A straightforward access to 3-trifluoromethyl-1H-indazoles via (3+2)-cycloaddition of arynes with nitrile imines derived from trifluoroacetonitrile

Article abstract of DOI:10.1016/j.jfluchem.2020.109691

In situ generated arynes react with nitrile imines derived from trifluoroacetonitrile at 0 °C in THF solutions yielding 3-trifluoromethyl-1H-indazole derivatives as the only intermolecular products. The reaction corresponds the expected (3 + 2)-cycloaddit

Full text of DOI:10.1016/j.jfluchem.2020.109691

Journal Pre-proof
A straightforward access to 3-trifluoromethyl-1H-indazoles via
(3+2)-cycloaddition of arynes with nitrile imines derived from
trifluoroacetonitrile
´
´
Anna Kowalczyk, Greta Utecht-Jarzynska, Grzegorz Mloston,
´
Marcin Jasinski
PII:
S0022-1139(20)30389-4
DOI:
https://doi.org/10.1016/j.jfluchem.2020.109691
FLUOR 109691
Reference:
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Journal of Fluorine Chemistry
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22 October 2020
12 November 2020
13 November 2020
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A straightforward access to 3-trifluoromethyl-1H-indazoles via (3+2)-cycloaddition of
arynes with nitrile imines derived from trifluoroacetonitrile
Anna Kowalczyk,a,b Greta Utecht-Jarzyńska,a Grzegorz Mlostoń,a Marcin Jasiński a,*
a Faculty of Chemistry, University of Lodz, Tamka 12, 91403 Łódź, Poland; e-mail:
mjasinski@uni.lodz.pl
b The University of Lodz Doctoral School of Exact and Natural Sciences, Banacha 12/16, 90237 Łódź,
Poland
Marcin Jasiński
Faculty of Chemistry, University of Lodz
Tamka 12, 91-403 Łódź, Poland
Tel.:
Fax:
+48 42 635 57 66
+48 42 665 51 62
e-mail: mjasinski@uni.lodz.pl
Graphical abstract
Highlights
 The N-aryl nitrile imines derived from trifluoroacetonitrile trap the in situ
generated arynes
 In these reactions the fluoride anion plays a dual role as a base and
desilylating reagent
 Under mild conditions the (3+2)-cycloadditions lead to 3-trifluoromethyl-
1H-indazoles in high yield
 The CAN mediated dearylation allows the synthesis of N-unsubstituted 3-
trifluoromethylindazole
 Fluorinated analogue of lonidamine was prepared via N-alkylation using
2,4-dichlorobenzyl chloride
1

Abstract
In situ generated arynes react with nitrile imines derived from trifluoroacetonitrile at 0 C in THF
solutions yielding 3-trifluoromethyl-1H-indazole derivatives as the only intermolecular products. The
reaction corresponds the expected (3+2)-cycloadditions which belong to the Type III (inverse-electron-
demand) of Sustmann’s classification. Subsequent CAN-mediated dearylation of the model N-(p-
methoxy)phenyl indazole leads to N-unsubstituted analogue, which easily undergoes alkylation and
acylation reactions. Presented protocol offers a superior method for preparation of the 3-CF3
substituted indazole derivatives.
Keywords: nitrile imines, arynes, (3+2)-cycloadditions, indazoles, fluorinated heterocycles
1. Introduction
In the current organic synthesis the (3+2)-cycloadditions (the Huisgen reaction) are
considered as a powerful and universal tool for the preparation of five-membered heterocycles [1].
Thus, reactions of ethylenic or acetylenic dipolarophiles with ‘nitrogen-centered’ 1,3-dipoles such as
nitrile imines, nitrile oxides, nitrile ylides, nitrones or azomethine ylides open access to variety of N-
heterocyclic systems i.e. pyrazole, isoxazole, pyrrole, isoxazoline, and pyrroline derivatives,
respectively [2a-f]. Moreover, the (3+2)-cycloadditions of organic azides with alkynes, performed in
the presence of Cu(I) salts (the click reactions) are known as a group of the most widely applied
transformations of organic compounds with great importance for interdisciplinary studies [2g]. In a
series of our recent publications, trifluoroacetonitrile imines of type 1 generated in situ from the
corresponding hydrazonoyl bromides 2 were demonstrated as a useful 1,3-dipoles for the efficient
introduction of the CF3 group into the 5-membered nitrogen heterocycles with diverse number of
heteroatoms. For example, trapping of in situ generated 1 with thiocarbonyl dipolarophiles such as
thioketones, thiochalcones or thioamides led to 1,3,4-thiadiazole derivatives of type 3 in a fully
chemo- and regioselective manner [3] (Scheme 1). On the other hand, trifluoroacetonitrile imines 1
were reported to react smoothly with electron-rich C=C dipolarophiles yielding the corresponding
pyrazole derivatives 4 also in a completely selective fashion [4]. In contrast, the (3+2)-cycloadditions
of 1 with acetylenic dipolarophiles are lesser explored presumably due to low regioselectivity [5]. In
these reactions, formation of complex mixtures of products resulting from the competitive additions of
acetylide ions derived from some terminal acetylenes is a serious limitation.
2

Scheme 1. Reactions of trifluoroacetonitrile imines 1 with exemplary C=S and C=C dipolarophiles leading to
2,3-dihydro-1,3,4-thiadiazoles 3 and pyrazoles 4, respectively.
Notably, there is a growing number of publications dealing with both (3+2)- and (4+2)-
cycloadditions of arynes 5 [6]. These highly congested and therefore very reactive intermediates can
be used either as dipolarophiles or dienophiles and they are currently easily accessible under mild
conditions via fluoride anion-induced elimination from ortho-substituted (trialkylsilyl)aryl triflates 6
as commercially available, common precursors (Scheme 2) [7]. In this context, preparation of 1-
substituted 1H-indazoles via the Huisgen reaction from the in situ generated benzynes 5 and C,N-
di(hetero)aryl-functionalized nitrile imines was described as a promising method to synthesize these
type of the fused heterocycles [8]. Prompted by these results reported for the first time by Moses’
group, we decided to examine a series of trifluoroacetonitrile imines 1 with selected arynes 5 in order
to prepare hitherto little known 3-trifluoromethylated 1H-indazoles [9]. Furthermore, the target
products seemed to be an interesting class of organic substrates for further functionalization, e.g. via
dearylation of the N(1) atom followed by alkylation or acylation at this position.
3

Scheme 2. Generation of benzyne (5a) and its cycloaddition reactions with selected heterodienes and 1,3-dipoles
leading to the respective benzo-fused systems 7 and 8 as initial products of cycloaddition reactions (for details
see, refs. [10] and [11]).
Hence, the goal of the present study was the synthesis and selected transformations of 3-
trifluormethyl-1H-indazoles via in situ trapping of arynes with the title fluorinated nitrile imines
derived from trifluoroacetonitrile.
2. Results and Discussion
The starting nitrile imines 1 were generated based on a procedure routinely applied in our
laboratory for a longer time, i.e. by dehydrobromination of hydrazonoyl bromides 2 with an organic or
inorganic base, in anhydrous aprotic solvents [3,4]. In a test experiment, corresponding precursor of
the nitrile imine 1a (0.5 mmol) bearing the NMR-diagnostic p-tolyl group, and o-trimethylsilyl-phenyl
triflate (6a, 0.75 mmol) were treated with tetrabutylammonium fluoride (TBAF, 1.3 mmol) in dry THF
at room temperature. As expected, the application of the two-fold amount of TBAF assured dual role
of the fluoride anion for both, smooth generation of benzyne (5a) as well as for dehydrohalogenation
of hydrazonoyl bromide 2a. According to the TLC tests, triflate 6a was fully consumed after 20 min,
and the 1H NMR spectrum registered for crude reaction mixture revealed the presence of the expected
(3+2)-cycloadduct 9a along with unreacted nitrile imine precursor 2a, which were isolated in 42% and
38% yield, respectively. Optimization of the reaction conditions revealed that the increased amounts
of both triflate 6a (2.0 equiv.) and TBAF (4.0 equiv.) are necessary for complete consumption of the
bromide 2a (Table 1). Neither the change of the solvent (MeCN) nor the decrease of the reaction
temperature to 20 C showed remarkable impact on the reaction outcome. Notably, the replacement
of TBAF by CsF as a source of fluoride anion was unsuccessful and the reduced solubility of the latter
in THF can be the explanation of that result. Thus, by running the reaction of 2a with two-fold excess
of benzyne precursor 6a and four-fold excess of TBAF, in THF at 0 C, the desired (3+2)-cycloadduct
9a was isolated in satisfactory yield of 74% (Table 1, entry 4; Scheme 3). The pure product was
isolated by column chromatography, and its structure was confirmed by spectroscopic methods. For
example, in the 19F NMR spectrum the signal of the CF3 group appeared as a singlet located at 60.8
ppm. Furthermore, in the 13C NMR the characteristic quartets attributed to the CF3 moiety and the C(3)
atom were found at 122.0 (1JC,F = 269.2 Hz) and 135.8 (2JC,F = 38.4 H Hz) ppm, respectively. Finally,
high resolution MS measurements for the sample confirmed the molecular formula of 1-(p-tolyl)-3-
trifluoromethyl-1H-indazole (9a) as C15H11F3N2.
Table 1. Optimisation of the reaction conditions by using 2a and 6a as model substrates.
4

Entry 6a (equiv.)a
Solvent
THF
Temp.
rt
Time
24 h
20 min
20 min
20 min
1 h
9a [%] b
NR
42 c
58 d
72
F source (equiv.)a
CsF, 2.5
1
2
3
3
4
5
6
7
1.5
1.5
1.5
2.0
2.0
2.0
2.0
2.0
TBAF, 2.5
TBAF, 3.0
TBAF, 4.0
TBAF, 4.0
TBAF, 4.0
TBAF, 4.0
TBAF, 4.0
THF
rt
THF
rt
THF
rt
THF
74
0 C
20 C
78 C
0 C
THF
1 h
70
THF
1 h
46
MeCN
1 h
71
a with respect to hydrazonoyl bromide 2a; all experiments were performed in a 0.5 mmol (2a) scale.
b isolated yield.
c unreacted 2a was recovered in 38% yield.
d traces (<5%) of starting 2a were found in the crude mixture.
5

Scheme 3. Synthesis of 3-trifluoromethyl-1H-indazole derivatives 9a-9i by the (3+2)-cycloaddition of arynes
5a-5c with nitrile imines 1a-1g.
The optimized conditions were applied for a series of experiments performed with diverse
para-substituted nitrile imines 1b-1g and the model benzyne (5a) (Scheme 3). In all the studied cases,
the desired indazoles of type 9 were isolated as sole intermolecular products in satisfactory to high
yields (58-80%) with one exception of the representative 9g (32%) functionalized with electron-
withdrawing NO2 group.
In extension of the study, two further arynes, namely 4,5-dimethoxybenzyne (5b) and
naphtyne (5c), were also examined in reactions with a model N-(p-tolyl)trifluoroacetohydrazonoyl
bromide (2a). Remarkably, introduction of two electron-donating OMe groups in 5b did not affect the
course of the (3+2)-cycloaddition, and the product 9h was isolated in satisfactory yield of 52%,
comparable with other studied reactions (see Table 1). However, the reaction performed with in situ
generated naphtyne (5c) led to a complex mixture and the expected product was isolated as a colorless
solid in 26% yield only.
The mechanism of the studied reaction requires a brief comment. Very likely, formation of the
fused indazole system 9 occurs via concerted but rather asynchronous (3+2)-cycloaddition. Taking
into account that the presented reactions occur with participation of electron-deficient 1,3-dipoles 1
and electron-rich arynes 5, they can be classified to Type 3 (inverse-electron-demand) according to
Sustmann’s classification of the 1,3-dipolar cycloadditions [12].
In the second part of the study, selected indazole derivative 9b bearing electron-rich p-
methoxyphenyl group was used for further transformations aimed at the preparation of new analogues
of some indazole-derived biologically active compounds which are of current interest [13]. The initial
conversion of a multi-step transformation of 9b was dearylation using ceric ammonium nitrate (CAN)
and this process is depicted in Scheme 4. The reaction was performed in a MeCN/H2O mixture, at 5
C. After standard aqueous workup followed by column chromatography, the expected indazole 10
lacking a substituent at N(1) was obtained in satisfactory 78% yield. Its structure was confirmed
spectroscopically, and the 13C NMR spectrum showed again the diagnostic signal of the C(3) atom as a
quartet located at 135.9 (2JC,F = 38.2 Hz) ppm, along with the signal of the CF3 group found at 122.0
(1JC,F = 268.9 Hz), indicating the presence of a single tautomeric form under the measurement
conditions (rt, CDCl3) within the NMR accuracy of >0.1%.
Next, the obtained NH-indazole derivative 10 was checked as a nucleophilic reagent in
alkylation and acylation at the N(1) atom using selected electrophiles. For example, treatment of 10
with an excess of 2,4-dichlorobenzyl chloride under mild conditions (room temperature, K2CO3, in
6

DMF) afforded after 2d the desired N-benzylated derivative 11 in excellent yield (94%). This is worth
of mentioning that this product constitutes a new structural analogue of lonidamine (12); the latter is a
well-known medicine used for the cancer treatment [14].
Scheme 4. Synthesis of N-unsubstituted indazole 10 by CAN-mediated dearylation of 9b and subsequent
alkylation leading to lonidamine analogue 11.
Two more functionalization of indazole 10 were also performed via alkylation using (S)-
citronellyl bromide and acylation with cholestanyl-functionalized succinyl monochloride. In both
cases, the expected enantiopure products 13 and 14 were obtained in good yields of 87% and 80%,
respectively. These results demonstrate that indazole 10 can be explored as a useful building block for
the preparation of new terpene- and steroid-containing conjugates. Compounds of this type are of
interest e.g. in the context of their antiviral activity [15].
Figure 1. Structures of chiral 3-trifluoromethylindazole-conjugates 13 and 14 obtained by alkylation or acylation
of 10 with (S)-(+)-citronellyl bromide (15) or cholestan-3-yloxycarbonylpropionyl chloride (16).
3. Conclusions
The presented method of the synthesis of 3-trifluoromethylated 1H-indazoles via the (3+2)-
cycloaddition of the in situ generated both trifluoroacetonitrile imines and arynes offers a convenient
access to these heterocycles which are of interest as versatile building blocks for preparation of
potentially biologically active, fluoromethylated N-heterocycles. The importance of fluorinated
indazoles is demonstrated by numerous original and review publications [16]. Due to synthetic
limitations in preparation of trifluoroacetonitrile imines, only N-arylated indazoles can be directly
accessed by the presented method. However, a straightforward CAN-mediated dearylation opens a
7

highly efficient access to known N(1)H-indazole in high yield. It is worth of mentioning that in
comparison to other reported methods the procedure described herein can be considered as a method
of choice for preparation of this relevant, fluorinated building block [17]. As demonstrated in the
present study, the latter indazole displays the expected nucleophilic behavior in alkylation and
acylation reactions. On the other side, described results show once more high utility of the in situ
generated arynes as highly reactive dipolarophiles for the synthesis of fused, functionalized nitrogen
heterocycles.
4. Experimental Part
4.1. General information
If not stated otherwise, reactions were carried out under inert atmosphere (argon) in a flame-
dried flasks with addition of the reactants by using syringes; subsequent manipulations were
conducted in air. Products were purified by standard column chromatography (CC) on silica gel (230–
400 mesh), deactivated prior to use with 2% Et3N in petroleum ether, by using freshly distilled
solvents (petroleum ether, CH2Cl2, EtOAc). THF was dried over sodiumbenzophenone and freshly
distilled before usage; anhydrous DMF is available commercialy and was used as received. NMR
spectra were measured on a Bruker AVIII instrument (1H at 600 MHz, 13C at 151 MHz, and 19F at 565
MHz). Chemical shifts are reported relative to solvent (CDCl3) residual peaks (1H NMR: δ = 7.26
ppm, 13C NMR: δ = 77.0 ppm) or to CFCl3 (19F NMR: δ = 0.00 ppm) used as external standard.
Multiplicity of the signals in 13C NMR spectra were assigned based on supplementary 2D
measurements (COSY, HMQC, HMBC). MS (ESI) were performed with a Varian 500-MS LC Ion
Trap; high resolution MS (ESI-TOF) measurements were measured with a Synapt G2-Si mass
spectrometer (Waters). IR spectra were measured with an Agilent Cary 630 FTIR spectrometer, in
neat. Elemental analyses were obtained with a Vario EL III (Elementar Analysensysteme GmbH)
instrument. Melting points were determined in capillaries with a MEL-TEMP apparatus (Aldrich) or
with a polarizing optical microscope (Opta-Tech), and are uncorrected. Hydrazonoyl bromides 2a-2g
were prepared by treatment of the respective trifluoroacetaldehyde arylhydrazones [18] with N-
bromosuccinimide in dry DMF as described [3a]. Cholestan-3-yloxycarbonylpropionyl chloride (16)
was prepared following the literature procedure [19].
4.2. General procedure for the synthesis of 3-trifluoromethyl-1H-indazoles 9
To a mixture of the respective hydrazonoyl bromide of type 2 (0.5 mmol) and benzyne
precursor 5 (1.0 mmol) in dry THF (5 mL) at 0 C was added dropwise TBAF (1M in THF, 2.0 mL,
2.0 mmol) and the resulting was stirred for 1 h. After solvent was removed under reduced pressure, the
resulting mixture was purified by standard column chromatography (CC) on SiO2 (washed with 2%
8

Et3N in petroleum ether) using petroleum ether – dichloromethane mixtures as an eluent to give
product 9 as spectroscopically pure samples.
4.2.1. 1-(p-Tolyl)-3-trifluoromethyl-1H-indazole (9a)
CC (SiO2, petroleum ether/CH2Cl2 4:1), 102 mg (74%), pale yellow oil. 1H NMR (600 MHz,
CDCl3): δ 2.46 (s, 3 H, Me), 7.34-7.36 (m, 1 H), 7.36 (dbr, J ≈ 8.2 Hz, 2 H, Tol), 7.47-7.51 (m, 1 H),
7.59 (dbr, J ≈ 8.2 Hz, 2 H, Tol), 7.71 (dbr, J ≈ 8.6 Hz, 1 H), 7.91-7.93 (m, 1 H) ppm; 13C NMR (151
MHz, CDCl3): δ 21.1 (Me), 111.0, 120.3 (2 CH), 121.2 (i-C), 122.0 (q, 1JC,F = 269.2 Hz, CF3), 123.2,
123.5, 127.9, 130.1 (CH, 2 CH, CH, 2 CH), 135.8 (q, 2JC,F = 38.4 Hz, C-3), 136.7, 138.0, 140.0 (3 i-C)
ppm; 19F NMR (565 MHz, CDCl3): δ 60.8 (s, CF3) ppm; IR (neat): ν 2925, 1612, 1502, 1433, 1352,
1173, 1128, 1030, 821, 746 cm-1; EI-HRMS: m/z [M]+ calcd for C15H11F3N2: 276.0874; found:
276.0878.
4.2.2. 1-(4-Methoxyphenyl)-3-trifluoromethyl-1H-indazole (9b)
CC (SiO2, petroleum ether/CH2Cl2 3:1), 117 mg (80%), colourless solid, mp 6566 C. 1H
NMR (600 MHz, CDCl3): δ 3.89 (s, 3 H, Me) 7.07 (d, J = 8.9 Hz, 2 H), 7.32-7.36, 7.46-7.50 (2 m, 1 H
each), 7.36 (d, J = 8.9 Hz, 2 H), 7.64 (dbr, J ≈ 8.6 Hz, 1 H), 7.91 (dbr, J = 8.2 Hz, 1 H) ppm; 13C NMR
(151 MHz, CDCl3): δ 55.6 (OMe), 110.9, 114.8, 120.2 (CH, 2 CH, CH), 121.0 (i-C), 122.0 (q, 1JC,F
269.0 Hz, CF3), 123.1, 125.3, 127.9, (CH, 2 CH, CH), 132.1 (i-C), 135.6 (q, 2JC,F = 38.3 Hz, C-3),
=
140.2, 159.3 (2 i-C) ppm; 19F NMR (565 MHz, CDCl3): δ 60.7 (s, CF3) ppm; IR (neat): ν 2926, 1526,
1502, 1431, 1253, 1188, 1154, 1132, 1030, 828, 741 cm-1; EI-HRMS: m/z [M]+ calcd for
C15H11F3N2O: 292.0823; found: 292.0828.
4.2.3. 1-Phenyl-3-trifluoromethyl-1H-indazole (9c)
CC (SiO2, petroleum ether/CH2Cl2 4:1), 76 mg (58%), yellow oil. 1H NMR (600 MHz,
CDCl3): δ 7.35-7.38, 7.44-7.46, 7.51-7.53 (3 m, 1 H each), 7.56-7.59 (m, 2 H), 7.72-7.74 (m, 2 H),
7.75 (d, J = 8.6 Hz, 1 H), 7.92-7.94 (m, 1 H) ppm; 13C NMR (151 MHz, CDCl3): δ 111.3, 120.4 (2
CH), 121.3 (i-C), 121.9 (q, 1JC,F = 269.3 Hz, CF3), 123.3, 123.6, 128.0, 128.1, 129.6 (CH, 2 CH, CH,
CH, 2 CH), 136.2 (q, 2JC,F = 38.4 Hz, C-3), 139.2, 140.0 (2 i-C) ppm; 19F NMR (565 MHz, CDCl3): δ
60.9 (s, CF3) ppm; IR (neat): ν 3064, 1660, 1599, 1497, 1433, 1352, 1298, 1259, 1128, 949, 748 cm-
1; EI-HRMS: m/z [M]+ calcd for C14H9F3N2: 262.0718; found: 262.0725.
4.2.4. 1-(4-Bromophenyl)-3-trifluoromethyl-1H-indazole (9d)
CC (SiO2, petroleum ether/CH2Cl2 4:1), 119 mg (70%), yellow oil. 1H NMR (600 MHz,
CDCl3): δ 7.37-7.39, 7.52-7.55 (2 m, 1 H each), 7.61-7.64 (m, 2 H), 7.68-7.73 (m, 3 H), 7.93 (dd, J =
0.8, 8.2 Hz, 1 H) ppm; 13C NMR (151 MHz, CDCl3): δ 110.8, 120.6 (2 CH), 121.4, 121.5 (2 i-C),
121.8 (q, 1JC,F = 269.4 Hz, CF3), 123.6, 124.9, 128.4, 132.8 (CH, 2 CH, CH, 2 CH), 136.7 (q, 2JC,F
=
9

38.5 Hz, C-3), 138.2, 139.8 (2 i-C) ppm; 19F NMR (565 MHz, CDCl3): δ 61.0 (s, CF3) ppm; IR
(neat): ν 2926, 1516, 1489, 1433, 1257, 1182, 1130, 1026, 949, 829, 746 cm-1; EI-HRMS: m/z [M]+
calcd for C14H8BrF3N2: 339.9823; found: 339.9829.
4.2.5. 1-(4-Fluorophenyl)-3-trifluoromethyl-1H-indazole (9e)
CC (SiO2, petroleum ether/CH2Cl2 4:1), 97 mg (69%), yellow oil. 1H NMR (600 MHz,
CDCl3): δ 7.24-7.30 (m, 2 H), 7.35-7.39, 7.49-7.54 (2 m, 1 H each), 7.65-7.70 (m, 3 H), 7.93 (dbr, J ≈
8.2 Hz, 1 H) ppm; 13C NMR (151 MHz, CDCl3): δ 110.7 (CH), 116.6 (d, 2JC,F = 23.1 Hz, 2 CH), 120.4
(CH), 121.2 (i-C), 121.8 (q, 1JC,F = 269.3 Hz, CF3), 123.4 (CH), 125.4 (d, 3JC,F = 8.6 Hz, 2 CH), 128.3
(CH), 135.2 (d, 4JC,F = 3.1 Hz, i-C), 136.2 (q, 2JC,F = 38.4 Hz, C-3), 140.0 (i-C), 161.9 (d, 1JC,F = 248.4
Hz, i-CF) ppm; 19F NMR (565 MHz, CDCl3): δ 60.9 (s, CF3), 113.0 (mc, Ar-F) ppm; IR (neat): ν
2929, 1606, 1523, 1501, 1433, 1259, 1236, 1177, 1154, 1127, 1026, 840, 746 cm-1; EI-HRMS: m/z
[M]+ calcd for C14H8F4N2: 280.0624; found: 280.0630.
4.2.6. 4-(3-Trifluoromethyl-1H-indazol-1-yl)benzonitrile (9f)
CC (SiO2, petroleum ether/CH2Cl2 1:1), 109 mg (76%), yellow solid, mp 127128 C. 1H
NMR (600 MHz, CDCl3): δ 7.42-7.44, 7.58-7.61 (2 m, 1 H each), 7.82 (dbr, J ≈ 8.6 Hz, 1 H), 7.86-
7.89, 7.92-7.97 (2 m, 2 H, 3 H) ppm; 13C NMR (151 MHz, CDCl3): δ 110.9 (CH), 111.1 (CN), 118.0
(i-C), 120.9 (CH), 121.5 (q, 1JC,F = 269.7 Hz, CF3), 121.9 (i-C), 123.0, 124.1, 129.0, 133.7 (2 CH, CH,
CH, 2 CH), 137.9 (q, 2JC,F = 38.7 Hz, C-3), 139.7, 142.7 (2 i-C) ppm; 19F NMR (565 MHz, CDCl3): δ
61.3 (s, CF3) ppm; IR (neat): ν 3310, 2225 (CN), 1605, 1506, 1287, 1159, 938, 748 cm-1; EI-HRMS:
m/z [M]+ calcd for C15H8F3N3: 287.0670; found: 287.0674.
4.2.7. 1-(4-Nitrophenyl)-3-trifluoromethyl-1H-indazole (9g)
CC (SiO2, petroleum ether/CH2Cl2 1:1), 49 mg (32%), yellow solid, mp 140141 C. 1H NMR
(600 MHz, CDCl3): δ 7.42-7.46, 7.61-7.64 (2 m, 1 H each), 7.86 (dbr, J ≈ 8.6 Hz, 1 H), 7.97 (dd, J =
0.7, 8.2 Hz, 1 H), 8.00, 8.46 (2 dbr, J ≈ 9.1 Hz, 2 H each) ppm; 13C NMR (151 MHz, CDCl3): δ 110.9,
121.0 (2 CH), 121.5 (q, 1JC,F = 269.7 Hz, CF3), 122.0 (i-C), 122.7, 124.3, 125.4, 129.2 (2 CH, CH, 2
CH, CH), 138.2 (q, 2JC,F = 38.8 Hz, C-3), 144.2, 146.3 (2 i-C) ppm; 19F NMR (565 MHz, CDCl3): δ
61.4 (s, CF3) ppm; IR (neat): ν 3090, 1522, 1496, 1344, 1174, 1121, 948, 773 cm-1; EI-HRMS: m/z
[M]+ calcd for C14H8F3N3O2: 307.0569; found: 307.0572.
4.2.8. 5,6-Dimethoxy-1-(p-tolyl)-3-trifluoromethyl-1H-indazole (9h)
CC (SiO2, petroleum ether/CH2Cl2 3:1), 87 mg (52%), orange solid, mp 112144 C. 1H NMR
(600 MHz, CDCl3): δ 2.46 (s, 3 H, Me), 3.93, 3.98 (2 s, 3 H each, OMe), 7.00, 7.14 (2 s, 1 H each),
7.35, 7.54 (2 dbr, J ≈ 8.2 Hz, 2 H each, Tol) ppm; 13C NMR (151 MHz, CDCl3): δ 21.1 (Me), 56.1,
56.2 (OMe), 91.9, 98.8 (2 CH), 114.5 (i-C), 122.1 (q, 1JC,F = 269.0 Hz, CF3), 123.4, 130.2 (2 CH each),
10

135.0 (q, 2JC,F = 38.0 Hz, C-3), 135.8, 136.7, 137.9, 147.9, 151.8 (5 i-C) ppm; 19F NMR (565 MHz,
CDCl3): δ 60.7 (s, CF3) ppm; IR (neat): ν 2927, 1614, 1510, 1475, 1432, 1290, 1214, 1150, 1007,
826, 734 cm-1; EI-HRMS: m/z [M]+ calcd for C17H15F3N2O2: 336.1086; found: 336.1088.
4.2.9. 1-(p-Tolyl)-3-trifluoromethyl-1H-benzo[f]indazole (9i)
CC (SiO2, petroleum ether/CH2Cl2 9:1), 42 mg (26%), yellow oil. 1H NMR (600 MHz,
CDCl3): δ 2.48 (s, 3 H, Me), 7.42 (dbr, J ≈ 8.2 Hz, 2 H, Tol), 7.44-7.47, 7.49-7.53 (2 m, 1 H each), 7.71
(dbr, J ≈ 8.2 Hz, 2 H, Tol), 7.92 (dbr, J ≈ 8.3 Hz, 1 H), 8.04 (dbr, J ≈ 8.3 Hz, 1 H), 8.18, 8.48 (2 s, 1 H
each) ppm; 13C NMR (151 MHz, CDCl3): δ 21.2 (Me), 106.7, 119.2 (2 CH), 121.4 (i-C), 122.0 (q, 1JC,F
= 269.2 Hz, CF3), 123.2 (2 CH) 124.8, 126.9, 128.0, 129.1 (4 CH), 129.9 (i-C), 130.2 (2 CH), 133.1 (i-
C), 135.8 (q, 2JC,F = 38.5 Hz, C-3), 137.0, 137.6, 138.3 (3 i-C) ppm; 19F NMR (565 MHz, CDCl3): δ
60.9 (s, CF3) ppm; IR (neat): ν 2922, 1608, 1524, 1510, 1489, 1358, 1105, 1010, 818, 744 cm-1;
HRMS (ESI-TOF): m/z [M+H]+ calcd for C19H14F3N2: 327.1109; found: 327.1111.
4.3. Synthesis of 3-trifluoromethyl-1H-indazole (10) [17]
To a magnetically stirred solution of 1-(4-Methoxyphenyl)-3-trifluoromethyl-1H-indazole (9b,
146 mg, 0.5 mmol) in MeCN (20 mL) at 5 C a solution of ceric ammonium nitrate (1.37 g, 2.4 mmol)
in H2O (12 mL) was added. The resulting mixture was stirred for 2 h at this temperature, then
neutralized to pH = 7 with saturated NaHCO3 solution and extracted with CH2Cl2 (3  20 mL). The
combined organic fractions were dried over MgSO4, filtered and the solvents were removed in vacuo.
The residue was purified by flash column chromatography (SiO2, petroleum ether/CH2Cl2 4:1) to give
N-unsubstituted indazole 10 (73 mg, 78%) as colourless solid.
Mp 9697 C. 1H NMR (600 MHz, CDCl3): δ 7.31-7.35, 7.50-7.54 (2 m, 1 H each), 7.62 (dbr,
J ≈ 8.5 Hz, 1 H), 7.89 (ddbr, J ≈ 0.7, 8.3 Hz, 1 H), 11.57 (sbr, 1 H, NH) ppm; 13C NMR (151 MHz,
CDCl3): δ 110.5 (CH), 119.5 (i-C), 119.9 (CH), 122.0 (q, 1JC,F = 268.9 Hz, CF3), 123.1, 128.1 (2 CH),
135.9 (q, 2JC,F = 38.2 Hz, C-3), 141.0 (i-C) ppm; 19F NMR (565 MHz, CDCl3): δ 60.8 (s, CF3) ppm;
IR (neat): ν 3184, 3161, 2936, 1475, 1432, 1230, 1186, 1153, 1115, 1028, 911, 743 cm-1; ()-ESI-MS
(m/z): 184.9 (100, [M−H]−); elemental analysis calcd (%) for C8H5F3N2 (186.1): C 51.62, H 2.71, N
15.05; found: C 51.65, H 3.01, N 14.97.
4.4. Synthesis of 1-(2,4-dichlorobenzyl)-3-trifluoromethyl-1H-indazole (11)
To a solution of 3-trifluoromethyl-1H-indazole (10, 93 mg, 0.5 mmol) and K2CO3 (207 mg,
1.5 mmol) in DMF (5 mL), 2,4-dichlorobenzyl chloride (117 mg, 0.6 mmol) in DMF (1 mL) was
added at room temperature. The reaction mixture was stirred for 48 h, then diluted with water (20 mL)
and extracted with ethyl acetate (3  10 mL). The combined organic layers were dried over Na2SO4
11

and the solvents were removed under reduced pressure. The residue was purified by column
chromatography (SiO2, petroleum ether/CH2Cl2 4:1) to afford 11 (162 mg, 94%) as a colourless oil.
1H NMR (600 MHz, CDCl3): δ 5.73 (s, 2 H, CH2), 6.76 (dbr, J ≈ 8.4 Hz, 1 H), 7.13 (dd, J =
2.0, 8.4 Hz, 1 H), 7.29-7.33 (m, 1 H), 7.40-7.48 (m, 3 H), 7.87-789 (m, 1 H) ppm; 13C NMR (151
MHz, CDCl3): δ 50.1 (CH2), 109.8, 120.3 (2 CH), 120.6 (i-C), 121.8 (q, 1JC,F = 269.0 Hz, CF3), 123.0,
127.7, 127.8, 129.5, 129.6 (5 CH), 132.0, 133.1, 134.6 (3 i-C), 134.9 (q, 2JC,F = 38.4 Hz, C-3), 140.6 (i-
C) ppm; 19F NMR (565 MHz, CDCl3): δ 60.7 (s, CF3) ppm; IR (neat): ν 2926, 1502, 1431, 1382,
1237, 1115, 1088, 987, 749 cm-1; HRMS (ESI-TOF): m/z [M+H]+ calcd for C15H10F3N2Cl2: 345.0173;
found: 345.0174.
4.5. Synthesis of (S)-1-(3,7-dimethyloct-6-en-1-yl)-3-trifluoromethyl-1H-indazole (13)
To a solution of N-unsubstituted indazole 10 (93 mg, 0.5 mmol) and K2CO3 (207 mg, 1.5
mmol) in DMF (5 mL), (S)-(+)-citronellyl bromide (131 mg, 0.6 mmol) in DMF (1 mL) was added at
room temperature. The reaction mixture was stirred for 24h, then diluted with water (20 mL) and
extracted with ethyl acetate (3  10 mL). The combined organic layers were dried over Na2SO4 and
solvents were removed under reduced pressure. The residue was purified by column chromatography
(SiO2, petroleum ether/CH2Cl2 4:1) to yield product 13 (141 mg, 87%) as a colourless oil.
[α]D20 = 1.73 (c = 0.11, CHCl3). 1H NMR (600 MHz, CDCl3): δ 1.00 (d, J = 6.6 Hz, 3 H,
Me), 1.19-1.28, 1.37-1.45, 1.45-1.53 (3 m, 1 H each), 1.58, 1.66 (2 s, 3 H each, 2 Me), 1.72-1.81 (m, 1
H), 1.90-2.05 (m, 3 H), 4.36-4.53 (m, 2 H, NCH2), 5.02-5.07 (m, 1 H), 7.28 (ddd, J = 2.5, 5.2, 8.0 Hz,
1 H), 7.44-7.48 (m, 2 H), 7.84 (dbr, J = 8.0 Hz, 1 H) ppm; 13C NMR (151 MHz, CDCl3): δ 17.6, 19.4
(2 Me), 25.3 (CH2), 25.6 (Me), 30.1 (CH), 36.5, 36.7, 47.8 (3 CH2), 109.6, 120.2 (2 CH), 120.4 (i-C),
122.0 (q, 1JC,F = 268.6 Hz, CF3), 122.4 (CH), 124.2 (=CH), 127.0 (CH), 131.6 (i-C), 133.6 (q, 2JC,F
=
38.1 Hz, C-3), 140.1 (i-C) ppm; 19F NMR (565 MHz, CDCl3): δ 60.4 (s, CF3) ppm; IR (neat): ν 2932,
1718, 1506, 1433, 1228, 1157, 1120, 1075, 978, 745 cm-1; HRMS (ESI-TOF): m/z [MH] calcd for
C18H22F3N2: 323.1735; found: 323.1740.
4.6. Cholestan-3-yl 4-(3-trifluoromethyl-1H-indazol-1-yl)-4-oxobutanoate (14)
To a solution of indazole 10 (186 mg, 1.0 mmol) and 4-dimethylaminopyridine (DMAP, 366
mg, 2.44 mmol) in dry DCM (10 mL), cholestan-3-yloxycarbonylpropionyl chloride (558 mg, 1.1
mmol) in dry DCM (10 mL) was added dropwise. The mixture was stirred under argon at room
temperature until the starting indazole was fully consumed (TLC monitoring, 1 h). The mixture was
quenched with water (20 mL) and diluted with CH2Cl2 (10 mL). The organic layer was separated and
washed with 2% HCl (10 mL), then with 5% NaHCO3 (10 mL) and water (3  25 mL). The organic
layer was dried (MgSO4), filtered and the solvent removed under reduced pressure. The crude product
12

was purified by standard column chromatography (SiO2, petroleum ether/AcOEt 8:1) to give 14 (525
mg, 80%) as a light yellow solid.
Mp 126128 C. [α]D20 = +11.96 (c = 0.27, CHCl3). 1H NMR (600 MHz, CDCl3): δ 0.58-0.63
(m, 1H), 0.64, 0.78 (2 s, 3 H each, 2 Me), 0.80-0.85 (m, 1 H), 0.85, 0.86 (2 d, J = 2.7 Hz, 3 H each, 2
Me), 0.89 (d, J = 6.5 Hz, 3 H, Me), 0.92-1.04 (m, 4 H), 1.04-1.17, 1.17-1.28, 1.28-1.38 (3 m, 5 H
each), 1.42-1.49, 1.49-1.56 (2 m, 2 H each), 1.56-1.61, 1.61-1.66 (2 m, 1 H each), 1.71 (dt, J = 3.5,
13.3 Hz, 1 H), 1.76-1.84 (m, 2 H), 1.95 (dt, J = 3.1, 12.5 Hz, 1 H), 2.82, 3.56 (2 t, J = 6.6 Hz, 2 H
each, 2 CH2), 4.70-4.76 (m, 1 H, OCH), 7.43-7.49, 7.60-7.66, 7.82-7.87, 8.46-8.48 (4 m, 1 H each)
ppm; 13C NMR (151 MHz, CDCl3): δ 12.0, 12.2, 18.6 (3 Me), 21.2 (CH2), 22.5, 22.8 (2 Me), 23.8,
24.2, 27.4 (3 CH2), 28.0 (CH), 28.2, 28.5, 28.8, 30.1, 32.0, 33.9 (6 CH2), 35.4 (i-C), 35.4, 35.8 (2 CH),
36.1, 36.7, 39.5, 39.9 (4 CH2), 42.6 (i-C), 44.6, 54.2, 56.2, 56.4 (4 CH), 74.4 (OCH), 115.8, 120.1 (2
CH), 120.8 (q, 1JC,F = 270.6 Hz, CF3), 121.8 (i-C), 125.7, 130.5 (2 CH), 140.1 (q, 2JC,F = 38.7 Hz, C-3),
140.1 (i-C), 171.6, 172.5 (2 C=O) ppm; 19F NMR (565 MHz, CDCl3): δ 62.5 (s, CF3) ppm; IR (neat):
ν 2930, 2855, 1730 (C=O), 1520, 1374, 1206, 1150, 1109, 1006, 913, 772 cm-1; ESI-MS (m/z): 679.8
(100, [M+Na]+); elemental analysis calcd (%) for C39H55F3N2O3 (656.9): C 71.31, H 8.44, N 4.26;
found: C 71.22, H 8.44, N 4.27.
Acknowledgements
The authors (GUJ and MJ) thank the National Science Center (NCN, Cracow, Poland) for
financial support in the framework of Preludium grant #2016/21/N/ST5/01254.
13

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