X.J. Ren, Organometallic Chemistry 692 (2007) 4182–4186.
[18] E.G. Gundersen, U.S. Pat. Appl., US 2005070592 (2005).
[19] (a) S.-J. Won, C.-T. Liu, L.-T. Tsao, J.-R. Weng, H.-H. Ko, J.-P. Wang, C.-N. Lin,
European Journal of Medical Chemistry 40 (2005) 103–112;
(b) H.-H. Ko, L.-T. Tsao, K.-L. Yu, C.-T. Liu, J.-P. Wang, C.-N. Lin, Bioorganic and
Medicinal Chemistry 11 (2003) 105–111.
NMR (100.5 MHz, CDCl3):
d
36.93 (q, J(C–F) = 2.20 Hz), 42.52 (q,
1
2J(C–F) = 29.70 Hz), 124.18, 126.25 (q, J(C–F) = 278.3 Hz), 127.05,
129.71, 135.28, 137.50, 147.08, 202.09; 19F NMR (376 MHz, CDCl3):
d
ꢂ70.78 (d, J(H–F) = 9.15 Hz); HRMS (EI) m/z calcd. for C10H7F3O
200.0449, found 200.0442.

302
G.K. Surya Prakash et al. / Journal of Fluorine Chemistry 143 (2012) 292–302
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