Metal-free [3+2] cycloaddition of glycosyl olefinic ester with in situ generated CF3CHN2: Access to CF3-substituted pyrazoline glycoconjugates

Article abstract of DOI:10.1016/j.carres.2020.108080

An efficient [3 + 2] cycloaddition of glycosyl olefinic ester with in situ generated CF₃CHN₂ for the syntheses of CF₃-substituted pyrazoline glycoconjugate has been developed. This mild, one-pot reaction condition avoiding the use of metallic catalyst and additive will be useful in the pharmaceutical industry. This reaction features are the broad substrate scope, good functional group tolerance with good to high yields.

Full text of DOI:10.1016/j.carres.2020.108080

Journal Pre-proof
Metal-free [3+2] cycloaddition of glycosyl olefinic ester with in situ generated
CF CHN : Access to CF -substituted pyrazoline glycoconjugates
3
2
3
Javed, Pintu Kumar Mandal
PII:
S0008-6215(20)30155-5
DOI:
https://doi.org/10.1016/j.carres.2020.108080
CAR 108080
Reference:
To appear in: Carbohydrate Research
Received Date: 10 March 2020
Revised Date: 10 June 2020
Accepted Date: 12 June 2020
Please cite this article as: Javed, P.K. Mandal, Metal-free [3+2] cycloaddition of glycosyl olefinic ester
with in situ generated CF CHN : Access to CF -substituted pyrazoline glycoconjugates, Carbohydrate
3
2
3
Research (2020), doi: https://doi.org/10.1016/j.carres.2020.108080.
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Metal-Free [3+2] cycloaddition of glycosyl olefinic ester with in
situ generated CF3CHN2: Access to CF3‑substituted pyrazoline
glycoconjugates
Javed,a and Pintu Kumar Mandala b*
aMedicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, BS-10/1, Sector 10,
Jankipuram extension, Sitapur Road, P.O. Box 173, Lucknow, 226 031, India.
bAcademy of Scientific and Innovative Research, New Delhi 110001, India
* Corresponding author; Email: pintuchem06@gmail.com / pk.mandal@cdri.res.in
Abstract: An efficient [3 + 2] cycloaddition of glycosyl olefinic ester with in situ generated
CF3CHN2 for the syntheses of CF3-substituted pyrazoline glycoconjugate has been
developed. This mild, one-pot reaction condition avoiding the use of metallic catalyst and
additive will be useful in the pharmaceutical industry. This reaction features are the broad
substrate scope, good functional group tolerance with good to high yields.
Keywords: Trifluoromethyl; Cycloaddition; pyrazoline glycoconjugate; trifluorodiazoethane
1. Introduction
Because of the distinctive properties of fluorine, the introduction of fluorine atoms or
fluoroalkylated groups into organic molecules has attracted significant interest from
researchers. The fluorine-containing compounds play significant roles in pharmaceutical
chemistry, agrochemistry, and materials science [1-3]. Generally selective installation of
fluorine or fluoroalkylated groups into a therapeutic or diagnostic small molecule candidate
can alter the properties of the parent compounds, including lipophilicity, metabolic stability,
enhanced bioactivity, and conformational behaviour [4,5]. Thus a new wave of fluorine

chemistry has been rapidly expanding its biomedical frontiers and a large number of
fluorinated compounds approved by the FDA for medical use [6]. Therefore synthesis of
fluorine containing motif has been paid much attention.
In particular, trifluoromethyl (CF3) group is the most prevalent fluorine-containing group in
various fluorine drugs because it has been proven to promote the metabolic stability and
bioavailability of many bioactive compounds [7].
On the other hand, pyrazoline derivatives are well known and important nitrogen containing
5-membered organic molecules because of their broad spectrum of biological activity and
widespread natural occurrence. Numerous pyrazoline derivatives have been found to possess
considerable biological activities, they are often often used as antitumor [8], antidepressant
[9], anti-inflammatory [10], antiviral [11], and antibacterial agents [12] as well as
cyclooxygenase(COX-2) inhibitors [13].
Besides, the trifluoromethyl group can also act as a bioisostere for methyl (CH3), chlorine
[14]. Among plenty of CF3-functionalized entities, some CF3-substituted pyrazolines and
pyazoles
exhibit
remarkable
biological
activities,
particularly
the
3-
trifluoromethylpyrazolines are prevalent motifs in many bioactive molecules and
pharmaceuticals (Figure 1) [15].
Figure 1: Some biologically active compounds having CF3-containing pyrazolines.

Apart from these impressive biological properties these compounds were found to be highly
versatile performers in various applications, such as electroluminescence [16], fluorescent
probes [17], and fluorescent whitening, recognition of transition metal ions, hole-transport
material, organic electronics agents [18].
In recent years, researchers has been paid much attention towards the combination of mixed
conjugates that made up of structural units of more than one variety of biopolymers, usually
carbohydrates, amino acids and heterocycles [19]. Considering the pivotal role of
carbohydrates in various physiological and pathological important processes [20, 21], various
methods for the synthesis of novel glycoconjugates has been developed.
Due to cooperative action of both the entirely distinct entities in the new conjugate, they are
known to exhibit unusual pharmacological activities. The glycoconjugates also exerted
important effects on many complex biological events, including cellular recognition in the
processes of immune response [22], inflammation [23], tumor metastasis [24], and viral &
bacterial infections [25]. Indeed, the modified sugars, where carbohydrate skeletons are
attached with biologically active heterocyclic derivatives to increase the biological function
and modulate the crucial parameters of a pharmaceutically active compound such as
pharmacodynamics and pharmacokinetic properties are attracted large attention from
chemists around the globe. Due to the importance of sugars in biological systems, the
development of more efficient synthetic methods to construct these sugar-based biomolecules
[26] with trifluoromethyl substituents have great significance in organic and medicinal
chemistry.

Previous work
(a)
R
F3C
R
F3C
HN
CF3
Et2O
rt
R1
R
or
N
R1
R1
N2
N
N
N
(b)
F3C
HN
R
F3C
HN
R
CF3
DMF, 40 °C /
R
or
R1
R1
Et3N,PhMe
40 °C
R1
O
N
N2
F3C
R1
(c)
CH3COOAg
Et3N
Cl
OCH3
O
OCH3
N
RHNN
CF3
PhMe, 40 °C
N
R
R1
(d) This Work
F3C
1
NH2
t-BuONO
AcOH
O
OMe
O
O
F3C
HN
O
F3C
CHCl3, rt, 48 h
OR
O
O
N2
CO2Me
N
in situ
2
O
RO
3
4
Scheme 1: Synthesis of CF3-Substituted Pyrazolines via [3 + 2] Cycloaddition.
Over the past decades, several synthetic approaches to access pyrazoline derivatives have
been widely reported but CF3-substituted pyrazolines remains less explored.
The [3+2]-cycloaddition of CF3CHN2 with electron-deficient alkynes was first reported by
Atherton and Fields [27] and later by Fields and Tomlinson [28]. To date, a diverse array of
elegant works have been established, and current methods for their synthesis include
cycloaddition reactions of 2,2,2-trifluorodiazoethane (CF3CHN2) with an electron-deficient
carbon multiple bond, such as alkenes, alkynes, and allenes, represents a straightforward
strategy to access CF3-substituted pyrazolines and pyazoles (Scheme 1a & 1b) [29]. Very

recently, a [3+2] cycloaddition reaction between trifluoromethylated hydrazonoyl chlorides
and α,β-unsaturated carbonyl compounds was reported to form the 3-
trifluoromethylpyrazolines in the presence of AgOAc (Scheme 1, method c) [30]. In view of
the importance of trifluoromethylated pyrazolines, more efficient methods for the
construction of diversely substituted CF3-containing pyrazolines are still in high demand.
Owing to the fact that diazo compounds are highly efficient 1,3-dipoles in the construction of
pyrazolines or pyrazoles [31,33] units have particularly emerged as attractive synthetic
targets because of their prevalence in numerous clinical pharmaceuticals and natural
alkaloids.
To the best of our knowledge, the direct use of glycosyl olefinic ester with in situ generated
CF3CHN2 to synthesize CF3-substituted pyrazoline glycoconjugate via metal free [3 + 2]
cycloaddition have not been explored to date in carbohydrate chemistry. Therefore it was
envisaged that linking of CF3-substituted pyrazoline scaffold to a carbohydrate unit might
lead to a new class of glycoconjugates that might have interesting biological profiles. Hence,
we report metal-free [3 + 2] cycloaddition of glycosyl olefinic ester with in situ generated
CF3CHN2 for the syntheses of CF3-substituted pyrazoline glycoconjugate (Scheme 1d).
2. Results and discussion
Our synthetic strategy begins with orthogonally protected glycosyl olefinic esters (3a-3l)
which were prepared from the reducing sugars following the literature reported reaction
conditions (Scheme 2). Initially, the synthesis was started from diacetone D-glucose 5 and D-
mannose 6 according to the reaction sequence shown in Scheme 1. The 3–OH group of
diacetone D-glucose 5 and 1-OH group of D-mannose 6 were then protected by several
common protecting group in the presence of sodium hydride in DMF, followed by the usual
aqueous workup, and column chromatography provided the resultant product 7 and 8 in
quantitative yield with the expected purity. Then intermediate 7 and 8 were hydrolysed

regioselectively using 70% acetic acid and oxidative cleavage of diol by sodium periodate in
water furnished aldehyde 9 or 10 in quantitative yield [33], which were directly treated with
phosphorus ylide [34], Ph3P=CHCO2Me to provide the corresponding glycosyl olefinic esters
(3a-3l) in good yield [35].
Scheme 2: General scheme for the synthesis of glycosyl olefinic ester 3a-3l.
Then we initiated our investigations by screening a series of solvents of the cycloaddition of
glycosyl olifinic ester (3a) with in situ generated CF3CHN2 (2) [36]. As shown in Table 1, the
1,3-dipolar cycloaddition reaction proceeded smoothly, affording the CF3-substituted
pyrazoline glycoconjugate 4a in 59% yield after 48 h in CH2Cl2 at room temperature (entry
1). The structure of the product 4a was unambiguously determined by NMR studies
especially by analysing nOes and HMBC correlation. (For details, please see the supporting
information). The formation of pyrazolines with CF3 and EWG at only 3- and 5-position was
observed and no other corresponding 3,4-disubstituted isomer was formed.

Further, we attempted to improve the yield of 4a (which was only 59% in CH2Cl2), wherein
for the optimization studies we have treated 3a with variety of solvents, temperature, and at
different reaction time periods as well (Table 1).
Table 1. Investigation of Reaction Conditionsa
O
OMe
BnO
O
O
O
F3C
t-BuONO, AcOH
F3C
HN
rt, 48 h
O
F3C
NH2
O
solvent, 40 C
20 min
N2
in situ
OBn
1
CO2Me
O
N
2
3a
4a
Entry
Solvent
CH2Cl2
CHCl3
CH3CN
PhMe
Time
48 h
48 h
48 h
48 h
48 h
48 h
48 h
72 h
24 h
Yield of 4a (%)
59
86
1
2
3
4
5
6
7
8
9e
42
33
Et2O
22
MTBE
CPME
CHCl3
CHCl3
18
15
86
trace
aUnless otherwise noted, all reactions were carried out with trifluoroethylamine (1, 1.2 mmol,
3.0 equiv.), tBuONO (1.44 mmol, 3.6 equiv.) and AcOH (0.24 mmol, 0.6 equiv.) in 15.0 mL
of solvent at 40 °C for 20 min. The mixture was cooled to room temperature followed by the

addition of 3a (0.4 mmol, 1.0 equiv.), and was allowed to stir at room temperature for 48 h.
e
bThe yield was obtained by column chromatography. The reaction was performed at 50 °C
for 24 h. MTBE = methyl tert-butyl ether. CPME = cyclopentyl methyl ether.
As a result from the optimization of reaction conditions, CHCl3 was found as the most
suitable solvent to furnish cycloaddition in comparison with other solvents such as MTBE
and CPME (Table 1, entries 3-7).
Additionally, extending the reaction time from 48 h to 72 h indicated that 48 h was optimal
for this reaction (Table 1, entry 8). As expected, the reaction was preceded smoothly in
CHCl3 at room temperature for 48 h, delivering the desired product 4a in 86% yield (Table 1,
entry 2). In order to accelerate the reaction rate, the reaction was further performed at 50 °C
for 24 h unfortunately only trace amount of 4a was obtained (entry 9).
Having optimized conditions in hand (entry 2, Table 1), substrate scope was evaluated
using a wide range of furanose glycosyl olifinic ester with different protecting groups. As
shown in Table 2, all substrates were smoothly transformed into the corresponding CF3-
containing pyrazoline glycoconjugate 4a-l in moderate to good yield (75–88% yield). In this
regard, the effect of furanose form of glucose and mannose with various protecting groups in
the glycosyl olefinic ester system were also investigated, where both of these functionalities
were found to be unaffected in general moderate to good yields of pyrazoline glycoconjugate.
It was observed that in case of benzyl protecting group, the yield was little higher rather than
n-propyl or OMe.
Table 2. Substrate scopea

aReaction conditions: trifluoroethylamine (1, 1.2 mmol, 3.0 equiv), tBuONO (1.44 mmol, 3.6
equiv), AcOH (0.24 mmol, 0.6 equiv), 3 (0.4 mmol, 1.0 equiv), CHCl3 (15 mL) at rt, 48 h.
bThe yield was obtained by column chromatography.

Finally, to showcase the synthetic utility of this protocol, an oxidative conversion of the
obtained pyrazoline to pyrazole glucoconjugate was attempted. A short survey using various
oxidizing agents was performed, and pleasingly, the oxidation of pyrazoline glycoconjugate
4k using MnO2 gave the desired pyrazole glucoconjugate 11 in 81% yield (Scheme 3).
Scheme 3: Oxidative Conversion of pyrazoline to pyrazole glucoconjugate.
In conclusion, we have developed straight forward one-pot protocol involving simple,
efficient, metal-free [3+2] cycloaddition reaction for the construction of CF3-substituted
pyrazoline glycoconjugates starting from glycosyl olefinic ester with in situ generated
CF3CHN2. The salient features of our protocol include synthesis of highly substituted
complex molecules from simple starting materials, high bond-forming efficiency, and good to
high yields. Although a lengthy period of time (48 h) was required, this strategy can construct
concisely the potential biological CF3-containing pyrazoline glycoconjugate without
multistep parallel synthesis. The synthetic potential of the strategy has been demonstrated by
the synthesis of pyrazoline to pyrazole glucoconjugate. We expect that insights gained from
our present study are helpful for providing a valuable synthetic tool that might have
interesting biological profiles.

3. Experimental
3.1.General methods
Unless otherwise specified, all reactions were carried out under air atmosphere in oven
dried round-bottom flasks. All solvents and reagents purchased from commercial
sources or synthesized via literature protocol and used without further purifications.
All reactions were monitored by thin layer chromatography over silica gel-coated TLC
plates. The spots on TLC were visualized by warming ceric sulfate [2% Ce(SO4)2 in
5% H2SO4 in EtOH]-sprayed plates on a hot plate. Silica gel 230-400 mesh was used
for column chromatography. All NMR spectra were recorded with Bruker DRX 400
1
13
MHz spectrometer (400 MHz for H, 100 MHz for C) at ambient temperature using
CDCl3 as solvents. Chemical shifts
δ
are given in ppm relative to the residual signals
1
13
of tetramethylsilane in CDCl3 for H and C NMR. Coupling constants are given in
hertz. HRMS was performed using QToF mass spectrometer (ESI). Commercially
available grades of organic solvents of adequate purity are used in all reactions. All
commercially available reagents were used as received. Analytical data is given if the
compound is novel or not fully characterized in the literature. Trifluorodiazoethane
was prepared by following a literature procedure [36].
3.2.
General procedure for the synthesis of glycosyl olifinic ester (3a-3l): Reaction of
aldehyde 9 or 10 with Ph3P=CHCO2Me. A solution of aldehyde (1.0 equiv) in benzene (6
mL) was treated, with phosphorus ylide, Ph3P=CHCO2Me (2.0 equiv). After stirring at room
temperature for 12 h, the crude mixture was then diluted with ether (4 mL) and washed with
water (2 x 4 mL). The combined organic extracts were dried (MgSO4) and concentrated in

vacuo. Purification by flash column chromatography (silica gel, EtOAc/hexanes 30:70)
provided alquene 3a-3l as a white oil.
3.3.General procedures for preparation of CF3-Substituted pyrazoline glycoconjugate
(4a-4l):
Preparation
of
Methyl
(4S,5R)-4-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-
dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-5-(trifluoromethyl)-4,5-dihydro-1H-
pyrazole-3-carboxylate (4a): To an oven-dried 50 ml round bottom flask with a stir bar was
charged with trifluoroethylamine (1, 122 mg, 0.9 mmol, 3.0 equiv), tert-butyl nitrite (333 mg,
3.2 mmol, 3.6 equiv), and AcOH (32 mg, 0.5 mmol, 0.6 equiv) in 15.0 mL of chloroform at
40 °C for 20 min. The mixture was cooled to room temperature followed by addition of
glycosyl olifinic ester 3a (100mg, 0.3 mmol, 1.0 equiv). After the mixture was stirred at room
temperature for 48 h, it was poured into water and extracted with CH2Cl2 (50 mL). The
organic layer was washed with water, dried (Na2SO4), and concentrated to give the crude
product, which was purified over SiO2 using hexane/ EtOAc (3:1) as eluant to give pure
compound 4a (113 mg, 86%) as yellowish oil.
3.3.1. Methyl (4S,5R)-4-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-dimethyltetrahydrofuro[2,3-
d][1,3]dioxol-5-yl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazole-3-carboxylate
(4a):
25
Following the general procedure, yellowish oil, 113.0 mg, 86% yield; [α]
D
−31 (c 1.0,
1
CHCl3); H NMR (400 MHz, δ ppm/CDCl3): δ 7.38‒7.29 (m, 5H), 6.44 (s, 1H), 5.89 (d, J =
3.78 Hz, 1H), 4.86 ‒ 4.79 (m, 1H), 4.64 (d, J = 11.8 Hz, 2H), 4.56 (d, J = 3.80 Hz, 1H), 4.46
(t, J = 3.80, 1H), 4.06 (d, J = 3.20 Hz, 1H), 3.86 (m, 1H), 3.83 (s, 3H), 1.44 (s, 3H), 1.29 (s,
3H). 13C NMR (100 MHz, δ ppm/CDCl3): δ 162.10, 141.0, 137.07, 128.53, 128.06, 127.97,
124.6 (q, JC-F = 279.6 Hz), 111.9, 104.65, 82.74, 81.95, 77.15, 71.96, 62.3 (q, JC-F = 30.3

Hz), 52.30, 44.64, 26.74, 26.24. 19F NMR (376 MHz, δ ppm/CDCl3): -77.7 (s); HRMS
+
(ESI): calcd for C20H24F3N2O6 [M+H]+ 445.1581, found 445.1588.
3.3.2. Methyl (4S,5R)-4-((3aR,5R,6S,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[2,3-
d][1,3]dioxol-5-yl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazole-3-carboxylate
(4b):
25
D
Following the general procedure, colourless oil, 107.01 mg, 75% yield; [
α
]
−54 (c 1.0,
CHCl3); 1H NMR (400 MHz, δ ppm/CDCl3): δ 6.47 (s, 1H), 5.88 (d, J = 3.78 Hz, 1H),
4.81‒ 4.74 (m, 1H), 4.58 (d, J = 3.84 Hz, 1H), 4.47 (t, J = 3.56 Hz, 1H), 3.85 (s, 3H), 3.80 (t,
J = 3.75, 2H), 3.42 (s, 3H), 1.46 (s, 3H), 1.32 (s, 3H); 13C NMR (100 MHz, δ ppm/CDCl3):
δ 162.14, 140.88, 124.76 (q, JC-F = 279.8 Hz), 111.96, 104.79, 84.97, 81.38, 76.70, 62.10 (q,
19
J
C-F = 30.2 Hz), 57.45, 52.29, 44.73, 26.73, 26.23; F NMR (376 MHz, δ ppm/CDCl3): -
+
77.9 (s); HRMS (ESI): calcd for C14H20F3N2O6 [M+H]+ 369.1268, found 369.1271.
3.3.3. Methyl (4S,5R)-4-((3aR,5R,6S,6aR)-6-ethoxy-2,2-dimethyltetrahydrofuro[2,3-
d][1,3]dioxol-5-yl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazole-3-carboxylate
(4c):
Following the general procedure, colourless oil, 108.23 mg, 77% yield; [α]
D
25 −36.5 (c 1.0,
CHCl3); 1H NMR (400 MHz, δ ppm/CDCl3): δ 6.44 (s, 1H), 5.89 (d, J = 3.84 Hz, 1H),
4.87‒4.81 (m, 1H), 4.56 (d, J = 3.84 Hz, 1H), 4.50 (t, J = 3.28 Hz, 1H), 3.90 (d, J = 3.28 Hz,
1H), 3.85 (s, 3H), 3.78 (t, J = 3.56 Hz, 1H), 3.69‒3.63 (m, 1H), 3.56‒3.52 (m, 1H), 1.45 (s,
3H), 1.31 (s, 3H), 1.20 (t, J = 6.96 Hz, 3H); 13C NMR (100 MHz, δ ppm/CDCl3): δ 162.12,
141.16, 124.6 (q, JC-F = 289.3 Hz), 111.90, 104.79, 83.40, 81.95, 76.69, 65.56, 61.9 (q, JC-F
19
= 30.2 Hz), 52.28, 44.85, 26.75, 26.26, 14.82; F NMR (376 MHz, δ ppm/CDCl3): -77.7
+
(s); HRMS (ESI): calcd for C15H22F3N2O6 [M+H]+ 383.1424, found 383.1419.
3.3.4. Methyl (4S,5R)-4-((3aR,5R,6S,6aR)-2,2-dimethyl-6-propoxytetrahydrofuro[2,3-
d][1,3]dioxol-5-yl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazole-3-carboxylate (4d):

25
D
Following the general procedure, colourless oil, 108.0 mg, 78% yield; [
α
]
+52 (c 1.0,
CHCl3); 1H NMR (400 MHz, δ ppm/CDCl3): δ 6.46 (s, 1H), 5.94 (d, J = 3.83 Hz, 1H),
5.88 (d, J = 3.80 Hz, 1H), 4.86 ‒ 4.81 (m, 1H), 4.55 (d, J = 3.84 Hz, 1H), 4.48 (t, J = 1.72,
1H), 3.99-3.96 (m, 1H), 3.90 (d, J = 3.23 Hz, 1H), 3.86 (s, 3H), 3.80 (t, J = 3.69 Hz, 1H),
13
3.54-3.47 (m, 1H), 3.46-3.37 (m, 1H), 1.60 (m, 2H), 1.48 (m, 3H), 1.31 (m, 3H); C NMR
(100 MHz, δ ppm/CDCl3): δ 162.10, 141.19, 124.67 (q, JC-F = 279.8 Hz), 111.90, 104.73,
83.45, 81.92, 76.09, 71.79, 62.00, (q, JC-F = 279.8 Hz), 52.27, 44.73, 26.76, 26.26, 22.64,
10.41; 19F NMR (376 MHz, δ ppm/CDCl3): -77.7 (s); HRMS (ESI): calcd for
+
C16H24F3N2O6 [M+H]+ 397.1581, found 397.1582.
3.3.5.
Methyl
(4S,5R)-4-((3aR,5R,6S,6aR)-6-(cyclopropylmethoxy)-2,2-
dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-5-(trifluoromethyl)-4,5-dihydro-1H-
pyrazole-3-carboxylate (4e): Following the general procedure, colourless oil, 106.76 mg,
1
78% yield; [
α
]
25 +45.5 (c 1.0, CHCl3); H NMR (400 MHz, δ ppm/CDCl3): δ 6.46 (s, 1H),
D
5.90 (d, J = 3.80 Hz, 1H), 4.92‒4.85 (m, 1H), 4.56 (d, J = 3.84 Hz, 1H), 4.50 (t, J = 3.33 Hz,
1H), 3.96 (d, J = 3.29 Hz, 1H), 3.85 (s, 3H), 3.81 (t, J = 3.64 Hz, 1H), 3.46‒3.42 (m, 1H),
3.37‒3.32 (m, 1H), 1.45 (s, 3H), 1.31 (s, 3H), 1.08‒1.01 (m, 1H), 0.57‒0.53 (m, 2H), 0.25‒
0.18 (m, 2H); 13C NMR (100 MHz, δ ppm/CDCl3): δ 162.14, 141.18, 124.87 (q, JC-F
=
280.0 Hz), 111.89, 104.77, 83.06, 82.17, 76.75, 74.92, 61.98 (q, JC-F = 24.0 Hz), 52.25,
44.85, 26.77, 26.28, 10.37, 3.15, 3.10; 19F NMR (376 MHz, δ ppm/CDCl3): -77.7 (s);
+
HRMS (ESI): calcd for C17H24F3N2O6 [M+H]+ 409.1581, found 409.1578.
3.3.6.
Methyl
(4S,5R)-4-((3aR,5R,6S,6aR)-2,2-dimethyl-6-((4-
methylbenzyl)oxy)tetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-5-(trifluoromethyl)-4,5-
dihydro-1H-pyrazole-3-carboxylate (4f): Following the general procedure, colourless oil,
114.55 mg, 87% yield; [α]
25 +26.5 (c 1.0, CHCl3); 1H NMR (400 MHz, δ ppm/CDCl3): δ
D

7.22‒7.15 (m, 4H), 6.45 (s, 1H), 5.88 (d, J = 3.80 Hz, 1H), 4.84‒4.81 (m, 1H), 4.59 (d, J =
2.08 Hz, 2H), 4.57 (d, J = 3.80 Hz, 1H), 4.46 (t, J = 3.64 Hz, 1H), 4.04 (d, J = 3.20 Hz, 1H),
3.83 (s, 4H), 2.35 (s, 3H), 1.44 (s, 3H), 1.29 (s, 3H); 13C NMR (100 MHz, δ ppm/CDCl3): δ
162.11, 141.10, 137.84, 134.02, 129.21, 128.12, 124.87 (q, JC-F = 280.0 Hz), 111.96, 104.69,
19
82.58, 81.99, 76.76, 71.81, 62.20 (q, JC-F = 23.6 Hz), 52.25, 44.71, 26.75, 26.26, 21.16; F
+
NMR (376 MHz, δ ppm/CDCl3): -77.6 (s); HRMS (ESI): calcd for C21H26F3N2O6
[M+H]+ 459.1737, found 459.1743.
3.3.7.
Methyl
(4S,5R)-4-((3aR,5R,6S,6aR)-6-((3-chlorobenzyl)oxy)-2,2-
dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-5-(trifluoromethyl)-4,5-dihydro-1H-
pyrazole-3-carboxylate (4g): Following the general procedure, colourless oil, 102.57 mg,
1
79% yield; [
α
]
25 +22 (c 1.0, CHCl3); H NMR (400 MHz, δ ppm/CDCl3): δ 7.31‒7.29 (m,
D
3H), 7.20‒7.19 (m, 1H), 6.48 (s, 1H), 5.91 (d, J = 3.80 Hz, 1H), 4.83‒4.80 (m, 1H), 4.63 (d, J
= 6.01 Hz, 2H), 4.59 (d, J = 3.84 Hz, 1H), 4.43 (q, J = 4.68 Hz, 1H), 4.06 (d, J = 3.12 Hz,
1H), 3.88 (t, J = 4.40 Hz, 1H), 3.84 (s, 3H), 1.46 (s, 3H), 1.31 (s, 3H); 13C NMR (100 MHz,
δ ppm/CDCl3): δ 162.12, 140.92, 139.20, 134.42, 129.80, 128.16, 127.87, 125.79, 124.77 (q,
J
C-F = 279.6 Hz), 112.08, 104.58, 82.98, 81.99, 77.15, 71.21, 62.40 (q, JC-F = 24.1 Hz),
19
52.32, 44.46, 26.71, 26.23; F NMR (376 MHz, δ ppm/CDCl3): -77.8 (s); HRMS (ESI):
+
calcd for C20H23ClF3N2O6 [M+H]+ 479.1191, found 479.1199.
3.3.8.
Methyl
(4S,5R)-4-((3aR,5R,6S,6aR)-2,2-dimethyl-6-((4-
(methylthio)benzyl)oxy)tetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-5-(trifluoromethyl)-4,5-
dihydro-1H-pyrazole-3-carboxylate (4h): Following the general procedure, colourless oil,
97.97 mg, 76% yield; [α]
25 +28 (c 1.0, CHCl3); 1H NMR (400 MHz, δ ppm/CDCl3): δ
D
7.56 (dd, J = 7.94, 0.96 Hz, 1H), 7.40 (dd, J = 7.64, 1.44 Hz, 1H), 7.32 (td, J = 7.44, 0.95 Hz,
1H), 7.18 (td, J = 7.71, 1.70 Hz, 1H), 6.45 (s, 1H), 5.91 (d, J = 3.76 Hz, 1H), 4.85‒4.79 (m,

1H), 4.73‒4.70 (m, 3H), 4.48 (q, J = 4.42 Hz, 1H), 4.15 (d, J = 3.08 Hz, 1H), 3.92 (t, J = 4.31
13
Hz, 1H), 3.84 (s, 3H), 1.47 (s, 3H), 1.31 (s, 3H); C NMR (100 MHz, δ ppm/CDCl3): δ
162.07, 140.9, 136.54, 132.61, 129.50, 129.43, 127.53, 124.7 (q, JC-F = 283.4 Hz), 122.91,
112.09, 104.67, 83.31, 81.83, 76.69, 71.33, 62.3 (q, JC-F = 30.2 Hz),, 52.33, 44.50, 26.73,
26.26; 19F NMR (376 MHz, δ ppm/CDCl3): -77.8 (s); HRMS (ESI): calcd for
C21H26F3N2O6S+ [M+H]+ 491.1458, found 491.1461.
3.3.9.
Methyl
(4S,5R)-4-((3aR,5R,6S,6aR)-2,2-dimethyl-6-(naphthalen-2-
ylmethoxy)tetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-5-(trifluoromethyl)-4,5-dihydro-1H-
pyrazole-3-carboxylate (4i): Following the general procedure, colourless oil, 96.46 mg, 75%
1
yield; [
α
]
25 −39 (c 1.0, CHCl3); H NMR (400 MHz, δ ppm/CDCl3): δ 7.85‒7.82 (m, 3H),
D
7.77 (s, 1H), 7.50‒7.48 (m, 2H), 7.45‒7.42 (m, 1H), 6.47 (s, 1H), 5.92 (d, J = 3.78 Hz, 1H),
4.88‒4.85 (m, 1H), 4.81 (m, 2H), 4.63 (d, J = 3.81 Hz, 1H), 4.47 (t, J = 3.84 Hz, 1H), 4.12 (d,
J = 3.16 Hz, 1H), 3.90 (t, J = 4.12 Hz, 1H), 3.83 (s, 3H), 1.45 (s, 3H), 1.29 (s, 3H); 13C NMR
(100 MHz, δ ppm/CDCl3): δ 162.11, 141.08, 134.57, 133.23, 133.10, 128.37, 127.94,
127.73, 126.86, 126.27, 126.15, 125.67, 124.86 (q, JC-F = 284.9 Hz), 112.02, 104.68, 82.85,
82.04, 76.70, 72.12, 62.30 (q, JC-F = 30.2 Hz), 52.31, 44.62, 26.75, 26.27; 19F NMR (376
+
MHz, δ ppm/CDCl3): -77.6 (s); HRMS (ESI): calcd for C24H26F3N2O6 [M+H]+ 495.1737,
found 495.1736.
3.3.10.
Methyl
(4S,5R)-4-((3aS,4R,6R,6aS)-6-(benzyloxy)-2,2-
dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-5-(trifluoromethyl)-4,5-dihydro-1H-
pyrazole-3-carboxylate (4j): Following the general procedure, colourless oil, 116 mg, 88%
yield; [α]
25 +42 (c 1.0, CHCl3); 1H NMR (400 MHz, δ ppm/CDCl3): δ 7.35 ‒ 7.24 (m,
D
5H), 6.47 (s, 1H), 5.10 (s, 1H), 4.84-4.79 (m, 1H), 4.65 (d, J = 5.87 Hz, 1H), 4.55 (d, J =
11.74 Hz, 1H), 4.43 (d, J = 11.74 Hz, 1H), 4.35 (t, J = 3.16 Hz, 1H), 3.90 (t, J = 3.47 Hz,

1H), 3.85 (s, 3H), 1.45 (s, 3H), 1.31 (s, 3H); 13C NMR (100 MHz, δ ppm/CDCl3): δ 161.99,
141.29, 137.15, 128.49, 128.03, 127.88, 124.73 (q, JC-F = 280.4 Hz), 112.72, 105.16, 85.12,
80.41, 76.41, 69.31, 61.66 (q, JC-F = 30.3 Hz), 52.33, 44.87, 25.45, 24.09; 19F NMR (376
+
MHz, δ ppm/CDCl3): -77.3 (s); HRMS (ESI): calcd for C20H24F3N2O6 [M+H]+ 445.1581,
found 445.1592.
3.3.11. Methyl (4S,5R)-4-((3aS,4R,6R,6aS)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-
d][1,3]dioxol-4-yl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazole-3-carboxylate
(4k):
25
Following the general procedure, colourless oil, 121 mg, 85% yield; [α]
D
+36 (c 1.0,
CHCl3); 1H NMR (400 MHz, δ ppm/CDCl3): δ 6.47 (s, 1H), 4.90 (s, 1H), 4.81‒4.79 (m,
1H), 4.56 (d, J = 5.82 Hz, 1H), 4.28 (t, J = 3.12 Hz, 1H), 3.90 (t, J = 3.52 Hz, 1H), 3.87 (s,
3H), 3.86 (s, 3H), 3.34 (s, 1H), 3.24 (s, 3H), 1.46 (s, 3H), 1.31 (s, 3H); 13C NMR (100 MHz,
δ ppm/CDCl3): δ 162.02, 141.39, 120.69 (q, JC-F = 281.0 Hz), 112.72, 106.76, 84.98, 80.38,
19
76.23, 61.65 (q, JC-F = 30.3 Hz), 54.72, 52.34, 44.87, 25.45, 24.09; F NMR (376 MHz, δ
ppm/CDCl3): -77.3 (s); HRMS (ESI): calcd for C14H20F3N2O6 [M+H]+ 369.1268, found
+
369.1272.
3.3.12.
Methyl
(4S,5R)-4-((3aS,4R,6R,6aS)-6-((2-bromobenzyl)oxy)-2,2-
dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-5-(trifluoromethyl)-4,5-dihydro-1H-
pyrazole-3-carboxylate (4l): Following the general procedure, colourless oil, 108.89 mg,
86% yield; [α]
25 +37 (c 1.0, CHCl3); 1H NMR (400 MHz, δ ppm/CDCl3): δ 7.54 (dd, J =
D
7.91, 1.01 Hz, 1H), 7.34 (dd, J = 7.63, 1.80 Hz, 1H), 7.30 (dd, J = 7.33, 1.17 Hz, 1H), 7.17-
7.13 (m, 1H), 6.46 (s, 1H), 5.15 (s, 1H), 4.88-4.83 (m, 1H), 4.69 (d, J = 2.03 Hz, 1H), 4.67
(d, J = 4.08 Hz, 1H), 4.47-4.42 (m, 2H), 3.91 (t, J = 3.44, 1H), 3.85 (s, 3H), 1.47 (s, 3H), 1.32
(s, 3H); 13C NMR (100 MHz, δ ppm/CDCl3): δ 162.02, 141.27, 136.41, 132.79, 130.11,
129.50, 127.48, 124.69 (q, JC-F = 283.7 Hz), 123.58, 112.78, 105.62, 85.12, 80.41, 69.12,

19
61.70 (q, JC-F = 30.5 Hz), 52.36, 44.85, 25.45, 24.09; F NMR (376 MHz, δ ppm/CDCl3): -
+
77.3 (s); HRMS (ESI): calcd for C20H23BrF3N2O6 [M+H]+ 523.0686, found 523.0694.
3.3.13.
Methyl
4-((3aS,4R,6R,6aS)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-
d][1,3]dioxol-4-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylate (11): colourless oil,
25 +52 (c 1.0, CHCl3); 1H NMR (400 MHz, δ ppm/CDCl3): δ
81.0 mg, 81% yield; [α]
D
11.25 (brs, 1 H), 5.57 (d, J = 3.8 Hz, 1H), 5.07 (brs, 1H), 5.01 (dd, J = 3.8, 5.9 Hz, 1 H), 4.65
13
(d, J = 5.9 Hz, 1 H), 3.97 (s, 3H), 3.38 (s, 3H), 1.37 (s, 3H), 1.25 (s, 3H); C NMR (100
MHz, δ ppm/CDCl3): δ 158.8, 141.9 (q, JC-F = 38.9 Hz), 127.8, 120.7 (q, JC-F = 267.9 Hz),
112.7, 107.2, 84.9, 80.5, 75.1, 54.9, 52.6, 24.8, 24.1; 19F NMR (376 MHz, δ ppm/CDCl3): -
59.2 (s); HRMS (ESI): calcd for C14H18F3N2O6 [M+H]+ 367.1111, found 367.1109.
+
Acknowledgements
Javed thanks UGC, New Delhi for providing Research Fellowship. The author gratefully
acknowledges financial support by DST-SERB (Scheme No.EMR/2017/001791), New Delhi
and SAIF Division of CSIR-CDRI for providing the spectroscopic and analytical data. CDRI
communication no. 872/2020/PKM.
References
[1] (a) (a) Fyaz. M. D. Ismail, Fluorine Chem. 118 (2002) 27-33.
https://doi.org/10.1016/S0022-1139(02)00201-4 (b) S. Purser, P. R. Moore, V.
Gouverneur, Chem. Soc. Rev. 37 (2008) 320-330. https://doi.org/10.1039/B610213C (c)
T. Liang, C. N. Neumann, T. Ritter, Angew. Chem., Int. Ed. 52 (2013) 8214-8264.
https://doi.org/10.1002/anie.201206566. (d) J. Wang, H. Liu, Chem. Rev. 114 (2014)
2432-2506. https://doi.org/10.1021/cr4002879. (e) C. Ni, M. Hu, J. Hu, Chem. Rev. 115
(2015) 765-825. https://doi.org/10.1021/cr5002386

[2] (a)
D.
O’Hagan,
J.
Fluorine
Chem.
131
(2010)
1071-1081.
https://doi.org/10.1016/j.jfluchem.2010.03.003. (b) B. H. Hoff, E. Sundby, Bioorg.Chem.
51 (2013) 31-47. https://doi.org/10.1016/j.bioorg.2013.09.003. (c) D. E. Yerien, S.
Bonesi,
https://doi.org/10.1039/C6OB00764C.
[3] (a) R. Filler, R. Saha, Future Med. Chem.
A.
Postigo,
Org.
Biomol.
Chem.
14
(2016)
8398-8472.
1
(2009) 777-791.
https://doi.org/10.4155/fmc.09.65. (b) J. Wang, M. Sanchez-Roselló, J. L. Aceña, C.
delPozo, A. E. Sorochinsky, S. Fustero, V. A. Soloshonok, H. Liu, Chem. Rev. 114
(2014) 2432-2506. https://doi.org/10.1021/cr4002879. (c) A. Harsanyi, G. Sandford,
Green Chem. 17 (2015) 2081-2094. https://doi.org/10.1039/C4GC02166E. (d) L. Xing,
D. C. Blakemore, A. Narayanan, R. Unwalla, F. Lovering, R. A. Denny, H. Zhou, M. E.
Bunnage,
Chem.
Med.
Chem.
10
(2015)
715-726.
https://doi.org/10.1002/cmdc.201402555. (e) D. E. Yerien, S. Bonesi, A. Postigo, Org.
Biomol. Chem. 14 (2016) 8398-8473. https://doi.org/10.1039/C6OB00764C.
[4] (a) Y. Zhou, J. Wang, Z. Gu, S. Wang, W. Zhu, J. L. Aceña, V. A. Soloshonok, K. Izawa,
H. Liu, Chem. Rev. 116 (2016) 422-518. https://doi.org/10.1021/acs.chemrev.5b00392.
(b) J. Wang, M. Sánchez-Roselló, J. L. Aceña, C. delPozo, A. E. Sorochinsky, S. Fustero,
V. A. Soloshonok, H. Liu, Chem. Rev. 114 (2014) 2432-2506.
https://doi.org/10.1021/cr4002879. (c) W. K. Hagmann, J. Med. Chem. 51 (2008) 4359-
4369. https://doi.org/10.1021/jm800219f.
[5] (a)
K.
L.
Kirk,
Org.
Process
Res.
Dev.
12
(2008)
305-321.
https://doi.org/10.1021/op700134j. (b) S. Purser, P. R. Moore, S. Swallow, V.
Gouverneur, Chem. Soc. Rev. 37 (2008) 320-330. https://doi.org/10.1039/B610213C. (c)
K. Müller, C. Faeh, F. Diederich, Science. 317 (2007) 1881-1887.
https://doi.org/10.1126/science.1131943.

[6] J. P. Begue, D. Bonnet-Delpon, J. Fluorine. Chem. 127 (2006) 992-1012.
https://doi.org/10.1016/j.jfluchem.2006.05.006. (b) C. Isanbor, D. O’Hagan, J. Fluorine.
Chem. 127 (2006) 303-319. https://doi.org/10.1016/j.jfluchem.2006.01.011.
[7] (a) X. Liu, C. Xu, M. Wang, Q. Liu, Chem. Rev. 115 (2015) 683-730.
https://doi.org/10.1021/cr400473a. (b) J. Charpentier, N. Früh, A. Togni, Chem. Rev. 115
(2015) 650-682. https://doi.org/10.1021/cr500223h. (c) C. Alonso, E. M. de Marigorta, G.
Rubiales,
F.
Palacios,
Chem.
Rev.
115
(2015)
1847-1935.
https://doi.org/10.1021/cr500368h. (d) J. Nie, H. C. Guo, D. Cahard, J. A. Ma, Chem.
Rev. 111 (2011) 455-529. https://doi.org/10.1021/cr100166a.
[8] (a) D. Havrylyuk, B. Zimenkovsky, O. Vasylenko, A. Gzella, R. Lesyk, J. Med. Chem. 55
(2012) 8630-8676. https://doi.org/10.1021/jm300789g. (b) V. Zsoldos-Mády, A.
Csámpai, R. Szabó, E. Mészáros-Alapi, J. Pásztor, F. Hudecz, P. Sohár, Chem. Med.
Chem. 1 (2006) 1119-1125. https://doi.org/10.1002/cmdc.200600052.
[9] (a) Z. Özdemir, H. B. Kandilci, B. Gümüşel, Ü. Çalış, A. Bilgin, Eur. J. Med. Chem. 42
(2007) 373-379. https://doi.org/10.1016/j.ejmech.2006.09.006. (b) Y. R. Prasad, A. L.
Rao, L. Prasoona, K. Murali, P. R. Kumar, Bioorg. Med. Chem. Lett. 15 (2005) 5030-
5034. https://doi.org/10.1016/j.bmcl.2005.08.040. (c) E. Palaska, M. Aytemir, İ. T.
Uzbay, D. Erol, Eur. J. Med. Chem. 36 (2001) 539-543. https://doi.org/10.1016/s0223-
5234(01)01243-0.
[10] S. K. Sahu, M. Banerjee, A. Samantray, C. Behera, M. A. Azam, Trop. J. Pharm. Res.
7 (2008) 961-968. https://doi.org/10.4314/tjpr.v7i2.14664.
[11] F. Puig-Basagoiti, M. Tilgner, B. M. Forshey, S. M. Philpott, N. G. Espina, D. E.
Wentworth, S. J. Goebel, P. S. Masters, B. Falgout, P. Ren, D. M. Ferguson, P. Y. Shi,
Antimicrob.
Agents
Chemother.
50
(2006)
1320-1329.
https://doi.org/10.1128/AAC.50.4.1320-1329.2006.

[12] (a) P. L. Zhao, F. Wang, M. Z. Zhang, Z. M. Liu, W. Huang, G. F. Yang, J. Agric.
Food. Chem. 56 (2008) 10767-10773. https://doi.org/10.1021/jf802343p. (b) M.
Shaharyar, A. A. Siddiqui, M. A. Ali, Bioorg. Med. Chem. Lett. 16 (2006) 4571-4574.
https://doi.org/10.1016/j.bmcl.2006.06.021.
[13] R. Fioravanti, A. Bolasco, F. Manna, F. Rossi, F. Orallo, F. Ortuso, S. Alcaro, R.
Cirilli,
Eur.
J.
Med.
Chem.
45
(2010)
6135-6138.
https://doi.org/10.1016/j.ejmech.2010.10.005.
[14] G. A. Patani, J. E. LaVoie, Chem. Rev. 96 (1996) 3147-3176.
https://doi.org/10.1021/cr950066q.
[15] (a) X. H. Liu, B. F. Ruan, J. Li, F. H. Chen, B. A. Song, H. L. Zhu, P. S. Bhadury, J.
Zhao,
Mini-Rev.
Med.
Chem.
11
(2011)
771-821.
https://doi.org/10.2174/138955711796355285. (b) O. G. Khudina, Y. V. Burgart, V. I.
Saloutin, M. A. Kravchenkob, Russ. Chem. Bull. 59 (2010) 1967-1973.
https://doi.org/10.1007/s11172-010-0341-7. (c) S. Kumar, S. Bawa, S. Drabu, R. Kumar,
H. Gupta, Recent Pat. Anti-Infect. Drug. Discovery.
4
(2009) 154-163.
https://doi.org/10.2174/157489109789318569. (d) M. V. R. Reddy, V. K. Billa, V. R.
Pallela, M. R. Mallireddigari, R. Boominathan, J. L. Gabriel, E. P. Reddy, Bioorg. Med.
Chem. 16 (2008) 3907-3916-. https://doi.org/10.1016/j.bmc.2008.01.047. (e) X. Zhang,
X. Li, G. F. Allan, T. Sbriscia, O. Linton, S. G. Lundeen, Z. Sui, J. Med. Chem. 50 (2007)
3857-3869. https://doi.org/10.1021/jm0613976. (f) W. Cunico, C. A. Cechinel, H. G.
Bonacorso, M. A. P. Martins, N. Zanatta, de M. V. N. Souza, I. O. Freitas, R. P. P.
Soares, A. U. Krettli, Bioorg. Med. Chem. Lett. 16 (2006) 649-653.
https://doi.org/10.1016/j.bmcl.2005.10.033.
[16] (a) H. B. Fu, J. N. Yao, J. Am. Chem. Soc. 123 (2001) 1434-1439.
https://doi.org/10.1021/ja0026298. (b) X. C. Gao, H. Cao, L. Q. Zhang, B. W. Zhang, Y.

Cao,
C.
H.
Huang,
J.
Mater.Chem.
9
(1999)
1077-1080.
https://doi.org/10.1039/A900276F.
[17] P. Wang, N. Onozawa-Komatsuzaki, Y. Himeda, H. Sugihara, H. Arakawa, K.
Kasuga, Tetrahedron. Lett. 42 (2001) 9199-9201. https://doi.org/10.1016/S0040-
4039(01)01970-0.
[18] (a) Y. Zhenglin, W. Shikang, J. Lumin. 54 (1993) 303-308.
https://doi.org/10.1016/0022-2313(93)90089-6. (b) D. E. Rivett, J. Rosevear, J. F. K.
Wilshire, Aust. J. Chem. 32 (1979) 1601-1612. https://doi.org/10.1071/CH9791601.
[19] J. Bottcher, S. A. Spengler, K. Essawy, Monastshefte Burger, Fur. Chemie. 135
(2004) 853-863. https://doi.org/10.1007/s00706-003-0145-7.
[20] (a) A. Varki, Nature. 446 (2007) 1023-1029. https://doi.org/10.1038/nature05816. (b)
A. Varki, Glycobiology. 3 (1993) 97-130. https://doi.org/10.1093/glycob/3.2.97. (c) C. R.
Bertozzi,
L.
L.
Kiessling,
Science.
291
(2001)
2357-2364.
https://doi.org/10.1126/science.1059820. (d) R. A. Dwek, Chem. Rev. 96 (1996) 683-720.
https://doi.org/10.1021/cr940283b (e) L. Cipolla, B. La Ferla, C. Airoldi, C. Zona, A.
Orsato, N. Shaikh, L. Russo, F. Nicotra, Future Med. Chem. 2 (2010) 587-599.
https://doi.org/10.4155/fmc.10.8.
[21] V. K. Tiwari, R. C. Mishra, A. Sharma, R. P. Tripathi, Mini- Rev. Med. Chem. 12
(2012) 1497-1519. https://doi.org/10.2174/138955712803832654.
[22] B. A. Cobb, D. L. Kasper, Eur. J. Immunol. 35 (2005) 352-356.
https://doi.org/10.1002/eji.200425889.
[23] B. Wang, G.J. Boons, In Carbohydrate Recognition: Biological Problems, Methods,
and Applications; Eds.; John Wiley & Sons: Hoboken, NJ, USA, 2011; 33.
[24] R. Kannagi, M. Izawa, T. Koike, K. Miyazaki, N. Kimura, Cancer. Sci. 95 (2004)
377-384. https://doi.org/10.1111/j.1349-7006.2004.tb03219.x.

[25] F. Backhed, R. E. Ley, J. L. Sonnenburg, D. A. Peterson, J. Gordon, I. Science. 307
(2005) 1915-1921. https://doi.org/10.1126/science.1104816.
[26] S. Nagarajan, T. Mohan Das, Carbohydr. Res. 344 (2009) 1028-1031.
https://doi.org/10.1016/j.carres.2009.03.009. (b) S. Nagarajan, P. Arjun, , N. Raaman, T.
Mohan
https://doi.org/10.1016/j.carres.2010.07.016. (c) V. Prasad, R. R. Kale, V. Kumar, V. K.
Tiwari, Curr. Org. Synth. (2010) 506-531.
Das,
Carbohydr.
Res.
345
(2010)
1988-1997.
7
https://doi.org/10.2174/157017910792246063. (d) V. P. Pandey, S. S. Bisht, M. Mishra,
A. Kumar, M. I. Siddiqi, A. Verma, M. Mittal, S. A. Sane, S. Gupta, R. P. Tripathi, Eur.
J. Med. Chem. 45 (2010) 2381-2388. https://doi.org/10.1016/j.ejmech.2010.02.018.
[27] J. H. Atherton, R. Fields, J. Chem. Soc. (1968) 1507-1513.
https://doi.org/10.1039/J39680001507.
[28] R. Fields, J. P. Tomlinson, J. J. Fluorine Chem, 13 (1979) 147-158.
https://doi.org/10.1016/S0022-1139(00)81083-0
[29] (a) O. S. Artamonov, E. Y. Slobodyanyuk, O. V. Shishkin, I. V. Komarov, P. K.
Mykhailiuk, Synthesis. 45 (2013) 225-230. https://doi.org/10.1055/s-0032-1316831. (b)
E. Y. Slobodyanyuk, O. S. Artamonov, O. V. Shishkin, P. K. Mykhailiuk, Eur. J. Org.
Chem. 2014 (2014) 2487-2495. https://doi.org/10.1002/ejoc.201301852. (c) F. Li, J. Nie,
L. Sun, Y. Zheng, J. A. Ma, Angew. Chem., Int. Ed. 52 (2013) 6255-6258.
https://doi.org/10.1002/anie.201301870.
[30] Hernandez, A. S.; Ellsworth, B. A.; Ewing, W. R.; Chen, B. US Patent US
16/0280659 A1, 2016.
[31] (a) P. K. Mykhailiuk, Angew. Chem., Int. Ed. 54 (2015) 6558-6561.
https://doi.org/10.1002/anie.201501529. (b) J. Li, X. L. Yu, J. Cossy, S. Y. Lv, H. L.

Zhang, F. Su, P. K. Mykhailiuk, Y. Wu, Eur. J. Org. Chem. 2017 (2017) 266-270.
https://doi.org/10.1002/ejoc.201601462.
[32] (a) M. P. Sibi, L. M. Stanley, T. Soeta, Org. Lett., 9 (2007) 1553-1556.
https://doi.org/10.1021/ol070364x. (b) L. Gao, G. S. Hwang, M. Y. Lee, D. H. Ryu,
Chem. Commun. 36 (2009) 5460-5462. https://doi.org/10.1039/B910321J.
[33] R, C. Sawant, Y. J. Liao, Y. J. Lin, S. S. Badsara, S. Y. Luo, RSC. Adv. 5 (2015)
19027-19033. https://doi.org/10.1039/C4RA17050D.
[34] F. Sarabia, L. M. Ortiz, J. F. López-Herrera, Org. Lett. 5 (2003) 3927-3930.
https://doi.org/10.1021/ol0355074.
[35] (a) J. Brimacombe, A. K. M. S. Kabir,. Carbohydrate Res.150 (1986) 35-51.
https://doi.org/10.1016/0008-6215(86)80004-0. (b) R. C. Sawant, Y.-J. Liao, Y.-J. Lin, S.
S.
Badsara,
S.-Y.
Luo,
RSC.
Adv.
5
(2015)
19027–19033.
https://doi.org/10.1039/C4RA17050D.
[36] G. A. Molander, D. Ryu, Angew. Chem., Int. Ed. 53 (2014) 14181-14185.
https://doi.org/10.1002/anie.201408191.

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CF3-Substituted pyrazoline glycoconjugates have been developed
Metal-free one-pot process along with mild reaction conditions at room temperature
[3 + 2] Cycloaddition of glycosyl olefinic ester with in situ generated CF3CHN2
Use of 2,2,2-trifluoroethylamine as an in situ generated CF3CHN2

Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests:
The authors declare no competing financial interest.