Methyl-2,2-difluoro-2-(fluorosulfonyl) acetate (MDFA)/copper (I) iodide mediated and tetrabutylammonium iodide promoted trifluoromethylation of 1-aryl-4-iodo-1,2,3-triazoles

Article abstract of DOI:10.1016/j.jfluchem.2020.109516

While several methods are available for the synthesis of a host of trifluoromethylated heterocycles, very few of them have been applied to access 4-trifluoromethylated 1,2,3-triazoles. We report herein a general methodology for the trifluoromethylation of 1-aryl-4-iodo-1, 2, 3-triazoles. Tetrabutylammonium iodide (TBAI) has been shown to provide enhanced conversion in these CuI-mediated reaction using methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (MDFA). The method exhibited broad functional group tolerance and was applied to the synthesis of a library of 1-aryl-4-trifluoromethyl-1,2,3-triazoles on the multi-gram scale.

Full text of DOI:10.1016/j.jfluchem.2020.109516

JournalofFluorineChemistry236(2020)109516
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Methyl-2,2-difluoro-2-(fluorosulfonyl) acetate (MDFA)/copper (I) iodide
mediated and tetrabutylammonium iodide promoted trifluoromethylation of
1-aryl-4-iodo-1,2,3-triazoles
Chiradeep Panjaa,*, Jayashankara Vaderapura Puttaramua,
Thirumurugan Kothandarama Chandrana, Roshan Y. Nimjea, Hemantha Kumara,
Anuradha Guptaa, Pirama Nayagam Arunachalama, James R. Corteb, Arvind Mathurb
a Department of Discovery Synthesis, Biocon Bristol-Myers Squibb Research Center, Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bangalore, 560100, India
b Discovery Chemistry, Bristol-Myers Squibb, P.O. Box 5400, Princeton, NJ, 08543-4000, United States
A R T I C L E I N F O
A B S T R A C T
Keywords:
While several methods are available for the synthesis of a host of trifluoromethylated heterocycles, very few of
them have been applied to access 4-trifluoromethylated 1,2,3-triazoles. We report herein a general methodology
for the trifluoromethylation of 1-aryl-4-iodo-1, 2, 3-triazoles. Tetrabutylammonium iodide (TBAI) has been
shown to provide enhanced conversion in these CuI-mediated reaction using methyl 2,2-difluoro-2-(fluor-
osulfonyl)acetate (MDFA). The method exhibited broad functional group tolerance and was applied to the
synthesis of a library of 1-aryl-4-trifluoromethyl-1,2,3-triazoles on the multi-gram scale.
1-Aryl-4-(trimethylsilyl)-1H-1,2,3-triazole
1-Aryl-4-iodo-1,2,3-triazole
Trifluoromethylation
Methyl 2,2-difluoro-2-(fluorosulfonyl)acetate
Tetrabutylammonium iodide
1-Aryl-4-(trifluoromethyl)-1H-1, 2, 3-triazole
1. Introduction
To support our drug discovery program, we were interested in
synthesizing several 1-aryl-4-trifluoromethyl-1,2,3-triazoles. While a
The 1,2,3-triazole is a common moiety, which can be found in many
biologically active compounds (Fig. 1) [1–3]. Some unique properties of
1,2,3-triazole are i) stability towards oxidation and reduction (ii) sta-
bility towards acidic and basic hydrolysis (iii) it can participate in hy-
drogen bonding interactions (iv) it can involve in π-stacking interaction
and dipole-dipole interactions [3]. The trifluoromethyl group (CF3) is
an important functional group, which is present in a various important
class of molecules, such as agrochemicals, pharmaceuticals, liquid
crystals, etc. [4a–c]. Considering the Van der Waals radii of 1.47 Å and
1.2 Å for fluorine and hydrogen respectively, the volume of a tri-
fluoromethyl group is about two times that of a methyl group [4d]. The
trifluoromethyl moiety can be considered as the bioisostere [4e] for the
isopropyl group. Adding a strong electron-withdrawing group like CF3
to a 1,2,3-triazole moiety can significantly make favorable changes to
the chemical and biological properties of the parent triazoles [4f].
In the last few decades, organic chemists have put substantial efforts
to develop new methodologies for the trifluoromethylation of aromatic
and heteroaromatic compounds [5a,b]. Among these methods, the
plethora of methods are available for the synthesis of various tri-
fluoromethylated heterocycles [4f,5–7], very few of them have been
applied to access trifluoromethylated triazoles. Cao and coworkers used
TMSCF3 as the trifluoromethyl source in the presence of CuI/KF/Phen/
Ag2CO3 for trifluoromethylation of 5-iodo triazoles [7a]. Ma et al. has
reported [8a] a silver-catalyzed [3 + 2] cycloaddition of isocyanides
with diazo compounds to access trifluoromethylated triazoles. Very
recently, Mohanan et al. has reported [8b] synthesis of tri-
fluoromethylated triazoles via cyclization of trifluorodiazoethane.
However, the lack of commercial availability of several substituted
isocyanides and gaseous nature of trifluorodiazoethane precluded the
use of these approaches for our SAR work. Other attractive approaches
to achieve this would be either a Cu-mediated Alkyne-Azide Click re-
action (CuAAC) using the appropriate azide and 3,3,3-trifluoroprop-1-
yne [5d] or by substituting a halogen group of a suitable precursor
molecule, using a CF3 source via metal catalysis [5e]. We envisioned
that the use of 3,3,3-trifluoroprop-1-yne [5f] could be problematic for
our SAR study due to the gaseous and flammable nature of this reagent,
and hence rationalized that the trifluoromethylation of the appropriate
iodo precursor would be the most expeditious route to the compounds
of interest. Herein, we describe such a strategy and development of the
coupling of the aromatic or heteroaromatic halides with
a tri-
fluoromethyl copper species is one of the most widely used methodol-
ogies in organofluorine chemistry [5a,c].
⁎ Corresponding author.
E-mail address: chiradeep.panja@syngeneintl.com (C. Panja).
https://doi.org/10.1016/j.jfluchem.2020.109516
Received 5 January 2020; Received in revised form 18 March 2020; Accepted 19 March 2020
Availableonline15May2020
0022-1139/©2020ElsevierB.V.Allrightsreserved.

C. Panja, et al.
JournalofFluorineChemistry236(2020)109516
Fig. 1. Examples of biologically active triazole compounds.
trifluoromethylation reaction to effect this transformation on 1,2,3-
triazole system.
[9b]. Our next goal was to convert the TMS triazole intermediate 4 to
the corresponding iodo intermediate 5a. Chlorination methodology on
such substrates using silica and NCS [9b] has been reported, however,
we did not find many references for the iodination [10,11]. Following
the same NCS/silica mediated chlorination procedure, iodination re-
action on intermediate 4 using NIS/silica was found to be extremely
sluggish, taking 3 days for completion. We rationalized that the rate of
the reaction could be enhanced by fine-tuning the acidity of the reac-
tion medium. A quick screening of acid additives revealed that the
addition of a catalytic amount of acetic acid to the reaction led to
complete conversion to 5a within 16 h. This methodology was later
applied to synthesize 1-aryl-4-iodotriazoles (5b–l). These compounds
could be coupled with a variety of partners leading to a large number of
substituted analogs.
2. Results and discussion
2.1. Synthesis of 4-iodo-substituted 1, 2, 3-triazole 5a as a model precursor
Trifluoromethylated triazole 6a was our initial target molecule and
would arise from the corresponding iodotriazole 5a (Scheme 1). The
iodotriazole 5a was synthesized in four steps starting from 2-bromo-4-
chloroaniline 1, which was converted to the pyrimidine intermediate 3
via Suzuki–Miyaura coupling [9a]. Following standard copper-cata-
lyzed click chemistry with t-butyl nitrite, TMS azide, and TMS-acet-
ylene, the TMS substituted triazolo intermediate 4 was synthesized
Scheme 1. Synthesis of iodo-substituted 1, 2, 3-triazole 5a as a model precursor.
2

C. Panja, et al.
JournalofFluorineChemistry236(2020)109516
Table 1
Table 2
Optimization of trifluoromethylation reaction of 5a using MDFA as the tri-
Screening of alkyl ammonium additives for the trifluoromethylation reaction.
fluoromethylating agent.
Entry
Additives
Cu-Regaent
Conversion (%)b
Entry
Cu-Source/Additives
Solvent
Temp. ºC
Conversion (%)b
1
2
3
4
5
nBu4N+I-
Cul
Cul
Cul
Cul
Cul
62
42
37
42
40
C6H5CH2N+[(CH2)3CH3]3I-
(CH3CH2CH2)4N+I-
[CH3(CH2)6]4N+I-
Et4N+I-
1
Cul
DMF
80
80
80
80
80
80
80
80
80
80
80
80
18
26
62
62
42
37
46
45
45
44
26
32
2
Cul
HMPA
3
Cul/Complex-A
Cul/TBAI
Cul/TBAI
Cul/KI
HMPA
4
HMPA
5
DMPU
6
DMF/HMPA(1:1)
HMPA
aConditions: HMPA (15 vol.), methyl fluorosulfonyldifluoroacetate
(FSO2CF2CO2Me) (5 equiv.), Cul (0.86 equiv.) and iodide salts (0.33 equiv.).
7
Cul/KI
8
Cul/Nal
HMPA
b
Monitored by LCMS.
9
Cul/KF
HMPA
10
11
12
Cul/CsF
CuSO4/TBAI
Cu(OTf)2/TBAI
HMPA
HMPA
advantage over TBAI was observed using other alkyl ammonium io-
dides (Table 2, entries 2–5). In summary, the best conversion (62 %)
and yield (43.6 %) were observed using 5–7 equiv. of MDFA in the
presence of CuI and TBAI in HMPA on a 30 g scale.
HMPA
aConditions: Solvent (15 vol.), methyl fluorosulfonyldifluoroacetate
(FSO2CF2CO2Me) (5 equiv.), Cu-salts (0.86 equiv.) and iodide salts (0.33
equiv.), 2h.
2.3. 19F NMR studies to understand the effect of additive TBAI
b
By LCMS.
The CuI-mediated trifluoromethylation reaction using MDFA is be-
lieved to proceed via in situ formation of ‘CuCF3’ species [5,13,14]. To
understand the role of the added TBAI and the nature of the CuCF3
species responsible for the trifluoromethylation reaction, two different
19F NMR experiments [15] were performed. In the first experiment 19F
NMR data was recorded. at 90 °C, mimicking the optimized reaction
conditions with and without added TBAI. The 19F NMR spectra with
added TBAI (0.4 equiv.) led to a significant increase in the intensity of
the peak at −34.5 ppm, which correlated with our experimental ob-
servation of improved conversions with added TBAI. Next, a variable
temperature 19F experiment (30 °C–90 °C) using CuI, MDFA, and TBAI
in HMPA was performed to find out the existence of various CuCF3
species at various temperatures. Results indicated the existence of two
prominent CuCF3 peaks at −28.8 and −32.3 ppm respectively, which
slowly disappeared at elevated temperature, while the peak at
−34.5 ppm was found to gradually increase as the NMR tube was he-
ated from 30 °C to 90 °C. These results indicated that the CuCF3 species
(peak at −34.5 ppm) plays a key role in the trifluoromethylation re-
action using TBAI as additive.
2.2. Optimization of the trifluoromethylation reaction of 5a
The iodo-compound 5a was used as a model precursor to screen
various conditions for the trifluoromethylation reaction. While most of
the known literature methods [5a] for the trifluoromethylation of aryl
iodides such as using Ruppert-Prakash reagent [11b], chlorodi-
fluoromethyl acetate [11c], sodium trifluoroacetate [11d], did not
provide any desired product, it was gratifying to note that, ∼18 %
product formation (Table1, entry 1) was observed in presence of CuI
and MDFA – Chen’s reagent, which was first reported by Chen et al.
[11e]. The ability of MDFA to be an efficient source of difluorocarbene
[11f, g] at a higher temperature, may be helpful for this transformation,
which required the addition of the MDFA under hot condition.
This initial result was encouraging; however, the low conversion
prompted further exploration of the reaction parameters including
solvent, Cu source, and additives. It is well documented in the review
article by Roy [5a] et al. that DMF and HMPA are the best solvent
systems for the trifluoromethylation reaction using MDFA as the re-
agent. While the reaction was sluggish in DMF, the use of HMPA as
solvent provided a marginal increase in the conversion (Table 1, entry
2). Next, additives, such as TBAI, KI, NaI, KF [12a], that have pre-
viously been used to provide rate enhancements of thio-tri-
fluoromethylation (SCF3) [12a] reactions were considered. It is known
in the literature [12b] that the addition of tetrabutylammonium iodide
(TBAI) to CuI increases the solubility of the Cu species by forming a
stable double salt. The use of this complex has been shown to sig-
nificantly improve the rates of Carbon—Nitrogen, Carbon—Oxygen,
bond formation [12b] and alkyne-azide Click reactions [12c].
2.4. General substrate scope for the trifluoromethylation reaction of 1-aryl
4-iodo-1, 2, 3-triazoles 5
Having established the optimized reaction conditions on the model
substrate 5a, we sought to explore the substrate scope of this reaction
with various 1-aryl-4-iodotriazoles. Once various 4-iodo-1-aryl-1,2,3-
triazoles 5b-l were in hand (Scheme 2), they were subjected to the
optimized trifluoromethylation condition and the results are shown in
(Table 3). It was observed that the reaction was not dependent on the
electronic nature of the substituent present in the aryl ring, and good to
moderate yield was obtained. Several sensitive functional groups such
as a ketone (Table 3, entry 8), ester (Table 3, entry 9) and nitrile
(Table 3, entry 10), were well-tolerated. More importantly, the reac-
tions were chemoselective, with bromo and chloro substituents staying
intact during the transformation. In most of these cases, the reactions
proceeded to > 60 % conversion; however, the isolated yields were
lower due to un-optimized isolation protocols on a small scale. Thus
this method was found to be generally applicable for the synthesis of a
Indeed, trifluoromethylation reaction with MDFA showed enhanced
conversion to 6a (62 %) (Table 1, entry 3) when the pre-formed
Complex-A [12b] was used with HMPA. Further, the reaction was just
as efficient when the complex was formed in situ by adding TBAI to the
reaction mixture (Table 1, entry 4). Attempts to substitute HMPA with
DMPU, did not improve the conversion (Table 1, Entry 5). Next, the
influence of other additives, such as KI, NaI, CsF, and KF (Table 1,
entries 6–10), were studied, but none of them resulted in further im-
provement. Other copper salts such as CuSO4, Cu(OTf)2 were not as
effective as CuI (Table 1, entries 11 & 12). Similarly, no added
3

C. Panja, et al.
JournalofFluorineChemistry236(2020)109516
Scheme 2. Synthesis of 4-Iodo-1, 2, 3-triazoles from anilines.
Table 3
Milli-Q Water were used. To measure the absorbance 220 nm wave-
length was used. HPLC data were recorded using Agilent 1200 series
using Triart C-8 (150 × 4.6 mm, 5μ) column and 10 mM ammonium
acetate: Acetonitrile; XBridge phenyl (150 × 4.6 mm, 3.5μ) sc/749
General substrate scope for the trifluoromethylation reaction of 1-aryl 4-iodo-1,
2, 3-triazoles.
using 0.05
% TFA in water: acetonitrile; and Sunfire C18
(150 × 4.6 mm, 3.5μ) columns. 1H NMR. 13C NMR and 19F NMR spectra
were acquired on Bruker 300 MHz and 400 MHz instruments at tem-
perature 300 K. Column chromatography was done using pre-packed
silica columns of 40–60 μ of Redisep® Rf200 (Teledyne ISCO) for < 50 g
scale and Torrent (Teledyne ISCO) for > 50 g batch size. LTQ Velos
Orbitrap mass spectrometer (Thermo Fisher Scientific, Bremen,
Germany) fitted with a heated electrospray ionization source and op-
erated in positive-ion mode was used to capture all HRMS data. The
data were recorded in a similar way as described in the literature [17].
To record electrospray mass spectrometry data, nitrogen was used both
as sheath gas and auxiliary gas, and helium was used for collision-in-
duced dissociation. The concentration of the compound was maintained
as 1 μM, with a flow rate of 5 μL/min, using gradient solvent acetoni-
trile: water (50 %–50 %) and the stock solution was made in DMSO.
Fourier transform mass spectrometry mode was used to operate the
Orbitrap to enable the acquisition of both full-scan mass spectra and
product-ion MS/MS spectra with mass accuracies within 5 ppm.
Entry
Ar
Product
Yield (%)
1
4-Cl-C6H4
6b
6c
6d
6e
6f
62
51
63
43
37
60
38
36
36
25
48
2
4-Br-C6H4
3
3-Cl-C6H4
4
4-F-C6H4
5
4-CH3-C6H4
C6H5
6
6g
6h
6i
7
3,5-(CF3)2-C6H3
4-COCH3-C6H4
4-CO2CH2CH3-C6H4
4-CN-C6H4
4-OCF3-C6H4
8
9
6j
10
11
6k
6l
variety of 1-aryl-4-trifluoromethyltriazoles from the corresponding
iodo-precursors.
4.2. Experimental procedures
4.2.1. 4-Chloro-2-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline
(2)
3. Conclusions
A mixture of 2-bromo-4-chloroaniline (1) (20 g, 97 mmol), bis (pi-
nacolato) diboron (27.1 g, 107 mmol), potassium acetate (24.72 g,
252 mmol), and PdCl2(dppf)−CH2Cl2 adduct (2.373 g, 2.91 mmol) was
taken in toluene (350 mL) at room temperature and the solution was
deoxygenated by purging nitrogen gas for 15 min. The reaction mass
was stirred at 90 °C for 16 h and the completion of the reaction was
determined by TLC (Ethyl acetate: petroleum ether; 3:7). The reaction
mixture was diluted with dichloromethane (400 mL) and filtered
through a pad of Celite. The filtrate was concentrated in vacuo to get
the crude material, which was subjected to column chromatography on
silica gel (petroleum ether/ethyl acetate as the eluent) to afford the
pure compound 2 as a white solid, 23 g, yield 64 %. 1H NMR (300 MHz,
CHLOROFORM-d) δ = 7.53 (d, J = 2.6 Hz, 1 H), 7.12 (dd, J = 2.6,
8.7 Hz, 1 H), 6.52 (d, J = 8.7 Hz, 1 H), 5.06−4.39 (m, 2 H), 1.34 (s,
12 H).
In summary, while several methods are available for the synthesis of
trifluoromethylated aromatic and heteroaromatic compounds from
their halo precursors, these were not amenable to the synthesis of tri-
fluoromethyl triazoles. We demonstrated that the combination of MDFA
with CuI and TBAI provided the trifluoromethyl triazoles.
Tetrabutylammonium iodide is believed to play a key role in affecting
better conversion, presumably by solubilizing the Cu and making it
available in the solution for the reaction. This methodology was scaled
up to multi-gram scale and enabled us to synthesize a host of 1-aryl-4-
trifluoromethyltriazoles, and rapidly expand the structure-activity re-
lationship (SAR) in the Discovery space for the program. Very recently,
this methodology has been successfully scaled up using continuous flow
chemistry to synthesize larger quantities of the target compound 6a,
and the results were communicated [16] by our Process Chemistry
Department.
4.2.2. 4-Chloro-2-(6-methoxypyrimidin-4-yl) aniline (3)
4. Experimental
A mixture of 4-chloro-2-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-
2-yl) aniline (2) (65 g, 256 mmol), 4-chloro-6-methoxypyrimidine
(37.1 g, 256 mmol) was taken in tetrahydrofuran (1.2 L) and the solu-
tion was deoxygenated by purging nitrogen gas for 15 min. In another
500 mL conical flask, tripotassium phosphate (136 g, 641 mmol) was
dissolved in water (300 mL), and was deoxygenated by purging ni-
trogen gas for 15 min. This aqueous solution was added to the above
reaction mixture, and purging of nitrogen was continued for another
15 min, followed by the addition of PdCl2(dppf)−CH2Cl2 adduct
(6.28 g, 7.69 mmol). The reaction mixture was stirred at 70 °C for 16 h.
4.1. General
All solvents and reagents were commercially available and were
used as such without further purification. All LCMS experiments were
done using Agilent 1200 coupled with Agilent 6140 Single Quad MS,
and Agilent 6330 single quad MS using ES-APCI method with an
Ascentis Express C18 (2.1 × 50 mm, 2.7 μm) column at ambient tem-
perature. A gradient of acetonitrile and 10 mM ammonium formate in
4

C. Panja, et al.
JournalofFluorineChemistry236(2020)109516
The mixture was cooled to room temperature and diluted with ethyl
acetate (700 mL), filtered through a pad of celite, washed with 400 mL
ethyl acetate. The combined filtrate was washed with brine solution
(500 mL), dried over anhydrous Na2SO4, filtered and concentrated in
vacuo to get the crude material, which was subjected to column chro-
matography on silica gel (petroleum ether/ethyl acetate as the eluent)
to afford pure compound 3 as a white solid, 72.8 g, yield 67.1 %. 1H
NMR (300 MHz, CHLOROFORM-d) δ = 8.7 (s, 1 H), 7.48 (d,
J = 2.4 Hz,1 H), 7.16 (dd, J = 2.4 Hz, 8.7 Hz,1 H), 6.98 (s,1 H), 6.65 (d,
J = 8.7 Hz,1 H),5.90 (bs, 2 H), 4.02 (s, 3 H). 13C NMR (75 MHz, CHL-
OROFORM-d) δ = 170.6, 165.7, 157.3, 146.3, 131.3, 128.67, 122.1,
120.0, 118.9, 104.27, 54.0. LCMS m/z (ESI); [M+H]+ 236.0.
hexamethylphosphoramide (240 mL, 1379 mmol), at 80 °C were added
copper (I) iodide (18 g, 95.0 mmol), and tetrabutylammonium iodide
(18 g, 48.7 mmol) followed by dropwise addition of methyl 2, 2-di-
fluoro-2-(fluorosulfonyl) acetate (MDFA) (64.6 mL, 508 mmol) from a
dropping funnel. The reaction was continued for 2 h at 90 °C and the
progress of the reaction was monitored by TLC (ethyl acetate: petro-
leum ether; 3:7). After completion, the reaction mixture was cooled to
room temperature and water (450 mL) was poured into it. The reaction
mixture was filtered through a celite bed and washed with ethyl acetate
(250 mL). Layers were separated and the aqueous layer was extracted
with ethyl acetate (2 × 250 mL). The combined organic layer was wa-
shed with brine solution (1 × 250 mL), dried over anhydrous Na2SO4,
filtered and concentrated in vacuum to get the crude material, which
was subjected to column chromatography on silica gel using petroleum
ether/ethyl acetate (8:2) as the eluent to afford the pure compound (6a)
as a white solid, 11.2 g, yield 43.6 %. 1H NMR (400 MHz, DMSO-d6): δ
3.94 (s, 3 H), 7.09 (d, J = 1.2 Hz, 1 H), 7.84–7.91 (m, 2 H), 8.01 (d,
J = 2.8 Hz, 1 H), 8.56 (d, J = 1.2 Hz, 1 H), 9.27 (s, 1 H). 19F NMR
(376.5 MHz, DMSO-d6): δ -59.65. 13C NMR (100 MHz, DMSO-d6): δ
169.7, 161.9, 157.7, 136.8 (q, J = 38.1 Hz), 135.6, 135.5, 132.7, 130.8,
130.7, 129.0, 127.9, 120.7 (q, J = 265.5 Hz), 107.4, 54.0. HRMS (ESI)
(m/z): calcd for C14H10ClF3N5O, 356.0520 [M+H]+, found 356.0517.
4.2.3. 4-(5-Chloro-2-(4-(trimethylsilyl)-1H-1, 2, 3-triazol-1-yl) phenyl)-6-
methoxypyrimidine (4)
4-Chloro-2-(6-methoxy pyrimidin-4-yl) aniline (3) (22.5 g,
95 mmol) was taken in acetonitrile (900 mL) and cooled to 0 °C. t-Butyl
nitrite (19.30 mL, 162 mmol) and trimethylsilyl azide (19.01 mL,
143 mmol) were added dropwise to it. The reaction mixture was al-
lowed to warm to room temperature and stirred for 2 h.
Trimethylsilylacetylene (53.6 mL, 382 mmol) was added dropwise to
the reaction mixture followed by the addition of copper (II) sulphate
pentahydrate (2.384 g, 9.55 mmol) and a solution of L-sodium ascor-
bate (9.46 g, 47.7 mmol) in water (270 mL). This mixture was stirred at
room temperature for 30 min, then warmed to 30 °C and stirred for one
hour. It was again cooled to room temperature (22 °C), diluted with
ethyl acetate (1 L) and water (500 mL). Organic layer was separated and
the aqueous layer was extracted with ethyl acetate (3 × 500 mL). The
combined organic layer was washed with brine solution (500 mL), dried
over anhydrous Na2SO4, filtered, and the filtrate was concentrated in
vacuo to give a brown liquid, which was subjected to column chro-
matography on silica gel (petroleum ether/ethyl acetate as the eluent)
to afford the pure compound 4 as a yellow-orange solid, 34 g, yield:
67.1 %. 1H NMR (400 MHz, CHLOROFORM-d) δ = 8.70 (s, 1 H), 7.81
(d, J = 2.4 Hz, 1 H), 7.58 (dd, J = 2.4 Hz, 8.7 Hz, 1 H), 7.51 (d,
4.3. General procedure for the synthesis of 1-aryll-4-(trimethylsilyl)-1H-1,
2, 3-triazole (8)
A solution of substituted aniline 7 (1.0 mmol) in acetonitrile
(40 mL), was cooled to 0 °C and t-butyl nitrite (1.69 mmol), and tri-
methylsilyl azide (1.4 mmol) were added dropwise to it. The reaction
mixture was allowed to warm to room temperature and stirred for 2 h.
Trimethylsilylacetylene (3.7 mmol) was added dropwise followed by
addition of Copper (II) sulfate pentahydrate (0.1 mmol) and a solution
of L-sodium ascorbate (0.5 mmol) in water (150 mL). This mixture was
stirred at room temperature for 30 min, then warmed to 30 °C and
stirred for one hour. It was again cooled to room temperature (22 °C),
diluted with ethyl acetate (250 mL), washed with brine solution
(100 mL), dried over sodium sulfate, filtered and the filtrate was con-
centrated to get the crude product. The resulting crude material was
subjected to column chromatography on silica gel (petroleum ether/
ethyl acetate as the eluent) to afford the desired compound of sub-
stituted phenyl-4-(trimethylsilyl)-1H-1, 2, 3-triazole 8.
J = 8.7 Hz, 1 H), 7.49 (s, 1 H), 6.2 (s, 1 H), 3.92 (s, 3 H), 0.3 (s, 9 H). 13
C
NMR (75 MHz, CHLOROFORM-d) δ = 170.1, 161.9, 158.4, 147.2,
136.2, 135.80, 133.9, 131.2, 130.9, 130.7, 128.2, 107.3, 54.2, -1.1.
LCMS m/z (ESI); [M+H]+ 360.1.
4.2.4. 4-(5-Chloro-2-(4-iodo-1H-1, 2, 3-triazol-1-yl) phenyl)-6-methox
ypyrimidine (5a)
A mixture of 4-(5-chloro-2-(4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)
phenyl)-6-methoxy pyrimidine (4) (100 g, 208 mmol), N-iodosuccini-
mide (281 g, 1250 mmol), silicon dioxide (288 g, 4793 mmol) (Silica gel
230–400 Mesh), acetic acid (2.386 mL, 41.7 mmol) was taken in acet-
onitrile (2000 mL) at room temperature. The heterogeneous reaction
mixture was vigorously stirred at 80 °C (pre-heated oil bath) for 12 h.
The heterogeneous mixture was cooled to room temperature, filtered
through a pad of Celite, and washed with ethyl acetate (2 × 1000 mL).
The combined filtrate and washing was concentrated in vacuum, di-
luted with ethyl acetate (1000 mL), washed with 10 % sodium thio-
sulphate solution (2 × 1000 mL), washed with brine solution (500 mL),
dried over anhydrous sodium sulphate, filtered and concentrated in
vacuo. The resulting crude material was subjected to column chroma-
tography on silica gel using petroleum ether/ethyl acetate (8:2) as the
eluent to afford the pure compound 5a as a white solid, 45 g, yield 60
%. 1H NMR (300 MHz, CHLOROFORM-d) δ = 8.68 (d, J = 1.1 Hz, 1 H),
7.75 (d, J = 2.3 Hz, 1 H), 7.71 (s, 1 H), 7.60 (dd, J = 2.3 Hz, 8.7 Hz,
1 H), 7.47 (d, J = 8.7 Hz,1 H), 6.48 (d, J = 1.1 Hz, 1 H), 3.96 (s, 3 H).
LCMS m/z (ESI); [M+H]+ 412.0.
4.4. General procedure for the synthesis 1-aryl-4-iodo-1H-1, 2, 3-triazole
(5)
A mixture of aryl-4-(trimethylsilyl)-1H-1,2,3-triazole (1.0 mmol), N-
iodosuccinimide (6.0 mmol), silicon dioxide (20.0 mmol) (Silica gel,
230–400 mesh), acetic acid (0.02 mmol) was taken in acetonitrile
(20 mL) and stirred at 80 °C (oil bath temperature) for 12 h. The reac-
tion mixture was cooled to room temperature, filtered through a celite
bed, washed with ethyl acetate (20 mL). The filtrate was washed with
10 % sodium thiosulfate solution (2 × 10 mL), brine solution (10 mL),
dried over sodium sulfate, filtered and the filtrate was concentrated
under reduced pressure to get the crude product. The resulting crude
material was subjected to column chromatography on silica gel (pet-
roleum ether/ethyl acetate as the eluent) to afford the pure desired
compound 4-iodo-substituted-aryl-1H-1, 2, 3-triazole 5.
4.5. Copper (I) iodide tetra-n-butylammonium iodide dimeric complex (n-
Bu4N+)2(Cu2I4)2− (complex A)
Complex A was prepared following the reported literature proce-
dure with slight modification [12a].
4.2.5. 4-(5-Chloro-2-(4-(trifluoromethyl)-1H-1, 2, 3-triazol-1-yl) phenyl)
-6-methoxypyrimidine (6a)
In a 100 mL three-neck round-bottom flask, fitted with a mechanical
stirrer, CuI (2.55 g, 1.0 equivalent), n-Bu4NI (4.95 g, 1.0 equivalent),
and anhydrous THF (20 mL) were added under nitrogen atmosphere.
To
a solution of 4-(5-chloro-2-(4-iodo-1H-1, 2, 3-triazol-1-yl)
phenyl)-6-methoxypyrimidine
(5a)
(30 g,
72.5 mmol)
in
5

C. Panja, et al.
JournalofFluorineChemistry236(2020)109516
Nitrogen gas was bubbled into the solution for 5 min. The mixture was
warmed to 48 °C. Once a homogeneous pale yellow solution was ob-
tained the reaction mixture was cooled to 10 °C and methyl tert-butyl
ether (25 mL) was added over 10 min. at 10 °C. The reaction mixture
was stirred at 10 °C for 30 min and the crystalline solid appeared was
filtered off and washed with 2:1 v/v t-BuOMe/THF (20 mL). The solid
was dried under nitrogen to provide (n-Bu4N+)2(Cu2I4)2− (5.0 g) of
quantitative yield as a white solid. 1H NMR (400 MHz, CHLOROF-
ORM-d) δ 3.33–3.28 (m, 16 H), 1.71–1.67 (m, 16 H), 1.52–1.46 (J
=7.3 Hz, 16 H), 1.05–1.01 (t, J =7.3 Hz, 24 H).
J = 265.75 Hz, 1C). HRMS: m/z calcd for C9H5ClF3N3 [M+H]+
248.0197, found 248.0186.
4.7.2. 1-(4-Bromophenyl)-4-(trifluoromethyl)-1H-1, 2, 3-triazole (6c) off
white solid
1H NMR (300 MHz, CHLOROFORM-d) δ = 8.26 (s, 1 H), 7.77−7.70
(m, 2 H), 7.70−7.60 (m, 2 H). 19F NMR (400 MHz, CHLOROFORM-d) δ
–61.26. 13C NMR (75 MHz, CHLOROFORM-d) δ = 139.7 (q,
J = 39.5 Hz, 1C), 135.1, 133.2, 123.7, 122.3, 121.4, 120.2 (q, J
=268.4 Hz, 1C). HRMS: m/z calcd for C9H5BrF3N3 [M+H]+ 291.9692,
found 291.9684.
4.6. Synthesis of 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)
phenyl)-6-methoxypyrimidine (6a) using dimeric Complex (n-
Bu4N+)2(Cu2I4)2− (Complex A)
4.7.3. 1-(3-Chlorophenyl)-4-(trifluoromethyl)-1H-1, 2, 3-triazole (6d)
white solid
1H NMR (400 MHz, CHLOROFORM-d) δ = 8.28 (s, 1 H), 7.85−7.77
(m, 1 H), 7.66 (td, J = 2.3, 6.6 Hz, 1 H), 7.57−7.47 (m, 2 H). 19F NMR
(400 MHz, CHLOROFORM-d) δ –61.30. 13C NMR (101 MHz, CHLOR-
OFORM-d) δ = 139.7 (q, J = 39.8 Hz, 1C), 136.9, 135.9, 131.1, 129.9,
124.2, 121.5 (q, J = 3.7 Hz), 120.2 (q, J = 265 Hz), 121.2, 118.9,
118.9. HRMS: m/z calcd for C9H5ClF3N3 [M+H]+ 248.0197, found
248.0192.
To a solution of 4-(5-chloro-2-(4-iodo-1H-1,2,3-triazol-1-yl)phenyl)-
6-methoxypyrimidine (5a) (1 g, 2.418 mmol) in hexamethylpho-
sphoramide (2.103 mL, 12.09 mmol), was added dimeric complex
(nBu4N+)2(Cu2I4)2− (Complex A) (0.089 g, 0.242 mmol). This solution
was stirred at 80 °C (pre-heated oil bath), and methyl 2,2-difluoro-2-
(fluorosulfonyl) acetate (0.616 mL, 4.84 mmol) was added dropwise
from a syringe. The reaction was continued for 2 h at 90 °C, with con-
tinuous monitoring of the reaction by TLC (ethyl acetate: petroleum
ether; 3:7). The reaction mixture was cooled to room temperature,
quenched with ice-cold water (6 mL) and filtered through celite bed.
The bed was washed with ethyl acetate (25 mL). Layers were separated
and the aqueous layer was extracted with ethyl acetate (2 × 25 mL).
The combined organic layer was washed with brine solution (25 mL),
dried over anhydrous Na2SO4, filtered and concentrated in vacuum to
give the crude material, which was subjected to column chromato-
graphy on silica gel using petroleum ether/ethyl acetate (8:2) as the
eluent to afford the pure compound 6c as a white solid, 0.370 g, yield
43 %; 1H NMR (400 MHz, DMSO-d6): δ 3.94 (s, 3 H), 7.09 (d,
J = 1.2 Hz, 1 H), 7.84–7.91 (m, 2 H), 8.01 (d, J = 2.8 Hz, 1 H), 8.56 (d,
J = 1.2 Hz, 1 H), 9.27 (s, 1 H). 19F NMR (376.5 MHz, DMSO-d6): δ-
59.65. 13C NMR (100 MHz, DMSO-d6): δ 169.7, 161.9, 157.7, 136.8 (q,
J = 38.1 Hz), 135.6, 135.5, 132.7, 130.8, 130.7, 129.0, 127.9, 120.7 (q,
J = 265.5 Hz), 107.4, 54.0. HRMS (ESI) (m/z): calcd for
4.7.4. 1-(4-Fluorophenyl)-4-(trifluoromethyl)-1H-1, 2, 3-triazole (6e)
white solid
1H NMR (300 MHz, CHLOROFORM-d) δ = 8.26 (s, 1 H), 7.80−7.71
(m, 2 H), 7.32−7.22 (m, 2 H). 19F NMR (400 MHz, CHLOROFORM-d) δ
–110.22, –61.24. 13C NMR (75 MHz, DMSO-d6) δ = 162.7 (d,
J = 247.3 Hz, 1C), 138.1 (q, J = 38.4 Hz, 1C), 132.9 (d, J = 2.7 Hz,
1C), 124.9 (q, J = 2.7 Hz, 1C), 123.7 (d, J = 9.5 Hz, 1C), 121.1 (q,
J = 267.3 Hz, 1C),117.3 (d, J = 23.2 Hz, 1C). HRMS: m/z calcd for
C9H5F4N3 [M+H]+ 232.0492 found 232.0487.
4.7.5. 1-(p-Tolyl)-4-(trifluoromethyl)-1H-1,2,3-triazole (6f) white solid
1
H NMR (300 MHz, CHLOROFORM-d) δ = 8.23 (s, 1 H), 7.61 (d,
J = 8.7 Hz, 2 H), 7.36 (d, J = 8.7 Hz, 2 H), 2.45 (s, 3 H). 19F NMR
(400 MHz, DMSO-d6)
δ
–61.16. 13C NMR (75 MHz, DMSO-d6)
δ = 139.8, 138.1 (q, J = 38.8 Hz, 1C), 134.1, 130.7, 124.5 (q,
J = 3.2 Hz, 1C), 121.1, 121.2 (q, J = 267.0 Hz, 1C), 21.0. HRMS: m/z
+
C
14H10ClF3N5O, 356.0520 [M+H]+, found 356.0517.
calcd for C10H8F3N3 [M+H] 228.0743 found 228.0737.
4.7. General procedure for the 1-aryl-4-(trifluoromethyl)-1H-1, 2, 3-
4.7.6. 1-(Phenyl)-4-(trifluoromethyl)-1H-1, 2, 3-triazole (6g) white solid
1H NMR (400 MHz, CHLOROFORM-d) δ = 8.30 (s, 1 H), 7.83−7.70
(m, 2 H), 7.65−7.52 (m, 3 H). 19F NMR (400 MHz, CHLOROFORM-d) δ
–61.2. 13C NMR (101 MHz, CHLOROFORM-d) δ = 139.6 (q,
J = 42 Hz),136.2, 130.00, 129.8, 121.7, 121.45121.0, 120.9, 120.4 (q,
triazole (6)
To
a
solution of 4-iodo-substituted-aryl-1H-1,2,3-triazole
5
(1.5 mmol) in hexamethylphosphoramide (HMPA) (15 mL) at 80 °C, Cu
(I)I (1.95 mmol), and tetrabutylammonium iodide (0.75 mmol) were
added, followed by dropwise addition of Methyl 2,2-difluoro-2-(fluor-
osulfonyl)acetate (10.5 mmol) (MDFA) over 5 min. The reaction mix-
ture was stirred at 90 °C for 2 h and the progress of the reaction was
monitored by TLC (8:2; Petroleum ether: EtOAc). Reaction mixture was
cooled to room temperature, quenched with ice-cold water (15 mL),
diluted with ethyl acetate (15 mL) and filtered through celite bed. The
bed was washed with ethyl acetate (7.5 mL). The layers were separated
and the organic layer was washed with water (7.5 mL), brine solution
(7.5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate
was concentrated to get the crude product. The resulting crude material
was subjected to column chromatography on silica gel using petroleum
ether/ethyl acetate (8:2) as the eluent to afford the pure 1-aryl-4-(tri-
fluoromethyl)-1H-1, 2, 3-triazole 6.
+
J = 265 Hz), 100. HRMS: m/z calcd for C11H10F3N3O2 [M+H]
214.0587 found 214.058.
4.7.7. 1-(3, 5-Bis (trifluoromethyl) phenyl)-4-(trifluoromethyl)-1H-1, 2, 3-
triazole (6 h) white solid
1H NMR (400 MHz, CHLOROFORM-d) δ = 8.44 (d, J = 1.0 Hz,
1 H), 8.28 (d, J = 1.5 Hz, 2 H), 8.07−8.03 (m, 1 H). 19F NMR
(400 MHz, CHLOROFORM-d) δ –63.05, –61.40. 13C NMR (75 MHz,
CHLOROFORM-d) δ = 140.4 (q, J = 39.8 Hz, 1C), 137.2, 134.0 (q,
J = 34.7 Hz, 1C), 123.3(q, J = 3.0 Hz, 1C), 122.3 (q, J = 273.2 Hz, 1C),
121.7, 121.0, 116.4 (q, J = 267.2 Hz, 1C). HRMS: m/z calcd for
+
C
11H4F9N3 [M+H] 350.0334 found 350.0323.
4.7.8. 1-(4-Acetylphenyl)-4-(trifluoromethyl)-1H-1, 2, 3-triazole (6i)
white solid
4.7.1. 1-(4-Chlorophenyl)-4-(trifluoromethyl)-1H-1, 2, 3-triazole (6b)
white solid
1H NMR (400 MHz, CHLOROFORM-d) δ = 8.36 (s, 1 H), 8.17 (d, J
= 9.0 Hz, 2 H), 7.90 (d, J = 9.0 Hz, 2 H), 2.68 (s, 3 H). 19F NMR
(400 MHz, CHLOROFORM-d) δ –61.30. 13C NMR (75 MHz, DMSO-d6)
δ = 197.4, 139.3, 137.6, 138.3 (q, J = 38.8 Hz, 1C), 130.5, 125.1 (q,
J = 2.7 Hz, 1C), 121.1, 121.1 (q, J = 267.5 Hz, 1C), 27.3. HRMS: m/z
calcld for C11H4F9N3 [M+H]+ 256.0692 found 256.0688.
1H NMR (400 MHz, DMSO-d6) δ = 9.63 (s, 1 H), 8.00 (d, J = 9.0 Hz,
2 H), 7.73 (d, J = 9.0 Hz, 2 H).19F NMR (400 MHz, CHLOROFORM-d) δ
–61.26. 13C NMR (101 MHz, DMSO-d6) δ = 138.2 (q, J = 38.3 Hz, 1C),
134.7, 134.0, 129.9, 124.5 (q, J = 2.5 Hz, 1C), 122.5,121.1 (q,
6

C. Panja, et al.
JournalofFluorineChemistry236(2020)109516
4.7.9. 1-(4-Ethoxycarbonylphenyl)-4-(trifluoromethyl)-1H-1, 2, 3-triazole
(6j) white solid
(f) Fluorine in Hetreocyclic Chemistry, Valentine Nenajdenko (Ed.), Volume-1; 5-
Membered Heterocylces and Macrocyles, Springer, 2014.
[5] (a) S. Roy, B.T. Gregg, G.W. Gribble, V.-D. Le, S. Roy, Trifluoromethylation of aryl
and heteroaryl halides, Tetrahedron 67 (2011) 2161–2195 and references there in;
3, 3, 3-Trifluoroprop-1-yne is a highly flammable and irritant gas.
(b) O.A. Tomashenko, V.V. Grushin, Aromatic trifluoromethylation with metal
complexes, Chem. Rev. 111 (2011) 4475–4521;
1H NMR (400 MHz, CHLOROFORM-d) δ = 8.35−8.34 (m, 1 H),
8.26 (d, J =8.5 Hz, 2 H), 7.86 (d, J = 9.0 Hz, 2 H), 4.44 (q, J = 8.0 Hz,
2 H), 1.46−1.41 (t, J =8.0 Hz, 3 H). 19F NMR (400 MHz, CHLOROF-
ORM-d) δ –61.29. 13C NMR (75 MHz, DMSO-d6) δ = 165.1, 139.5,
138.4 (q, J = 38.6 Hz, 1C), 131.3, 1301.0, 124.9 (q, J = 2.7 Hz, 1C),
121.0, 121.0 (q, J = 267.7 Hz, 1C), 61.6, 14.5. HRMS: m/z calcd for
(c) G.-b. Li, C. Zhang, C. Song, Y.-d. Ma, Progress in copper-catalyzed tri-
fluoromethylation, Beilstein J. Org. Chem. 14 (2018) 155–181;
(d) V.D. Bock, H. Hiemstra, J.H. van Maarseveen, CuI-catalyzed alkyne-azide
“Click” cycloadditions from a mechanistic and synthetic perspective, Eur. J. Org.
Chem. (2006) 51–68;
C
11H4F9N3 [M+H]+ 286.0798 found 286.0789.·
(e) T. Liu, Q. Shen, Progress in copper-mediated formation of trifluoromethylated
arenes, Eur. J. Org. Chem. (2012) 6679–6687
4.7.10. 4-(4-(Trifluoromethyl)-1H-1, 2, 3-triazol-1-yl) benzonitrile (6k)
white solid
[6] (a) J. Wei, J. Chen, J. Xu, L. Cao, H. Deng, W. Sheng, H. Zhang, W. Cao, Scope and
regioselectivity of the 1,3-dipolar cycloaddtion of azides with methyl-2-per-
fluoroalkylnoates for an easy, metal free route to perfluoroalkylated 1,2,3-triazoles,
J. Fluor. Chem. 133 (2012) 146–154;
1H NMR (400 MHz, CHLOROFORM-d) δ = 8.39−8.35 (m, 1 H),
7.99−7.87 (m, 4 H). 19F NMR (400 MHz, CHLOROFORM-d) δ –61.45.
13C NMR (75 MHz, CHLOROFORM-d) δ = 140.2 (q, J = 40.2 Hz, 1C),
138.9, 134.1, 121.4, 121.1, 120.2 (q, J = 267.7 Hz, 1C), 117.3, 113.7.
HRMS: m/z calcd for C10H5F3N4 [M+H]+ 239.0539 found 239.0534·
(b) Y. Kobayashi, H. Hamana, S. Fujino, A. Ohsawa, I. Kumadaki, Studies of or-
ganic fluorine compounds. 29. Cycloaddition reactions of hexakis(trifluoromethyl)-
1,4-diphosphabarrelene, J. Org. Chem. 44 (1979) 4930–4933;
(c) G. Meazza, G. Zanardi, Aryl trifluoromethyl-1,2,3-triazoles, J. Fluor. Chem. 55
(1991) 199–206;
(d) T. Hanamoto, Y. Hakoshima, M. Egashira, Tributyl(3,3,3-trifluoro-1-propynyl)
stannane as an efficient reagent for the preparation of various trifluoromethylated
heterocyclic compounds, Tetrahedron Lett. 45 (2004) 7573–7576;
(e) F. Wei, T. Zhou, Y. Ma, C.-H. Tung, Z. Xu, Bench stable5-stannyl triazoles by a
copper(I) catalyzed interrupted click reaction: bridge to trifluoromethyltriazoles
and trifluoromethylthiotriazoles, Org. Lett. 19 (2017) 2098–2101;
(f) A. Pace, S. Buscemi, N. Vivona, Org. Prep. Proced. Int. 37 (5) (2005) 447–506;
(g) W. Carpenter, A. Haymaker, D.W. Moore, Fluorinated 1,2,3-triazolines, J. Org.
Chem. 31 (1966) 789–792.
4.7.11. 1-(4-(Trifluoromethoxy)phenyl)-4-(trifluoromethyl)-1H-1,2,3-
triazole (6l) white solid
1H NMR (300 MHz, CHLOROFORM-d) δ = 8.26 (s, 1 H), 7.82−7.77
(m, 2 H), 7.44−7.40 (m, 2 H). 19F NMR (400 MHz, CHLOROFORM-d) δ
–66.03, –62.73. 13C NMR (75 MHz, CHLOROFORM-d) δ = 149.8 (q,
J = 2.25 Hz, 1C),139.8 (q, J = 40.0 Hz, 1C), 134.4, 122.5, 122.5,
121.6, 120.3 (q, J = 258.9 Hz, 1C), 120.2 (q, J = 267.7 Hz, 1C). HRMS:
m/z calcd for C10H5F6N3O [M+H]+ 298.0410 found 298.0402.
[7] (a) D. Fu, J. Zhang, S. Cao, Copper mediated trifluoromethylation of 5-iodotriazole
with (trifluoromethyl)trimethylsilane promoted by silver carbonate, J. Fluor. Chem.
156 (2013) 170–176;
(b) C. Hager, R. Miethchen, H. Reinke, New trifluoromethyl substituted 1,2,3-
triazoles linked to D-galactose and D-gulose, J. Prakt. Chem. 342 (2000) 414–420.
[8] (a) S. Wang, L.-J. Yang, J.-L. Zeng, Y. Zheng, J.-A. Ma, Silver-catalyzed [3 + 2]
cycloaddition of isocyanides with diazo compounds: new regioselective access to
1,4-disubstituted-1,2,3-triazoles, Org. Chem. Front. 2 (2015) 1468–1474;
(b) A. Kumar, S. Ahamad, R. Kant, K. Mohanan, Silver-catalyzed three-component
route to trifluoromethylated 1,2,3-triazolines using aldehydes, amines and tri-
fluorodiazoethane, Org. Lett. 21 (2019) 2962–2965.
Declaration of Competing Interest
I hereby declare that there is no conflict of interest associated with
the submitted manuscript.
Acknowledgments
[9] (a) K. Barral, A.D. Moorhouse, J.E. Moses, Efficient conversion of aromatic amines
into azides: a one-pot synthesis of triazole linkages, Org. Lett. 9 (2007) 1809–1811;
K.T. Mark, J. Rong, S. Xinyi, L. Phillip, C.M. Darin, Substituted Pyrimidinyl-Amines
as Protein Kinase Inhibitors, WO2009032861A1 (2009).
Authors are thankful to Discovery Analytical Department, Biocon
Bristol-Myers Squibb Research Centre (BBRC), Syngene, Bangalore
(India) for analytical support. We wish to thank Drs. Rajappa
Vaidyanathan, and James Kempson for their insights and review of this
manuscript.
[10] M.B. Avory, H.J. Wadsworth, R.J. Domett Nairne, Radioiodinated Fatty Acids,
US20130272960A1 (2013).
[11] (a) A. Darwish, M. Blacker, N. Janzen, S.M. Rathmann, S. Czorny, S.M. Hillier,
J.L. Joyal, J.W. Babich, J.F. Valliant, Triazole appending agent (TAAG): a new
synthon for preparing iodine-based molecular imaging and radiotherapy agents,
ACS Med. Chem. Lett. 3 (2012) 313–316;
Appendix A. Supplementary data
(b) G.K.S. Prakash, M. Mandal, Nucleophilic trifluoromethylation tamed, J. Fluor.
Chem. 112 (2001) 123–131;
(c) J.J. Van Veldhuizen, D.G. Gil-lingham, S.B. Garber, O. Kataoka, A.H. Hoveyda,
Chiral Ru-based complexes for asymmetric olefin metathesis: enhancement of cat-
alyst activity through steric and electronic modifications, J. Am. Chem. Soc. 125
(2003) 12502–12508;
Supplementary material related to this article can be found, in the
online version, at doi:https://doi.org/10.1016/j.jfluchem.2020.
109516.
(d) S. Hunig, R. Bau, M. Kemmer, H. Meixner, T. Metzenthin, K. Peters, K. Sinzger,
J. Gulbis, 2,5-Disubstituted N,N’-dicyanoquinone diimines (DCNQIs)—syntheses,
and redox properties, J. Eur. J. Org. Chem. (1998) 335–348;
References
(e) Q.-Y. Chen, S.-W. Wu, Methyl fluorosulphonyldifluoroacetate; a new tri-
fluoromethylating agent, J. Chem. Soc. Chem. Commun. (1989) 705–706;
(f) A.J. Mulder, R.P. Frutos, N.D. Patel, B. Qu, X. Sun, T.G. Tampone, J. Gao,
M. Sarvestani, M.C. Eriksson, N. Haddad, S. Shen, J.J. Song, C.H. Senanayake,
Development of a safe and economical synthesis of methyl 6-chloro-5-(tri-
fluoromethyl)nicotinate: trifluoromethylation on kilogram scale, Org. Process Res.
Dev. 17 (2013) 940–945;
[1] D.K. Dalvie, A.S. Kalgutkar, S.C. Khojasteh-Bakht, R.S. Obach, J.P. Donnell,
Biotransformation reactions of five-membered aromatic heterocyclic rings, Chem.
Res. Toxicol. 15 (2002) 269–299.
[2] (a) S.G. Agalave, S.R. Maujan, V.S. Pore, Click chemistry: 1,2,3-triazoles as phar-
macophores, Chem. Asian J. 6 (2011) 2696–2718;
(b) N. Boechat, V.F. Ferreira, S.B. Ferreira, M.L.G. Ferreira, F.C. da Silva,
M.M. Bastos, M.S. Costa, M.C.S. Lourenco, A.C. Pinto, A.U. Krettli, A.C. Aguiar,
B.M. Teixeira, N.V. da Silva, P.R.C. Martins, F.A.F.M. Bezerra, A.L.S. Camilo,
G.P. da Silva, C.C.P. Costa, Novel 1,2,3-triazole derivatives for use against
Mycobacterium tuberculosis H37Rv (ATCC 27294) strain, J. Med. Chem. 54 (2011)
5988–5999.
(g) S. Eusterwiemann, H. Martinez, W.R. Dolbier Jr, Methyl 2.,2-difluoro-2-
(fluorosulfonyl) acetate, a difluorocarbene reagent with reactivity comparable to
that of trimethylsilyl 2,2-difluoro-2-(fluorosulfonyl) acetate (TFDA), J. Org. Chem.
77 (2012) 5461–5464;
(h) Q. Xie, J. Hu, Chen’s reagent: a versatile reagent for trifluoromethylation, di-
fluoromethylation, and difluoroalkylation in organic synthesis, Chin. J. Chem. 38
(2) (2020) 202–212.
[3] S. Haider, M.S. Alam, H. Hamid, 1, 2, 3-Triazoles: scaffold with medicinal sig-
nificance, Inflamm. Cell Signal. 1 (2014) 1–10 e95.
[4] (a) D. Cartwright, R.E. Banks, B.E. Smart, J.C. Tatlow (Eds.), Organofluorine
Chemistry, Plenum, New York, 1994, pp. 237–262;
[12] (a) J.D. Adams, J.H. Clark, Preparation of trifluoromethyl aryl sulfides using silver
(I) trifluoromethanethiolate and an inorganic iodide, J. Org. Chem. 65 (2000)
1456–1460;
(b) P. Kirsch, Modern Fluoro-Organic Chemistry, Wiley-VCH, Weinheim, Germny,
2004;
(b) P.E. Maligres, S.W. Krska, P.G. Dormer, A soluble copper(I) source and stable
salts of volatile ligands for copper-catalyzed C−X couplings, J. Org. Chem. 77
(2012) 7646–7651;
(c) K. Müller, C. Faeh, F. Diederich, Fluorine in pharmaceuticals: looking beyond
intuition, Science, (2007), pp. 1881–1886;
(d) H.-J. Bohm, D. Banner, S. Bendels, M. Kan-sy, B. Kuhn, K. Muller, U.-O. Sander,
M. Stahl, Fluorine in medicinal chemistry, Chem-BioChem, (2004), pp. 637–643;
(e) N.A. Meanwell, Fluorine and fluorinated motifs in the design and application of
bioisosteres for drug design, J. Med. Chem. (2018), pp. 5822–5880;
(c) S. Ramasamy, C. Petha, S. Tendulkar, P. Maity, M.D. Eastgate, R. Vaidyanathan,
Synergistic effect of copper and ruthenium on regioselectivity in the alkyne-azide
click reaction of internal alkynes, Org. Process Res. Dev. 22 (2018) 880–887.
[13] (a) C.P. Zhang, Z.L. Wang, Q.Y. Chen, C.T. Zhang, Y.C. Gu, J.C. Xiao, Copper
7

C. Panja, et al.
JournalofFluorineChemistry236(2020)109516
mediated trifluoromethylation of heteroaromatic compounds by trifluoromethyl
chlorodifluoroacetate, J. Fluor. Chem. 55 (1991) 225–227;
sulfonium salts, Angew. Chem. Int. Ed. 50 (2011) 1896–1900;
(b) O.A. Tomashenko, E.C. Escudero-Adán, M. Martínez Belmonte, V.V. Grushin,
Simple, stable and easily accessible well-defined CuCF3 aromatic tri-
fluoromethylating agents, Angew. Chem. Int. Ed. 50 (2011) 7655–7659;
(c) H. Serizawa, K. Aikawa, K. Mikami, Direct synthesis of a trifluoromethyl copper
reagent from trifluoromethyl ketones: application to trifluoromethylation, Chem.
Eur. J. 19 (2013) 17692–17697;
(c) H. Liu, Q. Shen, Bistrifluoromethylated organocuprate [Ph4P]+[Cu(CF3)2]−
:
synthesis, characterization, and its application for trifluoromethylation of activated
heteroaryl bromides, chlorides and iodides, Org. Chem. Front. 6 (2019) 2334–2338.
[15] Please refer to the supporting information for the 19F NMR experiment data.
[16] R. Ayothiraman, A.S. Gangu, D. Bandaru, S.K. Guturi, T. Lakshminarasimhan,
M. Jaleel, K. Kanagavel, S. Rangaswamy, N.L. Cuniere, S. Zaretsky, K. Camacho,
M.D. Eastgate, R. Vaidyanathan, Two approaches to a trifluoromethyl triazole: a fit-
for-purpose trifluoromethylation in flow-mode and a long-term decarboxylative
click approach, Org. Process Res. Dev. 24 (2020) 207–215.
(d) Y. Nakamura, M. Fujiu, T. Murase, Y. Itoh, H. Serizawa, K. Aikawa, K. Mikami,
Cu-catalyzed trifluoromethylation of aryl iodides with trifluoromethylzinc reagent
prepared in situ from trifluoromethyl iodide, Beilstein J. Org. Chem. 9 (2013)
2404–2709.
[17] S. Sinha, D. Ahire, S. Wagh, D. Mullick, R. Sistla, K. Selvakumar, J.C. Cortes,
S.P. Putlur, S. Mandlekar, B.M. Johnson, Electrophilicity of pyridazine-3-carboni-
trile, pyrimidine-2-carbonitrile, and pyridine-carbonitrile derivatives: a chemical
model to describe the formation of thiazoline derivatives in human liver micro-
somes, Chem. Res. Toxicol. 27 (2014) 2052–2061.
[14] (a) D.M. Wiemers, D.J. Burton, Pregeneration, spectroscopic detection, and che-
mical reactivity of (trifluoromethyl)copper, an elusive and complex species, J. Am.
Chem. Soc. 108 (1986) 832–834;
(b) J.G. MacNeil, D.J. Burton, Generation of trifluoromethylcopper from
8