Development of Cyanopyrazoles as Building Blocks to Fungicide Fluxapyroxad and Analogues

Article abstract of DOI:10.1021/acs.joc.9b00819

Herein, we present a facile approach to a diverse collection of 1,4-disubstituted 3-di- or mono-fluoromethylpyrazoles utilizing our previously developed cyanopyrazoles as key building blocks. This method features several merits, such as easily accessible starting materials, broad substrate scope, mild reaction conditions, and simple operation. This protocol further deserves to be highlighted by the successful translation into the synthesis of commercialized fungicide fluxapyroxad and its analogues.

Full text of DOI:10.1021/acs.joc.9b00819

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Article
Development of Cyanopyrazoles as Building-
Blocks to Fungicide Fluxapyroxad and Analogues
Yue Zhang, Zhen Chen, Jing Nie, Fa-Guang Zhang, and Jun-An Ma
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00819 • Publication Date (Web): 06 May 2019
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The Journal of Organic Chemistry
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Development of Cyanopyrazoles as Building-Blocks to Fungicide
Fluxapyroxad and Analogues
Yue Zhang,§,† Zhen Chen,§,† Jing Nie,† Fa-Guang Zhang,†,* and Jun-An Ma†,‡,*
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† Department of Chemistry, Tianjin Key Laboratory of Molecular Optoelectronic Sciences, and Tianjin Collaborative Innova-
tion Center of Chemical Science & Engineering, Tianjin University, Tianjin 300072, P.R. of China.
‡ State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, P.R. of China.
Supporting Information
ABSTRACT: Herein we present a facile approach to a diverse collection of 1,4-disubstituted-3-di- or mono-fluoromethylpyrazoles
utilizing our previously developed cyanopyrazoles as key building blocks. This method features several merits, such as easily acces-
sible starting materials, broad substrate scope, mild reaction conditions, and simple operation. This protocol further deserves to be
highlighted by the successful translation into the synthesis of commercialized fungicide Fluxapyroxad and its analogues.
KEYWORDS: cyanopyrazoles, fluoroalkyl pyrazoles, SDHI fungicide, Fluxapyroxad
1. INTRODUCTION
3-Fluoroalkylpyrazoles belong to a family of heterocycles with
a significant application in the realm of organic chemistry, phar-
maceuticals, agrochemicals, and material science.1 Among the
numerous related derivatives, 1,4-disubstituted-3-difluoro-
methylpyrazoles particularly deserve to be highlighted as prev-
alent structural motifs with a significant value in various bioac-
tive molecules.2 These motifs can be found in a number of suc-
cinate dehydrogenase inhibitors (SDHIs) with a broad-spectrum
of fungicidal activity, which represent the fastest growing
mode-of-action (MoA) to protect crops against phytopathogens
on the fungicide market.3 Among them are Fluxapyroxad,4
Bixafen,5 Sedaxana,6 Isopyrazam,7 Benzovondiflupyr,8 and
Pydiflumetofen9 (Figure 1). As a consequence, the efficient
synthesis of these motifs is highly desired in the organic and
medicinal community.10 The most typical approach to 1,4-di-
substituted-3-difluoromethylpyrazoles resides in the cyclocon-
densations of 1,1-difluoro-4-dialkoxyl- or di(alkyl)amino-3-en-
2-ones with a substituted hydrazine, which features moderate to
high regioselectivity (Scheme 1A).11 To obtain a better control
Figure 1. Commercialized SDHIs Containing 1,4-Disubstituted 3-
on the regiochemistry of these reactions, a number of recent
studies have led to the discovery of protected hydrazines,
difluoromethylpyrazole Motifs
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namely hydrazones, as cyclization partners to yield the desired difluorination reaction. As shown in Scheme 2, in the presence
product as a single isomer.12 Other approaches to the 1,4-disub-
stituted-3-difluoromethylpyrazoles include the cyclization re-
action of difluoroacetic hydrazide with ethyl propargylate,13
late elaboration on a pyrazole scaffold14 as well as the succes-
sive transformation of 1,1,2,2-tetrafluoroehtyl-N,N-dimethyla-
mine (TFEDMA).15 However, the tedious procedure for the
preparation of the required starting materials severely limited
the substrate scope of these approaches, wherein only electron-
withdrawing groups can be incorporated into the C4-position of
the pyrazole motifs. Therefore, it is still of great importance to
develop novel methods for the access to more abundant 1,4-di-
substituted-3-difluoromethylpyrazoles.
of diisobutylaluminum hydride (DIBAL-H), a variety of 1,4-di-
substituted-3-cyanopyrazoles can be successfully transformed
into the corresponding pyraozle-3-carbaldehydes 2a-j in mod-
erate yields (49-65%). The subsequent fluorination was readily
achieved by utilizing diethylaminosulfur trifluoride (DAST) as
the fluorination reagent. In the case of 1-methyl-4-phenyl-1H-
pyrazole-3-carbonitriles 1a-e, this synthetic approach tolerated
a range of substitution patterns on the phenyl ring, including
methyl, fluoro, chloro, and trifluoromethyl groups to give the
corresponding products 3a-e. 2-Naphthyl-substituted cyanopy-
razole was found to be a competent substrate, thus affording the
desired product 3f in practical overall yield. Heteroaryl, such as
2-thiophenyl- and 3-pyridyl-substituted cyanopyrazoles, also
underwent the desired transformations uneventfully to deliver
the corresponding 1,4-disubstituted-3-difluoromethylpyrazoles
3g and 3h in good yields over two steps. 4-Alkyl-substituted-3-
cyanopyrazole also performed well under the same reaction
conditions (3i). Besides methyl group, other alkyl-substituent
such as benzyl was also compatible at the N1 position of the
pyrazole core (3j), which further highlights the mild reaction
conditions and broad substrate scope for this method.
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Scheme 1. Synthesis of 1,4-Disubstituted-3-difluoromethyl-py-
razoles.
While 1,4-disubstituted-3-tri- or di-fluoromethylpyrazoles
have gained much attention over the past few decades, the cor-
responding monofluoromethylpyrazole analogues have been
largely ignored.18 Therefore, we continued this work with eval-
uating the feasibility of converting the cyanopyrazoles 1 to 1,4-
disubstituted-3-monofluoromethylpyrazoles. As depicted in
Scheme 3, in the presence of sodium borohydride (NaBH4), the
previously obtained pyrazole-3-carbaldehydes 2 could be re-
duced to the corresponding alcohols 4 in excellent efficiencies
regardless of the substituent patterns at the C4 or N1 position
on the pyrazole ring. Phenyl, substituted phenyl, polycyclic aryl,
heteroaryl, and alkyl groups were all compatible with this trans-
formation, thereby providing the products 4a-j in 83-98%
yields. Subsequently, the fluorination reactions of alcohols 4
were evaluated with DAST as fluorination reagent. In the case
of 4-phenyl-substituted substrates 4a-e, the fluorination reac-
tions proceeded smoothly to deliver the desired 1,4-disubsti-
tuted-3-monofluoromethylpyrazoles 5a-e in good to high yields
(54-90%). 4-Polycyclic aryl- and heteroaryl-substituted alco-
hols also underwent this reactions despite in much lower yields
(5f-h). Lastly, 1-methyl-4-phenylethyl- and 1-benzyl-4-phenyl-
substituted-3-monofluoromethylpyrazoles 5i and 5j were also
readily isolated in 52% and 53% yields, respectively.
As part of our continuing interest in the construction of py-
razole derivatives,16 we recently developed a multi-component
reaction of nitroolefins with diazoacetonitrile and alkyl halides,
thus providing a direct approach to a variety of 1,4-disubsti-
tuted-3-cyanopyrazoles in one step.17 To pursue the further ap-
plication of these cyanopyrazoles, herein we present their facile
transformation to a diverse collection of 1,4-disubstituted-3-di-
or mono-fluoromethylpyrazoles via a successive reduction and
fluorination sequence (Scheme 1B). This transformation exhib-
its several features, such as easily accessible starting materials,
broad substrate scope, mild reaction conditions and simple op-
eration. Furthermore, this approach can be successfully trans-
lated into the total synthesis of the commercialized SDHI fun-
gicide Fluxapyroxad and its several analogues.
Having determined the broad substrate scope of the current
protocol, we then turned our attention to its implementation in
the synthesis of the commercialized SDHI fungicide Fluxapy-
roxad and its analogues. As shown in Scheme 4a, starting from
compound 3g, it was smoothly oxidized in the presence of
NaIO4 and catalytic amount of RuCl3, thus delivering the corre-
sponding carboxylic acid 7 in decent yield. The acid 7 was then
treated with phosphorus pentachloride (PCl5) and 3',4',5'-tri-
fluoro-[1,1'-biphenyl]-2-amine in a one-pot manner, and the de-
sired SDHI fungicide Fluxapyroxad (11) was isolated in 83%
yield.19 Utilizing a similar process, the monofluoromethyl-ana-
logue 12, cyano-analogue 13 and α-acetoxy-cyanoethyl-ana-
logue 14 were readily obtained in 36-56% total yields over three
steps, wherein the starting
2. RESULTS AND DISCUSSION
According to our previous study,17 we commenced this work
with investigating the substrate scope of the reduction reaction
of 1,4-disubstituted-3-cyanopyrazoles 1 and the follow-up
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Scheme 2. The Scope of (1H-pyrazol-3-yl)-carbaldehydes 2
and 3-Difluoromethylpyrazoles 3.
Scheme 3. The Scope of (1H-pyrazol-3-yl)-methanols 4 and 3-
Fluoromethylpyrazoles 5.
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Scheme 4. Synthesis of the Corresponding Intermediates and SDHI Fungicide Fluxapyroxad and Its Analogues.
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Table 1. Fungicidal Activity of Compounds 11-14 & 25-28 against 14 Kinds of Phytopathogensa
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2
3
4
5
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7
8
Fungicidal activity (%) / 50 μm/mL
Compd.
FC
CH
PP
RC
BM
CO
FM
AS
FG
PI
PC
SS
BC
RS
37.1
25.7
51.9
0
94.7
89.5
58.8
23.5
21.1
15.8
26.5
26.5
33.3
12.2
9.8
37.3
33.3
54.5
22.7
33.3
39.2
18.2
13.6
25.0
22.2
26.1
8.7
23.3
16.7
21.2
18.2
10.0
26.7
27.3
6.1
31.6
21.1
12.3
15.8
47.4
36.8
15.8
24.6
91.7
91.7
18.8
21.9
25.0
16.7
18.8
21.9
11.8
5.9
12.5
25.0
16.1
6.5
33.3
36.7
44.8
20.7
33.3
33.3
20.7
20.7
100
95.7
25.6
34.9
26.1
50.0
39.5
30.2
66.7
50.0
46.4
42.9
58.3
33.3
25.0
21.4
94.4
91.7
21.3
21.3
61.1
55.6
32.0
21.3
11
12
13
14
25
26
27
28
8.6
33.3
29.2
12.5
5.9
11.4
11.8
29.4
14.3
17.1
25.7
22.9
5.6
19.4
25.0
26.1
21.7
18.8
25.0
25.8
19.4
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11.1
66.7
aFC = Fusarium oxysporum sp cucumeris, CH = Cercospora ara-chidicola Hori, PP = Physalospora piricola, RC = Rhizoctonia cerealis, BM
= Bipolaris maydis, CO = Colletotrichum orbicu-lare, FM = Fusarium moniliforme, AS = Alternaria solani, FG = Fusarium graminearum,
PI = Phytophthora infestans, PC = Phytophthora capsica, SS = Sclerotinia sclerotiorum, BC = Botrytis cinereal, RS = Rhizoctonia solani.
material 6 was accessed through nucleophilic cyanation of the
aldehyde 2g followed by acetylation of the resulting O-trime-
thysilyl cyanohydrin intermediate (Scheme 4b). For comparison,
we also synthesized the corresponding 5-substituted analogues
25-28 via the oxidation/amidation sequence from 5-substituted-
1-methyl-4-(2-furyl)-1H-pyrazoles 1g’ & 15-20 in practical to-
tal yields (48-62%, Scheme 4c and 4d).
scope, mild reaction conditions, and simple operation. Further-
more, this protocol further deserves to be highlighted by the
successful translation into the synthesis of commercialized
SDHI fungicide Fluxapyroxad and its several analogues. Nota-
bly, the monofluoromethylated analogue 12 exhibited remarka-
ble in vitro fungicidal activity towards several phytopathogens,
including cercospora arachidicola hori, alternaria solani, sclero-
tinia sclerotiorum, and rhizoctonia solani at 50 μg/mL, which is
comparable with the Fluxapyroxad. Future investigations
including substrate scope expansion, and in vivo applications of
compound 12 are still ongoing in our laboratories, and these
results will be reported in due course.
With Fluxapyroxad and its analogues in hand, we next as-
sessed the in vitro fungicidal activity against 14 kinds of phyto-
pathogens,20 including Fusarium oxysporum sp cucumeris (FC),
Cercospora arachidicola Hori (CH), Physalospora piricola (PP),
Rhizoctonia cerealis (RC), Bipolaris maydis (BM), Colleto-
trichum orbiculare (CO), Fusarium moniliforme (FM), Alter-
naria solani (AS), Fusarium graminearum (FG), Phytophthora
infestans (PI), Phytophthora capsica (PC), Sclerotinia scleroti-
orum (SS), Botrytis cinereal (BC), and Rhizoctonia solani (RS).
As shown in Table 1, while no significant inhibitory activity
(<70%) was observed for analogues 13, 14 & 25-28, the 3-mon-
ofluoromethyl-analogue 12 demonstrated excellent fungicidal
activity towards several plant pathogens, including cercospora
arachidicola hori (89.5%), alternaria solani (91.7%), sclerotinia
sclerotiorum (95.7%) and rhizoctonia solani (91.7%) at 50
μg/mL, which is comparable to that of Fluxapyroxad (94.7%,
91.7%, 100.0% and 94.4%, respectively). These results indi-
cated that 3-fluoroalkyl group is of great importance for the
achievement of effective fungicidal activity. Moreover, 3-cyan-
opyrazole 13 exhibited better activity against a few kinds of
fungi than 11 and 12, such as fusarium oxysporum sp cucumeris,
rhizoctonia cerealis, bipolaris maydis, and phytophthora cap-
sica. On the contrary, the target compound 14 possessing an ex-
tended cyano group displayed very weak fungicidal activities
against the fungi tested. In addition, the 5-substituted analogues
25-28 displayed seriously decreased fungicidal activities, indi-
cating a crucial role of the 3-fluoroalkyl pyrazolic core in such
succinate dehydrogenase inhibitors.

EXPERIMENTAL SECTION
General information: 1H, 19F and 13C NMR were recorded at 400
MHz (1H NMR), 376 MHz (19F NMR) and 100 MHz (13C NMR)
or 600 MHz (1H NMR), 565 MHz (19F NMR) and 150 MHz (13C
NMR), respectively. Chemical shifts were reported in ppm from
tetramethylsilane with the solvent resonance as the internal stand-
ard (CDCl3: δH = 7.26 ppm, δC = 77.20 ppm; DMSO-d6: δH = 2.50
ppm, δC = 39.52 ppm; CD3OD: δH = 3.31 ppm, δC = 49.00 ppm).
Multiplicity was indicated as follows: s (singlet), d (doublet), t (tri-
plet), q (quartet), m (multiplet), and dd (doublet of doublets). Cou-
pling constants were reported in Hertz (Hz). High resolution mass
spectrometry (HRMS) spectra were obtained on a microTOF-QII
or Waters Micromass GCT Premier Instrument. Melting points
were measured on a WRS-1A digital melting point apparatus and
are uncorrected.
General procedure for the synthesis of pyraozle-3-carbalde-
hydes 2a-j: At –20 C, to a well-stirred solution of 3-cycnopyra-
o
zoles 1 (1 mmol) in THF (10 mL) under an argon atmosphere was
added DIBAL-H (1.0 M in hexane, 2 mL, 2 equiv) dropwise, and
the resulting mixture was stirred at the same temperature for 1 – 6
h. After completion of the reaction, it was quenched with 2 M HCl
(5 mL), and extracted with ethyl acetate (3 × 15 mL). The combined
organic layers were washed with brine, dried over anhydrous
Na2SO4 and concentrated under vacuum. The residue was purified
by flash column chromatography on silica gel [petroleum ether
(PE)/ethyl acetate (EA) = 8/1 to 6/1 as the eluent] to give the de-
sired products 2a-j.
1-Methyl-4-phenyl-1H-pyrazole-3-carbaldehyde (2a). White
solid; mp 83 – 84 °C; 111.7 mg, 60% yield; H NMR (400 MHz,
CDCl3) δ 10.00 (s, 1H), 7.54 – 7.48 (m, 2H), 7.44 (s, 1H), 7.36 –
7.29 (m, 2H), 7.28 – 7.22 (m, 1H), 3.85 (s, 3H). 13C{1H} NMR (100
MHz, CDCl3) δ 186.0, 146.0, 130.9, 130.4, 128.4, 128.1, 127.3,
3. CONCLUSIONS
In conclusion, we have successfully developed an efficient
approach to a diverse collection of 1,4-disubstituted-3-di- or
mono-fluoromethylpyrzoles via elaborations on cyanopyra-
zoles, which were synthesized previously by our group through
a multi-component reaction of nitroolefins with diazoacetoni-
trile and alkyl halides. This approach features several merits,
such as easily accessible starting materials, broad substrate
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125.4, 39.4; HRMS (ESI) m/z calculated for C11H11N2O+ [M + H]+:
187.0866, found: 187.0869.
127.6, 125.9, 56.9. HRMS (ESI): m/z calculated for C17H15N2O+
[M + H]+: 263.1179, found: 263.1181.
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1-Methyl-4-(p-tolyl)-1H-pyrazole-3-carbaldehyde (2b). Color-
less oil; 116.1 mg, 58% yield; 1H NMR (400 MHz, CDCl3) δ 10.04
(s, 1H), 7.50 (s, 1H), 7.47 – 7.43 (m, 2H), 7.22 – 7.18 (m, 2H), 4.01
(s, 3H), 2.37 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 186.3,
146.7, 137.7, 130.9, 129.3, 128.8, 127.8, 126.2, 39.9, 21.3; HRMS
(ESI): m/z calculated for C12H13N2O+ [M + H]+: 201.1022, found:
201.1030.
4-(4-Fluorophenyl)-1-methyl-1H-pyrazole-3-carbaldehyde (2c).
White solid; mp 122 – 123 °C; 110.3 mg, 54% yield; 1H NMR (400
MHz, CDCl3) δ 10.01 (s, 1H), 7.57 – 7.51 (m, 2H), 7.50 (s, 1H),
7.10 – 7.00 (m, 2H), 4.00 (s, 3H). 19F NMR (376 MHz, CDCl3) δ -
114.28 – -114.36 (m). 13C{1H} NMR (100 MHz, CDCl3) δ 186.4,
162.5 (d, J = 245.5 Hz), 146.5, 131.0, 130.5 (d, J = 8.0 Hz), 126.8
(d, J = 3.3 Hz), 124.7, 115.3 (d, J = 21.4 Hz), 39.9; HRMS (ESI):
m/z calculated for C11H10FN2O+ [M + H]+: 205.0772, found:
205.0775.
4-(4-Chlorophenyl)-1-methyl-1H-pyrazole-3-carbaldehyde (2d).
Colorless oil; 127.6 mg, 58% yield; 1H NMR (400 MHz, CDCl3) δ
10.00 (s, 1H), 7.53 – 7.46 (m, 3H), 7.35 – 7.29 (m, 2H), 4.00 (s,
3H). 13C{1H} NMR (100 MHz, CDCl3) δ 186.5, 146.6, 133.7,
131.1, 130.1, 129.3, 128.6, 124.5, 39.9; HRMS (ESI): m/z calcu-
lated for C11H10ClN2O+ [M + H]+: 221.0476, found: 221.0481.
1-Methyl-4-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carbal-
dehyde (2e). White solid; mp 91 – 92°C; 132.2 mg, 52% yield; 1H
NMR (400 MHz, CDCl3) δ 10.02 (s, 1H), 7.72 – 7.66 (m, 2H), 7.62
– 7.56 (m, 3H), 3.99 (s, 3H). 19F NMR (376 MHz, CDCl3) δ -62.53
(s). 13C{1H} NMR (100 MHz, CDCl3) δ 186.4, 146.5, 134.5, 131.6,
129.3 (q, J = 32.2 Hz), 128.8, 125.2 (q, J = 3.7 Hz), 124.2 (q, J =
270.3 Hz), 123.8, 39.7; HRMS (ESI): m/z calculated for
C12H10F3N2O+ [M + H]+: 255.0740, found: 255.0745.
General procedure for the synthesis of 1,4-disubsti-
tuted-3-difluoromethylpyraozles 3a-j: To a pre-cooled (–78 oC)
solution of 2 (0.5 mmol) in CH2Cl2 (5 mL) was added DAST (166
μL, 1.25 mmol, 2.5 equiv) dropwise. The resulting mixture was
then allowed to warm to room temperature and stirred at the same
temperature overnight before quenching with cooled water (10 mL).
The aqueous layer was extracted with CH2Cl2 (3 × 20 mL), and the
combined organic layers were washed with brine (30 mL), dried
over Na2SO4 and concentrated under vacuum. The residue was pu-
rified by flash column chromatography on silica gel (PE/EA = 8/1
to 4/1 as the eluent) to afford the desired products 3a-j.
3-(Difluoromethyl)-1-methyl-4-phenyl-1H-pyrazole (3a). Color-
less oil; 90.6 mg, 87% yield; 1H NMR (400 MHz, CDCl3) δ 7.48 –
7.46 (m, 3H), 7.41 –7.37 (m, 2H), 7.33 – 7.29 (m, 1H), 6.77 (t, J =
54.1 Hz, 1H), 3.90 (s, 3H). 19F NMR (376 MHz, CDCl3) δ -109.78
(d, J = 54.1 Hz). 13C{1H} NMR (100 MHz, CDCl3) δ 142.2 (t, J =
26.9 Hz), 131.2, 130.2, 128.7, 128.3 (t, J = 1.3 Hz), 127.3, 122.4,
111.7 (t, J = 233.9 Hz), 39.2; HRMS (ESI): m/z calculated for
C11H11F2N2+ [M + H]+: 209.0885, found: 209.0883.
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3-(Difluoromethyl)-1-methyl-4-(p-tolyl)-1H-pyrazole
(3b).
1
White solid; mp 52.5 – 53.5 °C; 105.6 mg, 95% yield; H NMR
(400 MHz, CDCl3) δ 7.46 (s, 1H), 7.36 (d, J = 8.1 Hz, 2H), 7.21 (d,
J = 7.9 Hz, 2H), 6.74 (t, J = 54.2 Hz, 1H), 3.94 (s, 3H), 2.38 (s, 3H).
19F NMR (376 MHz, CDCl3) δ -109.93 (d, J = 54.2 Hz). 13C{1H}
NMR (100 MHz, CDCl3) δ 142.4 (t, J = 26.8 Hz), 137.2, 130.1,
129.5, 128.3, 122.5, 111.7 (t, J = 234.0 Hz), 39.4, 21.3; HRMS
(ESI): m/z calculated for C12H13F2N2+ [M + H]+: 223.1041, found:
223.1044.
3-(Difluoromethyl)-4-(4-fluorophenyl)-1-methyl-1H-pyrazole
1
(3c). White solid; mp 53 – 54 °C; 97.3 mg, 86% yield; H NMR
1-Methyl-4-(naphthalen-2-yl)-1H-pyrazole-3-carbaldehyde (2f).
(400 MHz, CDCl3) δ 7.45 (s, 1H), 7.44 – 7.40 (m, 2H), 7.08 – 7.04
(m, 2H), 6.72 (t, J = 54.1 Hz, 1H), 3.93 (s, 3H). 19F NMR (376
MHz, CDCl3) δ -109.66 (d, J = 54.1 Hz), -115.07 – -115.19 (m).
13C{1H} NMR (100 MHz, CDCl3) δ 162.3 (d, J = 246.5 Hz), 142.4
(t, J = 27.5 Hz), 130.3, 130.1 (dt, J = 8.0, 1.7 Hz), 127.4 (d, J = 3.3
Hz), 121.4, 115.7 (d, J = 21.5 Hz), 111.9 (t, J = 233.8 Hz), 39.4;
HRMS (ESI): m/z calculated for C11H10F3N2+ [M + H]+: 227.0791,
found: 227.0792.
1
White solid; mp 82 – 83 °C; 118.1 mg, 50% yield; H NMR (400
MHz, CDCl3) δ 10.11 (s, 1H), 8.07 (s, 1H), 7.88 – 7.80 (m, 3H),
7.65 (dd, J = 8.5, 1.7 Hz, 1H), 7.62 (s, 1H), 7.52 – 7.45 (m, 2H),
4.04 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 186.4, 147.0,
133.5, 132.9, 131.3, 128.3, 128.2, 128.2, 127.8, 127.7, 127.0, 126.5,
126.3, 126.2, 40.0; HRMS (ESI): m/z calculated for C15H13N2O+
[M + H]+: 237.1022, found: 237.1027.
4-(Furan-2-yl)-1-methyl-1H-pyrazole-3-carbaldehyde
(2g).
4-(4-Chlorophenyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole
(3d). White solid; mp 67 – 68 °C; 115.3 mg, 95% yield; 1H NMR
(400 MHz, CDCl3) δ 7.48 (s, 1H), 7.37 (dd, J = 21.0, 8.6 Hz, 4H),
6.72 (t, J = 54.1 Hz, 1H), 3.94 (s, 3H). 19F NMR (376 MHz, CDCl3)
δ -109.65 (d, J = 54.1 Hz). 13C{1H} NMR (100 MHz, CDCl3) δ
142.5 (t, J = 27.7 Hz), 133.4, 130.4, 129.8, 129.7 (t, J = 1.7 Hz),
129.0, 121.2, 111.9 (t, J = 233.9 Hz), 39.5; HRMS (ESI): m/z cal-
culated for C11H10ClF2N2+ [M + H]+: 243.0495, found: 243.0494.
3-(Difluoromethyl)-1-methyl-4-(4-(trifluoromethyl)phenyl)-1H-
Yellow solid; mp 55 – 56 °C; 123.3 mg, 70% yield; 1H NMR (400
MHz, CDCl3) δ 10.07 (s, 1H), 7.73 (s, 1H), 7.38 – 7.35 (m, 1H),
7.30 – 7.29 (m, 1H), 6.46 – 6.44 (m, 1H), 4.00 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3) δ 186.1, 146.2, 145.5, 141.7, 129.4, 115.9,
111.7, 109.9, 39.9; HRMS (ESI): m/z calculated for C9H9N2O2+ [M
+ H]+: 177.0659, found: 177.0653.
1-Methyl-4-(thiophen-2-yl)-1H-pyrazole-3-carbaldehyde (2h).
Colorless oil; 121.1 mg, 63% yield; 1H NMR (400 MHz, CDCl3) δ
10.02 (s, 1H), 7.61 (dd, J = 3.6, 1.0 Hz, 1H), 7.55 (s, 1H), 7.21 (dd,
J = 5.1, 1.0 Hz, 1H), 7.01 (dd, J = 5.1, 3.6 Hz, 1H), 3.88 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ 185.8, 145.7, 131.9, 130.4,
127.5, 127.1, 124.7, 118.4, 39.5; HRMS (ESI): m/z calculated for
C9H9N2OS+ [M + H]+: 193.0430, found: 193.0431.
1
pyrazole (3e). Colorless oil; 121.5 mg, 88% yield; H NMR (400
MHz, CDCl3) δ 7.59 (q, J = 8.3 Hz, 4H), 7.52 (s, 1H), 6.75 (t, J =
54.1 Hz, 1H), 3.91 (s, 3H). 19F NMR (376 MHz, CDCl3) δ -62.55
(s, 3F), -109.57 (d, J = 54.1 Hz, 2F). 13C{1H} NMR (100 MHz,
CDCl3) δ 142.6 (t, J = 28.1 Hz), 135.0, 130.8, 129.2 (q, J = 32.5
Hz), 128.5 (t, J = 1.7 Hz), 125.6 (q, J = 3.7 Hz), 124.4 (q, J = 270.3
Hz), 120.8, 112.0 (t, J = 233.8 Hz), 39.3; HRMS (ESI): m/z calcu-
lated for C12H10F5N2+ [M + H]+: 277.0759, found: 277.0758.
3-(Difluoromethyl)-1-methyl-4-(naphthalen-2-yl)-1H-pyrazole
1-Methyl-4-phenethyl-1H-pyrazole-3-carbaldehyde (2i). White
solid; mp 54.5 – 55.5 °C; 130.7 mg, 61% yield; 1H NMR (400 MHz,
CDCl3) δ 9.89 (s, 1H), 7.18 – 7.14 (m, 2H), 7.09 – 7.06 (m, 3H),
6.97 (s, 1H), 3.78 (s, 3H), 2.96 – 2.92 (m, 2H), 2.79 – 2.75 (m, 2H).
13C{1H} NMR (100 MHz, CDCl3) δ 187.3, 148.1, 141.5, 130.9,
128.5, 128.3, 126.0, 124.3, 39.6, 36.3, 25.7; HRMS (ESI): m/z cal-
culated for C13H15N2O+ [M + H]+: 215.1179, found: 215.1180.
1-Benzyl-4-phenyl-1H-pyrazole-3-carbaldehyde (2j). White
1
(3f). White solid; mp 64 – 65 °C; 118.8 mg, 92% yield; H NMR
(400 MHz, CDCl3) δ 7.94 (s, 1H), 7.90 – 7.80 (m, 3H), 7.59 (dd, J
= 8.5, 1.7 Hz, 1H), 7.54 – 7.45 (m, 3H), 6.84 (t, J = 54.1 Hz, 1H),
3.92 (s, 3H). 19F NMR (376 MHz, CDCl3) δ -109.69 (d, J = 54.1
Hz). 13C{1H} NMR (100 MHz, CDCl3) δ 142.5 (t, J = 27.1 Hz),
133.6, 132.6, 130.5, 128.7, 128.4, 128.1, 127.8, 127.0 (t, J = 1.6
Hz), 126.7, 126.5, 126.1, 122.4, 111.9 (t, J = 234.0 Hz), 39.4.
1
solid; mp 97 – 98 °C; 152.1 mg, 58% yield; H NMR (400 MHz,
CDCl3) δ 10.06 (s, 1H), 7.52 (d, J = 7.2 Hz, 2H), 7.47 (s, 1H), 7.32
– 7.20 (m, 8H), 5.29 (s, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ
186.3, 146.4, 134.9, 130.6, 130.1, 128.9, 128.6, 128.5, 128.3, 127.9,
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HRMS (ESI): m/z calculated for C15H13F2N2+ [M + H]+: 259.1041,
CDCl3) δ -116.01 – -116.20 (m). 13C{1H} NMR (100 MHz, CDCl3)
found: 259.1042.
δ 161.8 (d, J = 245.5 Hz), 148.9, 129.4 (d, J = 7.9 Hz), 129.1, 128.7
(d, J = 3.2 Hz), 120.9, 115.6 (d, J = 21.3 Hz), 56.6, 38.7; HRMS
(ESI): m/z calculated for C11H12FN2O+ [M + H]+: 207.0928, found:
207.0935.
(4-(4-Chlorophenyl)-1-methyl-1H-pyrazol-3-yl)methanol (4d).
White solid; mp 140 – 141 °C; 70.1 mg, 63% yield; 1H NMR (400
MHz, CDCl3) δ 7.45 – 7.43 (m, 3H), 7.35 – 7.33 (m, 2H), 4.70 (s,
2H), 3.86 (s, 3H), 3.70 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3)
δ 149.0, 132.5, 131.2, 129.3, 129.0, 120.8, 57.1, 39.0; HRMS (ESI):
m/z calculated for C11H12ClN2O+ [M + H]+: 223.0633, found:
223.0639.
(1-Methyl-4-(4-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)meth-
anol (4e). White solid; mp 118 – 119 °C; 108.9 mg, 85% yield; 1H
NMR (400 MHz, CDCl3) δ 7. 65 – 7.59 (m, 4H), 7.50 (s, 1H), 4.71
(s, 2H), 4.38 (s, 1H), 3.84 (s, 3H). 19F NMR (376 MHz, CDCl3) δ -
62.36 (s). 13C{1H} NMR (100 MHz, CDCl3) δ 149.3, 136.4, 129.7,
128.5 (q, J = 32.4 Hz), 127.8, 125.8 (q, J = 3.7 Hz), 124.4 (q, J =
271.8 Hz), 120.6, 56.8, 38.8; HRMS (ESI): m/z calculated for
C12H12F3N2O+ [M + H]+: 257.0896, found: 257.0905.
(1-Methyl-4-(naphthalen-2-yl)-1H-pyrazol-3-yl)methanol (4f).
White solid; mp 127 – 128 °C; 111.9 mg, 94% yield; 1H NMR (400
MHz, CDCl3) δ 7.97 (s, 1H), 7.82 – 7.87 (m, 3H), 7.64 – 7.62 (m,
1H), 7.54 (s, 1H), 7.49 – 7.45 (m, 2H), 4.85 (s, 2H), 3.89 (s, 3H),
3.55 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 149.2, 133.9,
132.3, 130.2, 129.6, 128.5, 128.1, 127.8, 126.5, 126.4, 126.0, 125.8,
121.7, 57.5, 39.0; HRMS (ESI): m/z calculated for C15H15N2O+ [M
+ H]+: 239.1179, found: 239.1188.
1
2
3
4
5
6
7
8
3-(Difluoromethyl)-4-(furan-2-yl)-1-methyl-1H-pyrazole (3g).
Colorless oil; 67.4 mg, 68% yield; 1H NMR (400 MHz, CDCl3) δ
7.59 (s, 1H), 7.37 (d, J = 1.2 Hz, 1H), 6.82 (t, J = 54.1 Hz, 1H),
6.53 (d, J = 3.2 Hz, 1H), 6.41 (dd, J = 3.2, 1.8 Hz, 1H), 3.85 (s, 3H).
19F NMR (376 MHz, CDCl3) δ -112.98 (d, J = 54.1 Hz). 13C{1H}
NMR (100 MHz, CDCl3) δ 145.8, 141.4, 141.0 (t, J = 27.7 Hz),
129.1, 112.7, 111.6 (t, J = 232.3 Hz), 111.5, 106.8 (t, J = 3.1 Hz),
39.3; HRMS (ESI): m/z calculated for C9H9F2N2O+ [M + H]+:
199.0677, found: 199.0678.
3-(Difluoromethyl)-1-methyl-4-(thiophen-2-yl)-1H-pyrazole
(3h). Colorless oil; 87.8 mg, 82% yield; 1H NMR (400 MHz,
CDCl3) δ 7.50 (s, 1H), 7.23 (dd, J = 5.1, 0.9 Hz, 1H), 7.19 (d, J =
3.3 Hz, 1H), 7.04 (dd, J = 5.1, 3.6 Hz, 1H), 6.77 (t, J = 54.0 Hz,
1H), 3.88 (s, 3H). 19F NMR (376 MHz, CDCl3) δ -111.22 (d, J =
54.0 Hz). 13C{1H} NMR (100 MHz, CDCl3) δ 142.0 (t, J = 27.3
Hz), 132.1, 130.3, 127.9, 126.0 (t, J = 2.4 Hz), 124.7, 115.3, 111.5
(t, J = 234.0 Hz), 39.3; HRMS (ESI): m/z calculated for
C9H9F2N2S+ [M + H]+: 215.0449, found: 215.0447.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3-(Difluoromethyl)-1-methyl-4-phenethyl-1H-pyrazole
(3i).
Colorless oil; 95.7 mg, 81% yield; 1H NMR (400 MHz, CDCl3) δ
7.33 – 7.29 (m, 2H), 7.24 – 7.20 (m, 3H), 7.04 (s, 1H), 6.67 (t, J =
54.5 Hz, 1H), 3.82 (s, 3H), 2.95 – 2.87 (m, 4H). 19F NMR (376
MHz, CDCl3) δ -110.95 (d, J = 54.5 Hz). 13C{1H} NMR (100 MHz,
CDCl3) δ 143.7 (t, J = 28.3 Hz), 141.6, 130.5, 128.6, 128.5, 126.1,
119.8, 112.6 (t, J = 232.5 Hz), 39.0, 37.1, 25.2; HRMS (ESI): m/z
calculated for C13H15F2N2+ [M + H]+: 237.1198, found: 237.1198.
1-Benzyl-3-(difluoromethyl)-4-phenyl-1H-pyrazole (3j). White
solid; mp 110 – 111 °C; 120.8 mg, 85% yield; 1H NMR (400 MHz,
CDCl3) δ 7.52 – 7.50 (m, 3H), 7.43 – 7.31 (m, 8H), 6.83 (t, J = 54.1
Hz, 1H), 5.35 (s, 2H). 19F NMR (376 MHz, CDCl3) δ -109.71 (d, J
= 54.2 Hz). 13C{1H} NMR (100 MHz, CDCl3) δ142.5 (t, J = 27.3
Hz), 135.6, 131.2, 129.4, 129.1, 128.7, 128.6, 128.4 (t, J = 1.5 Hz),
128.1, 127.4, 122.7, 111.9 (t, J = 234.1 Hz), 56.6; HRMS (ESI):
(4-(Furan-2-yl)-1-methyl-1H-pyrazol-3-yl)methanol (4g). White
1
solid; mp 105.6 – 106.6 °C; 87.3 mg, 98% yield; H NMR (600
MHz, DMSO-d6) δ 7.93 (s, 1H), 7.60 (d, J = 1.1 Hz, 1H), 6.54 (d,
J = 3.2 Hz, 1H), 6.51 – 6.50 (m, 1H), 5.04 (t, J = 4.7 Hz, 1H), 4.51
(d, J = 4.5 Hz, 2H), 3.81 (s, 3H). 13C{1H} NMR (150 MHz, DMSO-
d6) δ 147.8, 147.7, 141.1, 128.6, 111.7, 111.5, 105.0, 56.2, 38.5;
HRMS (ESI): m/z calculated for C9H11N2O2+ [M + H]+: 179.0815,
found: 179.0812.
m/z calculated for C17H15F2N2 [M + H]+: 285.1198, found:
285.1197.
+
(1-Methyl-4-(thiophen-2-yl)-1H-pyrazol-3-yl)methanol
(4h).
White solid; mp 114 – 115 °C; 91.3 mg, 94% yield; 1H NMR (400
MHz, CDCl3) δ 7.43 (s, 1H), 7.19 – 7.16 (m, 2H), 7.02 (dd, J = 5.1,
3.6 Hz, 1H), 4.75 (s, 2H), 3.80 (s, 4H). 13C{1H} NMR (100 MHz,
CDCl3) δ 148.7, 134.1, 129.2, 127.8, 124.5, 123.8, 114.9, 57.1, 38.8.
HRMS (ESI): m/z calculated for C9H11N2OS+ [M + H]+: 195.0587,
found: 195.0594.
General procedure for the synthesis of 1,4-disubsti-
tuted-3-hydroxylmethylpyraozles 4a-j: A solution of 2 (0.5
mmol) in MeOH (5 mL) was cooled to 0 oC, and NaBH4 (37.8 mg,
1.0 mmol, 2 equiv) was added portion-wise over 10 min. The re-
sulting suspension was stirred at the same temperature for 1 – 3 h
until the disappearance of the starting material as monitored by thin
layer chromatography (TLC). The reaction was then quenched with
saturated aqueous solution of NH4Cl (10 mL). The aqueous phase
was extracted with ethyl acetate (3 × 20 mL), and the organic layers
were dried over NaSO4 and concentrated under vacuum. The resi-
due was purified by flash column chromatography on silica gel (EA
as the eluent) to give the desired products 4a-j
(1-Methyl-4-phenyl-1H-pyrazol-3-yl)methanol (4a). White solid;
mp 101 – 102 °C; 87.5 mg, 93% yield; 1H NMR (400 MHz, CDCl3)
δ 7.49 – 7.46 (m, 3H), 7.39 (t, J = 7.6 Hz, 2H), 7.29 – 7.26 (m, 1H),
4.76 (s, 2H), 3.89 (s, 3H), 3.07 (s, 1H). 13C{1H} NMR (100 MHz,
CDCl3) δ 148.9, 132.8, 129.3, 128.9, 127.8, 126.7, 121.7, 57.5, 39.0;
HRMS (ESI): m/z calculated for C11H13N2O+ [M + H]+: 189.1022,
found: 189.1019.
(1-Methyl-4-(p-tolyl)-1H-pyrazol-3-yl)methanol (4b). White
solid; mp 126 – 127 °C; 91.0 mg, 90% yield; 1H NMR (400 MHz,
CDCl3) δ 7.43 – 7.41 (m, 3H), 7.21 – 7.19 (m, 2H), 4.74 (s, 2H),
4.30 (s, 1H), 3.82 (s, 3H), 2.37 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ 148.9, 136.2, 129.7, 129.5, 129.0, 127.6, 121.6, 56.9, 38.7,
21.2; HRMS (ESI): m/z calculated for C12H15N2O+ [M + H]+:
203.1179, found: 203.1187.
(4-(4-Fluorophenyl)-1-methyl-1H-pyrazol-3-yl)methanol (4c).
White solid; mp 112 – 113 °C; 97.9 mg, 95% yield; 1H NMR (400
MHz, CDCl3) δ 7.48 – 7.45 (m, 2H), 7.38 (s, 1H), 7.06 – 7.01 (m,
2H), 4.67 (s, 2H), 4.47 (s, 1H), 3.81 (s, 3H). 19F NMR (376 MHz,
(1-Methyl-4-phenethyl-1H-pyrazol-3-yl)methanol (4i). White
solid; mp 101 – 102 °C; 97.3 mg, 90% yield; 1H NMR (400 MHz,
CDCl3) δ 7.31 – 7.28 (m, 2H), 7.23 – 7.18 (m, 3H), 7.01 (s, 1H),
4.55 (s, 2H), 3.77 (s, 3H), 2.87 – 2.81 (m, 4H). 13C{1H} NMR (100
MHz, CDCl3) δ 150.1, 141.7, 129.5, 128.5, 128.3, 126.0, 119.0,
56.5, 38.5, 37.2, 25.3; HRMS (ESI): m/z calculated for C13H17N2O+
[M + H]+: 217.1335, found: 217.1343.
(1-Benzyl-4-phenyl-1H-pyrazol-3-yl)methanol (4j). White solid;
mp 104 – 105 °C; 120.3 mg, 91% yield; 1H NMR (400 MHz, CDCl3)
δ 7.59 – 7.57 (d, J = 7.4 Hz, 2H), 7.50 (s, 1H), 7.45 – 7.41 (t, J =
7.6 Hz, 2H), 7.33 – 7.25 (m, 6H), 5.27 (s, 2H), 4.83 (s, 2H), 4.46
(s, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 149.1, 136.1, 132.6,
128.8, 128.8, 128.3, 128.2, 127.9, 127.7, 126.6, 122.0, 57.0, 55.9;
HRMS (ESI): m/z calculated for C17H17N2O+ [M + H]+: 265.1335,
found: 265.1345.
General procedure for the synthesis of 1,4-disubsti-
tuted-3-monofluoromethylpyraozles 5a-j: To a pre-cooled (–
78 oC) solution of 4 (0.5 mmol) in CH2Cl2 (5 mL) was added DAST
(133 μL, 1.0 mmol, 2.0 equiv) dropwise. The resulting mixture was
then allowed to warm to room temperature and stirred at the same
temperature overnight before quenching with cooled water (10 mL).
The aqueous layer was extracted with CH2Cl2 (3 × 20 mL), and the
combined organic layers were washed with brine (30 mL), dried
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The Journal of Organic Chemistry
over Na2SO4 and concentrated under vacuum. The residue was pu-
rified by flash column chromatography on silica gel (PE/EA = 4/1
2.1 Hz), 114.4 (d, J = 1.6 Hz), 111.5, 105.8 (d, J = 3.1 Hz), 77.3 (d,
J = 162.6 Hz), 39.3; HRMS (ESI): m/z calculated for C9H10FN2O+
[M + H]+: 181.0772, found: 181.0773.
1
2
3
to 2/1 as the eluent) to afford the desired products 5a-j.
3-(Fluoromethyl)-1-methyl-4-(thiophen-2-yl)-1H-pyrazole (5h).
3-(Fluoromethyl)-1-methyl-4-phenyl-1H-pyrazole (5a). Color-
1
1
White solid; mp 32 – 33 °C; 48.0 mg, 49% yield; H NMR (400
less oil; 64.0 mg, 67% yield; H NMR (400 MHz, CDCl3) δ 7.48
4
5
6
7
8
9
MHz, CDCl3) δ 7.52 (s, 1H), 7.24 (dd, J = 5.1, 0.9 Hz, 1H), 7.14
(dd, J = 3.5, 1.0 Hz, 1H), 7.06 (dd, J = 5.1, 3.6 Hz, 1H), 5.44 (d, J
= 49.0 Hz, 2H), 3.92 (d, J = 1.9 Hz, 3H). 19F NMR (377 MHz,
CDCl3) δ -202.02 (td, J = 49.0, 1.6 Hz). 13C{1H} NMR (100 MHz,
CDCl3) δ 144.1 (d, J = 19.9 Hz), 133.5 (d, J = 1.4 Hz), 129.5 (d, J
= 2.2 Hz), 128.0, 125.1 (d, J = 2.9 Hz), 124.4, 117.1 (d, J = 1.8 Hz),
76.8 (d, J = 162.4 Hz), 39.3; HRMS (ESI): m/z calculated for
C9H10FN2S+ [M + H]+: 197.0543, found: 197.0546.
3-(Fluoromethyl)-1-methyl-4-phenethyl-1H-pyrazole (5i). Col-
orless oil; 56.8 mg, 52% yield; 1H NMR (400 MHz, CDCl3) δ 7.31
– 7.28 (m, 2H), 7.23 – 7.17 (m, 3H), 7.05 (s, 1H), 5.28 (d, J = 49.2
Hz, 2H), 3.82 (d, J = 1.9 Hz, 3H), 2.90 – 2.81 (m, 4H). 19F NMR
(377 MHz, CDCl3) δ -204.45 (t, J = 49.2 Hz). 13C{1H} NMR (100
MHz, CDCl3) δ 145.5 (d, J = 20.2 Hz), 141.6, 129.8 (d, J = 2.2 Hz),
128.6, 128.4, 126.1, 121.0 (d, J = 1.7 Hz), 76.8 (d, J = 161.3 Hz),
38.9, 37.3, 25.4; HRMS (ESI): m/z calculated for C13H16FN2+ [M +
H]+: 219.1292, found: 219.1299.
1-Benzyl-3-(fluoromethyl)-4-phenyl-1H-pyrazole (5j). Colorless
oil; 70.6 mg, 53% yield; 1H NMR (400 MHz, CDCl3) δ 7.52 (s, 1H),
7.50 – 7.48 (m, 2H), 7.43 – 7.35 (m, 5H), 7.33 – 7.29 (m, 3H), 5.47
(d, J = 49.1 Hz, 2H), 5.35 (s, 2H). 19F NMR (377 MHz, CDCl3) δ -
199.35 (t, J = 49.1 Hz). 13C{1H} NMR (100 MHz, CDCl3) δ 144.3
(d, J = 19.8 Hz), 136.0, 132.2, 129.1, 128.9, 128.6 (d, J = 2.1 Hz),
128.5, 128.0, 128.0 (d, J = 2.4 Hz), 127.1, 124.2 (d, J = 2.0 Hz),
77.0 (d, J =162.2 Hz), 56.5; HRMS (ESI): m/z calculated for
C17H16FN2+ [M + H]+: 267.1292, found: 267.1306.
(dd, J = 7.9, 6.6 Hz, 3H), 7.41 (t, J = 7.6 Hz, 2H), 7.31 (t, J = 7.3
Hz, 1H), 5.41 (d, J = 49.2 Hz, 2H), 3.93 (d, J = 2.0 Hz, 3H). 19F
NMR (376 MHz, CDCl3) δ -199.09 (t, J = 49.2 Hz). 13C{1H} NMR
(100 MHz, CDCl3) δ 144.2 (d, J = 19.7 Hz), 132.2 (d, J = 1.0 Hz),
129.4 (d, J = 2.2 Hz), 129.0, 127.9 (d, J = 2.3 Hz), 127.0, 123.9 (d,
J = 2.2 Hz), 76.9 (d, J = 161.9 Hz), 39.2; HRMS (ESI): m/z calcu-
lated for C11H12FN2+ [M + H]+: 191.0979, found: 191.0981.
3-(Fluoromethyl)-1-methyl-4-(p-tolyl)-1H-pyrazole (5b). White
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
solid; mp 67 – 68 °C; 55.1 mg, 54% yield; H NMR (400 MHz,
CDCl3) δ 7.48 (s, 1H), 7.37 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 7.9 Hz,
2H), 5.41 (d, J = 49.2 Hz, 2H), 3.94 (d, J = 1.9 Hz, 3H), 2.39 (s,
3H). 19F NMR (377 MHz, CDCl3) δ -198.93 (td, J = 49.2, 1.4 Hz).
13C{1H} NMR (100 MHz, CDCl3) δ 144.1 (d, J = 19.7 Hz), 136.8,
129.7, 129.3, 129.2 (d, J = 2.2 Hz), 127.9 (d, J = 2.2 Hz), 123.9 (d,
J = 2.1 Hz), 76.9 (d, J = 161.8 Hz), 39.2, 21.3; HRMS (ESI): m/z
calculated for C12H14FN2+ [M + H]+: 205.1136, found: 205.1143.
3-(Fluoromethyl)-4-(4-fluorophenyl)-1-methyl-1H-pyrazole
1
(5c). White solid; mp 86 – 87 °C; 61.4 mg, 59% yield; H NMR
(400 MHz, CDCl3) δ 7.46 (s, 1H), 7.45 – 7.36 (m, 2H), 7.08 (t, J =
8.7 Hz, 2H), 5.37 (d, J = 49.2 Hz, 2H), 3.93 (d, J = 1.8 Hz, 3H). 19
F
NMR (377 MHz, CDCl3) δ -115.59 (m), -198.86 (td, J = 49.5, 1.7
Hz). 13C{1H} NMR (100 MHz, CDCl3) δ 162.2 (d, J = 246.1 Hz),
144.1 (d, J = 19.9 Hz), 129.6 (dd, J = 7.9, 2.5 Hz), 129.3 (d, J = 1.9
Hz), 128.3 (d, J = 2.3 Hz), 123.0 (d, J = 2.0 Hz), 115.8 (d, J = 21.4
Hz), 77.4 (d, J = 161.8 Hz), 39.3; HRMS (ESI): m/z calculated for
C11H11F2N2+ [M + H]+: 209.0885, found: 209.0889.
Syntheses of cyano(4-(furan-2-yl)-1-methyl-1-H-pyrazol-
3-yl)methyl acetate (6): A mixture of 2g (88.1 mg, 0.5 mmol),
LiClO4 (53.2 mg, 0.5 mmol) and TMSCN (130 μL, 1.0 mmol) in
CH2Cl2 (5 mL) was stirred at room temperature for 12 h until dis-
appearance of the starting material as monitored by TLC. Then wa-
ter (10 mL) was added, and the aqueous phase was extracted with
CH2Cl2 (3 × 5 mL). The combined organic layers were dried over
Na2SO4 and concentrated under vacuum to give the crude O-trime-
thysilyl cyanohydrin intermediate, which was directly dissolved in
THF (3 mL) and treated with 2 M HCl (2 mL) at room temperature
for 2 h. The organic layer was successively separated, dried over
Na2SO4, filtered, and treated with acetic anhydride (140 μL) and
pyridine (100 μL) at room temperature for 5 h. The reaction mixture
was then concentrated under reduced pressure and the residue was
purified by flash column chromatography on the silica gel to afford
the desired product 6. White solid; mp 121 – 122 °C; 58.3 mg, 80%
yield; 1H NMR (600 MHz, CDCl3) δ 7.62 (s, 1H), 7.38 (s, 1H), 6.75
(s, 1H), 6.42 (s, 1H), 6.36 (d, J = 2.6 Hz, 1H), 3.93 (s, 3H), 2.13 (s,
3H). 13C{1H} NMR (100 MHz, CDCl3) δ 169.1, 145.8, 141.9,
138.7, 129.2, 115.2, 113.4, 111.5, 106.2, 57.0, 39.7, 20.5. HRMS
4-(4-Chlorophenyl)-3-(fluoromethyl)-1-methyl-1H-pyrazole
1
(5d). White solid; mp 85 – 86 °C; 92.1 mg, 82% yield; H NMR
(400 MHz, CDCl3) δ 7.49 (s, 1H), 7.39 – 7.34 (m, 4H), 5.37 (d, J =
49.1 Hz, 2H), 3.93 (d, J = 1.8 Hz, 3H). 19F NMR (377 MHz, CDCl3)
δ -199.10 (td, J = 49.2, 1.4 Hz). 13C{1H} NMR (100 MHz, CDCl3)
δ 144.1 (d, J = 20.0 Hz), 133.0, 130.7, 129.5 (d, J = 2.1 Hz), 129.2
(d, J = 2.6 Hz), 129.1, 122.8 (d, J = 2.0 Hz),77.3 (d, J = 162.0 Hz),
39.3; HRMS (ESI): m/z calculated for C11H11ClFN2+ [M + H]+:
225.0589, found: 225.0600.
3-(Fluoromethyl)-1-methyl-4-(4-(trifluoromethyl)phenyl)-1H-
pyrazole (5e). White solid; mp 65 – 66 °C; 108.5 mg, 84% yield;
1H NMR (400 MHz, CDCl3) δ 7.65 – 7.63 (m, 2H), 7.58 – 7.56 (m,
3H), 5.40 (d, J = 49.1 Hz, 2H), 3.95 (d, J = 1.7 Hz, 3H). 19F NMR
(377 MHz, CDCl3) δ -62.46 (s, 3F), -199.10 (td, J = 49.2, 1.4 Hz,
1F). 13C{1H} NMR (100 MHz, CDCl3) δ 144.4 (d, J = 20.1 Hz),
136.0, 129.9 (d, J = 1.9 Hz), 129.0 (q, J = 32.4 Hz), 128.0 (d, J =
2.7 Hz), 125.9 (q, J = 3.7 Hz), 124.4 (q, J = 271.8 Hz), 122.6 (d, J
= 1.6 Hz), 76.9 (d, J = 162.2 Hz), 39.3; HRMS (ESI): m/z calculated
for C12H11F4N2+ [M + H]+: 259.0853, found: 259.0866.
3-(Fluoromethyl)-1-methyl-4-(naphthalen-2-yl)-1H-pyrazole
1
+
(ESI): m/z calculated for C12H11N3NaO3 [M + Na]+: 268.0693,
(5f). White solid; mp 75 – 76 °C; 36.0 mg, 30% yield; H NMR
(400 MHz, CDCl3) δ 7.95 (s, 1H), 7.87 (t, J = 8.3 Hz, 3H), 7.60 –
7.58 (m, 2H), 7.53 – 7.46 (m, 2H), 5.49 (d, J = 49.2 Hz, 2H), 3.95
(d, J = 1.8 Hz, 3H). 19F NMR (377 MHz, CDCl3) δ -198.89 (td, J =
49.2, 1.3 Hz). 13C{1H} NMR (100 MHz, CDCl3) δ 144.4 (d, J =
19.8 Hz), 133.8, 132.4, 129.7 (d, J = 2.2 Hz), 129.7, 128.6, 128.2,
127.8, 126.5, 126.4 (d, J = 2.1 Hz), 126.3 (d, J = 2.7 Hz), 126.0,
123.9 (d, J = 2.1 Hz), 77.1 (d, J = 161.9 Hz), 39.3; HRMS (ESI):
found: 268.0698.
Procedure for the synthesis of SDHI fungicide fluxapy-
roxad 11 and its analogues: To a solution of sodium periodate
(1.85 g, 8.0 mmol) in a co-solvent of CCl4/CH3CN/H2O (3/3/2, 6
mL) was added RuCl3•xH2O (20.7 mg, 0.1 mmol), and the resulting
mixture was stirred at room temperature for 15 min before addition
of the solution of 3g, or 5g, or 1g, or 6 (1.0 mmol) in CCl4 (1 mL)
in one portion. After stirred for a further 30 min, the reaction mix-
ture was diluted with water (10 mL) and extracted with ethyl ace-
tate (3 × 15 mL). The combined organic extracts were washed with
brine, dried over Na2SO4, filtered through Celite and evaporated in
vacuum. The residue was purified by flash column chromatography
on silica gel to afford the corresponding carboxylic acids 7-10.
+
m/z calculated for C15H14FN2 [M + H]+: 241.1136, found:
241.1144.
3-(Fluoromethyl)-4-(furan-2-yl)-1-methyl-1H-pyrazole
(5g).
1
Yellow oil; 11.7 mg, 13% yield; H NMR (400 MHz, CDCl3) δ
7.61 (s, 1H), 7.41 (t, J = 1.3 Hz, 1H), 6.44 (d, J = 1.2 Hz, 2H), 5.49
(d, J = 48.8 Hz, 2H), 3.91 (d, J = 1.9 Hz, 3H). 19F NMR (376 MHz,
CDCl3) δ -206.07 (t, J = 49.0 Hz). 13C{1H} NMR (100 MHz, CDCl3)
δ 147.1 (d, J = 1.6 Hz), 143.4 (d, J = 20.2 Hz), 141.5, 128.5 (d, J =
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 11
A suspension of carboxylic acids 7-10 (0.55 mmol) and PCl5
7.36 (m, 1H), 7.45 – 7.36 (m, 2H), 6.99 (t, J = 7.0 Hz, 2H), 5.35 (d,
(125.0 mg, 0.6 mmol) in anhydrous Et2O (2 mL) was stirred at
room temperature for 2 h under an argon atmosphere until a trans-
parent solution was formed (monitored by TLC, PE/EA=7/3). At
that point, the solvent was evaporated under vacuum, and the resi-
due containing the intermediate acylchloride was then dissolved in
anhydrous THF (1mL), and treated with anhydrous pyridine (88 μL,
1.1 mmol) and 3',4',5'-trifluoro-[1,1'-biphenyl]-2-amine (123.1 mg,
0.55 mmol). The resulting mixture was stirred at room temperature
for 2.5 h (monitored by TLC) before dilution with ethyl acetate (5
mL). The organic layer was sequentially washed with aqueous so-
lution of 4 % HCl (10 mL), 5% NaHCO3 (10 mL) and saturated
brine. The organic layer was then dried over NaSO4, filtered and
concentrated under vacuum. The residue was purified by flash col-
umn chromatography (PE/EA=4/1 as the eluent) to give the SDHI
Fungicide Fluxapyroxad 11 or its anagues 12-14, 25-28 as a white
solid.
3-(Difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid (7).
White solid; mp 203 – 204 °C; 158.5 mg, 90% yield; 1H NMR (400
MHz, CD3OD) δ 8.16 (s, 1H), 7.15 (t, J = 54.0 Hz, 1H), 3.96 (s,
3H). 19F NMR (376 MHz, CD3OD) δ -117.43 (d, J = 54.0 Hz).
13C{1H} NMR (100 MHz, CD3OD) δ 163.5, 146.2 (t, J = 24.0 Hz),
135.8, 113.1 (t, J = 3.5 Hz), 109.3 (t, J = 235.3 Hz), 38.3; HRMS
(ESI): m/z calculated for C6H7F2N2O2+ [M + H]+: 177.0470, found:
177.0471.
J = 48.4 Hz, 2H), 3.89 (s, 3H). 19F NMR (565 MHz, CDCl3) δ -
133.46 (dd, J = 21.3, 8.3 Hz), -159.31 – -168.09 (m), -204.17 (dd,
J = 60.4, 50.0 Hz). 13C{1H} NMR (150 MHz, CDCl3) δ 160.8,
151.4 (ddd, J = 251.4 Hz, 10.2 Hz, 4.3 Hz), 144.6 (d, J = 21.4 Hz),
139.6 (dt, J = 252.7 Hz, 15.0 Hz), 135.1, 134.8, 134.5 (dd, J = 7.3,
4.5 Hz), 131.3, 130.2, 129.4, 125.3, 123.7, 118.4, 113.8 (dd, J =
16.6, 4.6 Hz), 78.1 (d, J = 158.5 Hz), 39.5; HRMS (ESI): m/z cal-
culated for C18H14F4N3O+ [M + H]+: 364.1068, found: 364.1062.
3-Cyano-1-methyl-N-(3',4',5'-trifluoro-[1,1'-biphenyl]-2-yl)-
1H-pyrazole-4-carboxamide (13). Reaction performed on a 1.0
mmol scale utilizing the starting material 9, 13 was isolated as a
white solid: 235.2 mg, 66% yield; mp 203 – 204 °C; 1H NMR (400
MHz, DMSO-d6) δ 9.96 (s, 1H), 8.41 (s, 1H), 7.48 (d, J = 3.3 Hz,
2H), 7.45 – 7.40 (m, 2H), 7.34 (dd, J = 8.6, 7.1 Hz, 2H), 3.99 (s,
3H). 19F NMR (376 MHz, DMSO-d6) δ -135.64 (dd, J = 22.4, 9.4
Hz), -161.53 – -166.42 (m). 13C{1H} NMR (100 MHz, DMSO-d6)
δ 159.2, 150.5 (ddd, J = 246.6, 9.6, 4.0 Hz), 138.5 (dt, J = 31.4,
15.4 Hz), 136.40 (td, J = 8.3, 4.8 Hz), 134.9 (d, J = 103.2 Hz), 134.4,
133.3, 130.8, 129.5, 128.4, 127.5, 124.3, 122.0, 113.7 (dd, J = 16.2,
5.3 Hz), 113.6, 40.6; HRMS (ESI): m/z calculated for
C18H12F3N4O+ [M + H]+: 357.0958, found: 357.0960.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Cyano(1-methyl-4-((3',4',5'-trifluoro-[1,1'-biphenyl]-2-yl)car-
bamoyl)-1H-pyrazol-3-yl)methyl acetate (14). Reaction performed
on a 0.5 mmol scale utilizing the starting material 10, 14 was iso-
lated as a white solid: 186.0 mg, 70% yield; mp 185 – 186 °C; 1H
NMR (400 MHz, DMSO-d6) δ 9.82 (s, 1H), 8.32 (s, 1H), 7.49 –
7.37 (m, 4H), 7.33 (dd, J = 9.0, 6.9 Hz, 2H), 6.90 (s, 1H), 3.95 (s,
3H), 2.07 (s, 3H). 19F NMR (376 MHz, DMSO-d6) δ -135.77 (dd,
J = 22.4, 9.5 Hz), -158.88 – -170.32 (m). 13C{1H} NMR (100 MHz,
DMSO-d6) δ 169.3, 161.0, 150.5 (ddd, J = 246.6, 9.6, 4.1 Hz),
143.7, 138.4 (dt, J = 248.9, 15.5 Hz), 136.6 (td, J = 8.4, 4.7 Hz),
135.5, 134.6, 133.6, 130.7, 129.4, 128.6, 127.4, 116.2, 114.9, 113.7
(dd, J = 16.0, 5.2 Hz), 56.7, 39.9, 20.3; HRMS (ESI): m/z calculated
for C21H16F3N4O3+ [M + H]+: 429.1169, found: 429.1169.
3-(Fluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid (8).
Reaction performed on a 1.0 mmol scale utilizing the starting ma-
terial 5g, 8 was isolated as a white solid: 102.8 mg, 65% yield; mp
185 – 186 °C; 1H NMR (600 MHz, DMSO-d6) δ 12.54 (s, 1H), 8.25
(s, 1H), 5.48 (d, J = 48.0 Hz, 2H), 3.87 (s, 3H). 19F NMR (565 MHz,
DMSO-d6) δ -206.59 (t, J = 49.1 Hz). 13C{1H} NMR (150 MHz,
DMSO-d6) δ 163.6, 147.4 (d, J = 18.3 Hz), 135.9, 112.8, 76.0 (d, J
+
= 161.2 Hz), 38.8; HRMS (ESI): m/z calculated for C6H8FN2O2
[M + H]+: 159.0564, found: 159.0563.
3-Cyano-1-methyl-1H-pyrazole-4-carboxylic acid (9). Reaction
performed on a 3.0 mmol scale utilizing the starting material 1g, 9
was isolated as a white solid: 289.0 mg, 64% yield; mp 193 –
194 °C; 1H NMR (400 MHz, CD3OD) δ 8.26 (s, 1H), 4.02 (s, 3H).
13C{1H} NMR (100 MHz, CD3OD) δ 162.0, 135.4, 125.1, 118.8,
112.2, 39.1; HRMS (ESI): m/z calculated for C6H6N3O2+ [M + H]+:
152.0455, found: 152.0452.
Syntheses of 15-20: 1g’ was obtained according to the proce-
dure of literature 17 and could successfully be transformed to 1,4,5-
trisubstituted pyrazoles 15-20.
4-(Furan-2-yl)-1-methyl-1H-pyrazole-5-carbaldehyde (15). Re-
action performed on a 1.0 mmol scale utilizing the same procedure
for the preparation of 2g from the starting material 1g’, 15 was iso-
lated as a yellow solid: 52.9 mg, 30% yield; mp 55 – 56 °C; 1H
NMR (600 MHz, CDCl3) δ 10.22 (s, 1H), 7.61 (s, 1H), 7.42 (d, J =
1.3 Hz, 1H), 6.54 (d, J = 3.3 Hz, 1H), 6.42 (dd, J = 3.3, 1.8 Hz, 1H),
4.11 (s, 3H). 13C{1H} NMR (150 MHz, CDCl3) δ 181.4, 146.4,
143.1, 135.9, 134.0, 120.6, 111.8, 108.4, 40.3. HRMS (ESI): m/z
calculated for C9H9N2O2+ [M + H]+: 177.0659, found: 177.0654.
(4-(Furan-2-yl)-1-methyl-1H-pyrazol-5-yl)methanol (16). Reac-
tion performed on a 2.8 mmol scale utilizing the same procedure
for the preparation of 4g from the starting material 15, 16 was iso-
lated as a light yellow solid: 358.2 mg, 72% yield; mp 84 – 85 °C;
1H NMR (400 MHz, CDCl3) δ 7.53 (s, 1H), 7.37 (dd, J = 1.8, 0.6
Hz, 1H), 6.41 (dd, J = 3.3, 1.9 Hz, 1H), 6.33 (dd, J = 3.3, 0.5 Hz,
1H), 4.81 (s, 2H), 3.86 (s, 3H), 2.98 (s, 1H). 13C{1H} NMR (100
MHz, CDCl3) δ 148.1, 141.3, 137.5, 136.0, 112.9, 111.4, 105.0,
54.0, 36.8. HRMS (ESI): m/z calculated for C9H11N2O2+ [M + H]+:
179.0815, found: 179.0815.
2-(4-(Furan-2-yl)-1-methyl-1H-pyrazol-5-yl)-2-((trimethylsi-
lyl)oxy)acetonitrile (17). Reaction performed on a 1.0 mmol scale
utilizing the same procedure for the preparation of 6 from the start-
ing material 1g’, 17 was isolated as a yellow solid: 261.6 mg, 95%
yield; mp 122 – 123 °C;1H NMR (600 MHz, CDCl3) δ 7.58 (s, 1H),
7.41 (s, 1H), 6.43 (s, 1H), 6.38 (d, J = 3.2 Hz, 1H), 6.27 (s, 1H),
4.08 (s, 3H), 0.11 (s, 9H). 13C{1H} NMR (150 MHz, CDCl3) δ
146.7, 141.7, 135.9, 131.7, 117.0, 112.9, 111.5, 106.2, 54.5, 38.3, -
0.6. HRMS (ESI): m/z calculated for C13H18N3O2Si+ [M + H]+:
276.1163, found: 276.1161.
3-(Acetoxy(cyano)methyl)-1-methyl-1H-pyrazole-4-carboxylic
acid (10). Reaction performed on a 1.0 mmol scale utilizing start-
ing material 6, 10 was isolated as a white solid: 178.2 mg, 80%
1
yield; mp 163 – 164 °C; H NMR (400 MHz, CD3OD) δ 8.18 (s,
1H), 6.96 (s, 1H), 3.98 (s, 3H), 2.15 (s, 3H). 13C{1H} NMR (100
MHz, CD3OD) δ 169.1, 163.5, 144.2, 136.1, 114.8, 112.5, 56.3,
+
38.4, 18.7; HRMS (ESI): m/z calculated for C9H9N3NaO4 [M +
Na]+: 246.0485, found: 246.0485.
3-(Difluoromethyl)-1-methyl-N-(3',4',5'-trifluoro-[1,1'-bi-
phenyl]-2-yl)-1H-pyrazole-4-carboxamide (11, Fluxapyroxad).
White solid; mp 140 – 141 °C; 174.1 mg, 83% yield; 1H NMR (600
MHz, CDCl3) δ 8.12 (d, J = 8.2 Hz, 1H), 7.92 (s, 1H), 7.86 (s, 1H),
7.42 – 7.39 (m, 1H), 7.24 – 7.20 (m, 2H), 6.99 – 6.97 (m, 2H), 6.68
(t, J = 54.2 Hz, 1H), 3.89 (s, 3H). 19F NMR (565 MHz, CDCl3) δ -
109.06 (d, J = 56.4 Hz), -133.74 (dd, J = 21.2, 8.3 Hz), -158.26 – -
165.86 (m). 13C{1H} NMR (150 MHz, CDCl3) δ 159.6, 151.4 (ddd,
J = 251.2, 9.9, 4.1 Hz), 142.5 (t, J = 29.0 Hz), 139.6 (dt, J = 252.7,
15.3 Hz), 136.2, 134.6, 134.3 (td, J = 7.7, 5.6 Hz), 131.5, 130.2,
129.3, 125.4, 123.7, 116.7, 113.9 (dd, J = 16.6, 4.6 Hz), 111.7 (t, J
= 233.0 Hz), 39.6; HRMS (ESI): m/z calculated for C18H14F4N3O+
[M + H]+: 364.1068, found: 364.1062.
3-(Fluoromethyl)-1-methyl-N-(3',4',5'-trifluoro-[1,1'-biphenyl]-
2-yl)-1H-pyrazole-4-carboxamide (12). Reaction performed on a
0.8 mmol scale utilizing the starting material 8, 12 was isolated as
1
a white solid: 162.8 mg, 56% yield; mp 156 – 157 °C; H NMR
(600 MHz, CDCl3) δ 8.15 (d, J = 8.2 Hz, 1H), 7.86 (s, 2H), 7.45 –
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Page 9 of 11
The Journal of Organic Chemistry
5-(Difluoromethyl)-4-(furan-2-yl)-1-methyl-1H-pyrazole (18).
168.4, 163.7, 140.4, 134.9, 114.1, 113.6, 52.3, 37.6, 18.5. HRMS
(ESI): m/z calculated for C9H10N3O4+ [M + H]+: 224.0666, found:
224.0662.
Reaction performed on a 2.4 mmol scale utilizing the same proce-
dure for the preparation of 3g from the starting material 15, 18 was
isolated as a light yellow solid: 200.0 mg; 42% yield; mp 39 – 40 °C;
1H NMR (400 MHz, CDCl3) δ 7.62 (s, 1H), 7.42 (d, J = 1.0 Hz,
1H), 7.19 (t, J = 52.8 Hz, 1H), 6.44 – 6.41 (m, 2H), 4.05 (s, 3H).
19F NMR (376 MHz, CDCl3) δ -112.98 (d, J = 52.7 Hz). 13C{1H}
NMR (100 MHz, CDCl3) δ 146.3, 142.1, 135.9, 130.1 (t, J = 23.5
Hz), 115.4 (t, J = 5.9 Hz), 111.5, 108.7 (t, J = 234.0 Hz), 106.6,
38.9. HRMS (ESI): m/z calculated for C9H9F2N2O+ [M + H]+:
199.0677, found: 199.0676.
1
2
3
4
5
6
7
8
5-(Difluoromethyl)-1-methyl-N-(3',4',5'-trifluoro-[1,1'-bi-
phenyl]-2-yl)-1H-pyrazole-4-carboxamide (25). Reaction per-
formed on a 0.38 mmol scale utilizing the starting material 21, 25
was isolated as a white solid: 116.5 mg, 80% yield; mp 120 –
1
121 °C; H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 8.1 Hz, 1H),
7.61 (t, J = 48.3 Hz, 1H), 7.46 (d, J = 2.9 Hz, 2H), 7.36 (s, 1H),
7.29 (s, 1H), 7.28 (s, 1H), 7.08 (t, J = 6.9 Hz, 2H), 4.10 (s, 3H). 19
F
NMR (377 MHz, CDCl3) δ -116.00 (d, J = 53.1 Hz), -132.22 (dd,
J = 21.7, 8.2 Hz), -157.00 – -162.58 (m). 13C{1H} NMR (100 MHz,
CDCl3) δ 160.2, 151.6 (ddd, J = 252.5, 9.9, 4.3 Hz), 139.7 (dt, J =
30.2, 14.9 Hz), 136.9 (t, J = 24.1 Hz), 135.8, 134.2 (dd, J = 7.8, 5.1
Hz), 133.9, 130.8, 130.2, 129.7, 125.8, 123.3, 118.0 (t, J = 4.9 Hz),
113.7 (dd, J = 15.4, 6.0 Hz), 107.7 (t, J = 235.6 Hz), 39.4; HRMS
(ESI): m/z calculated for C18H13F5N3O+ [M + H]+: 382.0973, found:
382.0974.
9
5-(Fluoromethyl)-4-(furan-2-yl)-1-methyl-1H-pyrazole
(19).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Reaction performed on a 2.0 mmol scale utilizing the same proce-
dure for the preparation of 5g from the starting material 16, 19 was
1
isolated as yellow oil: 51.4 mg, 11% yield; H NMR (400 MHz,
CDCl3) δ 7.67 (s, 1H), 7.43 (d, J = 1.5 Hz, 1H), 6.44 (dd, J = 3.3,
1.8 Hz, 1H), 6.39 (d, J = 3.3 Hz, 1H), 5.60 (d, J = 49.0 Hz, 2H),
3.95 (s, 3H). 19F NMR (377 MHz, CDCl3) δ -207.84 (t, J = 49.3
Hz). 13C{1H} NMR (100 MHz, CDCl3) δ 147.4 (d, J = 2.6 Hz),
141.8, 136.3 (d, J = 2.7 Hz), 132.9 (d, J = 19.1 Hz), 115.1 (d, J =
4.2 Hz), 111.4, 105.8 (d, J = 1.6 Hz), 72.9 (d, J = 164.9 Hz), 37.1.
HRMS (ESI): m/z calculated for C9H10FN2O+ [M + H]+: 181.0772,
found: 181.0771.
Cyano(4-(furan-2-yl)-1-methyl-1H-pyrazol-5-yl)methyl acetate
(20). Reaction performed on a 1.5 mmol scale utilizing the same
procedure for the preparation of 6 from the starting material 1g’, 20
was isolated as a yellow solid: 330.0 mg, 90% yield; mp 89 – 90 °C;
1H NMR (600 MHz, CDCl3) δ 7.66 (s, 1H), 7.49 – 7.42 (m, 1H),
7.15 (s, 1H), 6.47 (dd, J = 3.4, 0.6 Hz, 1H), 6.45 (dd, J = 3.3, 1.8
Hz, 1H), 4.11 (s, 3H), 2.18 (s, 3H). 13C{1H} NMR (150 MHz,
CDCl3) δ 168.3, 146.0, 142.4, 136.4, 127.6, 115.1, 114.2, 111.5,
106.9, 53.2, 38.4, 20.4. HRMS (ESI): m/z calculated for
C12H12N3O3+ [M + H]+: 246.0873, found: 246.0870.
5-(Fluoromethyl)-1-methyl-N-(3',4',5'-trifluoro-[1,1'-biphenyl]-
2-yl)-1H-pyrazole-4-carboxamide (26). Reaction performed on a
0.27 mmol scale utilizing the starting material 22, 26 was isolated
as a white solid: 75.4 mg, 77% yield; mp 141 – 142 °C; 1H NMR
(600 MHz, CDCl3) δ 8.10 (d, J = 8.2 Hz, 1H), 7.51 (s, 1H), 7.41 –
7.39 (m, 2H), 7.23 – 7.21 (m, 2H), 7.01 – 7.03 (m, 2H), 5.74 (d, J
= 48.1 Hz, 2H), 3.94 (s, 3H). 19F NMR (377 MHz, CDCl3) δ -132.47
(dd, J = 21.3, 8.2 Hz), -156.44 – -166.83 (m), -213.58 (t, J = 48.4
Hz). 13C{1H} NMR (100 MHz, CDCl3) δ 160.9, 151.6 (ddd, J =
252.2, 9.9, 4.2 Hz), 139.7 (dt, J = 238.8,14.6 Hz), 139.2 (d, J = 17.7
Hz), 136.5 (d, J = 1.8 Hz), 134.4 (dd, J = 5.1, 2.7 Hz), 134.3, 130.6,
130.1, 129.7, 125.4, 123.2, 117.2 (d, J = 2.9 Hz), 113.7 (dd, J =
15.4, 6.1 Hz), 72.6 (d, J = 165.0 Hz), 37.7; HRMS (ESI): m/z cal-
culated for C18H14F4N3O+ [M + H]+: 364.1068, found: 364.1072.
5-Cyano-1-methyl-N-(3',4',5'-trifluoro-[1,1'-biphenyl]-2-yl)-
1H-pyrazole-4-carboxamide (27). Reaction performed on a 1.3
mmol scale utilizing the starting material 23, 27 was isolated as a
white solid: 337.0 mg, 73% yield; mp 199 – 200 °C; 1H NMR (400
MHz, DMSO-d6) δ 10.03 (s, 1H), 8.15 (s, 1H), 7.48 (dd, J = 12.5,
6.1 Hz, 3H), 7.43 (d, J = 7.1 Hz, 1H), 7.40 – 7.33 (m, 2H), 4.03 (s,
3H). 19F NMR (376 MHz, DMSO-d6) δ -135.74 (dd, J = 22.7, 9.7
Hz), -159.30 – -167.04 (m). 13C{1H} NMR (100 MHz, DMSO-d6)
δ 159.0, 150.5 (ddd, J = 246.8, 9.6, 3.8 Hz), 138.5 (dt, J = 249.0,
15.0 Hz), 138.2, 136.3 (td, J = 8.2, 4.8 Hz), 135.5, 134.3, 130.8,
129.5, 128.5, 127.7, 124.4, 117.0, 113.8 (dd, J = 16.0, 5.2 Hz),
110.3, 39.2; HRMS (ESI): m/z calculated for C18H12F3N4O+ [M +
H]+: 357.0958, found: 357.0959.
5-(Difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic
acid
(21). Reaction performed on a 0.63 mmol scale utilizing the same
procedure for the preparation of 7 from the starting material 18, 21
was isolated as a yellow solid: 86.9 mg, 78% yield; mp 148 –
1
149 °C; H NMR (400 MHz, CD3OD) δ 7.87 (s, 1H), 7.55 (t, J =
52.8 Hz, 1H), 4.07 (s, 3H). 19F NMR (376 MHz, CD3OD) δ -117.71
(d, J = 52.8 Hz). 13C{1H} NMR (100 MHz, CD3OD) δ 163.5, 140.2,
136.5 (t, J = 23.7 Hz),115.3 (t, J = 5.2 Hz), 107.8 (t, J = 234.2 Hz),
+
38.0; HRMS (ESI): m/z calculated for C6H7F2N2O2 [M + H]+:
177.0470, found: 177.0469.
5-(Fluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid (22).
Reaction performed on a 1.1 mmol scale utilizing the same proce-
dure for the preparation of 8 from the starting material 19, 22 was
isolated as a white solid: 132.2 mg, 76% yield; mp 123 – 124 °C;
1H NMR (400 MHz, CD3OD) δ 7.87 (s, 1H), 5.81 (d, J = 47.9 Hz,
2H), 3.97 (s, 3H). 19F NMR (377 MHz, CD3OD) δ -216.31 (t, J =
48.2 Hz). 13C{1H} NMR (100 MHz, CD3OD) δ 164.4, 140.4 (d, J
= 1.9 Hz), 140.0 (d, J = 17.5 Hz), 113.7, 71.7 (d, J = 162.6 Hz),
Cyano(1-methyl-4-((3',4',5'-trifluoro-[1,1'-biphenyl]-2-yl)car-
bamoyl)-1H-pyrazol-5-yl)methyl acetate (28). Reaction performed
on a 0.54 mmol scale utilizing the starting material 24, 28 was iso-
lated as a white solid: 188.0 mg, 70% yield; mp 163 – 164 °C; 1H
NMR (400 MHz, CD3OD) δ 7.83 (s, 1H), 7.43 – 7.35 (m, 3H), 7.35
– 7.31 (m, 2H), 7.07 (dd, J = 8.8, 6.8 Hz, 2H), 4.02 (s, 3H), 2.09 (s,
3H). 19F NMR (376 MHz, CD3OD) δ -137.52 (dd, J = 20.7, 9.2 Hz),
-157.84 – -171.78 (m). 13C{1H} NMR (100 MHz, CD3OD) δ 168.2,
161.9, 150.8 (ddd, J = 248.1, 9.9, 4.1 Hz), 138.8 (dt, J = 31.2, 15.4
Hz), 137.3, 136.0, 136.0 – 135.8 (m), 134.5, 133.5, 130.0, 128.9,
127.8, 127.3, 116.3, 113.7, 112.9 (dd, J = 16.1, 5.8 Hz), 52.3, 37.5,
+
36.0; HRMS (ESI): m/z calculated for C6H8FN2O2 [M + H]+:
159.0564, found: 159.0561.
5-Cyano-1-methyl-1H-pyrazole-4-carboxylic acid (23). Reac-
tion performed on a 3 mmol scale utilizing the same procedure for
the preparation of 9 from the starting material 1g’, 23 was isolated
as a white solid: 356.4 mg, 78% yield; mp 192 – 193 °C; 1H NMR
(400 MHz, CD3OD) δ 7.95 (s, 1H), 4.08 (s, 3H). 13C{1H} NMR
(100 MHz, CD3OD) δ 162.0, 140.5, 120.7, 117.5, 108.9, 37.9;
+
18.5; HRMS (ESI): m/z calculated for C21H16F3N4O3 [M + H]+:
429.1169, found: 429.1169.
+
HRMS (ESI): m/z calculated for C6H6N3O2 [M + H]+: 152.0455,


ASSOCIATED CONTENT
Supporting Information
found: 152.0454.
5-(Acetoxy(cyano)methyl)-1-methyl-1H-pyrazole-4-carboxylic
acid (24). Reaction performed on a 1 mmol scale utilizing the same
procedure for the preparation of 10 from the starting material 20,
24 was isolated as a white solid: 200.0 mg, 86% yield; mp 199 –
200 °C; 1H NMR (400 MHz, CD3OD) δ 7.91 (s, 1H), 7.55 (s, 1H),
4.13 (s, 3H), 2.21 (s, 3H). 13C{1H} NMR (100 MHz, CD3OD) δ
The Supporting Information is available free of charge on the ACS
Publications website at DOI: 10.1021/acs.joc.xxxx.
1
Scheme S1, H, 19F and 13C NMR spectra for new com-
pounds (PDF)
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 11
Agulló, C.; Abad-Fuentes, A. Fluxapyroxad Haptens and Antibodies

AUTHOR INFORMATION
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Corresponding Author
*E-mail: zhangfg1987@tju.edu.cn
*E-mail: majun_an68@tju.edu.cn
ORCID
Jun-An Ma: 0000-0002-3902-6799
Fa-Guang Zhang: 0000-0002-0251-0456
Zhen Chen: 0000-0002-6289-4332
9
Author Contributions
§ Y. Z. and Z. C. contributed equally to this work.
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Notes
The authors declare no competing financial interest.

ACKNOWLEDGMENT
This work was supported by the National Natural Science Founda-
tion of China (No. 21472137, 21532008, and 21772142), the Na-
tional Basic Research Program of China (973 Program,
2014CB745100), and Tianjin Municipal Science & Technology
Commission (14JCZDJC33400).

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