First practical synthesis of 2- or 3-fluoroalkylated indenols via cobalt-catalyzed [2 + 3] carbocyclization of fluorine-containing alkynes and 2-iodoaryl ketones

Article abstract of DOI:10.1016/j.tet.2019.05.042

[2 + 3] Cycloaddition reaction of fluorine-containing alkynes with various 2-iodoaryl ketones in the presence of CoCl₂(dppf) catalyst proceeded very smoothly to give the corresponding 2- or 3-fluoroalkylated indenols in 57–98% yields. These reg

Full text of DOI:10.1016/j.tet.2019.05.042

Accepted Manuscript
First practical synthesis of 2- or 3-fluoroalkylated indenols via cobalt-catalyzed [2+3]
carbocyclization of fluorine-containing alkynes and 2-iodoaryl ketones
Tatsuya Kumon, Kazuhiro Yoshida, Shigeyuki Yamada, Tomohiro Agou, Toshio
Kubota, Tsutomu Konno
PII:
S0040-4020(19)30594-0
https://doi.org/10.1016/j.tet.2019.05.042
TET 30363
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 11 April 2019
Revised Date: 17 May 2019
Accepted Date: 21 May 2019
Please cite this article as: Kumon T, Yoshida K, Yamada S, Agou T, Kubota T, Konno T, First
practical synthesis of 2- or 3-fluoroalkylated indenols via cobalt-catalyzed [2+3] carbocyclization of
fluorine-containing alkynes and 2-iodoaryl ketones, Tetrahedron (2019), doi: https://doi.org/10.1016/
j.tet.2019.05.042.
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First practical synthesis of 2- or 3-fluoroalkylated
indenols via cobalt-catalyzed [2+3] carbocyclization
of fluorine-containing alkynes and 2-iodoaryl ketones
Leave this area blank for abstract info.
Tatsuya Kumona, Kazuhiro Yoshidaa, Shigeyuki Yamadaa, Tomohiro Agoub, Toshio Kubotab, and Tsutomu Konnoa*
aFaculty of Molecular Chemistry and Engineering, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan
bDepartment of Quantum Beam Science, Graduate School of Engineering, Ibaraki University, 4-12-1 Nakanarusawa, Hitachi, Ibaraki 316-8551, Japan

1
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Tetrahedron
journal homepage: www.elsevier.com
First practical synthesis of 2- or 3-fluoroalkylated indenols via cobalt-catalyzed
[2+3] carbocyclization of fluorine-containing alkynes and 2-iodoaryl ketones
Tatsuya Kumona , Kazuhiro Yoshidaa, Shigeyuki Yamadaa, Tomohiro Agoub, Toshio Kubotab, and
Tsutomu Konnoa*
aFaculty of Molecular Chemistry and Engineering, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan
bDepartment of Quantum Beam Science, Graduate School of Engineering, Ibaraki University, 4-12-1 Nakanarusawa, Hitachi, Ibaraki 316-8551, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
[2+3] Cycloaddition reaction of fluorine-containing alkynes with various 2-iodoaryl ketones in
the presence of CoCl2(dppf) catalyst proceeded very smoothly to give the corresponding 2- or 3-
fluoroalkylated indenols in 57–98% yields. These regioisomers could be successfully separated
and obtained in a pure form. From X-ray crystallographic and NOESY analyses, major or minor
regioisomers were determined as 3- or 2-fluoroalkylated indenols, respectively.
Available online
©
2019 Elsevier Ltd. All rights reserved.
Keywords:
Fluoroalkylated indenols
Cobalt catalyst
[2+3] Carbocyclization
Fluorine-containing alkynes
2-Iodoaryl ketones
1. Introduction
However, these are multi-step reaction-involved scheme, and
the total yields are also extremely low. In addition, they are the
only reports on the synthesis of 3-fluoroalkyl indenols. To the
best of our knowledge, no publication has been made on indenols
having a fluoroalkyl group at the 2 position at all so far.6
The indenol skeleton 1 (Fig. 1) is frequently found not only in
the structure of naturally occurring substances but also in the
framework of various biologically active materials, such as
analgesics, insecticides or muscle relaxants.1,2 Therefore,
enormous attention has been paid to fluorine-containing indenol
derivatives these days, since biological activities are often
dramatically improved by introducing a small number of fluorine
atoms into organic substances.
However, there have been quite limited
studies
on
the
synthesis
of
fluoroalkylated indenols, despite such
great pharmaceutical as well as
agrochemical advantages imparted by
fluorine atom(s).3
Tidwell et al. have reported that the indenol derivative 3
having a trifluoromethyl (CF3) group at the same carbon with a
tosyloxy group, which could be prepared in 7 steps from the
corresponding indanone 2, underwent acid solvolysis to yield 3-
CF3 indenol derivatives 4 (Scheme 1. Eq. 1).4 According to
Yamazaki et al., on the other hand, the phthalide 6, readily
prepared from the reaction of diethyl phthalate 5 with the
Ruppert-Prakash reagent (TMSCF3) in the presence of a catalytic
amount of cesium fluoride, reacts smoothly with
phenylthiomethyllithium at −80 °C to give the corresponding
CF3-indanone 7. Then, a dehydration reaction of 7 and the
subsequent carbonyl-reduction provide the 3-CF3 indenol 8 (Eq.
2).5
Scheme 1. Precedent works for the preparation of CF -containing indenols.
3

2
Tetrahedron
Herein we report a facile and practical synthetic protocol for
coordinated by 1,2-bis(diphenylphosphino)ethane (dppe), 1,4-
ACCEPTED MANUSCRIPT
2- and 3-fluoroalkylated indenols via cobalt-catalyzed [2+3]
carbocyclization reaction which was developed by Cheng et al.
as a pioneering work,7 using fluorine-containing internal alkynes
with various 2-iodoaryl ketones in detail.
bis(diphenylphosphino)butane
(dppb),
or
(S)-2,2’-
bis(diphenylphosphino)-1,1’-binaphthyl ((S)-BINAP) resulted in
a significant improvement of the yield of the desired indenol
derivatives
(Entries
2-4).
When
1,1’-
bis(diphenylphosphino)ferrocene (dppf) was used as a ligand, in
particular, desired cycloadducts 11aA/12aA were obtained in
95% combined yields, together with very small amount of
trimerization adduct 13a (Entry 5). The use of 1,10-
phenanthroline (phen) as a ligand was also found to be efficient,
though the yield of fluorine-containing indenol derivatives was
slightly decreased (Entry 6). Even when the ligand was switched
from a bidentate to a monodentate ligand, like PPh3, the yield or
isomeric ratio of the reaction products did not change drastically
(Entry 7).
2. Results and discussion
An initial screening of the reaction conditions for the cobalt-
catalyzed [2+3] carbocyclization reaction was performed using
trifluoromethylated internal alkyne 9a8 and 2-iodoacetophenone
10A. The results are summarized in Table 1.
Table 1. Screening for the reaction conditions of [2+3] carbocyclization.
It should be noted that cobalt catalyst substituted by other
halogens (X = Br, I) also did not affect the yields and
regioselectivity (Entries 8 and 9). Lower temperature deterred the
reaction proceeding (Entry 10). Yields were somewhat eroded
with decreasing the amount of zinc powder (1.0 equiv, Entry 11)
or catalyst loading (3 mol%, Entry 12). Additionally, 11aA and
12aA were not obtained at all in the absence of cobalt catalyst,
and the starting alkyne was completely recovered (Entry 13).
Finally, the desired cyclization products were obtained in an
excellent yield even when only 1.1 equiv of 2-iodoacetophenone
was used (Entry 14). However, the use of 1.1 equiv of 2-
bromoacetophenone caused a significant decrease in the yield,
leading to trimerization product 13a in 31% yield (Entry 15). In
all cases, almost the same regioselectivity was detected.
Yielda /%
Entry
Ligand
11aA+12aA [11aA/12aA]b
13a
53
1
2
None
dppe
15 [72/28]
With the optimal reaction conditions (Table 1, Entry 14), we
carried out cobalt-catalyzed [2+3] carbocyclization reaction using
73 [66/34]
14
3
4
dppb
(S)-BINAP
dppf
83 [73/27]
84 [73/27]
95 [72/28]
81 [80/20]
81 [80/20]
89 [71/29]
99 [71/29]
84 [72/28]
75 [70/30]
54 [73/27]
0
13
13
various fluoroalkylated internal alkynes
9
and 2-
iodoacetophenone 10A. The results are summarized in Table 2.
As shown in Entries 1–3, the position of the substituent on the
benzene ring in the fluorinated alkynes, like para-, meta-, or
ortho-position, did not affect the reaction at all, giving the
corresponding products 11A/12A in excellent yields. Substrates
having various substituents on the benzene ring of the
fluoroalkylated alkynes, such as electron-donating (MeO) or
electron-withdrawing (CO2Et) group, were found to be applicable
in the present [2+3] cyclization to afford the fluoroalkylated
indenol derivatives (Entries 4 and 5), though a slight decrease in
the yield was observed in the case of the fluorinated alkynes
having a 4-biphenyl or a dimethylphenylsilyl group as an R1
(Entries 6 and 7). It should be noted that fluoroalkylated aliphatic
alkyne 9h could also be applied, giving the corresponding
products 11hA/12aH in moderate yield with the reverse of
regioselectivity (22:77) (Entry 8). Besides, fluoroalkylated
propargyl alcohols with a bulky substituent as an R1 were found
to be unsuitable for the cobalt-catalyzed [2+3] carbocyclization
reaction (Entries 9 and 10). Difluoromethylated alkyne could be
successfully applied to the present reaction (Entry 11), while n-
perfluorobutyl (n-C4F9)-containing alkyne was not suitable for
the reaction, resulting in complex mixtures (Entry 12).
Subsequently, we examined the cobalt-catalyzed [2+3]
carbocyclization reaction using alkyne 9a (R1 = 4-ClC6H4) and
alkyl or variously substituted aryl 2-iodoaryl ketones. The 2-
iodoaryl ketone 10B bearing a cyclohexyl group as an R2 also
provided the corresponding cycloadducts 11aB and 12aB in high
yield (Entry 13), whereas the reaction using 2-iodobenzophenone
10C (R2 = Ph) became somewhat sluggish, resulting in 57%
combined yields of 11aC and 12aC, along with a formation of
the trimerization product 13a in 26% yield (Entry 14). As shown
in Entries 15ꢀ17, electron-rich acetophenones 10D–F possessing
an electron-donating group on the aromatic ring gave the
corresponding fluoroalkylated indenols in acceptable yields,
5
trace
9
6
phen
PPh3
dppf
7
9
8c
trace
trace
8
9d
dppf
10e
11f
12g
13h
14i
15j
dppf
dppf
trace
6
dppf
−
0
dppf
98 [70/30]
32 [67/33]
trace
31
dppf
a Determined by 19F NMR.
b Values in brackets are isomeric ratios of 11aA and 12aA.
c With CoBr2(dppf).
d With CoI2(dppf).
e Carried out at 50 °C.
f With 1.0 equiv of Zn.
g With 3 mol% of CoCl2(dppf).
h Without any cobalt catalyst.
i With 1.1 equiv of 2-iodoacetophenone.
j With 1.1 equiv of 2-bromoacetophenone.
To a solution of 5 mol% of CoCl2 and 2.75 equiv of zinc
powder in acetonitrile was added 1.0 equiv of 9a and 1.5 equiv of
2-iodoacetophenone 10A, and the mixture was heated at 80 °C
for 3 h. As a result, [2+3] carbocyclization took place to give the
desired cyclized products 11aA and 12aA in only 15% yield as a
regioisomeric mixture (72:28), together with an undesired
formation of alkyne trimerization product 13a in 53% yield
(Entry 1). As shown in Entries 2–6, we carried out the reaction
using cobalt catalysts containing various bidentate phosphine
ligands. Carbocyclizations in the presence of cobalt catalysts

3
while a significant retard of the reaction was observed in the case
of electron-deficient substrates, e.g., 10G and 10H, with an
electron-withdrawing group on the aromatic ring, leading to the
corresponding 11a and 12a only in around 28% combined yields
(Entries 18 and 19). It was noteworthy that regioisomers 11 and
12 were easily separated from each other in many cases by
simple silica gel column chromatography, which becomes a
strong point for the practical applications.
carbocyclization reaction of 9a (Rf = CF3, R1 = 4-ClC6H4) and
ACCEPTED MANUSCRIPT
10F (R2 = Me, R3 = 4,5-OCH2O) was carried out (For the detail,
see Supporting Information), and as shown in Fig. 3, two strong
correlations between Hc and He, and Hd and He were detected,
whereas no cross-peak was observed between He and Hg, strongly
indicating that the major compound 11aF possessed a CF3 group
at the 3-position. The stereochemical assignments of other
products were performed on the basis of the chemical shifts in 19
F
Stereochemical assignment of the indenols 11 and 12 was
carried out by double elucidation using X-ray crystallographic
analysis and NMR technique. Thus, the major regioisomer 11aA
obtained through the reaction of 9a (Rf = CF3, R1 = 4-ClC6H4)
with 10A (R2 = Me, R3 = H) formed single crystal suitable for X-
ray crystallographic analysis by recrystallization from
hexane/CH2Cl2. As shown in Fig. 2, the major regioisomer 11aA
was found to possess a CF3 group at the 3-position. Additionally,
NOESY analysis of the major regioisomer 11aF obtained via the
NMR. Thus, comparing the chemical shifts in 19F NMR for
11aA/12aA or 11aF/12aF, the signals of the major isomers,
11aA, 11aF appear at higher magnetic field than those of the
minor regioisomers, 12aA, 12aF, respectively.9 The difference of
the chemical shifts was found to be qualitatively analogous to the
situation in other regioisomers 11/12. Therefore, the major
isomers 11 or the minor ones 12 were safely assigned as 3- or 2-
fluoroalkylated products, respectively.
Table 2. Cobalt-catalyzed [2+3] carbocyclization reaction of various fluorinated alkynes with various 2-iodoaryl ketones.
Combined yielda/% of 11+12
[Isolated yield of 11, 12]
Entry
Rf
R1
R2
R3
Product
Ratioa of 11/12
Yielda/% of 13
1
2
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
4-ClC6H4
3-ClC6H4
2-ClC6H4
4-MeOC6H4
4-EtO2CC6H4
4-PhC6H4
PhMe2Si
Me
Me
Me
Me
Me
Me
Me
Me
H
H
H
H
H
H
H
H
11aA/12aA
11bA/12bA
11cA/12cA
11dA/12dA
11eA/12eA
11fA/12fA
11gA/12gA
11hA/12hA
98 [52, 25]
93 [57, 25]
90 [77]b,c
91 [73]c
70/30
68/32
78/22
75/25
72/28
71/29
64/36
22/77
trace
trace
0
3
4
8
5
82 [73]c
8
6
66 [40, 14]
61 [49]c
20
5
7d
8
n-C6H13
48e
39
9
CF3
CF3
Me
Me
H
H
11iA/12iA
11jA/12jA
23
14
82/18
71/29
0
0
10
11
12
13
14
15
16
17
18
19
CHF2
n-C4F9
CF3
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
Me
Me
Cy
Ph
H
H
11kA/12kA
11lA/12lA
78 [61, 10]
16
88/12
75/25
71/29
73/27
70/30
63/37
59/41
64/36
67/33
0
0
H
11aB/12aB
11aC/12aC
11aD/12aD
11aE/12aE
11aF/12aF
11aG/12aG
11aH/12aH
84 [57, 23]
57 [37, 12]
88 [41, 24]
62 [23, 16]
63 [31, 20]
27
0
CF3
H
26
10
20
33
59
64
CF3
Me
Me
Me
Me
Me
4-Me
4-MeO
4,5-OCH2O
4-Cl
CF3
CF3
CF3
CF3
4-CF3
28
a Determined by 19F NMR.
b Atropisomers of 11cA and 12cA were detected.
c Combined isolated yield.
d Performed using 2.0 equiv of 10A and 10 mol% of cobalt catalyst.
e Unable to be purified because of undesired byproducts.
The above results allow us to propose the following reaction
mechanism which is similar to the previously reported one,10 as
shown in Scheme 2. Thus, the reaction presumably proceeds as
follows: (1) reduction of cobalt(II) catalyst by zinc metal
generates the cobalt(I) species, (2) oxidative addition of Co(I) to
C–I bond of 2-iodoaryl ketone gives the corresponding arylcobalt
complex Int-1, (3) insertion of alkyne 9 into the Co-CAr bond
(Int-2),11 (4) intramolecular nucleophilic addition of carbon
attached with Co metal to the carbonyl moiety to afford the
corresponding cobalt alkoxide Int-3, (5) reduction of cobalt(III)
complex by zinc metal brings about a cobalt(I) alkoxide Int-4,
(6) transmetalation with ZnX2 (X = Cl or I) forms zinc alkoxide
Int-5, together with regeneration of Co(I) species, and (7)

4
Tetrahedron
hydrolysis of Int-5 gives rise to the desired fluoroalkylated
residual proton signal of the NMR solvent. 19F NMR (376 MHz)
ACCEPTED MANUSCRIPT
indenol derivatives 11 or 12.
spectra were obtained using AVANCE III 400 NMR
The formation of tris(trifluoromethyl)benzene derivative 13 as
a side product can be explained by cobalt-catalyzed [2+2+2]
cyclotrimerization of fluorinated alkynes of 9, as described in the
previous literature.12 Thus, the generated Co(I) interacts with two
molecules of fluorinated alkyne 9 to form cobaltacyclopentadiene
complex Int-1’. Subsequent [4+2] cycloaddition of Int-1’ with
another molecule of the alkyne furnishes cobaltanorbornadiene
Int-2’, followed by the reductive elimination, affording the
corresponding trimerization product 13.
spectrometer in CDCl3 with CFCl3 (δ = 0 ppm) as an internal
F
standard (Bruker, Germany). The Bruker AVANCE III 400 NMR
spectrometer was used for determining the yield of the products
with trifluoromethylbenzene (CF3C6H5) or hexafluorobenzene
(C6F6) as internal references. IR spectra were recorded using the
KBr method with FT/IR-4100 typeA spectrometer (JASCO,
Japan); all spectra are reported in wavenumbers (cm-1). High-
resolution mass spectra were recorded on a JMS-700MS
spectrometer (JEOL, Japan) using the fast- atom bombardment
(FAB) method.
CF3
Cl
Me
HO
11aA
Fig. 2. X-ray crystallographic analysis of 11aA
.
Fig. 3. NOE correlations of 11aF observed by NOESY measurement.
3. Conclusion
In conclusion, we accomplished the convenient synthesis of 2-
and 3-fluoroalkylated indenols via cobalt-catalyzed [2+3]
carbocyclization reaction of fluorine-containing alkynes with 2-
iodoaryl ketones. Although the reaction did not proceed
regioselectively, 2- and 3-fluoroalkylated indenol derivatives
could be successfully separated in many cases by a simple silica
gel column chromatography. The present cobalt-catalyzed
carbocyclization was also applicable for various fluorinated
alkynes and 2-iodoaryl ketones, giving rise to various fluorine-
containing indenols in good to high yields. This process would
become useful synthetic protocol for fluorine-containing
carbocycles of biological interest.
Scheme 2. Proposed reaction mechanism.
All reactions were carried out using dried glassware with a
magnetic stirrer bar and routinely monitored by 19F NMR
spectroscopy or thin-layer chromatography (TLC). All chemicals
were of reagent grade and, if necessary, purified in the usual
manner prior to use. Cobalt catalysts used in this research were
prepared according to the literature.13 Column chromatography
was carried out on silica gel (Wako gel® 60N, 38−100 ꢀm) and
4. Experimental section
4.1. General information
1H and 13C NMR spectra were obtained using an AVANCE III
400 NMR spectrometer (1H: 400 MHz and 13C: 100 MHz) in
chloroform-d (CDCl3) (Bruker, Germany), and the chemical
shifts are reported in parts per million (ppm) based on the

5
TLC analysis was performed on silica gel TLC plates (Merck,
Silica gel 60F254).
X-ray Crystallography: A colorless prismic crystal of 11aA
having approximate dimensions of 0.13×0.12×0.10 mm was
mounted on a glass fiber. All measurements for 11aA were made
on a diffractometer with filtered MoKα radiation (λ= 0.71073 Å)
24.4 (CH3), 82.3 (C-OH), 122.2 (Ar), 122.7 (Ar), 123.5 (q, J =
ACCEPTED MANUSCRIPT
272.3 Hz, CF3), 128.90 (Ar), 129.2 (Ar), 129.4 (Ar), 129.8 (d, J =
1.3 Hz, Ar), 130.6 (Ar), 135.07 (Ar), 135.09 (q, J = 32.9 Hz,
CF3-C), 139.7 (Ar), 146.7 (q, J = 4.9 Hz, CF3-C=C), 149.0 (Ar);
19F NMR (CDCl3, CFCl3): δ −55.94 (s, 3F); IR (neat) 3371, 3073,
2982, 2934, 1632, 1491, 1353, 1253, 1195, 1147, 1022, 817, 762,
727 cm-1; HRMS (FAB): calcd for [M+] C17H12ClF3O: 324.0529,
Found: 324.0529.
and
a rotating anode generator using a VariMax with
PILATUS/DW (Rigaku); Compound 11aA. tetragonal, a =
23.8638(15) Å, b = 23.8638(15) Å, c = 10.6175(12) Å, α = 90°, β
= 90°, γ = 90°, V = 6046.5(10) Å3, T = 173(2) K, space group I
41/a (no. 88), Z = 16 reflection measured, 3726 unique which
were used in all calculations. The final R1 and wR2 were 0.1645
and 0.1909 (I > 2σ(I)). All calculations were performed using the
CrystalStructure crystallographic software package. The structure
was solved by direct methods and expanded using Fourier
techniques. The structural model was refined by a full-matrix
least-squares method using SHELXL-2014/6.14 All calculations
were performed using the SHELXL program. Crystallographic
data for this compound has been deposited with the Cambridge
Crystallographic Data Centre as supplementary data no. CCDC
1817768. Copy of the data can be obtained free of charge by
applying to The Cambridge Crystallographic Data Centre, 12
4.2.3. 2-(3-Chlorophenyl)-1-methyl-3-trifluoromethyl-1H-inden-
1-ol (11bA).
Yield: 57%; white solid, M.p. 89.8−90.1 °C, eluent of the
column chromatography: Hexane/EtOAc
=
5/1; 1H NMR
(CDCl3): δ 1.46 (s, 3H, CH3), 2.00 (s, 1H, OH), 7.26 (dt, J = 7.3,
2.1 Hz, 1H, ArH), 7.32−7.43 (m, 5H, ArH), 7.44−7.55 (m, 2H,
ArH); 13C NMR (CDCl3): δ 23.6 (CH3), 83.5 (C-OH), 121.8 (d, J
= 1.3 Hz, Ar), 122.55 (q, J = 272.6 Hz, CF3), 122.64 (Ar), 127.0
(d, J = 1.4 Hz, Ar), 128.0 (Ar), 128.2 (q, J = 32.8 Hz, CF3-C),
128.6 (d, J = 1.2 Hz, Ar), 129.0 (Ar), 129.4 (Ar), 129.6 (Ar),
134.3 (Ar), 134.4 (Ar), 136.1 (Ar), 147.8 (Ar), 154.0 (q, J = 4.1
Hz, CF3-C=C); 19F NMR (CDCl3, CFCl3): δ −60.23 (s, 3F); IR
(KBr) 3360, 3073, 2968, 1564, 1471, 1373, 1334, 1198, 1171,
1156, 1088, 760, 735, 716 cm-1; HRMS (FAB): calcd for [M+]
C17H12ClF3O: 324.0529, Found: 324.0520.
Union
Road,
Cambridge
CB2
1EZ,
UK
(https://summary.ccdc.cam.ac.uk/structure-summary-form).
4.2.4. 3-(3-Chlorophenyl)-1-methyl-2-trifluoromethyl-1H-inden-
1-ol (12bA).
4.2. Typical procedure for the [2+3] carbocyclization of
fluoroalkylated alkynes and 2-iodophenyl ketones
Yield: 25%; white solid, M.p. 70.8−71.2 °C, eluent of the
column chromatography: Hexane/EtOAc
In a 30 mL two-necked round bottomed-flask, equipped with a
magnetic stirring bar, were placed fluoroalkylated alkyne 9a
(0.123 g, 0.60 mmol), 2-iodoacetophenone 10A (0.089 mL, 0.66
mmol), zinc powder (0.108 g, 1.65 mmol), and CoCl2(dppf) (21
mg, 31 ꢀmol) in acetonitrile (3.0 mL), and the resulting mixture
was stirred at 80 °C with an oil bath. After 3 h, the reaction
mixture was cooled to r.t., diluted with CH2Cl2 and then stirred in
the air for 15 min. Subsequently, the reaction mixture was
subjected to flash column chromatography using silica gel as
stationary phase and CH2Cl2 as mobile phase. After removal of
the solvent from the eluent under reduced pressure, the residue
was purified by silica gel column chromatography
=
5/1; 1H NMR
(CDCl3): δ 1.82 (s, 3H, CH3), 2.24 (s, 1H, OH), 7.05 (d, J = 7.5
Hz, 1H), 7.24−7.30 (m, 1H, ArH), 7.31 (td, J = 7.5, 1.0 Hz, 1H,
ArH), 7.36−7.47 (m, 4H, ArH), 7.54 (d, J = 7.4 Hz, 1H, ArH);
13C NMR (CDCl3): δ 24.4 (CH3), 82.3 (C-OH), 122.2 (Ar), 122.8
(Ar), 123.5 (q, J = 272.2 Hz, CF3), 126.7 (d, J = 1.4 Hz, Ar) ,
128.4 (d, J = 1.7 Hz, Ar), 129.15 (Ar), 129.23 (Ar), 129.4 (Ar),
129.9 (Ar), 134.0 (Ar), 134.6 (Ar), 135.3 (q, J = 29.9 Hz, CF3-C),
139.6 (Ar), 146.3 (q, J = 5.0 Hz, CF3-C=C), 148.9 (Ar); 19F NMR
(CDCl3, CFCl3): δ −56.03 (s, 3F); IR (neat) 3377, 3072, 2983,
2935, 1636, 1588, 1566, 1475, 1461, 1419, 1352, 1250, 1198,
1119, 1055, 1021, 790, 502 cm-1; HRMS (FAB): calcd for [M+]
C17H12ClF3O: 324.0529, Found: 324.0524.
(Hexane/AcOEt
= 5:1) to give the corresponding 2-(4-
chlorophenyl)-1-methyl-3-trifluoromethyl-1H-inden-1-ol 11aA
(0.102 g, 0.314 mmol) and 3-(4-chlorophenyl)-1-methyl-2-
trifluoromethyl-1H-inden-1-ol 12aA (0.049 g, 0.15 mmol).
4.2.5. 2-(2-Chlorophenyl)-1-methyl-3-trifluoromethyl-1H-inden-
1-ol (11cA) and 3-(2-chlorophenyl)-1-methyl-2-trifluoromethyl-
1H-inden-1-ol (12cA).
4.2.1. 2-(4-Chlorophenyl)-1-methyl-3-trifluoromethyl-1H-inden-
1-ol (11aA).
Combined yield: 77%; Isometric ratio (11cA:12cA) = 78:22
Yield: 52%; white solid, M.p. 105.1−105.3 °C, eluent of the
column chromatography: Hexane/EtOAc
(inseparable), yellow oil, eluent of the column chromatography:
=
5/1; 1H NMR
Hexane/EtOAc/Benzene = 5/1/2;–
11cA: (atropisomer 1): 1H
(CDCl3): δ 1.41 (s, 3H, CH3), 2.21 (s, 1H, OH), 7.29−7.43 (m,
6H, ArH), 7.45−7.50 (m, 2H, ArH); 13C NMR (CDCl3): δ 23.6
(CH3), 83.4 (C-OH), 121.3 (Ar), 122.56 (Ar), 122.63 (q, J =
272.5 Hz, CF3), 127.88 (Ar), 127.93 (q, J = 32.6 Hz, CF3-C),
128.6 (Ar), 129.4 (Ar), 130.0 (Ar), 131.0 (Ar), 135.0 (Ar), 136.2
(Ar), 147.8 (Ar), 154.0 (q, J = 4.1 Hz, CF3-C=C); 19F NMR
(CDCl3, CFCl3): δ −60.16 (s, 3F); IR (KBr) 3347, 3070, 2973,
2926, 1493, 1474, 1375, 1335, 1200, 1128, 1092, 773, 762, 725,
697 cm-1; HRMS (FAB): calcd for [M+] C17H12ClF3O: 324.0529,
Found: 324.0533.
NMR (CDCl3): δ 1.52 (s, 3H, CH3), 1.96−2.40 (m, 1H, OH),
7.20−7.60 (m, 8H, ArH); 19F NMR (CDCl3): δ −63.48 (s, 3F);
(atropisomer 2): 1H NMR (CDCl3): δ 1.56 (s, 3H, CH3),
2.17−2.23 (m, 1H, OH), 7.20−7.60 (m, 8H, ArH); 19F NMR
(CDCl3): δ −62.51 (s, 3F); 12cA: (atropisomer 1): 1H NMR
(CDCl3): δ 1.86 (s, 3H, CH3), 2.17−2.23 (m, 1H, OH), 7.10−7.60
(m, 8H, ArH); 19F NMR (CDCl3): δ −57.95 (s, 3F); (atropisomer
1
2): H NMR (CDCl3): δ 1.83 (s, 3H, CH3), 2.44−2.47 (m, 1H,
OH), 7.10−7.60 (m, 8H, ArH); 19F NMR (CDCl3): δ −57.83 (s,
3F); IR (neat) 3402, 3390, 3056, 2981, 1378, 1200, 1173, 1147,
1131, 1118, 1093, 1064, 1052, 752, 752 cm-1; HRMS (FAB):
calcd for [M+] C17H12ClF3O: 324.0529, Found: 324.0519.
4.2.2. 3-(4-Chlorophenyl)-1-methyl-2-trifluoromethyl-1H-inden-
1-ol (12aA).
4.2.6. 2-(4-Methoxyphenyl)-1-methyl-3-trifluoromethyl-1H-
inden-1-ol (11dA) and 3-(4-methoxyphenyl)-1-methyl-2-
trifluoromethyl-1H-inden-1-ol (12dA).
Yield: 25%; yellow oil, eluent of the column chromatography:
Hexane/EtOAc = 5/1; H NMR (CDCl3): δ 1.82 (s, 3H, CH3),
2.16 (s, 1H, OH), 7.04 (d, J = 7.5 Hz, 1H, ArH), 7.29−7.34 (m,
3H, ArH), 7.40 (tm, J = 7.5 Hz, 1H, ArH), 7.46 (d, J = 8.6 Hz,
2H, ArH), 7.54 (d, J = 7.5 Hz, 1H, ArH); 13C NMR (CDCl3): δ
1

6
Tetrahedron
Combined yield: 73%; Isometric ratio (11dA:12dA) = 75:25
759, 733, 705 cm-1; HRMS (FAB): calcd for [M+] C23H17F3O:
ACCEPTED MANUSCRIPT
(inseparable), yellow oil, eluent of the column chromatography:
Hexane/EtOAc = 5/1; 11dA: H NMR (CDCl3): δ 1.45 (s, 3H,
366.1232, Found: 366.1238.
1
4.2.9. 3-(4-Biphenyl)-1-methyl-2-trifluoromethyl-1H-inden-1-ol
HO-C-CH3), 2.00 (s, 1H, OH), 3.85 (s, 3H, OCH3), 6.96 (d, J =
8.8 Hz, 2H, ArH), 7.26−7.41 (m, 4H, ArH), 7.45 (d, J = 7.2 Hz,
1H, ArH), 7.50 (d, J = 7.3 Hz, 1H, ArH); 13C NMR (CDCl3): δ
23.7 (HO-C-CH3), 55.2 (OCH3), 83.3 (C-OH), 113.7 (Ar), 121.4
(d, J = 1.17, Ar), 122.5 (Ar), 123.8 (q, J = 272.0 Hz, CF3), 124.8
(Ar), 126.6 (q, J = 32.3 Hz, CF3-C), 127.4 (Ar), 129.1 (Ar), 136.5
(Ar), 140.1 (Ar), 147.9 (Ar), 155.2 (d, J = 3.5 Hz, CF3-C=C),
159.9 (Ar); 19F NMR (CDCl3, CFCl3): δ -60.07 (s, 3F); 12dA: 1H
NMR (CDCl3): δ 1.82 (s, 3H, HO-C-CH3), 2.18 (s, 1H, OH), 3.87
(s, 3H, OCH3), 7.00 (d, J = 8.8 Hz, 2H, ArH), 7.12 (d, J = 7.4 Hz,
1H, ArH), 7.26−7.40 (m, 4H, ArH), 7.53 (d, J = 7.3 Hz, 1H,
ArH); 13C NMR (CDCl3): δ 24.1 (HO-C-CH3), 55.2 (OCH3), 82.1
(C-OH), 113.9 (Ar), 122.0 (Ar), 122.8 (Ar), 123.3 (q, J = 272.6
Hz, CF3), 124.3 (d, J = 2.7 Hz, Ar), 128.9 (Ar), 129.0 (Ar), 129.8
(d, J = 1.0 Hz, Ar), 133.9 (q, J = 29.2 Hz, CF3-C), 140.1 (Ar),
147.4 (d, J = 4.8 Hz, CF3-C=C), 149.2 (Ar), 159.9 (Ar); 19F NMR
(CDCl3, CFCl3): δ −55.76 (s, 3F); IR (neat) 3377, 3074, 2976,
2934, 2840, 1606, 1511, 1461, 1377, 1356, 1335, 1290, 1252,
1199, 1174, 1146, 1121, 1035, 762, 733, cm-1; HRMS (FAB):
calcd for [M+] C18H15F3O2: 320.1024, Found: 320.1033.
(12fA).
Yield: 14%; yellow solid, M.p. 142.7−143.0 °C, eluent of the
column chromatography: Hexane/EtOAc = 17/3; 1H NMR
(CDCl3): δ 1.86 (s, 3H, CH3), 2.21 (s, 1H, OH), 7.15 (d, J = 7.4
Hz, 1H, ArH), 7.32 (td, J = 7.5, 1.1 Hz, 1H, ArH), 7.34−7.44 (m,
2H, ArH), 7.45−7.52 (m, 4H, ArH), 7.56 (d, J = 7.3 Hz, 1H,
ArH), 7.64−7.69 (m, 2H, ArH), 7.71 (d, J = 8.5 Hz, 2H, ArH);
13C NMR (CDCl3): δ 24.5 (CH3), 82.3 (C-OH), 122.2 (Ar), 122.4
(q, J = 272.16 Hz, CF3), 123.0 (Ar), 127.2 (Ar), 127.3 (Ar), 127.8
(Ar), 128.9 (d, J = 1.7 Hz, Ar), 129.0 (Ar), 129.1 (Ar) 129.2 (Ar),
131.1 (Ar), 134.6 (q, J = 29.6 Hz, CF3-C), 140.1 (Ar), 140.6 (Ar),
141.8 (Ar), 147.6 (q, J = 4.8 Hz, CF3-C=C), 149.1 (Ar); 19F NMR
(CDCl3, CFCl3): δ −55.79 (s, 3F); IR (KBr) 3549, 3933, 2990,
2942, 1489, 1357, 1319, 1253, 1209, 1195, 1149, 1109, 1027,
1014, 765, 732 cm -1; HRMS (FAB): calcd for [M+] C23H17F3O:
366.1232, Found: 366.1231.
4.2.10. 2-(Dimethylphenylsilyl)-1-methyl-3-trifluoromethyl-1H-
inden-1-ol (11gA) and 3-(dimethylphenylsilyl)-1-methyl-2-
trifluoromethyl-1H-inden-1-ol (12gA).
4.2.7. Ethyl 4-(1-hydroxy-1-methyl-3-trifluoromethyl-1H-inden-
2-yl)benzoate (11eA) and ethyl 4-(1-hydroxy-1-methyl-2-
trifluoromethyl-1H-inden-3-yl)benzoate (12eA).
Combined yield: 49%; Isometric ratio (11gA:12gA) = 64:36
(inseparable), yellow oil, eluent of the column chromatography:
1
Hexane/EtOAc = 9/1; 11gA: H NMR (CDCl3): δ 0.66 (s, Si-
Combined yield: 73%; Isometric ratio (11eA:12eA) = 72:28
(inseparable), yellow solid, eluent of the column
chromatography: Hexane/EtOAc/benzene = 5/1/2; 11eA: 1H
NMR (CDCl3): δ 1.38−1.43 (m, 3H, CH2CH3), 1.45 (s, 3H, C-
CH3), 2.23 (s, 1H, OH), 4.35−4.42 (m, 2H, CH2CH3), 7.27−7.55
(m, 6H, ArH), 8.08 (d, J = 6.7 Hz, 2H, ArH); 13C NMR (CDCl3):
δ 14.3 (CH2CH3), 23.6 (C-CH3), 61.4 (CH2CH3), 83.5 (C-OH),
121.7 (Ar), 122.576 (Ar), 122.582 (q, J = 272.6 Hz, CF3), 127.9
(Ar), 128.0 (q, J = 30.7 Hz, CF3-C), 128.7 (d, J = 1.1 Hz, Ar),
129.3 (Ar), 129.7 (Ar), 130.5 (Ar), 136.0 (Ar), 137.6 (Ar), 148.1
(Ar), 154.4 (q, J = 4.0 Hz, CF3-C=C), 166.4 (C=O); 19F NMR
CH3, 6H), 1.63 (s, 3H, C-CH3), 1.93 (s, 1H, OH), 7.28−7.48 (m,
7H, ArH), 7.57−7.65 (m, 2H, ArH); 19F NMR (CDCl3, CFCl3): δ
1
−60.01 (s, 3F); 12gA: H NMR (CDCl3): δ 0.66 (s, 6H, Si-CH3),
1.75 (s, 3H, C-CH3), 2.14 (s, 1H, OH), 7.01 (d, J = 7.68 Hz, 1H,
ArH), 7.09 (td, J = 7.57, 1.03 Hz, 1H, ArH), 7.25 (t, 7.08 Hz, 1H,
ArH) 7.28−7.48 (m, 4H, ArH), 7.53−7.65 (m, 2H, ArH); 19F
NMR (CDCl3, CFCl3): δ −54.43 (s, 3F); (11gA+12gA): 13C NMR
(CDCl3): δ −0.87 (q, J = 8.8 Hz, Si-CH3), −0.53 (q, J = 9.0 Hz,
Si-CH3), −0.40 (m, 2C, Si-CH3,), 24.8 (C-CH3), 25.3 (C-CH3),
83.6 (C-OH), 87.5 (C-OH), 121.2 (d, J = 1.9 Hz, Ar), 121.89
(Ar), 121.94 (Ar), 123.1 (q, J = 272.8 Hz, CF3), 124.0 (q, J =
273.0 Hz, CF3), 125, 5 (Ar), 128.0 (Ar), 128.1 (Ar), 128.3 (Ar),
128.6 (Ar), 129.0 (Ar), 129.5 (Ar), 129.7 (Ar), 134.0 (Ar), 134.1
(Ar), 136.6 (Ar), 137.5 (Ar), 138.0 (Ar), 140.6 (q, J = 29.8 Hz,
CF3-C, Ar), 142.0 (Ar), 146.9 (q, J = 14.3 Hz, CF3-C=C), 149.3
(Ar), 149.8 (q, J = 30.2 Hz, CF3-C), 151.9 (Ar), 157.1 (q, J = 3.5
Hz, CF3-C=C), the signal of one carbon was overlapped with
other signals. ; IR (neat) 3348, 3071, 2980, 1428, 1363, 1336,
1311, 1254, 1196, 1168, 1156, 1119, 826, 785, 759 cm-1; HRMS
(FAB): calcd for [M+Na]+ C19H19F3NaOSi: 371.1055, Found:
371.1057.
1
(CDCl3, CFCl3): δ −60.23 (s, 3F); 12eA: H NMR (CDCl3): δ
1.38−1.43 (m, 3H, CH2CH3), 1.83 (s, 3H, C-CH3), 2.33 (s, 1H,
OH), 4.35−4.42 (m, 2H, CH2CH3), 6.99 (d, J = 7.5 Hz, 1H, ArH),
7.25−7.60 (m, 5H, ArH), 8.13 (d, J = 6.7 Hz, 2H, ArH); 13C
NMR (CDCl3): δ 14.3 (CH2CH3), 24.3 (C-CH3), 61.3 (CH2CH3),
82.3 (C-OH), 122.2 (Ar), 122.6 (Ar), 123.4 (q, J = 272.4 Hz,
CF3), 128.4 (d, J = 1.2, Ar), 129.1 (Ar). 129.2 (Ar), 129.3 (Ar),
130.8 (Ar), 135.4 (q, J = 29.8 Hz, CF3-C), 136.9 (Ar), 139.5 (Ar),
146.7 (q, J = 4.7 Hz, CF3-C=C), 149.1 (Ar), 166.5 (C=O); 19
F
NMR (CDCl3, CFCl3): δ −56.03 (s, 3F); IR (KBr) 3461, 3074,
2980, 2931, 1698, 1606, 1310, 1297, 1201, 1173, 1115, 1058,
1023, 762, 717 cm-1; HRMS (FAB): calcd for [M+] C20H17F3O3:
362.1130, Found: 362.1118.
4.2.11. 2-Hexyl-3-trifluoromethyl-1H-inden-1-ol (11hA) and 3-
Hexyl-2-trifluoromethyl-1H-inden-1-ol (12hA).
Combined yield: 48%; Isometric ratio (11hA:12hA) = 77:23
4.2.8. 2-(4-Biphenyl)-1-methyl-3-trifluoromethyl-1H-inden-1-ol
(11fA).
(inseparable), yellow oil, eluent of the column chromatography:
1
Hexane/EtOAc = 9/1; 11hA: H NMR (CDCl3): δ 0.82-0.98 (m,
Yield: 40%; yellow solid, M.p. 117.5−118.2 °C, eluent of the
column chromatography: Hexane/EtOAc = 17/3; 1H NMR
(CDCl3): δ 1.51 (s, 3H, CH3), 2.06 (s, 1H, OH), 7.31−7.43 (m,
3H, CH2-CH3, 6H), 1.21-1.77 (m, 9H, CH2-C4H8-CH3, OH) 1.54
(s, 3H, C(OH)-CH3), 2.39−2.61 (m, 2H, C=C-CH2), 7.21−7.56
(m, 4H, ArH), 7.71−7.84 (m, 1H, ArH); 19F NMR (CDCl3,
3H, ArH), 7.44−7.56 (m, 6H, ArH), 7.62−7.72 (4H, Ar-H); 13
C
1
CFCl3): δ −61.55 (s, 3F); 12hA: H NMR (CDCl3): δ 0.82−0.98
NMR (CDCl3): δ 23.8 (CH3), 83.6 (C-OH), 121.7 (d, J = 1.3 Hz,
Ar), 122.6 (Ar), 122.8 (q, J = 272.7 Hz, CF3), 127.0 (Ar), 127.2
(Ar), 127.68 (q, J = 32.0 Hz, CF3-C), 127.71 (Ar), 129.0 (Ar),
129.1 (d, J = 1.2 Hz, Ar), 129.3 (Ar), 131.6 (Ar), 136.5 (Ar),
140.6 (Ar), 141.6 (Ar), 147.9 (Ar), 155.1 (q, J = 4.0 Hz, CF3-
C=C), the signal of one carbon was overlapped with other
signals.; 19F NMR (CDCl3, CFCl3): δ −60.09 (s, 3F); IR (KBr)
3278, 3032, 2981, 2928, 1376, 1200, 1158, 1113, 1061, 908, 828,
(m, 3H, CH2-CH3, 6H), 1.21−1.77 (m, 8H, CH2-C4H8-CH3) 1.73
(s, 3H, C(OH)-CH3), 2.01 (s, 1H, OH), 2.61−2.70 (m, 2H, C=C-
CH2), 7.21−7.56 (m, 3H, ArH), 7.71−7.84 (m, 1H, ArH); 19F
NMR (CDCl3, CFCl3): δ −57.03 (s, 3F); HRMS (FAB): calcd for
[M+] C17H21F3O: 298.1544, Found: 298.1545.
4.2.12. 2-(4-Chlorophenyl)-3-difluoromethyl-1-methyl-1H-inden-
1-ol (11kA).

7
Yield: 61%; yellow solid, M.p. 52.0−53.0 °C, eluent of the
(Ar), 146.7 (Ar), 148.2 (q, J = 4.9 Hz, CF3-C=C); 19F NMR
ACCEPTED MANUSCRIPT
column chromatography: Hexane/EtOAc
=
7/3; 1H NMR
(CDCl3, CFCl3): δ −55.97 (s, 3F); IR (neat) 3459, 3071, 2932,
2855, 1633, 1491, 1454, 1399, 1349, 1251, 1200, 1150, 1104,
1091, 826, 789, 764 cm-1; HRMS (FAB): calcd for [M+]
C22H20ClF3O: 392.1155, Found: 392.1154.
(CDCl3): δ 1.47 (s, 3H, CH3), 1.95 (s, 1H, OH), 6.46 (t, J = 54.1
Hz, 1H, CF2H), 7.32 (td, J = 7.4, 1.4 Hz, 1H ArH), 7.36 (td, J =
7.4, 1.4 Hz, 1H, ArH), 7.44 (d, J = 8.6 Hz, 2H, ArH), 7.49 (d, J =
8.6 Hz, 2H, ArH), 7.50 (d, J = 7.4 Hz, 1H ArH), 7.60 (d, J = 7.4
Hz, 1H, ArH); 13C NMR (CDCl3): δ 23.6 (CH3), 83.4 (C-OH),
112.6 (q, J = 233.2 Hz, CF2H), 122.3 (Ar), 122.4 (d, J = 2.17 Hz,
Ar), 127.6 (Ar), 129.1 (Ar), 129.2 (Ar), 130.3 (Ar), 130.9 (Ar),
131.6 (dd, J = 25.0, 23.0 Hz, CF2H-C), 135.3 (Ar), 136.7 (Ar),
148.4 (Ar), 153.2 (t, J = 10.2 Hz, CF2H-C=C); 19F NMR (CDCl3,
CFCl3): δ −116.99 (dd, J = 321.2, 54.1 Hz, 2F), −114.45 (dd, J =
321.2, 54.1 Hz, 2F); IR (KBr) 3351, 3068, 2974, 2926, 1490,
1379, 1119, 1092, 1073, 1027, 823, 759, 731 cm-1; HRMS
(FAB): calcd for [M+] C17H13ClF2O: 306.0623, Found: 306.0625.
4.2.16. 2-(4-Chlorophenyl)-1-phenyl-3-trifluoromethyl-1H-inden-
1-ol (11aC).
Yield: 37%; yellow oil, eluent of the column chromatography:
Hexane/EtOAc = 9/1; 1H NMR (CDCl3): δ 2.38 (s, 1H, OH), 6.93
(d, J = 8.9 Hz, 2H, ArH), 7.18−7.32 (m, 9H, ArH), 7.39 (td, J =
7.5, 1.4 Hz, 1H, ArH), 7.52−7.54 (m, 1H, ArH); 13C NMR
(CDCl3): δ 87.6 (C-OH), 121.9 (d, J = 1.4 Hz, Ar), 122.6 (q, J =
272.8 Hz, CF3), 124.0 (Ar), 125.5 (Ar), 128.1 (Ar), 128.3 (Ar),
128.4 (Ar), 128.6 (Ar), 129.0 (q, J = 32.7 Hz, CF3-C), 129.6 (Ar),
130.1 (d, J = 1.3 Hz, Ar), 130.6 (Ar), 135.0 (Ar), 137.3 (Ar),
138.5 (Ar), 149.2 (Ar), 155.1 (q, J = 3.9 Hz, CF3-C=C); 19F NMR
(CDCl3, CFCl3): δ −60.13 (s, 3F); IR (neat) 3541, 3454, 3067,
3030, 1597, 1491, 1375, 1329, 1202, 1170, 1124, 1095, 729, 699
cm-1; HRMS (FAB): calcd for [M+] C22H14ClF3O: 386.0685,
Found: 386.0676.
4.2.13. 3-(4-Chlorophenyl)-2-drifluoromethyl-1-methyl-1H-
inden-1-ol (12kA).
Yield: 10%; yellow oil, eluent of the column chromatography:
1
Hexane/EtOAc = 7/3; H NMR (CDCl3): δ 1.84 (s, 3H, CH3),
2.30 (s, 1H, OH), 6.47 (t, J = 54.0 Hz, 1H, CF2H), 7.14 (d, J =
7.4 Hz, 1H, ArH), 7.31 (td, J = 7.4, 1.1 Hz, 1H, ArH), 7.34−7.41
(m, 3H, ArH), 7.49 (d, J = 8.5 Hz, 2H ArH), 7.54 (d, J = 7.4 Hz,
1H, ArH); 13C NMR (CDCl3): δ 24.8 (CH3), 82.3 (C-OH), 113.7
(dd, J = 234.1, 231. 1 Hz, CF2H), 122.1 (Ar), 122.3 (Ar), 127.6
(t, J = 77.2 Hz, CF2H-C), 128.8 (t, J = 34.4 Hz, Ar), 128.9 (d, J =
2.5 Hz, Ar), 129.2 (Ar), 130.2 (Ar), 135.3 (Ar), 138.0 (dd, J =
21.7, 20.0 Hz, Ar), 139.7 (Ar), 145.6 (t, J = 10.3 Hz, Ar), 149.5
(Ar); 19F NMR (CDCl3, CFCl3): δ −115.94 (dd, J = 316.6, 54.0
Hz, 1F), −109. 55 (dd, J = 316.6, 54.0 Hz, 1F); IR (neat) 3584,
3385, 3070, 2978, 2930, 2866, 1491, 1403, 1377, 1347, 1178,
1129, 1088, 1017, 806, 761, 733, 427 cm-1; HRMS (FAB): calcd
for [M+] C17H13ClF2O: 306.0623, Found: 306.0614.
4.2.17. 3-(4-Chlorophenyl)-1-phenyl-2-trifluoromethyl-1H-inden-
1-ol (12aC).
Yield: 12%; yellow oil, eluent of the column chromatography:
Hexane/EtOAc = 9/1; H NMR (CDCl3): δ 2.68 (s, 1H, OH),
1
7.08−7.14 (m, 1H, ArH), 7.21−7.39 (m, 6H, ArH), 7.41−7.47 (m,
2H, ArH), 7.47−7.55 (m, 4H, ArH); 13C NMR (CDCl3): δ 86.0
(C-OH), 122.9 (Ar), 123.1 (q, J = 272.4 Hz, CF3), 123.6 (Ar),
124.5 (Ar), 128.0 (Ar), 128.8 (Ar), 129.1 (Ar), 129.2 (Ar), 129.9
(Ar), 130.3 (Ar), 135.4 (Ar), 136.1 (q, J = 29.6 Hz, CF3-C), 139.3
(Ar), 140.1 (Ar), 148.6 (q, J = 4.6 Hz, CF3-C=C), 150.2 (Ar), the
signal of one carbon was overlapped with other signals. ; 19F
NMR (CDCl3, CFCl3): δ −55.11 (s, 3F); IR (neat) 3550, 3457,
3069, 3030, 3452, 1722, 1631, 1589, 1491, 1458, 1350, 1281,
1250, 1190, 1149, 1121, 1090, 1043, 1016, 857, 835, 800, 761
cm-1; HRMS (FAB): calcd for [M+] C22H14ClF3O: 386.0685,
Found: 386.0687.
4.2.14. 2-(4-Chlorophenyl)-1-cyclohexyl-3-trifluoromethyl-1H-
inden-1-ol (11aB).
Yield: 57%; yellow oil, eluent of the column chromatography:
1
4.2.18. 2-(4-Chlorophenyl)-1,5-dimethyl-3-trifluoromethyl-1H-
Hexane/EtOAc = 9/1; H NMR (CDCl3): δ 0.30−0.43 (m, 1H,
inden-1-ol (11aD).
Cy), 0.85−1.18 (m, 3H, Cy), 1.25−1.66 (m, 5H, Cy), 1.70−1.80
(m, 1H, Cy), 1.97 (s, 1H, OH), 2.01−2.11 (m, 1H, Cy), 7.30 (td, J
= 7.4, 1.2 Hz, 1H, ArH), 7.34−7.47 (m, 6H, ArH), 7.50 (d, J =
7.2 Hz, 1H, ArH); 13C NMR (CDCl3): δ 26.1 (Cy), 26.2 (Cy),
26.4 (Cy), 26.5 (Cy), 26.7 (Cy), 44.2 (Cy), 88.7 (C-OH), 121.6
(d, J = 1.7 Hz, Ar), 122.6 (q, J = 272.8 Hz, CF3), 123.8 (Ar),
127.2 (Ar), 128.6 (Ar), 129.2 (Ar), 129.4 (q, J = 32.1 Hz, CF3-C),
130.0 (d, J = 1.1 Hz, Ar), 131.6 (Ar), 134.9 (Ar), 137.6 (Ar),
145.9 (Ar), 153.4 (q, J = 4.0 Hz, CF3-C=C); 19F NMR (CDCl3,
CFCl3): δ −60.29 (s, 3F); IR (neat) 3443, 3073, 2932, 2855, 1490,
1471, 1378, 1203, 1169, 1126, 1094, 1021, 945, 813, 762, 732
cm-1; HRMS (FAB): calcd for [M+] C22H20ClF3O: 392.1155,
Found: 392.1144.
Yield: 41%; white solid, M.p. 129.6−130.4 °C, eluent of the
column chromatography: Hexane/EtOAc
=
9/1; 1H NMR
(CDCl3): δ 1.42 (s, 3H, HO-C-CH3), 1.91 (s, 1H, OH), 2.42 (s,
3H, Ar-CH3), 7.15 (d, J = 7.5 Hz, 1H, ArH), 7.27 (s, 1H, ArH),
7.34 (d, J = 8.6 Hz, 2H, ArH), 7.38 (d, J = 7.5 Hz, 1H, ArH),
7.40 (d, J = 8.6 Hz, 2H, ArH); 13C NMR (CDCl3): δ 21.7 (HO-C-
CH3), 23.7 (Ar-CH3), 83.2 (C-OH), 122.3 (Ar), 122.5 (d, J = 1.2
Hz, Ar), 122.7 (q, J = 272.7 Hz, CF3), 127.9 (q, J = 32.6 Hz, CF3-
C), 128.4 (Ar), 128.6 (Ar), 130.1 (d, J = 1.2 Hz, Ar), 131.2 (Ar),
134.9 (Ar), 136.4 (Ar), 139.5 (Ar), 145.0 (Ar), 154.2 (q, J = 3.9
Hz, CF3-C=C); 19F NMR (CDCl3, CFCl3): δ −60.11 (s, 3F); IR
(KBr) 3333, 3034, 2976, 2927, 1483, 1369, 1224, 1176, 1129,
1063, 940, 823, 728 cm-1; HRMS (FAB): calcd for [M+]
C18H14ClF3O: 338.0685, Found: 338.0690.
4.2.15. 3-(4-Chlorophenyl)-1-cyclohexyl-2-trifluoromethyl-1H-
inden-1-ol (12aB).
4.2.19. 3-(4-Chlorophenyl)-1,5-dimethyl-2-trifluoromethyl-1H-
inden-1-ol (12aD).
Yield: 23%; yellow oil, eluent of the column chromatography:
Hexane/EtOAc = 9/1; H NMR (CDCl3): δ 0.43−0.58 (m, 1H,
1
Cy), 0.83−1.45 (m, 4H, Cy), 1.56−1.72 (m, 3H, Cy), 1.80−1.90
(m, 1H, Cy), 2.15−2.34 (m, 2H, Cy), 2.19 (s, 1H, OH), 6.99 (d, J
= 7.3 Hz, 1H, ArH), 7.25−7.37 (m, 4H, ArH), 7.45 (d, J = 8.5 Hz,
2H, ArH), 7.52 (d, J = 7.1 Hz, 1H, ArH); 13C NMR (CDCl3): δ
26.4 (Cy), 26.5 (Cy), 26.8 (Cy), 27.1 (Cy), 27.4 (Cy), 45.0 (Cy),
88.3 (C-OH), 122.5 (Ar), 123.6 (q, J = 272.5 Hz, CF3), 124.1
(Ar), 128.6 (Ar), 128.88 (Ar), 128.94 (Ar), 129.8 (d, J = 1.3 Hz,
Ar), 130.9 (Ar), 134.6 (q, J = 29.4 Hz, CF3-C), 135.0 (Ar), 141.2
Yield: 24%; yellow oil, eluent of the column chromatography:
Hexane/EtOAc = 9/1; H NMR (CDCl3): δ 1.80 (s, 3H, HO-C-
1
CH3), 2.15 (s, 1H, OH), 2.32 (s, 3H, ArCH3), 6.83 (s, 1H, ArH),
7.20 (d, J = 7.5 Hz, 1H, ArH), 7.32 (d, J = 8.5 Hz, 2H, ArH),
7.42 (d, J = 7.5 Hz, 1H, ArH), 7.47 (d, J = 8.5 Hz, 2H, ArH); 13C
NMR (CDCl3): δ 21.6 (HO-C-CH3), 24.4 (Ar-CH3), 82.0 (HO-
C), 122.0 (Ar), 123.4 (Ar), 123.6 (q, J = 272.3 Hz, CF3), 128.9

8
Tetrahedron
ACCEPTED MANUSCRIPT
(Ar), 129.8 (d, J = 1.5 Hz, Ar), 130.0 (Ar), 130.7 (Ar), 135.0
Hz, 2H, ArH); 13C NMR (CDCl3): δ 24.6 (CH3), 81.7 (C-OH),
(Ar), 135.3 (q, J = 29.7 Hz, CF3-C), 139.3 (Ar), 139.9 (Ar), 146.2
(Ar), 146.7 (q, J = 5.0 Hz, CF3-C=C); 19F NMR (CDCl3, CFCl3):
δ −55.93 (s, 3F); IR (neat) 3384, 2980, 2927, 1491, 1354, 1254,
1223, 1186, 1153, 1116, 1090, 1022, 837, 822, 734 cm -1; HRMS
(FAB): calcd for [M+] C18H14ClF3O: 338.0685, Found: 338.0688.
101.9 (Ar), 103.6 (Ar), 103.9 (Ar), 123.4 (q, J = 271.6 Hz, CF3),
128.9 (Ar), 129.7 (d, J = 1.4 Hz, Ar), 130.7 (Ar), 133.3 (Ar),
133.9 (q, J = 29.8 Hz, CF3-C), 135.1 (Ar), 143.9 (d, J = 1.7 Hz,
Ar), 146.4 (q, J = 4.9 Hz, CF3-C=C ), 148.5 (Ar), 149.1 (Ar); 19
F
NMR (CDCl3, CFCl3): δ −55.82 (s, 3F); IR (neat) 3395, 3070,
2979, 2898, 1614, 1592, 1502, 1398, 1371, 1330, 1301, 1263,
1232, 1176, 1107, 1230, 1014, 1003 cm-1.
4.2.20. 2-(4-Chlorophenyl)-5-methoxy-1-methyl-3-
trifluoromethyl-1H-inden-1-ol (11aE).
Acknowledgments
Yield: 23%; white solid, M.p. 141.2−141.8 °C, eluent of the
column chromatography: Hexane/EtOAc
=
5/1; 1H NMR
We sincerely thank Tosoh Finechem Corp. for a generous gift
of 2-bromo-3,3,3-trifluoroprop-1-ene.
(CDCl3): δ 1.42 (s, 3H, HO-C-CH3), 1.85 (s, 1H, OH), 3.85 (s,
3H, OCH3), 6.84 (dd, J = 8.2, 2.3 Hz, 1H, ArH), 7.00 (m, 1H,
ArH), 7.35 (d, J = 8.6 Hz, 2H, ArH), 7.40−7.42 (m, 3H, ArH);
13C NMR (CDCl3): δ 23.8 (HO-C-CH3), 55.8 (OCH3), 82.9 (HO-
C), 108.2 (d, J = 1.4 Hz, Ar), 112.7 (Ar), 122.6 (q, J = 272.7 Hz,
CF3), 123.3 (Ar), 127.6 (q, J = 31.9 Hz, CF3-C), 128.6 (Ar),
130.0 (d, J = 1.4 Hz, Ar), 131.1 (Ar), 135.0 (Ar), 137.7 (Ar),
139.8 (Ar), 155.3 (q, J = 3.8 Hz, CF3-C=C), 160.9 (Ar); 19F NMR
(CDCl3, CFCl3): δ −60.05 (s, 3F); IR (KBr) 3461, 2983, 2948,
1478, 1434, 1374, 1334, 1226, 1197, 1174, 1149, 1106, 1092,
1058, 1024, 1016, 815 cm-1; HRMS (FAB): calcd for [M+]
C18H14ClF3O2: 354.0634, Found: 354.0637.
Supplementary Material
Supplementary data to this article can be found online at
https://.
References
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Yield: 16%; yellow oil, eluent of the column chromatography:
1
hexane/EtOAc = 5/1; H NMR (CDCl3): δ 1.80 (s, 3H, HO-C-
CH3), 2.04 (s, 1H, OH), 3.75 (s, 3H, OCH3), 6.54 (d, J = 2.3 Hz,
1H, ArH), 6.89 (dd, J = 8.2, 2.3 Hz, 1H, ArH), 7.31 (d, J = 8.5
Hz, 2H, ArH), 7.43 (d, J = 8.2 Hz, 1H, ArH), 7.46 (d, J = 8.5 Hz,
2H, ArH); 13C NMR (CDCl3): δ 24.5 (HO-C-CH3), 55.8 (OCH3),
81.8 (HO-C), 109.1 (Ar), 114.1 (Ar), 123.0 (Ar), 123.5 (q, J =
271.6 Hz, CF3), 128.9 (Ar), 129.8 (d, J = 1.5 Hz, Ar), 130.1 (Ar),
135.1 (Ar), 136.6 (q, J = 29.7 Hz, CF3-C), 141.0 (Ar), 141.3 (Ar),
146.3 (q, J = 4.9 Hz, CF3-C=C), 160.9 (Ar); 19F NMR (CDCl3,
CFCl3): δ −56.09 (s, 3F); IR (neat) 3412, 2978, 2938, 2839, 1607,
1594, 1490, 1465, 1353, 1256, 1221, 1192, 1154, 1117, 1090,
1019, 835, 811, 750 cm-1; HRMS (FAB): calcd for [M+]
C18H14ClF3O2: 354.0634, Found: 354.0639.
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4.2.22. 6-(4-Chlorophenyl)-5-methyl-7-trifluoromethyl-5H-
indeno[5,6-d]-1,3-dioxol-5-ol (11aF).
Yield: 31%; brown solid, M.p. 174.2−174.9 °C, eluent of the
column chromatography: Hexane/EtOAc
=
9/1; 1H NMR
(CDCl3): δ 1.38 (s, 3H, CH3), 2.00 (s, 1H, OH), 6.00 (d, J = 1.3
Hz, 1H, CH2), 6.03 (d, J = 1.3 Hz, 1H, CH2), 6.93 (d, J = 1.3 Hz,
1H, ArH), 6.98 (s, 1H, ArH), 7.32 (d, J = 8.6 Hz, 2H, ArH), 7.39
(d, J = 8.6 Hz, 2H, ArH); 13C NMR (CDCl3): δ 23.9 (CH3), 82.9
(C-OH), 101.8 (Ar), 103.7 (d, J = 1.2 Hz, Ar), 104.3 (Ar), 122.6
(q, J = 272.6 Hz, CF3), 127.7 (q, J = 32.6 Hz, CF3-C), 128.6 (Ar),
129.6 (Ar), 130.1 (d, J = 1.4 Hz, Ar), 131.2 (Ar), 134.9 (Ar),
142.3 (Ar), 147.8 (Ar), 148.6 (Ar), 153.0 (q, J = 4.0 Hz, CF3-
C=C); 19F NMR (CDCl3, CFCl3): δ −60.25 (s, 3F); IR (KBr)
3321, 3014, 2974, 2900, 1505, 1382, 1299, 1240, 1187, 1108,
1093, 1017, 940, 830 cm-1; HRMS (FAB): calcd for [M+]
C18H12ClF3O3: 368.0427, Found: 368.0439.
4.2.23. 7-(4-Chlorophenyl)-5-methyl-6-trifluoromethyl-5H-
indeno[5,6-d]-1,3-dioxol-5-ol (12aF).
Yield: 20%; brown solid, M.p. 107.2−108.0 °C, eluent of the
column chromatography: Hexane/EtOAc
=
9/1; 1H NMR
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(CDCl3): δ 1.76 (s, 3H, CH3), 2.18 (s, 1H, OH), 5.98 (d, J = 1.6
Hz, 1H, CH2), 5.97 (d, J = 1.6 Hz, 1H, CH2), 6.47 (s, 1H, ArH),
7.01 (s, 1H, ArH), 7.29 (d, J = 8.5 Hz, 2H, ArH), 7.44 (d, J = 8.5

9
[9] Generally, the signal of the major isomers (3-CF3-indenols) appears at
ACCEPTED MANUSCRIPT
−60 ppm, and that of the minor isomers (2-CF3-indenols) appears at
−54 to −56 ppm.
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