Reactions of CF3-enones with arenes under superelectrophilic activation: A pathway to trans-1,3-diaryl-1-CF3-indanes, new cannabinoid receptor ligands

Article abstract of DOI:10.1039/c5ob01072a

4-Aryl-1,1,1-trifluorobut-3-en-2-ones ArCHCHCOCF₃ (CF₃-enones) react with arenes in excess of Bronsted superacids (TfOH, FSO₃H) to give, stereoselectively, trans-1,3-diaryl-1-trifluoromethyl indanes in 35-85% yields. The r

Full text of DOI:10.1039/c5ob01072a

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Kazakova, V. Muzalevkiy, A. Ivanov, I. A. Boyarskaya, A. Chicca, V. Petrucci, J. Gertsch, M. Krasavin, G. L.
Starova, A. A. Zolotarev, M. S. Avdontceva, V. Nenajdenko and A. Vasilyev, Org. Biomol. Chem., 2015, DOI:
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Reactions of CF -enones with arenes under superelectrophilic activation: a stereoselective
pathway to trans-1,3-diaryl-1-trifluoromethyl indane scaffold as a new core for cannabinoid
receptor ligand design
a
a
b
c
Roman O. Iakovenko, Anna N. Kazakova, Vasiliy M. Muzalevskiy, Alexander Yu. Ivanov, Irina A.
a
d
d
d
a
Boyarskaya, Andrea Chicca, Vanessa Petrucci, Jürg Gertsch, Mikhail Krasavin,* Galina L.
a
a
a
b
Starova, Andrey A. Zolotarev, Margarita S. Avdontceva, Valentine G. Nenajdenko,* and
a,e
Aleksander V. Vasilyev*
a
Institute of Chemistry, SaintꢀPetersburg State University, 198504 SaintꢀPetersburg, Petrodvorets,
Universitetsky pr., 26, Russia, Eꢀmail: m.krasavin@spbu.ru
b
Department of Chemistry, Lomonosov Moscow State University, 119899 Moscow, Russia,
Fax: +7ꢀ495ꢀ9328846, Tel.: +7ꢀ495ꢀ9392276, Eꢀmail: nen@acylium.chem.msu.ru
c
Center for Magnetic Resonance, Research park, St. Petersburg State University, Universitetskiy pr.
2
6, Saint Petersburg, Petrodvorets, 198504 , Russia
d
Institute of Biochemistry and Molecular Medicine, NCCR TransCure, University of Bern, Bühlstrasse
2
8, 3012 Bern, Switzerland
e
Department of Chemistry, Saint Petersburg State Forest Technical University, Institutsky per., 5,
Saint Petersburg, 194021, Russia, Fax: +7ꢀ812ꢀ6709390, Tel.: +7ꢀ812ꢀ6709352, Eꢀmail:
aleksvasil@mail.ru
*
Corresponding authors: M. Krasavin, V.G. Nenajdenko, and A.V. Vasilyev.
Keywords
CF ꢀenones, Brønsted superacids, trifluoromethyl group, indanes, endocannabinoid system,
cannabinoid receptor ligands
3
1

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Abstract
4ꢀArylꢀ1,1,1ꢀtrifluorobutꢀ3ꢀenꢀ2ꢀones ArCH=CHCOCF
3
(CF
3
ꢀenones) react with arenes in
3
excess of Brønsted superacids (TfOH, FSO H) to give, stereoselectively, transꢀ1,3ꢀdiarylꢀ1ꢀ
trifluoromethyl indanes in 35ꢀ85% yields. The reaction intermediates, the Oꢀprotonated
+
+
+
3 2 3
ArCH=CHC(OH )CF and the O,Cꢀdiprotonated ArHC CH C(OH )CF species, have been studied by
1
13
19
means of H, C, F NMR, and DFT calculations. Both types of the cations may participate in the
reaction, depending on their electrophilicity and electronꢀdonating properties of the arenes. The
formation of CF
regioꢀ and stereoselectively three new CꢀC bonds. The obtained transꢀ1,3ꢀdiarylꢀ1ꢀtrifluoromethyl
indanes were investigated as potential ligands for cannabinoid receptors CB and CB types. The most
potent compound showed subꢀmicromolar affinity for both receptor subtypes with a 6ꢀfold selectivity
toward CB receptor with no appreciable cytotoxicity toward SHSY5Y cells.
3 3
ꢀindanes is a result of cascade reaction of protonated CF ꢀenones to form chemoꢀ,
1
2
2
Graphical Abstract
OMe
R
R
F3C
F3C
OMe
hCB K = 0.12 ꢀM
O
TfOH
+
1
i
Ar
CF3
o
20 C, 1 h
MeO
MeO
hCB K = 0.75 ꢀM
R
2
i
Ar
5-85% trans-diaryl
3
Cl
Introduction
3
,1,1ꢀTrifluorobutꢀ3ꢀenꢀ2ꢀones (CF ꢀenones) are important fluorinated building blocks having
1
rich chemistry and are used frequently for preparation of practically valuable fluorineꢀcontaining
1
substances. Several approaches to synthesis of CF
3
ꢀenones have been developed. The combination of
a conjugated carbonꢀcarbon double bond and a CF
3
COꢀgroup present in these compounds, results in
2

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2
their unique electrophilic properties, leading to the reactions at either the carbonyl group or the double
3
4
bond ꢀ or at both of these structural fragments. CF
3
ꢀenones are known to react with various Oꢀ, Sꢀ, Nꢀ
,
Cꢀnucleophiles to give numerous polyfunctional derivatives, carboꢀ and heterocycles bearing a
5
trifluoromethyl group. Many of those have been shown to possess diverse biological activities.
6
3
In continuation of our previous studies of reactions of CF ꢀalkynes in Brønsted superacids, and
7
CF ꢀallyl alcohols under action of Lewis acids, we became interested in studying of the fate of CF ꢀ
3
3
enones 1a-h (Figure 1) under similar superelectrophilic activation. In preliminary short
8
communication we showed that 1,1,1ꢀtrifluoroꢀ4ꢀphenylbutꢀ3ꢀenꢀ2ꢀone 1a reacted with benzene, oꢀ
9
xylene, and veratrole in TfOH. We chose Brønsted superacids (TfOH, FSO
enhancement of electrophilic properties of CF
3
H) to significant
3
ꢀenones system by protonation. The main goal of this
work was to investigate the protonation of butenones 1a-h in superacids, the subsequent reactions of
the resulting carbocations with arenes, as πꢀnucleophiles, and to test physiological activity of the
resulting trifluoromethylated compounds.
O
O
O
CF3
n-BuO
CF3
Me N
2
CF
3
1a-f
1g
1h
R
R = H (a), 3-Me (b), 4-Me (c),
4-Cl (d), 3-MeO (e), 4-MeO (f)
Figure 1. Starting CF
3
ꢀenones 1a-h used in this study
Results and discussion
DFT calculation of cations derived from of 4ꢀarylꢀ1,1,1ꢀtrifluorobutꢀ3ꢀenꢀ2ꢀones
9a,b
9c
Protonation of conjugated enones or ynones in Brønsted superacids proceeds in two steps:
first, protonation of the carbonyl oxygen occurs, followed by second protonation of unsaturated
3
carbonꢀcarbon bond. In the same way protonation of CF ꢀenones system of compounds 1 gives
consequently cations A and dications B (Scheme 1). The latter species are considered as
9b
superelectrophiles. Both the Oꢀprotonated (A) and the O,Cꢀdiprotonated (B) forms can be reactive
3

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2
4
electrophiles. They have two carbocationic centers (at C and C ) that may participate in further
reactions.
OH
OH
O
H+
H+
4
4
2
2
CF
CF
3
4
2
CF
3
3
3
3
3
1
1
1
1a-f
A1-A6
B1-B6
R
R
R
Scheme 1 Protonation of CF
3
ꢀenones
To have insight into the nature of formed electrophilic species we decided to study the reaction
ꢀenones with acids theoretically. In order to estimate the charge distribution in these species (as
well as their electrophilicity), we performed DFT calculations for carbocations, derived from CF
of CF
3
3
ꢀ
enones 1a-f (Scheme 1). Selected electronic characteristics of the Oꢀprotonated forms (A1-A6), the
O,Cꢀdiprotonated forms (B1-B6) are presented in SI (Table S9). The global electrophilicity index can
be used quite effectively to sort various electrophiles qualitatively and provide a good estimation of the
10
activity of electrophiles. This parameter is easily calculated from the HOMO and LUMO levels.
The data obtained shows that the highest value of global electrophilicity index ω 30.3ꢀ47.5 eV
9
,11
belongs to dication B1-B6. That is quite predictable for doubly charged species.
Apart from that,
these dications have a large positive charge (0.66ꢀ0.69 e) and a great contribution of an atomic orbital
2
in LUMO on C atom (18.2ꢀ34.6%) which indicates a combined effect of charge and orbital control on
reactivity of that carbon atom. This also reveals that the O,Cꢀdiprotonated species B should be
9b
2
extremely reactive electrophiles (superelectrophiles ) with the C atom being more reactive compared
4
C .
2
The Oꢀmonoprotonated cations A1ꢀA6 also carries a bigger positive charge on C (0.40ꢀ0.43e)
4
atom compared C (0.02ꢀ0.07 e). However, the latter has a slightly bigger contribution of atomic
orbital to LUMO (26.5ꢀ29.7 %). It may determine the predominance of orbital control in reactivity of
4
C atom for cations A1-A6.
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Thus, the DFT calculations predict that in principle both cationic species A and B derived from 1
2
(
Scheme 1) may act as electrophiles. Atom C is the reactive center in dications B. Cations A may
2
4
possess two centers (atoms C and C ) for the reaction with nucleophiles.
3
NMR study of CF ꢀenones protonation in superacids
In order to confirm DFT predictions we investigated protonation of CF ꢀenones in TfOH and
3
FSO
3 3
H at various temperatures by means of NMR. It was found, that CF ꢀenones 1a,c,d,f,h afforded
1
13
stable Oꢀprotonated species A1, A3, A4, A6, A7, respectively, at temperatures below ꢀ20 °C. H, C,
19
and F NMR data of these carbocations and the corresponding starting materials are given in SI (Table
1
3
S1). C NMR signals of ions A1, A3, A4, A6, A7 were carefully assigned using HSQC (C–H)
experiments. The signal of proton bounded to the carbonyl oxygen was not detected, due to a fast
9
proton exchange with superacidic media. At higher temperatures (above ꢀ20 °C), subsequent
protonation of the carbonꢀcarbon double bond can take place and the corresponding superelectrophilic
dications B are formed. Unfortunately, we failed to detect these dications in the NMR spectra, due to
9b
their extreme instability and high reactivity, which is peculiar to superelectrophiles. At higher
temperatures (ꢀ20…0 °C), the spectral data pointed out the formation of complex mixtures of
oligomeric reaction products (vide infra). Contrary to other CF
3
ꢀenones, compound 1h gave extremely
stable (even at 60 °C) and unreactive cation A7 .
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O
o
i
m
OMe
4
2
CF
3
3
1
o
MeO
p
m
1e
2
H
o
2H
m
H
4
H
3
CHCl
3
OH
o
i
m
2
4
CF
OMe
3
3
1
o
MeO p
m
2
H
m
A6
CH
Cl
2 2
H
4
H
o
H
o
H
3
CDCl
3
O
o
OMe
m
i
4
2
CF
3
3
1
o
MeO p
m
2
C
o
2C
m
C
3
1
e
C
p
Ci
C
4
CF3
C=O
OH
o
i
m
2
4
CF
3
OMe
3
1
o
MeO p
m
C
i
A6
C
p
C
4
2
CH Cl2
C
m
C
m
C
o
C
o
C
3
C=O
CF
3
1
13
Figure 2 Comparison of H and C NMR spectra of 1f (CDCl
3
, 20 °C) and cation A6 (FSO
3
H, ꢀ60 °C).
6

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Comparison of the spectra of aryl substituted cations A1, A3, A4, A6 and their neutral precursors
4
4
1
a,c,d,f revealed that the signals corresponding to proton H and carbon C underwent substantial
1
13
downfield shifts: ꢁδ
H
~ 1.1ꢀ1.7 ppm in H NMR and ꢁδ
C
~ 20ꢀ30 ppm in C NMR (Table S1, Figure
4
2
). Such spectral changes indicated a partial positive charge delocalization on carbon C and
contribution of the corresponding resonance structure A′ (Table S1). On the other hand, the carbonyl
2
13
carbon C (in C NMR) underwent only slight upfield shifts upon protonation. That additionally
1
13
argues in favor of form A′. Apart from that, in H and C NMR spectra of species A1, A3, A4, A6 the
signals of the orthoꢀ and metaꢀ protons and carbons of the aromatic ring are nonꢀequivalent. That
indicates a contribution of another resonance structure A′′ (Table S1), in which restricted rotation
4
around bond C –C
i
is possible. This resonance form has a significant contribution in case of paraꢀ
methoxy substituted cation A′′6, in which the signal of C atom is shifted to 180.8 ppm, compared to
p
1
50.1 ppm in the nonꢀprotonated starting material 1f (see Figure 2). Dimethylamino substituted cation
is also characterized by resonance A′7 (Table S1).
2
4
Thus, NMR data indicates a significant delocalization of positive charge from C to C in the Oꢀ
protonated species A, despite the fact that the DFT calculations did not predict a substantial charge reꢀ
distribution (see Table S9). These data suggest that carbocations A are likely to react with nucleophiles
4
primarily at C .
Reaction of CF
Having gathered the NMR data relevant to the protonation of CF
study the behavior of compounds 1 in superacids. In TfOH at 20 °C, CF
quantitatively into mixtures of oligomers consisting of at least 6 units of the starting butanone
according to MALDI mass spectrometry data, see SI). Indeed, the observed oligomerization is a likely
fate for dications B formed in the absence of intercepting nucleophiles in the reaction medium.
3
ꢀenones with arenes in superacids
3
ꢀenones 1, we proceeded to
3
ꢀenones 1a-c,e are converted
(
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Table 1. Reactions of CF ꢀenone 1a with benzene (12 equiv.) under the action of various acids
F3C Ph
O
Acid
+
Ph
CF3
1a
Ph
2a
Reaction conditions
Acid T, °C t, h
Reaction products
(yield, %)
Entry
a
1
TfOH (50 equiv.)
20
1
2a (84%)
TfOH (5 equiv.),
a
2
20
1
2a (8%)
CH
TfOH (1 equiv.),
CH Cl (coꢀsolvent)
H SO (750 equiv.)
2 2
Cl (coꢀsolvent)
b
3
4
5
20
20
1
18
3
traces of 2a
2
2
a
2a (15%)
2
4
FSO H (80 equiv.),
3
c
ꢀ40
1a (100%)
SO
2
(coꢀsolvent)
6
7
8
FSO
3
H (80 equiv.)
20
ꢀ20
20
1
3
oligomers
c
TfOH (50 equiv.)
1a (100%)
a
AlBr
AlBr
CH Cl
AlCl
CH Cl
FeCl
3
(5 equiv.)
(5 equiv.),
0.5
oligomers
3
c
9
ꢀ40
1
1a (100%)
2
2
(coꢀsolvent)
(5 equiv.),
3
a
1
0
1
20
20
1
1
oligomers
2
2
(coꢀsolvent)
c
1
3
(5 equiv.)
1a (100%)
a
b
c
Notes. Complete conversion of initial 1a. Inсomplete conversion (~30%) of initial 1a. Quantitative recovery
of unreacted initial 1a.
8

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We were then curious to see if addition of carbocation aromatic traps, such as benzene or other
arenes, would change the course of the transformation of butenones 1 in superacids (Table 1, Schemes
2
, 3). Under the conditions that give rise to species A1 (ꢀ40…ꢀ20 °C, FSO H or TfOH), CF ꢀenones 1a
3
3
demonstrated no appreciable conversion in the presence of an excess amount of benzene (Entries 5, 7,
Table 1). Also, in TfOH cations A3 (at ꢀ20 °C) and A7 (even on heating up to 60 °C), derived from
compounds 1c and 1h, correspondingly, did not react with benzene. Thus, these particular Oꢀ
protonated forms (A1, A3, A7) are not reactive toward benzene under these conditions.
The reaction of compound 1a with benzene in neat TfOH at 20 °C (i.e. when intermediate
dication B1 is likely to be formed) afforded indane 2a in 84 % yield (Entry 1, Table 1). Use of less
amount of TfOH gave unsatisfactory results (Entries 2,3). Compared to TfOH, other Brønsted (Entries
4
, 6) or Lewis (Entries 8ꢀ11) acids were not as efficient in promoting of the same transformation.
The obtained indane 2a is the result of a very deep transformation of 1a, in which both carbons
2
4
C and C participate in the reaction. It should be pointed out that two molecules of benzene
participated in the reaction and three new carbonꢀcarbon bonds are formed. Quite significant is also
stereochemistry of the reaction. According to the NMR data, only one diastereomer is formed having
transꢀarranged phenyl groups in cyclopentane ring of indane system.
1
2aꢀc
For comparison, other conjugated enones, such as alkene carbaldehydes or ketones,
alkene
1
2dꢀj
12kꢀl
mꢀq
carboxylic acids
and their chloro anhydrides
or amides, undergo hydroarylation of carbonꢀ
carbon double bond in reactions with arenes under activation with Bronsted superacids, strong Lewis
acids or acidic zeolites. But in the reactions of these enones carbonyl group remains unaffected.
Introduction of electronꢀwithdrawing CF
3
ꢀsubstituent to enone system of 1a leads to additional
2
electrophilic activation of carbonyl carbon C , which takes part in reaction with benzene (Table 1). It
12f,qꢀt
should be also noted that for some enones
the formation of stable O,Cꢀdiprotonated species (like
dications B, Scheme 1) in superacids was detected by means of NMR.
1
13
19
The structures of indanes 2 (vide infra) were unambiguously determined by means of H, C, F
NMR spectroscopy, highꢀresolution massꢀspectrometry, and Xꢀray (Figure 4). The relative
9

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stereochemistry of products 2 was established by NOESY experiments (Figure 3). It should be noted
that this reaction is highly stereoselective, leading to indane with exclusively transꢀorientation of aryl
groups. In addition we studied the molecular structure of 2a by Xꢀray crystallography. The structure
was totally in agreement with NMR data to confirm transꢀorientation of phenyl rings (see Figure 4a).
R2
R2
H
H
F3C
F3C
Hb
H
Hb
H
H
Ha
Ha
H
H
H
R1
R1
R3
R3
1
1
1
19
Figure 3. H, H NOESY (left) and H, F HOESY (right) correlations, proving stereochemical configuration
of indanes 2
a
b
c
d
e
Figure 4. Xꢀray crystal structures of compounds 2a (a), 2b (b), 2e (c), 2g (d), 2h (e) (ellipsoid contour of
probability levels are 50%)
1
0

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Indane (indene) fragment is a very important structural unit of a large number of bioactive and
pharmaceutically interesting molecules as well as modern catalysts for polymerization. 2ꢀ
Trifluormethylated indanes are an important type of indane derivatives, which have been used in
biological study as well as precursors for indene synthesis. However, so far the existing approaches to
1
2i, 13
trifluoromethylated indanes have some restrictions.
quite straightforward to construct highly desirable CF
corresponding CF ꢀenones in oneꢀpot sequence.
The synthesis proposed in this investigation is
3
ꢀindane derivatives from arene and the
3
Having found the reaction conditions leading to the formation of indane 2a (TfOH, 20 °C, 1 h)
we decided to study scope of the reaction and possible mechanism of the transformation. For this aim a
set of arenes and CF ꢀenones 1a-h were studied under conditions of superelectrophilic activation (see
3
Experimental). It was found, that enone 1a reacts in a similar way with other arenes, for example, oꢀ
xylene and 1,2ꢀdimethoxybenzene (veratrol) to form trifluoromethylated indanes 2b, 2c in high yields
(Scheme 2). Similar adducts 2e-h were isolated in good to high yields by the reaction of enone 1d with
benzene, oꢀ and mꢀxylenes and veratrol (electron rich aromatics). Compound 2d was obtained from
reaction of 1c with benzene. It should be pointed out that in all cases we observed the highly
stereoselective formation of trifluoromethylated indanes. Accordingly to the reaction mechanism (vide
infra) the cyclization in the case of the reaction of enones with aromatics having different substituents
could result in formation of mixture of cyclization products, however as a rule the reaction proceeds
highly chemoselectively and the cyclization proceeds into the most nucleophilic aromatic ring. The
structures of some indanes were confirmed using Xꢀray data (Figure 4).
1
1

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R1
O
R2
1
2
3
Ar = Ph, R = R = Me, R = H, 2b, 77%
Ar
CF3
1
2
3
Ar = Ph, R = R = MeO, R = H, 2c, 75%
R3
1a, d
F3C
1
2
3
TfOH
Ar = 4-ClC H R = R = R = H, 2e, 80%
6
4,
+
1
2
3
R3
Ar = 4-ClC
6
H
4, R = R = Me, R = H, 2f, 57%
20 °C, 1h
R1
1
3
2
Ar = 4-ClC H R = R = Me, R = H, 2g, 54%
6
4,
1
2
3
Ar = 4-ClC H R = R = MeO, R = H, 2h, 73%
R2
6 4,
R2
Ar
R1
R3
F3C
O
Ph
TfOH
20 °C, 1h Me
+
CF3
1c
Me
Ar
2d, 35%
3
Scheme 2. Reaction of CF ꢀenones 1a,c,d with electron rich aromatics
We found that the reaction is extremely sensitive to steric demands. To our surprise the reaction
of enone 1d with mꢀxylene resulted not in the expected product of the attack to 4ꢀposition of mꢀxylene
but the formation of 2ꢀtrifluoromethylated indane 2g, bearing 3,5ꢀdimethylphenyl group at Cꢀ2 atom.
Accordingly Xꢀray data (Figure 4d) exactly this aromatic ring is attached to the indane core. We
3
believe that this regiochemistry can be explained by high steric bulkness of CF group which has quite
14
significant conformation energy 2.1 kcal/mol. As a result in the case of the reaction with mꢀxylene
thermodynamically controlled electrophilic substitution is observed.
For molecules of all studied compounds 2a,b,e,g,h (Figure 4) pentagonal ring of the indane
1
3
4
5
1
2
3
system is a regular envelope with atoms С , С , С , С as base and С , С , С as lid. Angle between
base and lid planes of envelope change from 35.66(9)° for 2g to 32.0(1)° for 2c. CF ꢀgroup deviates to
3
the envelope lid (the angle of deviation change weakly from 110.6 (1)° for 2h to 111.9(1)° for 2g). The
benzene ring plane of the indane system has no deviation from envelope base plate practically (limits
are from 0.3(1)° for 2b to 3.1(1)° for 2g). Planes of aryl substituents are bended to envelope base with
angle 72.33(6)° for 2g ÷ 77.1(1)° for 2a and 66.74(9)° for 2h ÷ 76.90(6)° for 2b of the indane
1
3
system atoms С and С , correspondingly. The analysis of molecule conformations of these five
2
studied compounds (Figure 4), having no substituents at atom C of indane system, and published
1
2

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1
3
earlier compounds 11g, 13 shows that variation of substituents at atoms C and C of indane system
13f,15
changes very slightly the configuration of indane core.
2
4
The formation of indanes 2 indicates that both electrophilic carbons C and C of cationic
intermediates A or B participated in the reaction. Interestingly, electronꢀrich substrates, such as oꢀ
3 3
xylene or thiophene, reacted with CF ꢀenones 1a,c in FSO H at ꢀ80…ꢀ60 °C, i.e. under the conditions
that favor the formation of Oꢀprotonated species A1, A3 (see Table S1). We also obtained very
interesting results under these conditions to give clues to the reaction mechanism. We were able to
stop reaction at the first step and isolate in very good yields the products of hydroarylation of enones 2,
which are most probably the intermediates of this reaction formed on the first step of the reaction
sequence. For example, the reaction of enone 1c with thiophene (ꢀ80 °C, FSO
corresponding 3,3ꢀdiarylbutanone 3a in 77 % yield (Scheme 3). The reaction of CF
benzene in FSO H at ꢀ60 °C gave CF ꢀenone 3b in 68 % yield (Scheme 3). In addition we confirmed
3
H) gave only the
3
ꢀenone 1e with
3
3
that these type of compounds can be transformed into indanes. For instance, the reaction of 3b with
benzene in TfOH at 20 °C gave the expected indane 2i in 76 % yield (Scheme 3).
S
O
O
FSO H
3
CF3
+
CF3
S
-80 °C, 2 h
1c
3
a, 77%
Me
Me
F3C
Ph
O
Ph
O
PhH, FSO H
PhH, TfOH
20 °C, 1 h
3
CF3
CF3
-60 °C, 2 h
1
e
Ph
MeO
3
b, 68%
OMe
OMe
2i, 76%
3
Scheme 3. Stepwise addition of arenes to CF ꢀenones 1
4
All these data clearly demonstrate that cations A are generally able to react at C with electron
rich arenes and heteroarenes. However, the highly electrophilic versions of these cations, like A5
(based on its ω values presented in Table S9) generated from 1e, can also react with less nucleophilic
1
3

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4
arenes like benzene, also at C (Scheme 3). Finally, we believe that the reactions of CF ꢀenones 1a-d,f
3
with benzene in TfOH at 20 °C are likely to proceed via the intermediate formation of dications B.
Discussion on reaction mechanism
Analyzing DFT calculations obtained for cations A, B (Tables S9), NMR (Table S1) and
experimental data (Table 1, Schemes 2,3), we conclude that species A and B initially can react with
4
2
nucleophiles at C and C respectively. Based on this conclusion, one can propose the following
3
reaction pathways for the transformation of CF ꢀenones 1 into indanes 2 (Scheme 4). The reaction of
4
arenes with cation A at carbon C can give compound 3, subsequent protonation leads to formation of
cation D. The latter one can react further in two ways: intermolecularly, with the arene, to give rise to
compound 4, or intramolecularly ꢀ to afford after cyclization indanol 5. Compounds 4 and 5 may also
2
be obtained via the reaction of dication B with an arene at C to result in the formation of cation E.
Subsequent transformations of 4 and 5 can proceed with an intermediate formation of cations F and G,
respectively, culminating the formation of indanes 2.
1
4

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O
OH
OH
OH
Ar'
Ar'H
Ar'H
CF3
Ar'
CF3
Ar'
4
-H+
-H+
Ar
4
2
CF
Ar
2
CF3
Ar
Ar
3
3
1
1
B
E
H+
-H O
4
H+
-H+
H+
2
OH
CF3
F
3
C
OH
F3C
CF3
Ar'
Ar'
H+
4
2
Ar
Ar
Ar
-
H O
2
A
R
R
F
Ar
Ar
5
G
OH
Ar'H
-
H+
4
2
CF3
A'
H+
F3C
Ar'
-
Ar'H
+
-H
R
2
Ar
Ar'
O
Ar' OH
Ar CF3
H+
Ar'H
-H+
Ar
CF3
D
3
q 0.21 e
CF3
1
H
3
1
20o
G1
H
Scheme 4. Possible mechanism of the transformation of CF ꢀenones 1 into indanes 2. DFT
3
calculations of parameters of cation G1.
In order to validate the abovementioned mechanistic interpretation, we synthesized compounds
3
c, 5a, 4a, 6a (see their synthesis and Xꢀray structure of 13 in SI) all of which can be implicated as
intermediates on route from 1 to 2, and exposed them in TfOH with excess of benzene (Scheme 5).
The reaction of diarylbutanone 3c with benzene under activation with triflic acid gave indane 2a
in high yield. Analogously compound 3b afforded 2l (Scheme 3). Indanol 5a can also be transformed
into 2a in the same conditions in 79 % yield. Interestingly, while alkenol 6a had not initially been
thought to be an intermediate in the proposed mechanistic rationale (Scheme 5), we also found it to
give rise to 2a under the reaction conditions. However, isolation of diarylbutanones 3 under lower
temperature indicates that this route to the final indanes is most probable, therefore participation of 6a
1
5

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can be discussed as a minor reaction route. In contrast, compound 4a was not transformed into indane
a (Scheme 5), making us question its involvement in the above transformations.
2
Ph
O
Ph
CF3
3
c
TfOH
PhH
86 %
HO
CF3
F3C
Ph
TfOH
PhH
TfOH
PhH
OH
CF3
Ph
79 %
Ph
88 %
6
a
Ph
5
a
2a Ph
Ph OH
TfOH
PhH
oligomers
CF3
Ph
Ph
4a
Scheme 5. Transformations of compounds 3c, 5a, 4a, 6a with benzene in TfOH (20 °C, 10 min.)
Thus, there are two most likely reaction pathways: 1) through cation A to structures 3, D, 5, G,
and 2; or 2) through cation B to structures E, 5, G, and 2. Cation G is one of the key intermediates of
this reaction for both pathways. The addition of an aromatic molecule to the latter leads to transꢀ
orientation of the bulky aromatic groups, probably due to steric reasons. DFT calculation of charge
distribution in cation G1 and its geometry was done (see SI). Large positive charge (0.21 e) is
1
localized on reactive center C of indane system (Scheme 4). Geometry of this species exhibits that
3
cone angle with the apex at atom C and orthoꢀprotons of phenyl ring is around 120° (Scheme 4),
revealing rather great steric restriction for attack of arene molecule from this side of indane plane.
Apart from that, DFT calculations have shown that difference between the Gibbs energies of cisꢀ and
transꢀisomers 2a is 1.1 kcal/mol in favor of the transꢀisomer (see SI).
Concerning mechanisms of superelectrophilic activation of conjugated enones, in 1990s Shudo
1
2a,b
and Ohwada
postulated formation of reactive O,Oꢀdiprotonated at carbonyl oxygen species, which
1
6

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may lie on reaction pathways. One may not exclude the participation of the dications in reactions, but
up to the moment these species have not been yet detected by NMR or other physical methods,
12f,qꢀt
contrary to reliably characterized O,Cꢀdiprotonated forms of enones.
Additionally we observed two unusual reaction for CF ꢀenones 1f and 1g. In both cases, the
3
formation of indane 2a was observed (Scheme 6). That means that an exchange of pꢀanisyl (for 1f) or
nꢀBuO (for 1g) substituents takes place under superacidic reaction conditions. In the case of
3
buthoxyenone the transformation to 1a takes place and some examples of similar transformations CF ꢀ
1h,16
enones are known in literature.
However, it is more difficult to explain the results of reaction with
1
f. It is clear that electrophilic substitution with removal of anisole (good electrofuge) takes place.
However, it is most probable that the enone 1a is not the major intermediate of the reaction because a
mixture of cisꢀ and transꢀ indanes 2a is formed. In addition, substitution of anisole may take place
from the initially formed indane structure.
F3C Ph
TfOH
PhH
TfOH
PhH
O
O
+
CF3
BuO
CF3
20 °C, 1h
20 °C, 1h
1
g
1a
Ph
2a (48%)
F3C Ph
F C
3
Ph
O
TfOH
+
+
CF3
20 °C, 1h
-
anisole
Ph
Ph
cis-2a (40%)
MeO
1f
2a (40%)
Scheme 6. Reactions of compounds 1f, 1g with benzene in TfOH
Summarizing the discussion of reaction mechanism, one may conclude that both Oꢀprotonated A
and O,Cꢀdiprotonated B species take part in the reactions of 1 with arenes in superacids. The
electrophilicity of these cations as well as its match to the electronꢀdonating properties of the arenes
defines the outcome of the reaction. Strongly electrophilic cations A react even with poorly
nucleophilic arenes, such as benzene. On the other hand, cations A, having moderate electrophilicity,
1
7

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react primarily with electronꢀrich arenes (xylenes, veratrol, etc.). Dications B are highly reactive
superelectrophiles, reacting with all aromatic substrates. In some cases this reaction may proceed
through mixed mechanisms with participation of both cations A and B.
Effects of 1,3ꢀdiarylꢀ1ꢀtrifluoromethyl indanes on the endocannabinoid system
The new transꢀ1,3ꢀdiarylꢀ1ꢀtrifluoromethyl indanes 2a-h,l, which we succeeded obtaining as
individual substances in this work, are distinctly lipophilic compounds (Table 2). With the aim of
investigating the biological effects of this newly conceived scaffold, we assessed the binding
properties of these compounds on cannabinoid receptors, which are the target of endogenous
molecules called endocannabinoids that are also distinctly lipophilic.
Table 2. cLogP values calculated (using ACD/Labs 6.00 software) for transꢀ1,3ꢀdiarylꢀ1ꢀ
trifluoromethyl indanes synthesized in this work.
Compound
cLogP value
Compound
cLogP value
6.62 ± 0.65
Compound
cLogP value
8.60 ± 0.66
Ph
F
3
C
Ph
Me
3
F C
6
.16 ± 0.64
Me
F
3
C
Me
Me
Ph
Ph
2d
2a
Me
2g
Cl
Me
Me
F3C
Ph
OMe
OMe
8
.00 ± 0.65
6.76 ± 0.65
8.60 ± 0.66
6.23 ± 0.70
6.08 ± 0.65
F
3
C
3
F C
MeO
MeO
Me
Me
Ph
2e
2
b
Cl
2h
Cl
OMe
OMe
Me
F3C
Ph
5
.64 ± 0.69
F
3
C
Me
3
F C
Me
Me
MeO
MeO
Ph
MeO
2l
Ph
2c
2f
Cl
1
8

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The highly lipophilic Nꢀarachidonoylethanolamine (AEA or anandamide) and 2ꢀ
arachidonoylglycerol (2ꢀAG) are the most abundant and wellꢀstudied endocannabinoids and exert their
17
1 2
biological activity primarily by binding to typeꢀ1 (CB ) and typeꢀ2 (CB ) cannabinoid receptors.
Most of the nonꢀendogenous ligands for CB
1
and CB
2
are also characterized by high lipophilicity, as
9
9
for example the phytocannabinoid ꢁ ꢀtetrahydrocannabinol (ꢁ ꢀTHC) and the synthetic nonꢀclassical
18
19
20
cannabinoids ꢀ SR141716A, JWH015 and LY320135 (Figure 5). It is the lipophilic nature of
transꢀ1,3ꢀdiarylꢀ1ꢀtrifluoromethyl indanes and the obvious similarity with the above synthetic
cannabinoids (in terms of the arrangement of the aromatic periphery – vide infra) further supported our
hypothesis of investigating the potential binding affinity of these molecules toward cannabinoid
receptors.
HO
O
O
HO
HO
N
O
H
OH
H
H
O
AEA
ꢁ9
-THC
O
2-AG
Cl
Cl
CN
N
N
N
OMe
H
Cl
O
MeO
N
N
O
O
SR141716A
JWH015
LY320135
9
Figure 5. Endogenous (AEA and 2ꢀAG) and natural (ꢁ ꢀTHC) and synthetic (SR141716A, JWH015 and
LY320135) cannabinoid receptor ligands
3
Eight compounds 2a, 2c, 2d-h,l were screened for their ability to displace [ H]CP55,940 (the
21
1 2 1
radiolabelled analogue of CP55,940, a potent, nonꢀselective classical CB and CB ligand ) from CB
1
9

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and CB receptors. To our delight, three compounds (2c, 2e and 2h) showed a significant (higher than
2
3
5
0%) displacement of [ H]CP55,940 at the screening concentration of 1 ꢀM. In addition, none of these
compounds showed significant cytotoxicity at the concentration of 10 ꢀM after 72 hours of incubation
with SHSY5Y human neuroblastoma cells (Figure 6). Compound 2b was insoluble under the assay
conditions and could not be tested.
1
1
20
00
1
1
20
00
CB1
CB2
8
6
4
2
0
0
0
0
0
8
6
4
2
0
0
0
0
0
2
a
2c
2d
2e
2f
2g
2h
2l
a
b
Figure 6 (a) Binding properties of compound 2a, 2c, 2d-h,l tested at the concentration of 1 ꢀM to CB
1 2
and CB
receptors (N = 3: n = 6, data shown are mean ± standard deviation); (b) cytotoxicity of the same compounds
22
tested at 10 ꢀM on SHSY5Y cells (SRB method, 72 hours of incubation N = 2ꢀ3: n = 4ꢀ6, data shown are
mean ± standard deviation).
The binding properties of compound
Compounds 2c, 2e and 2h were further investigated by generating full concentrationꢀdependent
3
curves (Figure 7). All three compounds showed total displacement of the radioligand [ H]CP55,940 to
both cannabinoid receptors with the most potent compound (2h) displaying a Ki value (calculated
2 1
applying the ChengꢀPrusoff equation) of 120 nM towards CB receptor and a 6ꢀfold selectivity vs. CB
receptor (Ki value of 750 nM) (Figure 7). The highest affinity shown by compound 2h could be
explained by an interaction with the receptor similar to other nonꢀclassical synthetic cannabinoids
(SR141716A (rimonabant), JWH015 and LY320135 shown in Figure 4), considering quite an effective
2
0

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spatial overlay of 2h with these three known CB /CB ligands, especially with LY320135, suggesting
1
2
23
potentially similar functional signaling by our transꢀdiaryl indanes (Figure 8).
1
1
20
00
120
100
80
60
40
20
0
120
100
80
60
40
20
0
8
6
4
2
0
0
0
0
0
CB1
CB1
CB1
CB2
CB2
CB2
-
10 -9 -8 -7 -6 -5 -4
-10 -9 -8 -7 -6 -5 -4
-1 2- 1 1- 10-9 -8 -7 -6 -5 -4
Log [2c] (M)
Log [2e] (M)
Log [2h] (M)
Ki value (mean and 95%, CI) µM
hCB
1
hCB
2
2
2
2
c
e
h
1.35 (0.91ꢀ2.05)
6.55 (4.92ꢀ8.71)
0.75 (0.48ꢀ1.15)
0.55 (0.42ꢀ0.73)
1.19 (0.75ꢀ1.68)
0.12 (0.07ꢀ0.20)
Figure 7. Concentrationꢀdependent binding curves and Ki values calculated for compounds 2c, 2e and
2
h (N = 3ꢀ6: n = 9ꢀ18, data shown are mean ± standard deviation for the binding curves and mean and
9
5% confidence interval for Ki values)
2
1

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Figure 8. Spatial overlay of the structure of compound 2h (shown in grey) with (a) SR141716A, (b)
JWH015 and (c) LY320135 – all shown in orange.
The trifluoromethyl indanes 2a, 2c and 2d-h,l were also tested for potential inhibition of the key
components of the endocannabinoid system such as the hydrolytic enzymes fatty acid amide hydrolase
(FAAH) for AEA and monoacylglycerol lipase (MAGL) and α/β hydrolase domain (ABHDs) for 2ꢀ
AG, the oxidative enzyme cyclooxygenaseꢀ2 for 2ꢀAG and arachidonic acid and the putative
24
endocannabinoid membrane transporter. Interestingly, the compounds showed negligible effects on
all these targets (see SI), clearly indicating that 2c, 2e and 2h selectively bind to cannabinoid receptors,
2
particularly CB receptors which are a highly promising pharmacological target for treating
25
26
inflammatory and neuropathic pain and neurodegenerative diseases.
Conclusions
Novel efficient stereoselective synthesis of transꢀ1,3ꢀdiarylꢀ1ꢀtrifluoromethyl indanes was
developed on the basis of superelectrophilic activation of 4ꢀarylꢀ1,1,1ꢀtrufluorobutꢀ3ꢀenꢀ2ꢀones and
subsequent reaction with arenes. The reaction intermediates, Oꢀprotonated and O,Cꢀdiprotonated forms
1
13
19
of 4ꢀarylꢀ1,1,1ꢀtrufluorobutꢀ3ꢀenꢀ2ꢀones have been studied by H, C, F NMR, and DFT
calculations. Both of these cations take part in the reaction, depending on electrophilicity of the cations
and electron donating properties of arenes.
2
2

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Among the novel transꢀ1,3ꢀdiarylꢀ1ꢀtrifluoromethyl indanes obtained in this work, three
moderately potent ligands of cannabinoid receptors have been identified. The most potent compound
2 1
(2h) displayed a 120 nM affinity toward CB receptor and a 6ꢀfold selectivity vs. CB receptor. In the
absence of cytotoxicity and any effect on the other key components of the endocannabinoid system,
the new transꢀ1,3ꢀdiarylꢀ1ꢀtrifluoromethyl indane scaffold clearly has a value for the design on
selective modulators of cannabinoid (in particular, CB ) receptors.
2
Experimental
The NMR spectra of solutions of compounds in CDCl were recorded on Bruker AVANCE III
3
1
19
13
4
00 (at 400, 376 and 100 MHz for H, F and C NMR spectra respectively) or Bruker DPX 300 (at
1
13
3
00 and 75 MHz for H and C NMR spectra respectively) spectrometers at 25 °C. The residual
1
protonꢀsolvent peak CDCl
3
(δ 7.26 ppm) for H NMR spectra and the carbon signal of CDCl
3
(δ 77.0
13
ppm) for C NMR spectra were used as references. NMR experiments in the superacids TfOH or
1
19
FSO H were performed on Bruker AVANCE III spectrometer (at 500, 476 and 125 MHz for H, F
3
1
3
and C NMR spectra respectively). NMR spectra in superacids were referenced to the signal of
1
13
2 2
CH Cl added as internal standard: δ 5.32 ppm for H NMR spectra, and δ 53.84 ppm for C NMR
spectra. HRMS was carried out at instruments Bruker maXis HRMSꢀESIꢀQTOF and Varian 902ꢀMS
MALDI Mass Spectrometer. Chromatoꢀmassꢀspectrometry data were obtained at Shimadzu QPꢀ2010
Ultra with a SPBꢀ1 SULFUR capillary column (30 m × 0.32 mm), thickness of the stationary phase
1
.25 ꢂm. The preparative reactions were monitored by thinꢀlayer chromatography carried out on silica
gel plates (Alugram SIL G/UVꢀ254), using UV light for detection. Preparative column
chromatography was performed on silica gel 60 Merck with hexanesꢀethyl acetate mixture eluation.
For single crystal Xꢀray diffraction experiments, crystals of all compounds were fixed on a micro
mount and placed on a Agilent Technologies Excalibur Eos diffractometer using monochromated
MoKα radiation (2a, 2b) and Agilent Technologies SuperNova using monochromated CuKα (2e, 2g,
2
h) (Oxford Diffraction) diffractometer and measured at a temperature of 100K. The structures have
2
3

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been solved by the direct methods SHELXS and refined for unique reflections with |F
o
F
| ≥ 4σ by
2
7
28
means of the SHELXL program incorporated in the OLEX2 program package. The carbonꢀbound H
atoms were placed in calculated positions and were included in the refinement in the ‘riding’ model
approximation, with Uiso(H) set to 1.5Ueq(C) and C–H 0.96 Å for the CH
.2Ueq(C) and C–H 0.97 Å for the CH groups, Uiso(H) set to 1.2Ueq(C) and C–H 0.93 Å for the CH
groups. CCDC 1047066 – (2a), CCDC 1047331 – (2b), CCDC 1047468 – (2e), CCDC 1047315 –
2g), CCDC 1047593 – (2h) contain the supplementary crystallographic data, which can be obtained
3
groups, Uiso(H) set to
1
2
(
free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html or from the Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; Fax: (internat.) + 44ꢀ1223ꢀ336ꢀ033; Eꢀmail:
deposit@ccdc.cam.ac.uk.
All computations has been carried out at the DFT/HF hybrid level of theory using Becke’s threeꢀ
parameter hybrid exchange functional in combination with the gradientꢀcorrected correlation
2
9
functional of Lee, Yang, and Parr (B3LYP) by using GAUSSIAN 2003 program packages The
geometries optimization were performed using the 6ꢀ311+G(2d,2p) basis set The Hessian matrix was
calculated analytically for the optimized structures in order to prove the location of correct minima (no
imaginary frequencies) and to estimate the thermodynamic parameters. Enthalpies and Gibbs free
energies were calculated for 25°С.
Starting 4-aryl-1,1,1-trufluorobut-3-en-2-ones 1a-i were prepared according to the literature
1b,fꢀh
procedures.
3 3
General procedure for reaction of compounds 1a-g with arenes in superacids CF SO H or
FSO H. Synthesis of compounds 2a-n, cis-2a, 3a,b.
3
CF
3
ꢀenone 1a-g (0.23 mmol) was added to mixture of TfOH (at 20 °C) (1ꢀ2 mL) or FSO
3
H (at ꢀ
8
0…ꢀ60 °C) (1 mL, coꢀsolvents SO
2
or CH Cl ) with benzene (0.3 ml) or another arene (1 mmol).
2
2
Reaction mixture was magnetically stirred for 1ꢀ2 h. Then in case of TfOH the mixture was poured
into ice water (30 mL) and extracted with chloroform (2×40 mL). The extracts were combined, washed
with water, a saturated aqueous solution of NaHCO , water again, and dried over Na SO . The solvent
3
2
4
2
4

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was distilled off under reduced pressure, and the residue was recrystallized from methanol or subjected
to chromatographic separation on silica gel using hexanesꢀethyl acetate mixtures (20:1 to 10:1) as an
eluent. For FSO
10 mL), diluted with water (20 ml), then extracted and worked up as described above. Yields of the
obtained compounds are given in Table 1 and Schemes 2, 3, 6.
3
H the reaction mixture was quenched with frozen at ꢀ80 °C concentrated aqueous HCl
(
(1RS,3RS)-1-Trifluoromethyl-1,3-diphenylindane (2a). Yield 65 mg, 84%. Colorless solid,
1
mp 106ꢀ108°С (МеОН). H NMR (CDCl
3
, 400 MHz) δ, ppm: 2.80 (dd, J = 11.2 Hz, 12.5 Hz, 1H),
3
.05 (dd, J = 6.8 Hz, 12.5 Hz, 1H), 4.09 (dd, J = 11.2 Hz, 6.8 Hz, 1H), 6.95 (d, J = 7.5 Hz, 1H), 7.21
(d, J = 6.8 Hz, 2H), 7.29 (d, J = 7.2 Hz, 1H), 7.25ꢀ7.38 (m, 8H), 7.40 (t, J = 7.5 Hz, 1H), 7.64 (d, 1H,
13
J = 7.9 Hz). C NMR (CDCl
3 2 3
, 100 MHz) δ, ppm: 46.9 (CH), 48.3 (CH ), 60.8 (q, CꢀCF , J = 26.4
Hz), 125.7, 125.9 (d, J = 1.3 Hz), 127.17, 127.20, 127.6 (q, CF , J = 281.5 Hz), 128.0, 128.5, 128.6
3
1
9
(
3
2CH), 128.8, 129.0, 137.5, 140.7 (d, J = 1.4 Hz), 142.8, 147.5. F NMR (CDCl , 376 MHz) δ, ppm: ꢀ
+
6
9.16 (s, CF
3
). MS (GCꢀMS, EI), m/z, (Irel., %) – 338 M (3), 260 (100), 191 (50). HRMS: C22
H F
17 3
found 338.1285 М+; calcd. 338.1282.
(1SR,3RS)-1-Trifluoromethyl-1,3-diphenylindane (cis-2a). Obtained as 1:1 mixture with
1
indane 2a. Yield 25 mg, 80%. H NMR (CDCl , 400 MHz) δ, ppm: 2.52 (dd, J = 8.4 Hz, 14.4 Hz, 1H),
3
3
.43 (dd, J = 8.4 Hz, 14.4 Hz, 1H), 4.63 (t, J = 8.4 Hz, 1H), 7.08 (d, J = 7.0 Hz, 1H), 7.15 (d, J = 7.1
1
3
Hz, 2H), 7.20ꢀ7.24 (m, 1H), 7.25ꢀ7.35 (m, 8H), 7.47 (d, J = 7.7 Hz, 2H). C NMR (CDCl
δ, ppm: 48.1 (CH ), 49.9 (CH), 61.7 (q, CꢀCF , J = 25.3 Hz), 127.6 (q, CF , J = 281 Hz), 141.2,
41.51, 141.52, 144.4, 148.4. F NMR (CDCl , 376 MHz) δ, ppm: ꢀ69.36 (s, CF ). MS (GCꢀMS, EI),
3
, 100 MHz)
2
3
3
19
1
3
3
+
m/z, (I , %) – 338 M (100), 269 (100), 260 (90), 191 (100). HRMS: C H F found 338.1285 М+;
rel.
22 17 3
calcd. 338.1282.
(1RS,3RS)-1-Trifluoromethyl-5,6-dimethyl-1-(3,4-dimethylphenyl)-3-phenylindane
(2b).
1
Yield 80 mg, 77%. Colorless solid, mp 106ꢀ108°С (МеОН). H NMR (CDCl
3
, 300 MHz) δ, ppm:
2
1
.25 (s, 3H, CH ), 2.28 (s, 6H, 2CH ), 2.38 (s, 3H, CH ), 2.74 (dd, 1H, J = 12.5 Hz, 11 Hz), 3.00 (dd,
3 3 3
H, J = 6.5 Hz, 12.5 Hz), 4.06 (dd, 1H, J = 6.5 Hz, 11 Hz), 6.72 (s, 1H), 7.01ꢀ7.12 (m, 2H), 7.17 (s,
2
5

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13
1
H), 7.22ꢀ7.25 (m, 2H), 7.29ꢀ7.36 (m, 4H). C NMR (CDCl , 75 MHz) δ, ppm: 19.3 (CH ), 19.9
3 3
(
CH
3
), 20.1 (CH
3
), 47.0 (CH
2
), 47.8 (CH), 60.1 (q, CꢀCF
, J = 275 Hz), 135.2, 135.3, 136.2, 136.4, 138.4,
, 470 MHz) δ, ppm: ꢀ69.19 (s, CF ). MS (GCꢀMS, EI), m/z, (Irel., %) –
found 394.1911 М+; calcd. 394.1908.
3
, J = 25 Hz), 125.8, 126.0, 126.3, 126.5,
1
1
3
26.8, 128.5, 128.6, 129.5, 129.55, 129.6 (q, CF
3
1
9
43.2, 144.8. F NMR (CDCl
3
3
+
94 (5) [М] , 325 (30), 289 (100), 219 (34). HRMS: C26
H
25
F
3
(1RS,3RS)-1-Trifluoromethyl-5,6-dimetoxy-1-(3,4-dimetoxyphenyl)-3-phenylindane
(2c).
1
Yield 77 mg, 75%. Colorless solid, mp 104ꢀ108°С (МеОН). H NMR (CDCl
3
, 500 MHz) δ, ppm: 2.68
(dd, 1H, J = 11 Hz, 12.5 Hz), 2.90 (dd, 1H, 12.5 Hz, 7 Hz), 3.72 (s, 3H, OCH
3
), 3.78 (s, 3H, OCH
3
),
3
.84 (s, 3H, OCH
H), 6.88 (s, 1H), 7.03 (s, 1H), 7.18 (d, 2H, J = 7 Hz), 7.22ꢀ7.25 (m, 1H), 7.31 (t, 2H, J = 7.4 Hz). C
3 3
), 3.91 (s, 3H, OCH ), 4.04 (dd, 1H, J = 7 Hz, 11 Hz), 6.40 (s, 1H), 6.70ꢀ6.78 (m,
1
3
2
NMR (CDCl , 125 MHz) δ, ppm: 47.8 (CH ), 48.2 (CH), 55.82 (OMe), 55.83 (OMe), 56.0 (OMe),
3
2
5
1
4
6.3 (OMe), 60.2 (q, CꢀCF
3
, J = 26 Hz), 107.9, 108.1, 110.6, 111.7, 121.0, 127.0, 128.4, 128.7, 128.8,
19
30.5, 132.4, 133.4 (q, CF
3
3
, J = 275 Hz ), 139.6, 143.1, 148.56, 148.62 (2C), 150.0. F NMR (CDCl ,
+
70 MHz) δ, ppm: ꢀ69.22 (s, CF
3
). MS (GCꢀMS, EI), m/z, (Irel., %) – 458 M (32), 389 (33), 320 (100).
25 3 4
HRMS: C26H F O
found 458.1708 М+; calcd. 458.1705.
(1RS,3RS)-1-Trifluoromethyl-6-methyl-1,3-diphenylindane (2d). Yield 31 mg, 35%.
1
Colorless solid, mp 102ꢀ105°С (МеОН). H NMR (CDCl
3
, 400 MHz) δ, ppm: 2.38 (s, 3H, CH
3
), 2.68
(dd, 1H, J = 12.5 Hz, 11 Hz), 2.93 (dd, 1H, J = 6.8 Hz, 12.5 Hz), 3.96 (dd, 1H, J = 6.8 Hz, 11 Hz),
1
3
6
.75 (d, 1H, J = 7.8 Hz), 7.07 (d, 1H, J = 7.8 Hz), 7.11ꢀ7.14 (m, 9H), 7.18 (s, 1H), 7.34 (s, 1H). C
NMR (CDCl , 100 MHz) δ, ppm: 21.7 (CH ), 47.2 (CH ), 47.9 (CH), 60.8 (q, CꢀCF , J = 29 Hz),
3
3
2
3
1
24.7, 125.4, 126.3 (q, CHCCCF
3
, J = 1.1 Hz), 127.1, 128.0, 128.5, 128.5 (q, CF
3
, J = 256 Hz), 128.6
19
(
2CH), 128.8, 129.8, 137.0, 137.7, 140.8, 143.1, 144.6. F NMR (CDCl
3
, 376 MHz) δ, ppm: ꢀ69,01 (s,
+
CF
3
). MS (GCꢀMS, EI), m/z, (Irel., %) – 352 M (15), 274 (100), 205 (40). HRMS: C23
H
19
F
3
found
3
52.1441 М+; calcd. 352.1439.
(1RS,3RS)-3-(4-Chlorophenyl)-1-trifluoromethyl-1-phenylindane (2e). Yield 53 mg, 80%.
1
Colorless solid, mp 109ꢀ112°С (МеОН). H NMR (CDCl
3
, 400 MHz) δ, ppm: 2.72 (dd, 1H, J = 12.5
2
6

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DOI: 10.1039/C5OB01072A
Hz, 11.2 Hz), 3.03 (dd, 1H, J = 12.5 Hz, 6.8 Hz), 4.06 (dd, 1H, J = 11.2 Hz, 6.8 Hz), 6.93 (d, 1H, J =
.6 Hz), 7.14 (d, 2H, J = 8.4 Hz), 7.36ꢀ7.28 (m, 8H), 7.40 (t, 1H, J = 7.5 Hz), 7.63 (d, 1H, J = 7.6 Hz).
7
1
3
C NMR (CDCl
3
, 100 MHz) δ, ppm: 46.9 (q, CH
2 3
, J = 1.3 Hz), 47.7 (CH), 60.8 (q, CꢀCF , J = 25
3
Hz), 125.5, 126.0 (J 1.2 Hz), 127.4, 127.6 (q, CF , J = 281 Hz), 128.1, 128.5, 128.6 (q, J = 0.8 Hz),
19
1
29.0, 129.9, 133.0, 137.3, 140.7 (q, J = 1.3 Hz), 141.9, 147.0. F NMR (CDCl
3
, 376 MHz) δ, ppm: ꢀ
+
6
9.19 (s, CF ). MS (GCꢀMS, EI), m/z, (I , %) – 372 M (15), 337 (15), 303 (10), 294 (100). HRMS:
3
rel.
C
22
H
16
F
3
Cl found 372.0893 М+; calcd. 372.0893.
(1RS,3RS)-3-(4-Chlorophenyl)-1-trifluoromethyl-5,6-dimethyl-1-(3,4-dimethylphenyl)
1
indane (2f). Yield 50 mg, 57%. Colorless solid, mp 113ꢀ115°С (МеОН). H NMR (CDCl , 300
3
MHz) δ, ppm: 2.23 (s, 3H, CH
3
), 2.25 (s, 6H, 2CH
3 3
), 2.36 (s, 3H, CH ), 2.65 (dd, 1H, J = 12.4 Hz,
1
1
0.6 Hz), 2,96 (dd, 1H, J = 10.6 Hz, 6.5 Hz), 4.02 (dd, 1H, J = 6.5 Hz, 10.6 Hz), 6.67 (s, 1H), 7.00 (d,
1
3
H, J = 8.0 Hz), 7.07 (d, 1H, J = 8.0 Hz), 7.14 (m, 3H), 7.30 (d, 2H, J = 8.4 Hz), 7.36 br (s, 1H). C
, 100 MHz) δ, ppm: 19.5 (CH ), 20.1 (2CH ), 20.3 (CH ), 47.2 (d, CH , J = 0.8 Hz), 47.4
CH), 60.3 (q, CꢀCF , J = 26.2 Hz), 126.1, 126.3 (d, J = 4.9 Hz), 126.8 (d, J = 0.7 Hz), 127.8 (q, CF
NMR (CDCl
3
3
3
3
2
(
3
3
,
1
9
J = 282 Hz), 128.9, 126.8, 129.6, 130.0, 132.7, 135.1, 135.8, 136.46, 136.63, 137.5, 141.9, 144.5. F
+
NMR (CDCl , 376 MHz) δ, ppm: ꢀ69.22 (s, CF ). MS (GCꢀMS, EI), m/z, (I , %) – 428 M (10), 359
3
3
rel.
24 3
(7), 322 (100), 253 (12). HRMS: C26H F Cl found 428.1514 М+; calcd. 428.1519.
(1RS,3RS)-3-(4-Chlorophenyl)-1-trifluoromethyl-4,6-dimethyl-1-(3,5-dimethylphenyl)
1
indane (2g). Yield 46 mg, 54%. Colorless solid, mp 103ꢀ105°С (МеОН). H NMR (CDCl
3
, 300 MHz)
δ, ppm: 1.71 (s, 3H, CH ), 2.27 (s, 6H, 2CH ), 2.41 (s, 3H, CH ), 2.60 (dd, 1H, J = 13.2 Hz, 9.8 Hz),
3
3
3
3
7
1
.01 (dd, 1H, J = 13.2 Hz, 7.6 Hz), 4.15 (t, 1H, J = 8.6 Hz), 6.85 (s, 2H), 6.96 (s, 1H), 6.97 (s, 1H),
1
3
.08 (d, 2H, J = 8.2 Hz), 7.22 (s, 1H), 7.27 (d, 1H, J = 8.2 Hz). C NMR (CDCl
9.9 (CH ), 21.5 (CH ), 21.7 (2CH ), 47.5 (CH), 48.0 (d, CH , J = 1 Hz), 60.7 (q, CꢀCF
, J = 282 Hz), 129.0, 129.4, 129.6,
3
, 100 MHz) δ, ppm:
3
3
3
2
3
, J = 26.2
Hz), 124.3 (d, J = 1.1 Hz), 126.0 (d, J = 0.9 Hz), 127.8 (q, CF
32.0, 132.3, 135.3, 137.5, 137.8, 138.8, 141.3, 141.58, 141.59, 143.5. F NMR (CDCl , 376 MHz) δ,
3
19
1
3
2
7

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DOI: 10.1039/C5OB01072A
+
ppm: ꢀ68.72 (s, CF ). MS (GCꢀMS, EI), m/z, (I , %) – 428 [M] (30), 359 (15), 322 (100), 253 (20).
3
rel.
24 3
HRMS: C26H F Cl found 428.1517 М+; calcd. 428.1519.
(1RS,3RS)-3-(4-Chlorophenyl)-1-trifluoromethyl-5,6-dimethoxy-1-(3,4-dimethoxyphenyl)
1
indane (2h). Yield 64 mg, 73%. Colorless solid, mp 111ꢀ114°С (МеОН). H NMR (CDCl , 400 MHz)
3
δ, ppm: 2.65 (dd, 1H, J = 12.6 Hz, 10.6 Hz), 2.91 (dd, 1H, J = 12.6 Hz, 6.9 Hz), 3.77 (s, 3H, OCH
3
),
3
.80 (s, 3H, OCH ), 3.86 (s, 3H, OCH ), 3.94 (s, 3H, OCH ), 4.05 (dd, 1H, J = 10.6 Hz, 6.8 Hz), 6.38
3
3
3
(
(
(
s, 1H, H), 6,73 (dd, 1H, J = 8.5 Hz, 1.8 Hz), 6.88 (d, 1H, J = 8.5 Hz), 6.89 (d, 1H, J = 1.8 Hz), 7.05
1
3
s, 1H), 7.14 (d, 2H, J = 8.4 Hz), 7.31 (d, 2H, J = 8.4 Hz). C NMR (CDCl
CH), 48.0 (CH ), 55.97 (OMe), 55.99 (OMe), 56.12 (OMe), 56.40 (OMe), 60.4 (q, CꢀCF
, J = 282 Hz), 129.4, 129.9, 130.5,
3
, 100 MHz) δ, ppm: 47.7
2
3
, J = 26.3
Hz), 107.8, 108.3 (d, J = 0.8 Hz), 110.7, 111.8, 121.1, 127.7 (q, CF
3
19
1
32.5, 132.9, 139.2, 141.8, 148.8 (q, J = 4.1 Hz), 150.3. F NMR (CDCl , 376 MHz) δ, ppm: ꢀ69.25
3
+
(
s, CF
3
). MS (GCꢀMS, EI), m/z, (Irel., %) – 492 [M] (50), 423 (40), 354 (100). HRMS: C26
H
24
F
3
O
4
Cl
found 492.1318 М+; calcd. 492.1315.
(1RS,3RS)-1-Trifluoromethyl-5-methoxy-1,3-diphenylindane (2i). Yield 11 mg, 76%.
1
Colorless solid, mp 102ꢀ104°С (МеОН). H NMR (CDCl
3
, 400 MHz) δ, ppm: 2.79 (t, 1H, J = 12.5
Hz), 3.01 (dd, 1H, J = 12.5 Hz, 11 Hz), 3.74 (3H, OMe), 4.03 (dd, 1H, J = 11 Hz, 12.5 Hz), 6.45 (d,
1
7
5
H, J = 2.4 Hz), 6.93 (dd, 1H, J = 8.4 Hz, 2.4 Hz), 7.19ꢀ7.23 (m, 2H), 7.28 (d, 1H, J = 7.1 Hz), 7.30ꢀ
13
.36 (m, 7H), 7.51 (d, 1H, J = 8.4 Hz). C NMR (CDCl
3 2
, 100 MHz) δ, ppm: 47.3 (CH ), 48.4 (CH),
5.6 (OMe), 60.2 (q, CꢀCF , J = 29.5 Hz), 110.6, 113.5, 126.6 (q, CHCCCF
3
3
, J = 1 Hz), 127.2, 127.7
(
q, CF , J = 282 Hz), 128.0, 128.4, 128.6 (d, J = 0.8 Hz), 128.7, 128.9, 132.8, 138.0, 142.7, 149.2,
3
19
+
1
60.6. F NMR (CDCl
3
, 376 MHz) δ, ppm: ꢀ69,46 (s, CF
3
). MS (GCꢀMS, EI), m/z, (Irel., %) – 368 M
(80), 299 (100), 290 (25), 221 (30). HRMS: C23
H
19
F
3
O found 368.1385 М+; calcd. 368.1388.
1,1,1-Trifluoro-4-(4-methylphenyl)-4-(thiophen-2-yl)butan-2-one (3a). Yield 44 mg, 77%.
1
Yellow oil. H NMR (CDCl
3
, 400 MHz) δ, ppm: 2.32 (s, 3H, OMe), 3.40ꢀ3.52 (m, 2H, ABꢀsystem,
CH ), 4.86 (t, 1H, CH, J = 7.3 Hz), 6.83 (d, 1H, J = 3.5 Hz), 6.91 (dd, 1H, J = 5 Hz, 3.5 Hz), 7.10ꢀ
2
13
7
3 3 2 3
.19 (m, 5H). C NMR (CDCl , 100 MHz) δ, ppm: 21.2 (CH ), 40.0 (CH), 44.0 (CH ), 115.5 (CF , J
2
8

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=
292 Hz), 124.40, 124.27, 126.9, 127.4, 129.7, 137.2, 139.3, 146.9, 189.0 (q, COCF , J = 35.7 Hz).
3
1
9
+
3
F NMR (CDCl , 376 MHz) δ, ppm: ꢀ79.39 (s, CF
3
). MS (GCꢀMS, EI), m/z, (Irel., %) – 298 M (20),
+
+
+
2
83 [MꢀCH
3
] (15), 229 [MꢀCF
3
] (7), 187 [MꢀCH
2
COCF
3
] (100). HRMS: C14
H
13
F
3
OS found
2
86.0640 М+; calcd. 286.0640.
,1,1-Trifluoro-4-(3-methoxyphenyl)-4-phenylbutan-2-one (3b). Yield 44 mg, 68%. Colorless
oil. H NMR (CDCl , 400 MHz) δ, ppm: 3,48 (d, 2H, CH , J = 7.5 Hz), 3.77 (s, 3H, OMe), 4.63 (t,
1
1
3
2
1
2
H, CH, J = 7.5 Hz), 6.73ꢀ6.77 (m, 2H), 6.82 (d, 1H, J = 7.8 Hz), 7.20ꢀ7.25 (m, 4H), 7.28ꢀ7.34 (m,
13
3 2 3
H). C NMR (CDCl , 100 MHz) δ, ppm: 42.6 (CH ), 44.7, 55.3, 109.8, 112.0, 115.6 (CF , J = 292
1
9
Hz), 117.5, 127.1, 127.6, 129.0, 130.0, 142.4, 144.2, 160.0, 189.4 (q, COCF
CDCl , 376 MHz) δ, ppm: ꢀ79.38 (s, CF
97 (95). HRMS: C H F O found 308.1021 М+; calcd. 308.1024.
3
, J = 35.5 Hz). F NMR
+
(
3
3
). MS (GCꢀMS, EI), m/z, (Irel., %) – 308 M (100), 239 (23),
1
17
15
3
2
Acknowledgements
This work was supported by Saint Petersburg State University (grants no. 12.50.1558.2013, and no.
[b]
[b]
1
2.38.195.2014) and Russian Scientific Fund (project grant 14ꢀ13ꢀ00083 for V.M. , and V.N. ).
Spectral studies were performed at the Center for Magnetic Resonance, the Center for Chemical
Analysis and Materials Research, and the Research Center for Xꢀray Diffraction Studies of Saint
Petersburg State University. Investigation of the biological activity of indanes 2aꢀh,l, was supported by
the Russian Scientific Fund (project grant 14ꢀ50ꢀ00069).
1
13
19
Supporting information: Figures of H, C, F NMR spectra, Xꢀray data of obtained compounds,
additional biological profile of compounds 2aꢀh,l, details of DFT calculations.
2
9