Tri- and difluoromethoxylated N-based heterocycles ? Synthesis and insecticidal activity of novel F3CO- and F2HCO-analogues of Imidacloprid and Thiacloprid

Article abstract of DOI:10.1016/j.jfluchem.2017.08.006

The preparation of F₃CO- and F₂HCO-analogues of Imidacloprid and Thiacloprid and the evaluation of their biological activity have been performed. For this purpose, a first synthetic approach allowed the preparation of a desired F₃CO-containing key intermediate. To allow a facile access to the second F₂HCO-containing key intermediate, the difluoromethylation of hydroxylated N-based heterocycles has been developed using difluoromethyl triflate (a liquid non-ODS reagent) under air in aqueous conditions and with very short reaction time. The broad diversity of compatible heterocycles includes a large series of substituted hydroxy-pyridines, but also ?pyrazoles, ?pyrazine, ?pyridazine, and ?quinolines. The couplings of both key intermediates with the required 4,5-dihydro-N-nitro-1H-imidazol-2-amine and [N(Z)]-N-2-thiazolidinylidene-cyanamide were successfully achieved using literature conditions. This work enables the preparation of valuable building blocks, which could lead to the discovery of new bioactive entities.

Full text of DOI:10.1016/j.jfluchem.2017.08.006

Accepted Manuscript
Title: Tri- and difluoromethoxylated N-based heterocycles −
Synthesis and insecticidal activity of novel F3CO- and
F2HCO-analogues of Imidacloprid and Thiacloprid
Authors: Gregory Landelle, Etienne Schmitt, Armen
Panossian, Jean-Pierre Vors, Sergiy Pazenok, Peter Jeschke,
´ ´
Oliver Gutbrod, Frederic R. Leroux
PII:
S0022-1139(17)30300-7
DOI:
http://dx.doi.org/doi:10.1016/j.jfluchem.2017.08.006
Reference:
FLUOR 9032
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Received date:
Revised date:
Accepted date:
4-7-2017
10-8-2017
10-8-2017
Please cite this article as: Gregory Landelle, Etienne Schmitt, Armen Panossian, Jean-
´ ´
Pierre Vors, Sergiy Pazenok, Peter Jeschke, Oliver Gutbrod, Frederic R.Leroux, Tri-
and difluoromethoxylated N-based heterocycles − Synthesis and insecticidal activity
of novel F3CO- and F2HCO-analogues of Imidacloprid and Thiacloprid, Journal of
Fluorine Chemistryhttp://dx.doi.org/10.1016/j.jfluchem.2017.08.006
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Tri- and difluoromethoxylated N-based heterocycles
– Synthesis and insecticidal activity of novel F3CO-
and F2HCO-analogues of Imidacloprid and
Thiacloprid
Gregory Landellea, Etienne Schmitta, Armen Panossiana, Jean-Pierre Vorsb, Sergiy Pazenokc,
Peter Jeschkec, Oliver Gutbrodc, and Frédéric R. Lerouxa,*
a University of Strasbourg, CNRS, LCM, UMR 7509, ꢀ 25 Rue Becquerel, 67087 Strasbourg,
France
b
Bayer S.A.S., Crop Science Division, ꢀ 14 Impasse Pierre Baizet, BP99163, 69263 Lyon
Cedex 09, ꢀ France ꢀ
c Bayer AG, Crop Science Division, ꢀ Alfred-Nobel-Strasse 50, 40789 Monheim, Germany ꢀ
Email: frederic.leroux@unistra.fr; http://coha.unistra.fr ꢀ
Graphical abstract:
Synthesis of F3CO- and F2HCO-heterocyclic building blocks; preparation and evaluation of
biological properties of novel analogues of Imidacloprid and Thiacloprid
Highlights:
 F3CO- and F2HCO-heterocyclic building blocks
 Difluoromethylation of hydroxylated heterocycles
 F3CO- and F2HCO-analogues of Imidacloprid & Thiacloprid
1

Abstract
The preparation of F3CO- and F2HCO-analogues of Imidacloprid and Thiacloprid and the
evaluation of their biological activity have been performed. For this purpose, a first synthetic
approach allowed the preparation of a desired F3CO-containing key intermediate. To allow a
facile access to the second F2HCO-containing key intermediate, the difluoromethylation of
hydroxylated N-based heterocycles has been developed using difluoromethyl triflate (a liquid
non-ODS reagent) under air in aqueous conditions and with very short reaction time. The
broad diversity of compatible heterocycles includes a large series of substituted hydroxy-
pyridines, but also -pyrazoles, -pyrazine, -pyridazine, and -quinolines. The couplings of both
key intermediates with the required 4,5-dihydro-N-nitro-1H-imidazol-2-amine and [N(Z)]-N-
2-thiazolidinylidene-cyanamide were successfully achieved using literature conditions. This
work enables the preparation of valuable building blocks, which could lead to the discovery
of new bioactive entities.
Keywords:
Trifluoromethoxy; difluoromethoxy; difluorocarbene; heterocycles; agrochemicals
1. Introduction
Since some years ago, the electron-withdrawing trifluoromethoxy (F3C-O) and
difluoromethoxy (F2HC-O) groups are becoming more and more important in modern crop
protection but also in pharmaceutical chemistry[1-6], because they can protect an aromatic
ring system against oxidative (or electrophilic) attacks. An increased stability towards
degradation is observed for active ingredients or fragments containing this special substitution
pattern. Based on its electronic properties, which are close to the halogen atoms chlorine and
fluorine[7], the F3C-O group has been referred as a super-[8] or a pseudo[9]-halogen. The
fluorinated carbon adjacent to an oxygen atom increases lipophilicity as shown by the high
value of the F3C-O hydrophobic substituent parameter[10-12]. It appears that the F3C-O
substituent is far more lipophilic ( = +1.04) than the halogens and lies between a F3C ( =
+0.88) and a F3C-S ( = +1.44) group. It may thus replace advantageously a fluorine atom (
= +0.14) in most molecules with the benefit of increased lipid solubility.
The trifluoromethoxy substituent can induce particular conformational changes due to its
anisotropic character (in difference to the isotropic trifluoromethyl group)[13] and adopt an
orthogonal orientation with respect to an arene plane, in contrast to the methoxy group, which
normally lies in the plane of the arene[14, 15]. In fact, the electron density of the non-bonding
p-orbitals at oxygen is very low. The electrons of the oxygen p-orbital are delocalized into the
antibonding orbitals of the trifluoromethyl C–F bonds[16]. As a consequence, the oxygen
non-bonding orbitals are not conjugated with the aromatic ring system; therefore the F3C-
group of F3C-O lies out of the arene plane, and the rotational barrier is significantly lower
than that for a methoxy group[17-19]. This behaviour can be used to tune the binding affinity
in drug-target complexes. The use of the F3C-O-motif in pharmaceuticals led to major
2

breakthroughs; Riluzole was the first drug approved for amylotropic lateral sclerosis
treatment; Delamanid is included in the World Health Organization List for essential
medicines as prodrug for tuberculosis treatment; Celikalim is a vasorelaxing agent protecting
cardiac muscles. In addition, marketed agrochemicals bearing the F3CO-motif display various
possible MoAs; Indoxacarb is a Voltage-gated sodium channel (VgSoCh) blocker;
Thifluzamide is a fungicide (SDH Complex II inhibitor); Flurprimidol is Plant Growth
Regulator (or PGR) (Figure 1).
The difluoromethoxy group shares several key properties with its renowned trifluoromethoxy
analogue (high electronegativity, excellent lipophilicity, specific electronic distribution,
thermal/chemical stability), but is not as bulky and displays an additional H-bonding capacity.
This combination of properties makes the F2CH-O-group more and more popular. It is found
in medicinally relevant compounds that include enzyme inhibitors (e.g.: Roflumilast, a
selective and long-acting phosphodiesterase-4 inhibitor, anti-HIV agents and antimicrobial
agents). Pantoprazole is a nice example of F2CH-O-containing drug found in the top 100
selling drugs in 2013, as well as several cardiovascular medications, such as Riodipine
(Figure 1)[1]. Surprisingly, most of marketed drugs are commonly bearing an aryl-OCHF2
motif, but no example is known with heteroaryl-OCHF2 motif.
Difluoromethoxy compounds are less described in marketed agrochemicals; only several
examples containing a F2CH-O-heteroaryl moiety are currently on the market: Diflumetorim
is a fungicide (SDH Complex I inhibitor); Pyroxasulfone is a VLCFAs (Very Long Chain
Fatty Acids) biosynthesis inhibitor; Flucythrinate, an insecticide acting as Voltage-gated
sodium channel blocker, also contains this group (Figure 1)[2].
These examples clearly illustrate the large potential of both F3CO- and F2HCO-substituents
for the development of new bioactive ingredients. Therefore, we became interested in
preparing new analogues of pyridine-containing neonicotinoid insecticides Imidacloprid and
Thiacloprid, containing either 6-trifluoromethoxy- or 6-difluoromethoxy-pyridin-3-yl-methyl
moieties.
2. Results and discussion
Trifluoromethoxy-derivatives
Our group was the first to report on the modular synthesis of a library of
trifluoromethoxylated pyridines[17]. This approach has been applied in the synthesis of
F3CO-analogues of Imidacloprid and Thiacloprid.
According to our procedure, 2-chloro-6-hydroxypyridine was converted in situ into the
corresponding chlorothionoformate and submitted to a chlorination with elemental chlorine in
chloroform at room temperature yielding the corresponding trichloromethyl ether 1 in 60%
yield (Scheme 1). Subsequent fluorination in the presence of antimony trifluoride and
catalytic antimony pentachloride provided 2-chloro-6-trifluoromethoxypyridine 2 in 53%
yield. Next, pyridine 2 was protected in the 3-position with a TMS group by metalation with
lithium diisopropyl amide (LDA) and subsequent trapping with trimethylsilyl chloride
(TMSCl). The nicotinic acid 4 was then prepared by metalation of 3 with lithium tetramethyl
piperidide (LiTMP) followed by trapping with carbon dioxide and direct deprotection of the
TMS group. Palladium-catalysed dechlorination to afford the 2-(trifluoromethoxy)nicotinic
acid 5 was performed with 76% yield. The reduction of the acid into the corresponding
primary alcohol was performed with 70% yield with BH3·THF. The expected chlorinated
product 7 was obtained by an in situ mesylation-chlorination in 56% yield. This product was
further coupled with 4,5-dihydro-N-nitro-1H-imidazol-2-amine or N-(4,5-dihydro-2-thiazolyl)
3

cyanamide, to provide the two desired trifluoromethoxy analogues of Imidacloprid and
Thiacloprid (8 and 9) in 38% and 74 % yield respectively (Scheme 1).
Difluoromethoxy-precursors
The synthesis of F2HCO-compounds was reported either by the use of ozone-depleting
CHF2Cl gas, or by means of many other difluorocarbene precursors. The generated
difluorocarbene is reacted with an alkoxide/phenoxide to provide the corresponding F2HCO-
product. Elevated temperatures or poor functional group tolerance were sometimes important
drawbacks of these approaches[20]. Hartwig reported a new approach for the preparation of
difluoromethoxylated aromatics by means of a non-ODS-based reagent, namely
difluoromethyl triflate (TfO-CHF2), which displays difluorocarbene reactivity[21]. This
reagent can be conveniently prepared from the Ruppert-Prakash reagent (TMSCF3) and triflic
acid, and can be used as an air-stable liquid. The difluoromethylation of a diversity of phenols
(and sulphides) was reported with good to excellent yields within minutes in aqueous solvent.
A broad functional group tolerance and mild reaction conditions enabled the
difluoromethylation of phenols generated in situ by catalytic and oxidative processes (from
aryl boronic acids, arenes or aryl halides), despite slightly lower yields. Surprisingly, only two
examples of hydroxychromenones and that of 8-hydroxyquinoline (i.e. where the OH group is
borne by the benzo ring, not the pyrido one) were included into this report; the
difluoromethylation of other hydroxylated heterocycles thus remained untapped, and it
seemed important to complete the study. Therefore, we developed the difluoromethylation of
a variety of hydroxylated heterocycles, including pyridines, pyridazines, pyrazines, pyrazoles
or quinolines.
Our first model substrate, 6-chloropyridone, was submitted to Hartwig et al.'s reaction
conditions (3 equiv. of 10, 12 equiv. of KOH in MeCN at room temperature), affording the
desired product in 85% yield (Table 1, entry 8). Attempts to deviate from these conditions, in
terms of solvent, base or amount of base could not provide any improvement (Table 1).
Difluoromethyl triflate was prepared using Dilman’s procedure[22].
After this first study, the scope extension was achieved using a selection of hydroxy-
pyridines, -pyrazoles, -pyrazine, -pyridazine and -quinoline (11a-o, Table 2). The
difluoromethylation reaction of these substrates using difluoromethyl triflate was achieved
with moderate to good yields. Interestingly, all heterocycles used to illustrate this study were
successfully difluoromethylated, showing the versatility of this method. The possibility of
using difluoromethyl-nonaflate (F2HC-ONf) to avoid the formation of aryl triflate side-
products was not investigated in this case (as previously achieved by Hartwig’s group). The
low yields observed in the cases of light substrates can be explained by the volatility of the
corresponding products (e.g.: entries 7, 8, 12, Table 2).
It is important to note that several reports have recently described the preparation of
difluoromethoxylated
heterocycles
using
different
difluorocarbene
precursors
([Cu(phen)2][O2CCF2Cl] or fluoroform). In the majority of cases, the reported yields were
lower, heating the reaction mixture was required, as well as the use of less environmentally
friendly organic solvents[23, 24].
4

As previously mentioned, the F2HC-O-group possesses similar electronic properties to those
of F3C-O, but with specific features (H-bonding capacity, different conformational behaviour,
size). Therefore, we decided to apply this approach to the synthesis of F2HC-O-analogues of
Imidacloprid and Thiacloprid.
For this purpose, the key intermediate 14 was prepared starting from readily available 6-
hydroxynicotinic acid. First, this starting material was converted into 5-
(hydroxymethyl)pyridin-2(1H)-one (12) after esterification in acidic medium followed by
ester reduction. The resulting product 12 was then O-protected via a TBS group, in order to
successfully achieve the O-difluoromethylation of the pyridine core providing intermediate
13. After a TBAF-mediated O-desilylation, the chlorination of the resulting primary alcohol
using thionyl chloride was performed providing the desired product 14. This product was
further coupled with 4,5-dihydro-N-nitro-1H-imidazol-2-amine or N-(4,5-dihydro-2-thiazolyl)
cyanamide, to provide the two desired difluoromethoxy analogues of Imidacloprid and
Thiacloprid (15 and 16) in 74% and 72 % yield respectively (Scheme 2).
F3CO- and F2HCO-analogues of Imidacloprid and Thiacloprid –
Biological evaluation
The activity of neonicotinoids towards inhibition of an enzymatic reaction can be
approximately evaluated as the pI50 index (I50 = quantity of neonicotinoid required for 50%
inhibition)[25]. Both 6-difluoromethoxy- (15; logP-value = 1.59) and 6-trifluoromethoxy-
analogues (8; logP-value = 1.82) of Imidacloprid have the same low pI50-values (5.3 vs 5.2)
in vitro, which are significantly lower than the one measured for Imidacloprid (logP-value =
0.6; pI50 = 9.1). Despite the fact that 15 (100 g a.i. ha-1) is 5 times more active in vivo against
green-peach aphid (M. persicae) than 8 (500 g a.i. ha-1), both derivatives are much less active
(by a factor of 625) than Imidacloprid (0.16 g a.i. ha-1). A similar result was obtained for the
two Thiacloprid analogues (9 and 16). Both 6-difluoromethoxy- (16; logP-value = 1.92) and
6-trifluoromethoxy-analogues (9; logP-value = 2.08) have the same low pI50-values (4.9 vs
4.8) in vitro, which are significantly lower than the one measured for Thiacloprid (logP-value
= 1.6; pI50 = 9.2). Contrary to the case of Imidacloprid and of its derivatives 8 and 15, the
OCF3-Thiacloprid analogue 9 (100 g a.i. ha-1) is 5 times more active in vivo against M.
persicae than the OCHF2- one (16; 500 g a.i. ha-1); however —as for 8 and 15 compared to
Imidacloprid— both derivatives 9 and 16 are much less active (by a factor of 125) than
Thiacloprid (0.8 g a.i. ha-1) (Table 3).
5

While it has been difficult to obtain crystals of any nAChR of sufficient quality to conduct
high-resolution X-ray crystallography, both the crystal structure of a soluble homopentameric
acetylcholine binding protein isolated from the seawater mollusc Aplysia californica (Ac-
AChBP) and the only recently added crystal structure of the human 42 acetylcholine
receptor[27] can be used to provide considerable support to the understanding of ligand–
receptor interactions[28]. Figure 2 compares the mode of binding of Imidacloprid and its 6-
difluoromethoxy-analogue (15) as well as Thiacloprid and its 6-trifluoromethoxy-analogue
(9) to Ac-AChBP from A. californica. The Figure 2 has been created from PDB entry 3C79
(Imidacloprid in complex with Ac-AChBP)[29] following the procedure described by Beck et
al.[30]. In both cases, the positively polarized N-nitroguanidine and N-cyano-amidine π-
systems of Imidacloprid and 15 as well as Thiacloprid and 9 demonstrate a perfect overlay as
shown in Figures 2b and 2d.
In addition, a strikingly conserved water molecule mediates a hydrogen bridge between the
pyridine nitrogen atoms of all neonicotinoids and the loop D backbone, which is known to be
important for ligand binding. However, the overlay of Imidacloprid and 15 with the focus on
6-F2HC-O- and 6-Cl-pyridin-3-yl residues (Figure 2c) as well as Thiacloprid and 9 with the
focus on 6-F3C-O- and 6-Cl-pyridin-3-yl residues (Figure 2e) clearly demonstrates the
differences between the two commercial neonicotinoids and their fluoroalkoxy-containing
analogues. Both the F2HCO- and F3CO-groups in 6-position of the pyridine are much larger
(see dotted circles in Figure 2c and 2e) compared to a chlorine atom and therefore disruptive
for the ligand-receptor interaction. In addition, the groups tend to adopt perpendicular position
as described for (hetero)aromatic ring systems[31, 32]. As a consequence of these structural
modifications the insecticidal activity of 15 and 9 decreased remarkably.
3. Conclusion
To illustrate the potential of the F3CO- and F2HCO-groups as emergent fluorinated
substituents (EFS), analogues of Imidacloprid and Thiacloprid displaying a replacement of the
key chlorine atom by these two groups have been prepared and evaluated. For the preparation
of the key intermediates, we have developed an efficient synthetic route to prepare the desired
F3CO-intermediate; in a second hand, we have developed a novel strategy to prepare F2HCO-
substituted heterocycles, and this strategy was applied to the preparation of the desired
F2HCO-intermediate. With both key intermediates, F3CO- and F2HCO-analogues of
Imidacloprid and Thiacloprid were prepared. While the in-vitro activity of these analogues is
promising, their in-vivo activity revealed to be much less elevated. However, this
investigation opens the route to a new access to analogues of bioactive ingredients and their
further evaluation, which could possibly lead to large activity enhancements.
4. Experimental
General
6

All reactions were performed in flame-dried glassware using sealed tube or Schlenk tube.
Liquids and solutions were transferred with syringes. Air- and moisture- sensitive materials
were stored protected and handled under an atmosphere of argon, with appropriate glassware.
Solvents were purified and dried following standard procedures: tetrahydrofuran (THF) was
distilled from sodium or sodium + benzophenone prior to use. Anhydrous MeCN was used
from commercial source and was stored under Argon. Technical grade solvents for extraction
and chromatography (cyclohexane, dichloromethane, n-pentane, ether, toluene, and ethyl
acetate) were used without purification. All reagents were purchased from standard suppliers
(Sigma Aldrich, ABCR, Alfa Aesar and Apollo scientific). Starting materials, if commercial,
were purchased and used as such, provided that adequate checks (NMR) had confirmed the
claimed purity. Analytical thin-layer chromatography (TLC) was performed on silica gel.
Flash column chromatography was performed on silica gel 60 (40–63 μm, 230–400 mesh,
1
13
19
ASTM) by Merck using the indicated solvents. H, C, and F-NMR spectra were recorded
in CDCl3 on Bruker AV 400 instruments (1H: 400MHz, 19F: 376MHz, 13C: 100MHz, 11B:
128MHz). Chemical shifts are reported in parts per million (ppm) downfield from
tetramethylsilane and are referenced to the residual solvent resonance as the internal standard
(chloroform (δ [1H] 7.26 and accordingly δ [13C] 77.16 ppm), CD3CN (δ [1H] 1.94 and
accordingly δ [13C] 1.32 ppm, MeOD-d4 (δ [1H] 3.31 and accordingly δ [13C] 49.00 ppm),
DMSO-d6 (δ [1H] 2.50 and accordingly δ [13C] 39.52 ppm) or Acetone-d6 (δ [1H] 2.05 and
accordingly δ [13C] 29.84 ppm). Data are reported as follows: chemical shift, multiplicity (br s
= broad singlet, s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet, m = multiplet,
br d = broad doublet), coupling constant (Hz) and integration. Fluorobenzene ( [19F] -113.15
ppm) was used as internal standard to measure yields in-situ. The spectra were processed with
the program NMR Notebook (Version 2.70, NMRtec). Experiments under microwave
irradiation were carried out on an InitiatorTM apparatus from Biotage, exact parameters are
given with the procedures. Melting points (M.p.) were determined for crystalline or solid
compounds with a Melting Point Apparatus M-560 and are not corrected. High resolution
mass spectrometry (HRMS) analysis and elemental analysis (Anal.) were performed by the
analytical facility at the University of Strasbourg (measurement accuracy ≤ 15 ppm). Spectral
data were recorded from samples purified by Hickmann distillation when necessary.
F3CO-Imidacloprid and F3CO-Thiacloprid
2-Chloro-6-trichloromethoxypyridine (1)
Thiophosgene (3.0 mL, 39 mmol, 1 equiv.) in dichloromethane (24 mL) was added dropwise
to a solution of 2-chloro-6-hydroxypyridine (5.0 g, 39 mmol) in aqueous sodium hydroxide
(5%, 34 mL) at 0 °C. The reaction mixture was vigorously stirred for 2 h at 0 °C before being
extracted with dichloromethane (3 x 20 mL). The combined organic layers were washed with
1M HCl (20 mL) and water (20 mL) and dried with sodium sulphate before being evaporated.
The crude product was taken up in chloroform (40 mL) and the reaction mixture was then
saturated with chlorine at 25 °C until the reaction mixture began to warm up. After 2 h at 25
°C, excess chlorine was again added until a yellow solution was obtained. After 24 h at 25 °C,
excess chlorine was removed with a stream of argon and the solution was concentrated. The
crude pale-yellow oil was distilled under reduced pressure to afford pure 2-chloro-6-
trichloromethoxypyridine (1). Colourless oil (5.7 g, 60% yield), b.p. = 80–82 °C (1 mbar); 1H
NMR (CDCl3, 300 MHz, 25 °C): δ 7.70 (t, 1 H, J = 7.9 Hz, H-4), 7.19 (d, 1 H, J = 7.9 Hz, H-
5), 7.02 (d, J = 7.9 Hz, 1 H, H-3) ppm; 13C NMR (CDCl3, 75 MHz, 25 °C): δ 151.8 (C), 149.0
(C), 141.7 (CHarom), 122.2 (CHarom), 112.7 (CHarom), 109.1 (OCCl3). Spectroscopic data
were in agreement with literature values[17].
7

2-Chloro-6-trifluoromethoxypyridine (2)
2-Chloro-6-trichloromethoxypyridine (1, 5.9 g, 24 mmol, 1 equiv.) was added dropwise at
120 °C to a mixture of SbF3 (8.7 g, 48 mmol, 2 equiv.) and SbCl5 (0.60 mL, 4.8 mmol, 0.2
equiv.) and the mixture was stirred for 3 h at 140 °C. GC monitoring indicated 100%
conversion and disappearance of the -OCF2Cl byproduct. The mixture was then cooled to
room temperature and dissolved in dichloromethane (100 mL). The solution was washed with
2M HCl (150 mL) and the aqueous layer was extracted with dichloromethane (2 x 50 mL).
The combined organic layers were dried over sodium sulphate and the solvent was evaporated
at atmospheric pressure. The crude product was distilled under reduced pressure to afford
pure 2-chloro-6-trifluoromethoxypyridine (2). Colourless oil (2.5 g, 53% yield), b.p. = 42–44
°C (20 mbar); 1H NMR (CDCl3, 300 MHz, 25 °C): δ 7.67 (t, 1 H, J = 7.9 Hz, H-4), 7.18 (d, 1
H, J = 7.9 Hz, H-5), 6.87 (d, 1 H, J = 7.9 Hz, H-3) ppm; 13C NMR (CDCl3, 75 MHz, 25 °C): δ
155.6 (C), 149.3 (C), 142.0 (CHarom), 122.2 (CHarom), 119.8 (q, JC-F = 262.1 Hz, OCF3),
19
111.1 (CH); F NMR (CDCl3, 282 MHz, 25 °C): δ -57.2 ppm. Spectroscopic data were in
agreement with literature values[17].
2-Chloro-6-(trifluoromethoxy)-5-(trimethylsilyl)pyridine (3)
Butyllithium (1.56 M in hexanes, 5.7 mL, 8.9 mmol, 1.1 equiv.) was added dropwise at 0 °C
to a solution of diisopropylamine (1.2 mL, 8.9 mmol, 1.1 equiv.) in THF (15 mL). A solution
of 2-chloro-6-(trifluoromethoxy)pyridine 2 (1.6 g, 8.1 mmol, 1 equiv.) in THF (5 mL) was
added dropwise at -78 °C, and the reaction mixture was stirred for 2 h at this temperature.
Chlorotrimethylsilane (1.0 g, 1.13 mL, 8.9 mmol, 1.1 equiv.) was then added dropwise and
the mixture was allowed to reach 25 °C before being neutralised with water (20 mL) and
extracted with diethyl ether (3 x 10 mL). The combined organic layers were dried over
sodium sulphate and concentrated in vacuo. The crude product was distilled under reduced
pressure to afford pure 2-chloro-6-(trifluoromethoxy)-5-(trimethylsilyl)pyridine (3).
Colourless oil (1.5 g, 68%), b.p. = 89–93 °C (14 mbar); 1H NMR (CDCl3, 300 MHz, 25 °C): δ
7.78 (d, 1 H, J = 7.6 Hz, H-3), 7.22 (d, 1 H, J = 7.6 Hz, H-4), 0.34 (s, 9 H, SiMe3) ppm.
Spectroscopic data were in agreement with literature values[17].
2-Chloro-6-trifluoromethoxynicotinic acid (4)
Butyllithium (1.56 M in hexanes, 3.7 mL, 5.7 mmol, 1.1 equiv.) was added dropwise at 0 °C
to a solution of 2,2,6,6-tetramethylpiperidine (1.0 mL, 5.7 mmol, 1.1 equiv.) in THF (10 mL).
A solution of 2-chloro-6-(trifluoromethoxy)-5-(trimethylsilyl)pyridine 3 (1.4 g, 5.2 mmol, 1
equiv.) in THF (5 mL) was added dropwise at -78 °C, and the reaction mixture was stirred for
2 h at this temperature. The mixture was then poured onto an excess of freshly crushed dry ice
before being treated with an aqueous solution of sodium hydroxide (5%, 10 mL). The
resulting aqueous layer was collected, washed with diethyl ether (10 mL), and acidified to pH
= 1 by dropwise addition of 6M HCl (4 mL). After extraction with ethyl acetate (3 x 10 mL),
the combined organic layers were dried over sodium sulphate and evaporated. The crude oil
was treated with tetrabutylammonium fluoride (1M in THF, 5.7 mL, 5.7 mmol, 1.1 equiv.) for
20 h at 25 °C. The mixture was then neutralised by addition of 2M HCl (10 mL) and extracted
with ethyl acetate (3 x 10 mL). The combined organic layers were dried over sodium sulphate
and evaporated to afford pure 2-chloro-6-(trifluoromethoxy)nicotinic acid (4). Colourless
powder (0.92 g, 70%); 1H NMR (CD3OD, 300 MHz, 25 °C): δ 8.44 (d, 1H, J = 8.3 Hz, H-4),
7.21 (d, 1 H, J = 8.3 Hz, H-5) ppm. Spectroscopic data were in agreement with literature
values[17].
6-Trifluoromethoxynicotinic acid (5)
8

Palladium (10% on charcoal, 2.1 g, 2.0 mmol, 10 mol%) was added at 25 °C with stirring to a
solution of 2-chloro-6-trifluoromethoxynicotinic acid 4 (4.8 g, 20 mmol, 1 equiv.) and
ammonium formate (2.5 g, 40 mmol, 2 equiv.) in methanol (40 mL). The reaction mixture
was stirred for 16 h at room temperature before being filtered on Celite®, the filtrate was
concentrated and the residue was taken up in ethyl acetate (50 mL). The organic layer was
washed with 2M HCl (2 x 20 mL) and water (20 mL). The organic layer was dried over
sodium sulphate and evaporated in vacuo to afford pure 6-(trifluoromethoxy)nicotinic acid
(5). Colourless powder (3.2 g, 76%); 1H NMR (CD3OD, 300 MHz, 25 °C): δ 8.91 (d, 1 H, Jm
= 2.3 Hz, H-2), 8.48 (dd, 1 H, Jo = 8.4, Jm = 2.3 Hz, H-4), 7.24 (d, 1 H, Jo = 8.4 Hz, H-5)
ppm. Spectroscopic data were in agreement with literature values[17].
(6-(Trifluoromethoxy)pyridin-3-yl)methanol (6)
BH3 THF(1M in THF, 36 mL, 36 mmol, 5 equiv.) was added dropwise to 6-trifluoromethoxy
.
nicotinic acid 5 (1.5 g, 7.3 mmol, 1 equiv.) in solution in THF (25 mL) at 0 °C. The reaction
mixture was stirred 30 min at this temperature, and allowed to reach room temperature
overnight. It was quenched with methanol (25 mL), diluted with diethyl ether (100 mL) and
the organic layer was washed with brine (2 x 100 mL). The combined organic layers were
dried with sodium sulphate and the solvent was distilled off. The crude product was purified
by column chromatography on silica gel with pentane/diethyl ether (6:4 to 3:7) as eluent,
which afforded 6. Colourless oil (1.0 g, 70%); 1H NMR (CDCl3, 300 MHz, 25 °C): δ 8.28 (d,
J = 2.4 Hz, 1 H, H-2), 7.82 (dd, 1 H, Jo = 8.4 Hz, Jm = 2.4 Hz, H-4), 7.03 (d, 1 H, J = 8.4 Hz,
13
H-5), 4.73 (s, 2H, CH2), 2.36 (brs, 1H, -OH) ppm.; C NMR (CDCl3, 75 MHz, 25 °C): δ
156.5 (C-6), 146.7 (C-2), 139.7 (C-4), 135.6 (C-3), 120.6 (q, JC-F = 259.2 Hz, OCF3), 62.1
(CH2) ppm; 19F NMR (CDCl3, 282 MHz, 25 °C): δ -56.7 ppm; HRMS (ESI Positive) for
C7H7F3NO2 [M+H]: calcd. 194.043; found 194.044.
3-(Chloromethyl)-6-(trifluoromethoxy) pyridine (7)
Mesyl chloride (0.28 mL, 3.6 mmol, 1.5 equiv.) was added dropwise to a solution of (6-
(trifluoromethoxy)pyridin-3-yl)methanol 6 (0.50 g, 2.4 mmol, 1 equiv.) in dichloromethane (8
mL) in presence of triethylamine (0.60 g, 0.79 mL, 5.7 mmol, 2.4 equiv.) at 0 °C. The
reaction mixture was allowed to reach room temperature overnight. It was then poured into a
saturated solution of sodium hydrogen carbonate (10 mL). The aqueous layer was extracted
with dichloromethane (3 x 15 mL) and washed with water (2 x 10 mL). The combined
organic layers were dried over sodium sulphate and the solvent was distilled off. The crude
product was purified by column chromatography on silica gel with pentane/diethyl ether (9:1)
as eluent, which afforded 7. Pale yellow oil (0.31 g, 56%);1H NMR (CDCl3, 300 MHz, 25
°C): δ 8.32 (d, 1 H, J = 2.4 Hz, H-2), 7.85 (dd, 1 H, Jm = 2.4 Hz, Jo = 8.4 Hz, H-4), 7.03 (d, 1
H, J = 8.4 Hz, H-5), 4.59 (s, 2H, CH2) ppm; 13C NMR (CDCl3, 75 MHz, 25 °C): δ 156.5 (C-
6), 147.4 (C-2), 140.6 (C-4), 131.6 (C-3), 120.0 (q, OCF3, JC-F = 260.1 Hz), 42.0 (CH2) ppm;
19F NMR (CDCl3, 282 MHz, 25 °C): δ -56.6 ppm; MS (EI): m/z = 211.1 [M+], 176.0 [M+-Cl].
N-(1-((6-(Trifluoromethoxy)pyridin-3-yl)methyl)-4,5-dihydro-1H-imidazol-2-
yl)nitramide (8)
3-(Chloromethyl)-6-(trifluoromethoxy)pyridine 7 (0,15 g, 0.69 mmol, 0.90 equiv.) was added
dropwise to a solution of 4,5-dihydro-N-nitro-1H-imidazol-2-amine (0,10 g, 0.76 mmol, 1
equiv.), potassium carbonate (0.10 g, 0.73 mmol, 0.96 equiv.) and caesium chloride (5.0 mg,
0.030 mmol, 0.03 equiv.) in acetonitrile (5 mL) at room temperature. The reaction mixture
was stirred 5 hours at room temperature. It was then filtrated and the solvent was distilled off.
The crude product was purified by HPLC on reverse phase with water/acetonitrile gradient,
1
which afforded 8 (89.0 mg, 38% yield); H NMR (DMSO-d6, 150 MHz): δ 3.50 (m, 2H,
9

CH2), 3.63 (m, 2H, CH2), 4.50 (s, 2H, CH2), 7.31 (d, 2H, C-H, Py, J = 8.4 Hz), 7.96 (dd, 1H,
13
C-H, Py, J = 8.4 Hz, J = 2.5 Hz), 8.32 (d, 1H, C-H, Py, J = 2.5 Hz), 9.00 (s, 1H, NH); C
NMR (proton-decoupled) (DMSO-d6, 150 MHz): δ 41.8, 44.6, 45.3 (CH2), 113.4 (C-H, Ph),
119.9 (OCF3), 131.5 (C, Ph), 141.3, 147.3 (C-H, Ph), 155.5 (C-O, Ph), 160.5 (C=N) ppm; 19F
NMR (DMSO-d6, 566 MHz): δ = -54.7 ppm. HRMS (ESI) calcd for C10H11F3N5O3 [M+H]+:
306.0814. Found: 306.0816.
N-(3-((6-(Trifluoromethoxy)pyridin-3-yl)methyl)thiazolidin-2-
ylidene)cyanamide (9)
3-(Chloromethyl)-6-(trifluoromethoxy)pyridine 7 (0.15 g, 0.69 mmol, 0.90 equiv.) was added
dropwise to a solution of N-(4,5-dihydro-2-thiazolyl)cyanamide (98 mg, 0.76 mmol, 1
equiv.), potassium carbonate (0.10 g, 0.73 mmol, 0.96 equiv.) and caesium chloride (5.0 mg,
0.030 mmol, 0.03 equiv.) in acetonitrile (5 mL) at room temperature. The reaction mixture
was stirred 5 hours at room temperature. It was then filtrated and the solvent was distilled off.
The crude product was purified by HPLC on reverse phase with water/acetonitrile gradient,
which afforded 9 (172.6 mg, 74% yield); 1H NMR (CD3CN, 150 MHz): δ 3.41 (m, 2H,
CH2), 3.85 (m, 2H, CH2), 4.61 (s, 2H, CH2), 7.12 (d, 2H, C-H, Py, J = 8.4 Hz), 7.87 (dd, 1H,
C-H, Py, J = 8.4 Hz, J = 2.5 Hz), 8.23 (d, 1H, C-H, Py, J = 2.5 Hz); 13C NMR (proton-
decoupled) (CD3CN, 150 MHz): δ 28.3, 47.4, 53.6 (CH2), 114.1 (C-H, Py), 121.1 (OCF3),
131.0 (C, Py), 142.0, 148.4 (C-H, Py), 157.1 (C-O, Py), 176.3 (C=N); 19F NMR (CDCN, 566
MHz): δ = -55.8 ppm. HRMS (ESI) calcd for C10H10F3N4OS [M+H]+: 303.0527. Found:
303.0526.
F2HCO-Imidacloprid and F2HCO-Thiacloprid
Preparation of 2-chloro-6-(difluoromethoxy)pyridine (11a). General
procedure for the difluoromethylation of hydroxyl-substituted heteroaromatics
To a vigorously stirred solution of 2-chloro-6-hydroxypyridine (0.13 g, 1.0 mmol) in
acetonitrile (2 mL) at room temperature was added a 6M aqueous solution of potassium
hydroxide (2 mL). Difluoromethyltriflate (0.38 mL, 3.0 mmol, 3 equiv.) was added dropwise
to the reaction mixture which was maintained at room temperature by means of a water bath
(the reaction is exothermic), and the medium was stirred for 30 min. The mixture was diluted
with water (20 mL) and extracted with diethyl ether (2 x 10 mL) and ethyl acetate (3 x 10
mL). The combined organic layers were dried over Na2SO4, filtered and evaporated under
reduced pressure. The crude material was purified by column chromatography on silica gel
with pentane/diethyl ether (100:0 to 70:30) as eluent to afford the pure title compound (129
1
mg, 72% yield); H-NMR (400 MHz, CDCl3): δ 7.62 (t, 1H, J = 7.9 Hz), 7.37 (t, 1H, J =
72.2 Hz), 7.07 (d, 1H, J = 7.9 Hz), 6.76 (d, 1H, J = 8.0 Hz) ppm. 13C-NMR (101 MHz,
CDCl3): δ 158.3, 148.5, 142.1, 120.1, 113.8 (t, J = 259 Hz), 109.6 ppm. 19F-NMR (376
MHz, CDCl3): δ -89.3 (d, 2F, J = 71.4 Hz) ppm. HRMS (ESI) calcd for C6H5ClF2NO
[M+H]+: 180.002. Found: 180.000. Spectroscopic data were in agreement with literature
values[17].
2-Chloro-5-(difluoromethoxy)pyridine (11b).
The crude material was purified by column chromatography on silica gel with pentane/diethyl
1
ether (100:0 to 70:30) as eluent to afford the pure title compound (133 mg, 74%). H-NMR
(400 MHz, CDCl3): δ 8.16 (d, 1H, J = 2.8 Hz), 7.37 (dd, 1H, J = 8.8 Hz, J = 2.8 Hz), 7.24
13
(d, 1H, J = 8.8 Hz), 6.44 (t, 1H, J = 72.2 Hz) ppm. C-NMR (101 MHz, CDCl3): δ 147.8,
146.2, 141.9, 130.8, 124.9, 115.1 (t, J = 266 Hz) ppm. 19F-NMR (376 MHz, CDCl3): δ -81.9
10

(d, 2F, J = 72.5 Hz) ppm. HRMS (ESI) calcd for C6H5ClF2NO [M+H]+: 180.002. Found:
180.004. Spectroscopic data were in agreement with literature values[17].
2-Chloro-4-(difluoromethoxy)pyridine (11c).
The crude material was purified by column chromatography on silica gel with pentane/diethyl
1
ether (100:0 to 70:30) as eluent to afford the pure title compound (74 mg, 41%). H-NMR
(400 MHz, CDCl3): δ 8.36 (d, 1H, J = 5.6 Hz), 7.08 (s, 1H), 6.99 (m, 1H), 6.65 (t, 1H, J =
71.6 Hz) ppm. 13C-NMR (101 MHz, CDCl3): δ 158.9, 152.9, 151.1, 114.6 (t, JC-F = 265.2
Hz), 113.7, 112.4 ppm. 19F-NMR (376 MHz, CDCl3): δ -83.6 (d, 2F, J = 72.6 Hz) ppm.
HRMS (ESI) calcd for C6H5ClF2NO [M+H]+: 180.0022. Found: 180.0038.
2-Bromo-3-(difluoromethoxy)pyridine (11d).
The crude material was purified by column chromatography on silica gel with pentane/diethyl
1
ether (100:0 to 70:30) as eluent to afford the pure title compound (170 mg, 76%). H-NMR
(400 MHz, CDCl3): δ 8.28 (d, 1H, J = 4.6 Hz), 7.56 (d, 1H, J = 8.4 Hz), 7.31 (m, 1H), 6.60
(t, 1H, J = 73.0 Hz) ppm. 13C-NMR (101 MHz, CDCl3): δ 146.7, 145.1, 135.9, 129.3, 123.5,
19
115.3 (t, JC-F = 264.5 Hz) ppm. F-NMR (376 MHz, CDCl3): δ -82.0 (d, 2F, J = 72.6 Hz)
ppm. HRMS (ESI) calcd for C6H5BrF2NO [M+H]+: 223.952. Found: 223.952. Spectroscopic
data were in agreement with literature values[17].
3-Bromo-2-(difluoromethoxy)pyridine (11e).
The crude material was purified by column chromatography on silica gel with pentane/diethyl
1
ether (100:0 to 70:30) as eluent to afford the pure title compound (101 mg, 45%). H-NMR
(400 MHz, CDCl3): δ 8.13 (d, 1H, J = 4.6 Hz), 7.94 (d, 1H, J = 7.7 Hz), 7.46 (t, 1H, J = 72.4
Hz), 7.01 (dd, 1H, J = 7.5 Hz, J = 4.8 Hz) ppm. 13C-NMR (101 MHz, CDCl3): δ 155.5,
19
145.5, 143.2, 121.1, 114.2 (t, JC-F = 257.2 Hz), 106.8 ppm. F-NMR (376 MHz, CDCl3): δ -
89.3 (d, 2F, J = 72.1 Hz) ppm. HRMS (ESI) calcd for C6H5BrF2NO [M+H]+: 223.952. Found:
223.952.
2,4-Dichloro-5-(difluoromethoxy)pyridine (11f).
The crude material was purified by column chromatography on silica gel with pentane/diethyl
1
ether (100:0 to 70:30) as eluent to afford the pure title compound (141 mg, 66%). H-NMR
13
(400 MHz, CDCl3): δ 8.32 (s, 1H), 7.47 (s, 1H), 6.60 (t, 1H, J = 72.1 Hz) ppm. C-NMR
19
(101 MHz, CDCl3): δ 148.5, 143.1, 138.8, 125.7, 115.0 (t, JC-F = 267.1 Hz), 110.2 ppm. F-
NMR (376 MHz, CDCl3): δ -81.8 (d, 2F, J = 72.0 Hz) ppm. HRMS (ESI) calcd for
C6H4Cl2F2NO [M+H]+: 213.964. Found: 213.963.
5-(Difluoromethoxy)-2-methylpyridine (11g).
The crude material was purified by column chromatography on silica gel with pentane/diethyl
1
ether (100:0 to 70:30) as eluent to afford the pure title compound (49 mg, 31%). H-NMR
(400 MHz, CDCl3): δ 8.20 (s, 1H), 7.23 (m, 1H), 7.00 (d, 1H, J = 8.8 Hz), 6.35 (t, 1H, J =
73.0 Hz), 2.40 (s, 3H) ppm. 13C-NMR (101 MHz, CDCl3): δ 154.5, 143.9, 140.1, 126.8,
19
122.3, 114.1 (t, JC-F = 262.1 Hz), 22.4 ppm. F-NMR (376 MHz, CDCl3): δ -81.2 (d, 2F, J
= 74.8 Hz) ppm. HRMS (ESI) calcd for C7H8F2NO [M+H]+: 160.057. Found: 160.058.
3-(Difluoromethoxy)pyridine (11h).
11

The crude material was purified by column chromatography on silica gel with pentane/diethyl
ether (100:0 to 70:30) as eluent to afford the pure title compound (46 mg, 32%).
Spectroscopic data were in agreement with literature values[17].
Ethyl 2-(difluoromethoxy)nicotinate (11i).
The crude material was purified by column chromatography on silica gel with pentane/diethyl
1
ether (100:0 to 60:40) as eluent to afford the pure title compound (61 mg, 28%). H-NMR
(400 MHz, CDCl3): δ 8.32 (dd, 1H, J = 4.8 Hz, J = 2.0 Hz), 8.27 (dd, 1H, J = 7.7 Hz, J = 2.0
Hz), 7.53 (t, 1H, J = 72.4 Hz), 7.19 (dd, 1H, J = 7.6 Hz, J = 4.8 Hz), 4.41 (q, 2H, J = 7.3 Hz),
1.41 (t, 3H, J = 7.2 Hz) ppm. 13C-NMR (101 MHz, CDCl3): δ 163.9, 157.1, 150.2, 142.1,
19
119.7, 115.4, 114.0 (t, JC-F = 251.8 Hz), 61.8, 14.1 ppm. F-NMR (376 MHz, CDCl3): δ -
89.3 (d, 2F, J = 71.7 Hz) ppm. HRMS (ESI) calcd for C9H9F2NNaO3 [M+Na]+: 240.0443.
Found: 240.0414.
5-(Difluoromethoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole (11j).
The crude material was purified by column chromatography on silica gel with pentane/diethyl
1
ether (100:0 to 60:40) as eluent to afford the pure title compound (149 mg, 75%). H-NMR
(400 MHz, CDCl3): δ 6.48 (t, 1H, J = 55.0 Hz), 6.47 (t, 1H, J = 71.9 Hz), 6.04 (s, 1H), 3.69
(s, 3H) ppm. 13C-NMR (101 MHz, CDCl3): δ 145.3, 145.1 (t, JC-F = 29.8 Hz), 114.9 (t, JC-F
19
= 268.2 Hz), 111.0 (t, JC-F = 235.6 Hz), 89.4, 34.8 ppm. F-NMR (376 MHz, CDCl3): δ -
83.9 (d, 2F, J = 71.8 Hz), -112.3 (d, 2F, J = 55.0 Hz) ppm. HRMS (ESI) calcd for C6H7F4N2O
[M+H]+: 199.049. Found: 199.050.
Ethyl
3-bromo-5-(difluoromethoxy)-1-methyl-1H-pyrazole-4-carboxylate
(11k).
The crude material was purified by column chromatography on silica gel with pentane/diethyl
1
ether (100:0 to 60:40) as eluent to afford the pure title compound (120 mg, 40%). H-NMR
(400 MHz, CDCl3): δ 6.98 (t, 1H, J = 74.0 Hz), 4.34 (q, 2H, J = 7.5 Hz), 3.78 (s, 3H), 1.38
13
(t, 3H, J = 7.5 Hz) ppm. C-NMR (101 MHz, CDCl3): δ 160.5, 146.8 (t), 126.9, 116.7 (t),
19
101.9, 61.1, 35.3, 14.1 ppm. F-NMR (376 MHz, CDCl3): δ -83.3 (d, 2F, J = 74.7 Hz) ppm.
HRMS (ESI) calcd for C8H9BrF2N2NaO3 [M+Na]+: 320.966. Found: 320.965.
5-(Difluoromethoxy)-1,3-dimethyl-1H-pyrazole (11l).
The crude material was purified by column chromatography on silica gel with pentane/diethyl
1
ether (100:0 to 60:40) as eluent to afford the pure title compound (57 mg, 35%). H-NMR
(400 MHz, CDCl3): δ 6.47 (t, 1H, J = 72.5 Hz), 5.65 (s, 1H), 3.66 (s, 3H), 2.21 (s, 3H) ppm.
13C-NMR (101 MHz, CDCl3): δ 147.3, 145.2, 115.1 (t, JC-F = 264.2 Hz), 90.8, 34.0, 14.3
ppm. 19F-NMR (376 MHz, CDCl3): δ -83.6 (d, 2F, J = 72.3 Hz) ppm. HRMS (ESI) calcd for
C6H9F2N2O [M+H]+: 163.0677. Found: 163.0674.
3-Chloro-6-(difluoromethoxy)pyridazine (11m).
The crude material was purified by column chromatography on silica gel with pentane/diethyl
1
ether (100:0 to 60:40) as eluent to afford the pure title compound (107 mg, 59%). H-NMR
(400 MHz, CDCl3): δ 7.52 (t, 1H, J = 71.1 Hz), 7.48 (d, 1H, J = 9.0 Hz), 7.06 (d, 1H, J = 9.0
13
Hz) ppm. C-NMR (101 MHz, CDCl3): δ 160.9, 153.9, 132.4, 119.9, 113.4 (t, JC-F = 259.2
Hz) ppm. 19F-NMR (376 MHz, CDCl3): δ -88.9 (d, 2F, J = 71.0 Hz) ppm. HRMS (ESI)
calcd for C5H4ClF2N2O [M+H]+: 180.997. Found: 180.997.
12

2-Bromo-5-(difluoromethoxy)pyrazine (11n).
The crude material was purified by column chromatography on silica gel with pentane/diethyl
1
ether (100:0 to 60:40) as eluent to afford the pure title compound (119 mg, 53%). H-NMR
(400 MHz, CDCl3): δ 8.19 (d, 1H, J = 1.2 Hz), 8.10 (d, 1H, J = 1.2 Hz), 7.25 (t, 1H, J = 71.8
Hz) ppm. 13C-NMR (101 MHz, CDCl3): δ 155.0, 143.4, 135.2, 134.5, 113.8 (t) ppm. 19F-
NMR (376 MHz, CDCl3): δ -89.1 (d, 2F, J = 72.0 Hz) ppm. HRMS (ESI) calcd for
C5H4BrF2N2O [M+H]+: 224.9470. Found : 224.9473.
4-(Difluoromethoxy)quinoline (11o).
The crude material was purified by column chromatography on silica gel with pentane/diethyl
1
ether (100:0 to 60:40) as eluent to afford the pure title compound (61 mg, 31%). H-NMR
(400 MHz, CDCl3): δ 8.73 (d, 1H, J = 4.8 Hz), 8.10 (d, 1H, J = 8.4 Hz), 8.02 (d, 1H, J = 8.4
Hz), 7.68 (t, 1H, J = 7.2 Hz), 7.50 (t, 1H, J = 7.8 Hz), 6.93 (s, 1H), 6.75 (t, 1H, J = 72.2 Hz)
ppm. 13C-NMR (101 MHz, CDCl3): δ 154.4, 150.7, 149.8, 130.5, 129.2, 127.0, 121.5, 120.8,
19
115.3 (t, JC-F = 261.1 Hz), 105.8 ppm. F-NMR (376 MHz, CDCl3): δ -82.9 (d, 2F, J = 72.6
Hz) ppm. HRMS (ESI) calcd for C10H8F2NO [M+H]+: 196.057. Found: 196.058.
5-(Hydroxymethyl)pyridin-2-ol or 5-(hydroxymethyl)pyridin-2(1H)-one (12).
To a stirred solution of 6-hydroxynicotinic acid (10 g, 72 mmol) in absolute ethanol (500 mL)
was added sulfuric acid (4 mL) at room temperature. The mixture was heated to reflux for 48
h. After cooling down to room temperature, water (50 mL) was added and the reaction
mixture was neutralized to pH = 6-7 by portionwise addition of sodium hydrogen carbonate
(caution: gas evolution). The mixture was evaporated under reduced pressure (most of ethanol
was removed), and the residue was extracted with ethyl acetate (3 x 50 mL). The combined
organic extracts were washed with brine, dried over Na2SO4 and evaporated under reduced
1
pressure leading to the pure ethyl 6-hydroxynicotinate[30] (10 g, 86%). H-NMR (400 MHz,
CDCl3): δ 13.07 (s, 1H), 8.14 (s, 1H), 7.94 (d, 1H, J = 9.9 Hz), 6.51 (d, 1H, J = 9.4 Hz), 4.25
(q, 2H, J = 7.1 Hz), 1.29 ppm.
To a stirred solution of lithium aluminium hydride (1.4 g, 37 mmol, 1.2 equiv.) in anhydrous
THF (20 mL) at room temperature was added dropwise over 1 h a solution of ethyl 6-
hydroxynicotinate (5.1 g, 31 mmol) in anhydrous THF (150 mL) at the same temperature. The
mixture was stirred at room temperature for 2 h and then heated to reflux for 30 min. The
reaction mixture was cooled down to 0 °C and quenched with ethyl acetate (12 mL) and water
(6 mL). The solvents were removed and the residue was taken up in refluxing ethanol (200
mL). The solution was filtered through Celite® and ethanol was evaporated under reduced
pressure. The crude material was purified by column chromatography on silica gel with ethyl
1
acetate/methanol (75:25) as eluent to afford the pure title compound 12 (2.3 g, 60%). H-
NMR (400 MHz, DMSO-d6): δ 11.56 (s, 1H), 7.43 (dd, 1H, J = 9.1 Hz, J = 2.5 Hz), 7.25 (d,
1H, J = 2.5 Hz), 6.30 (d, 1H, J = 9.1 Hz), 5.22 (t, 1H, J = 5.6 Hz), 4.20 (d, 2H, J = 5.6 Hz)
ppm. 13C-NMR (101 MHz, DMSO-d6): δ 162.6, 142.0, 133.0, 120.1, 119.6, 60.1 ppm.
HRMS (ESI) calcd for C6H8NO2 [M+H]+: 126.056. Found: 126.055.
5-(((tert-Butyldimethylsilyl)oxy)methyl)-2-(difluoromethoxy)pyridine (13).
To a stirred solution of 5-(hydroxymethyl)pyridin-2-ol (1.3 g, 10 mmol) and imidazole (1.7 g,
25 mmol, 2.5 equiv.) in DMF (2.5 mL) was added tert-butyldimethylsilyl chloride (1.8 g, 12
mmol, 1.2 equiv.) at room temperature, and the reaction medium was stirred overnight. Water
(20 mL) was added and the mixture was extracted with ethyl acetate (3 x 20 mL). The
combined organic extracts were washed with brine, dried over Na2SO4 and evaporated under
13

reduced pressure. The crude material was purified by column chromatography on silica gel
with pentane/diethyl ether (100:0 to 80:20) as eluent to afford pure 5-(((tert-
butyldimethylsilyl)oxy)methyl)pyridin-2-ol (1.3 g, 54%). 1H-NMR (400 MHz, DMSO-d6): δ
11.36 (s, 1H), 7.31 (dd, 1H, J = 9.4 Hz, J = 2.7 Hz), 7.20 (m, 1H), 6.27 (d, 1H, J = 9.4 Hz),
13
4.36 (s, 2H), 0.81 (s, 9H), 0.00 (s, 6H) ppm. C-NMR (101 MHz, DMSO-d6): δ 162.5, 141.3,
133.0, 120.4, 118.2, 61.8, 26.3, 18.4, -4.7 ppm. HRMS (ESI) calcd for C12H22NO2Si [M+H]+:
240.142. Found: 240.141.
To a vigorously stirred solution of 5-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-ol (0.48
g , 2 mmol) in acetonitrile (4 mL) at room temperature was added a 6M aqueous solution of
potassium hydroxide (4 mL). Difluoromethyltriflate (0.76 mL, 6 mmol, 3 equiv.) was added
dropwise to the reaction mixture which was maintained at room temperature by means of a
water bath (the reaction is exothermic), and the medium was stirred for 30 min. The mixture
was diluted with water (20 mL) and extracted with diethyl ether (2 x 10 mL) and ethyl acetate
(3 x 10 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated
under reduced pressure. The crude material was purified by column chromatography on silica
gel with pentane/diethyl ether (100:0 to 90:10) as eluent to afford the pure title compound 13
1
(0.40 g, 70%). H-NMR (400 MHz, CDCl3): δ 8.02 (m, 1H), 7.59 (dd, 1H, J = 8.1 Hz, J =
2.5 Hz), 7.35 (t, 1H, J = 73.1 Hz), 6.73 (d, 1H, J = 8.4 Hz), 4.60 (s, 2H), 0.82 (s, 9H), 0.00 (s,
13
6H) ppm. C-NMR (101 MHz, CDCl3): δ 158.3, 144.8, 138.5, 133.2, 114.1 (t, JC-F = 255.4
Hz), 111.1, 62.2, 25.9, 18.3, -5.3 ppm. 19F-NMR (376 MHz, CDCl3): δ -88.6 (d, 2F, J = 72.9
Hz) ppm. HRMS (ESI) calcd for C13H22F2NO2Si [M+H]+: 290.139. Found: 290.138.
5-(Chloromethyl)-2-(difluoromethoxy)pyridine (14).
To a stirred solution of 5-(((tert- butyldimethylsilyl)oxy)methyl)-2-(difluoromethoxy)pyridine
13 (1.4 g, 5 mmol) in THF (10 mL) was added a solution of TBAF (1.0 M solution in THF,
10 mmol, 2 equiv.) at room temperature, and the mixture was stirred for 4 h. The reaction was
quenched with saturated ammonium chloride and brine, and extracted with ethyl acetate (3x
20 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated under
reduced pressure. The crude material was purified by column chromatography on silica gel
with ethyl acetate/pentane (60:40) as eluent to afford pure (6-(difluoromethoxy)pyridin-3-
1
yl)methanol (761 mg, 87%). H-NMR (400 MHz, CDCl3): δ 8.15 (d, 1H, J = 2.5 Hz), 7.76
(dd, 1H, J = 8.5 Hz, J = 2.5 Hz), 7.45 (t, 1H, J = 73.7 Hz), 6.90 (d, 1H, J = 8.5 Hz), 4.68 (m,
2H), 2.04 (m, 1H) ppm. 13C-NMR (101 MHz, CDCl3): δ 158.7, 145.6, 139.4, 132.5, 114.1 (t,
JC-F = 253.9 Hz), 111.4, 62.1 ppm. 19F-NMR (376 MHz, CDCl3): δ -88.7 (d, 2F, J = 73.5
Hz) ppm. HRMS (ESI) calcd for C7H8F2NO2 [M+H]+: 176.0518. Found: 176.0530.
To a stirred solution of thionyl chloride (0.16 mL, 2.2 mmol, 1.1 equiv.) in toluene (1 mL) at
room temperature was added dropwise a solution of (6-(difluoromethoxy)pyridin-3-
yl)methanol (0.35 g, 2 mmol) in toluene (2 mL). After 1 h at room temperature, vacuum was
1
applied leading to the pure title compound 14 (0.34 g, 89%) without further purification. H-
NMR (400 MHz, CDCl3): δ 8.18 (d, 1H, J = 2.6 Hz), 7.78 (dd, 1H, J = 8.5 Hz, J = 2.6 Hz),
13
7.46 (t, 1H, J = 72.8 Hz), 6.92 (d, 1H, J = 8.5 Hz), 4.56 (s, 2H) ppm. C-NMR (101 MHz,
19
CDCl3): δ 158.9, 146.7, 140.6, 129.8, 114.0 (t, JC-F = 256.7 Hz), 111.4, 42.5 ppm. F-NMR
(376 MHz, CDCl3): δ -89.1 (d, 2F, J = 72.5 Hz) ppm. HRMS (ESI) calcd for C7H7ClF2NO
[M+H]+: 194.018. Found: 194.018.
N-(1-((6-(Difluoromethoxy)pyridin-3-yl)methyl)-4,5-dihydro-1H-imidazol-2-
yl)nitramide (15)
14

5-(Chloromethyl)-2-(difluoromethoxy)pyridine 14 (0.13 g, 0.69 mmol, 0.90 equiv.) was
added dropwise to a solution of 4,5-dihydro-N-nitro-1H-imidazol-2-amine (0.10 g, 0.76
mmol, 1 equiv.), potassium carbonate (0.10 g, 0.73 mmol, 0.96 equiv.) and caesium chloride
(5.0 mg, 0.030 mmol, 0.03 equiv.) in acetonitrile (5 mL) at room temperature. The reaction
mixture was stirred 5 hours at room temperature. It was then filtrated and the solvent was
distilled off. The crude product was purified by HPLC on reverse phase with
water/acetonitrile gradient, which afforded 15 (163.9 mg, 74%); 1H (DMSO-d6, 150 MHz): δ
3.47 (m, 2H, CH2), 3.62 (m, 2H, CH2), 4.45 (s, 2H, CH2), 7.10 (d, 2H, C-H, Py, J = 8.4 Hz),
7.70 (t, 1H, OCHF2, JC-F = 72.8 Hz), 7.86 (dd, 1H, C-H, Py, J = 8.4 Hz, J = 2.5 Hz), 8.22 (d,
13
1H, C-H, Py, J = 2.5 Hz); 8.96 (s, 1H, NH); C NMR (proton-decoupled) (DMSO-d6, 150
MHz): δ 41.7, 44.6, 45.1 (CH2), 111.5 (C-H, Ph), 114.9 (OCHF2), 128.9 (C, Ph), 141.0,
19
146.7 (C-H, Ph), 158.1 (C-O, Ph), 160.5 (C=N); F NMR (DMSO-d6, 566 MHz): δ = -86.8
(d, 2F, J = 72.9 Hz) ppm. HRMS (ESI) calcd for C10H12F2N5O3 [M+H]+: 288.0908. Found:
288.0917.
N-(3-((6-(Difluoromethoxy)pyridin-3-yl)methyl)thiazolidin-2-
ylidene)cyanamide (16)
5-(Chloromethyl)-2-(difluoromethoxy)pyridine 14 (0.13 g, 0.69 mmol, 0.90 equiv.) was
added dropwise to a solution of N-(4,5-dihydro-2-thiazolyl)cyanamide (98 mg, 0.76 mmol, 1
equiv.), potassium carbonate (0.10 g, 0.73 mmol, 0.96 equiv.) and caesium chloride (5.0 mg,
0.030 mmol, 0.03 equiv.) in acetonitrile (5 mL) at room temperature. The reaction mixture
was stirred 5 hours at room temperature. It was then filtrated and the solvent was distilled off.
The crude product was purified by HPLC on reverse phase with water/acetonitrile gradient,
which afforded of 16 (158.5 mg, 72%); 1H (DMSO-d6, 150 MHz): δ 3.49 (m, 2H, CH2), 3.90
(m, 2H, CH2), 4.62 (s, 2H, CH2), 7.11 (d, 2H, C-H, Py, J = 8.4 Hz), 7.71 (t, 1H, OCHF2, JC-F
= 72.7 Hz), 7.85 (dd, 1H, C-H, Py, J = 8.4 Hz, J = 2.5 Hz), 8.23 (d, 1H, C-H, Py, J = 2.5 Hz);
13C NMR (proton-decoupled) (DMSO-d6, 150 MHz): δ 27.5, 46.4, 52.9 (CH2), 111.5 (C-H,
Py), 114.9 (OCHF2), 128.0 (C, Py), 141.2, 147.0 (C-H, Py), 158.2 (C-O, Py), 174.8 (C=N);
19F NMR (DMSO-d6, 566 MHz): δ = -86.88 (d, 2F, J = 72.8 Hz) ppm. HRMS (ESI) calcd for
C11H11F2N4OS [M+H]+: 285.0622. Found: 285.0618.
Receptor binding studies (pI50-values in vitro)
Radioligand [3H]imidacloprid displacement studies were conducted according to established
protocols by using membranes isolated from frozen (−80 °C) housefly (Musca domestica L.)
heads.[33, 34] Briefly, 5 g heads were homogenised in 100 mL of 0.1 MK-phosphate buffer,
pH 7.4, 320 mM of sucrose and 1 mM of EDTA using an Ultra Turrax at 4 °C. After
centrifugation for
15 min at 1200 × g and 4 °C, the pellet was resuspended and centrifuged again. Both
supernatants were combined and filtered through Miracloth, and the filtrate was subsequently
centrifuged at 105.000 × g for 60 min at 4 °C. The resulting pellet was resuspended in buffer
and adjusted to approximately 0.5 mg protein mL−1. The assay was conducted in a total
volume of 1 mL,
consisting of 850 μL of homogenate and 50 μL of [3H]imidacloprid (25.000 dpm; 1.406 GBq
μmol−1) in 0.1 MK-phosphate buffer, pH 7.4, containing 1 g L−1 of BSA and 5% ethanol
(0.25% final concentration). After 5 min, different concentrations of the F3CO- and F2HCO-
analogues of imidacloprid (8, 15) and thiacloprid (9, 16) were added (1000, 100, 10, 3, 1, 0.3,
0.1 and 0.01 nM, containing up to 0.1% DMSO). After incubation for 60 min at 22 °C while
shaking, the samples were filtered through prewetted Whatman GF/C glass fibre filters,
15

followed by two rinseswith 3 mL of ice-cold 0.1 MK-phosphate buffer (pH 7.4).
Subsequently, the filters were dried (55 °C, 40 min), and 3.5 mL of scintillation cocktail was
added. After 16 h at room temperature, the samples were subjected to liquid scintillation
counting.
Myzus persicae – spray test (in vivo)
Solvent:
78.0 parts by weight acetone
1.5 parts by weight N,N-dimethylformamide
Emulsifier: alkylarylpolyglycol ether
To produce a suitable preparation of active compound, 1 part by weight of the F3CO- and
F2HCO-analogues of imidacloprid (8, 15) and thiacloprid (9, 16) is mixed with the stated
amount of solvents and is diluted with water, containing an emulsifier concentration of 1000
ppm, to the desired concentration. Further test concentrations are prepared by dilution with
emulsifier containing water.
Chinese cabbage (Brassica pekinensis) leaf disks infected with all instars of the green peach
aphid (Myzus persicae), are sprayed with a preparation of the active ingredient of the desired
concentration.
After 5-6 days mortality in % is determined. 100 % means all aphids have been killed and 0
% means none of the aphids have been killed.
In this test, for example, the compounds 8 and 16 from the preparation examples showed
good activity of 100 % at an application rate of 500 g ha-1 and the compounds 9 and 15 from
the preparation examples showed good activity of 100 % at an application rate of 100 g ha-1.
Acknowledgment
The authors thank the Centre National de la Recherche Scientifique (CNRS) France and are
very much grateful to Bayer for grants to E. S. and G. L. The French Fluorine Network (GIS
Fluor) is also acknowledged. The authors thank the analytical platform (GDS3648) and the
mass spectroscopy service of the Chemistry Institute of Strasbourg for both microanalysis and
HRMS results.
References
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17

Figure 1. F3CO- and F2HCO-bearing drugs and agrochemicals.
18

Figure 2. Binding modes of Imidacloprid and Thiacloprid to Ac-AChBP. a) Overlay of two
neighbouring monomers generated from PDB entry 3C79. The remaining panels zoom into
the respective structures, but adopt similar perspectives. b) Overlay of Imidacloprid and its 6-
trifluoromethoxy-analogue (8) with the focus on the [O2N-N=]-pharmacophores. c) Overlay
of Imidacloprid and its 6-difluoromethoxy-analogue (15) with the focus on 6-F2HC-O- and 6-
Cl-pyridin-3-yl residues. d) Overlay of Thiacloprid and its 6-difluoromethoxy-analogue (16)
with the focus on the [NC-N=]-pharmacophores. e) Overlay of Thiacloprid and its 6-
trifluoromethoxy-analogue (9) with the focus on 6-F3C-O- and 6-Cl-pyridin-3-yl residues.
Parts of the cysteine loop covering the active site were undisplayed to allow a complete view
on the ligand orientations. The images shown above were generated using the molecular
modeling software suite SYBYLx2.2.[26]
19

Scheme 1. Synthesis of F3CO-Imidacloprid (8) and Thiacloprid (9).
Scheme 2. Synthesis of F2HCO-Imidacloprid (15) and Thiacloprid (16).
20

Table 1: Optimization of the reaction conditions for the difluoromethylation of 6-
chloropyridin-2-ol using difluoromethyl triflate.
Entry
Base
Solvent
Yield [11a]
1
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOHa
LiOH
NaOH
DMSO
DMF
iPrOH
acetone
DME
6%
2
3
8%
34%
67%
66%
76%
83%
85%
71%
36%
55%
4
5
6
7
dioxane
THF
8
9
MeCN
MeCN
MeCN
MeCN
10
11
Reactions were performed on a 0.5 mmol scale and the yields were determined by 19F NMR spectroscopic
analysis on the crude product using PhCF3 as internal standard. a: 0.5mL KOH instead of 1.0 mL.
Table 2: Difluoromethylation of various N-based heterocycles using difluoromethyl triflate.
Entry
Substrate
Product
Yield
72%
1
11a
2
3
11b
11c
74%
41%
21

4
11d
11e
11f
76%
45%
(+ 50% N-
CHF2)
5
6
66%
31%
32%
7
11g
11h
11i
8
28%
(+ 15% N-
CHF2)
9
10
11
12
13
14
11j
75%
40%
35%
59%
53%
11k
11l
11m
11n
51%a
15
11o
22

The reactions were performed on a 1 mmol scale.
a: yield measured by 19F NMR spectroscopic analysis on the crude product using PhCF3 as internal standard.
Table 3. Biological evaluation of the F3CO- and F2HCO-analogues of imidacloprid (8, 15)
and thiacloprid (9, 16).
Compound
Activity in vitro
(pI50-value)
Activity in vivo
(Myzus persicae) [in g a.i. ha-1]
Imidacloprid
9.1
5.2
4.8
9.2
5.3
4.9
0.16
500
100
0.8
100
500
8
9
Thiacloprid
15
16
23