A Practical Synthesis of the Key Intermediate for Fluxapyroxad

Full text of DOI:10.1080/00304948.2020.1765658

Organic Preparations and Procedures International
The New Journal for Organic Synthesis
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/uopp20
A Practical Synthesis of the Key Intermediate for
Fluxapyroxad
Zhenhua Li , Xuchao Zhang , Zhiyong Tan , Jinjing Qin , Meizhen Han & Yao
Ma
To cite this article: Zhenhua Li , Xuchao Zhang , Zhiyong Tan , Jinjing Qin , Meizhen Han & Yao
Ma (2020): A Practical Synthesis of the Key Intermediate for Fluxapyroxad, Organic Preparations
and Procedures International, DOI: 10.1080/00304948.2020.1765658
To link to this article: https://doi.org/10.1080/00304948.2020.1765658
Published online: 14 Jul 2020.
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ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
https://doi.org/10.1080/00304948.2020.1765658
EXPERIMENTAL PAPER
A Practical Synthesis of the Key Intermediate for
Fluxapyroxad
a,b
a
b
a
b
Zhenhua Li a
, Xuchao Zhang , Zhiyong Tan , Jinjing Qin , Meizhen Han ,
and Yao Ma
a
Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of
Education, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, China;
b
National Engineering Research Center for Process Development of Active Pharmaceutical Ingredients,
Collaborative Innovation Center of Yangtze River Delta Region, Green Pharmaceuticals, Zhejiang
University of Technology, Hangzhou, China
ARTICLE HISTORY Received 11 August 2019; Accepted 23 February 2020
Fluxapyroxad (Figure 1), a broad-spectrum pyrazole-carboxamide fungicide, is com-
monly employed for the treatment of a large variety of commercial crops. More specif-
ically, the application of Fluxapyroxad results in the inhibition of spore germination,
1
–3
germ tube formation, and mycelial growth within the target fungus species.
Literature reports have indicated that 3’,4’,5’-trifluoro-[1,1’-biphenyl]-2-amine (1) is
4–7
considered to be a key intermediate in the synthesis of Fluxapyroxad.
In the past few decades, scientists have made numerous efforts to develop efficient
8
routes to 1. For example, Zierke and co-workers developed the route presented in
Scheme 1, whereby 3,4,5-trifluorophenylzinc bromide was initially prepared by treating
3
,4,5-trifluorobromobenzene with Mg and ZnCl , and 1 was subsequently obtained fol-
2
lowing Negishi coupling of the appropriate aromatic chloride with the organozinc
reagent. This was achieved through the use of 0.5 mol% [1,3-bis(2,6-diisopropylphenyl)im-
idazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride (PEPPSI-IPr) as the catalyst,
whereby a turnover number (TON) of 184 was achieved.
Unfortunately, the high cost of PEPPSI-IPr renders this route unsuitable for larger-
scale applications, and protection/deprotection of the amine moiety required a lengthy
9
sequential operation. In addition, Heinrich et al. reported the preparation of 1 from
3,4,5-trifluorophenylhydrazine as a radical source for the coupling reaction (Scheme 2).
However, the commercially unavailability of 3,4,5-trifluorophenylhydrazine, the use of
MnO and the requirement for an excess of aniline (20 equiv.) may result in serious
2
,
pollution and expense upon scale-up of this route. Moreover, an undesired para-substi-
tuted byproduct was also obtained in 16% yield, thereby requiring the use of column
chromatography to facilitate its removal. In recent years, it has also been suggested that
10–13
the biaryl structure could be constructed via a Suzuki-Miyaura reaction,
which
would provide a promising approach to the preparation of 1 from aryl boric acid
1
4–15
and o-haloaniline (Scheme 3).
However, the requirement for large quantities of
CONTACT Zhenhua Li
lizhenhua@zjut.edu.cn
Key Laboratory for Green Pharmaceutical Technologies and Related
Equipment of Ministry of Education, College of Pharmaceutical Sciences, Zhejiang University of Technology, 310014,
Hangzhou, China
ß 2020 Taylor & Francis Group, LLC

2
Z. LI ET AL.
Figure 1. Structure of fluxapyroxad.
7
Scheme 1. Synthesis of compound 1 based on a Negishi coupling reaction.
Pd-catalysts to achieve poor TONs (e.g., 3 mol% Pd(PPh ) Cl (TON ¼ 28), or 5 mol%
3
2
2
Pd(PPh ) (TON ¼ 18.4)) rendered this process too expensive.
3
4
Thus, we herein report an improved synthesis of 1. More specifically, the commer-
cially available (3,4,5-trifluorophenyl)boronic acid (2) was selected as the starting mater-
ial, and a new and pragmatic route employing a Suzuki-Miyaura coupling/hydrolysis/
Hofmann degradation reaction was developed to generate the key intermediate com-
pound 1 in 99.79% purity and 93% overall yield (Scheme 4). Importantly, the critical
Suzuki-Miyaura coupling reaction was catalyzed by 0.02 mol% Pd(PPh ) to give a high
3
4
TON of 4900. In this procedure, 3’,4’,5’-trifluoro-[1,1’-biphenyl]-2-carbonitrile (3) was
synthesized by the reaction of 1.3 equiv of (3,4,5-trifluorophenyl) boronic acid (2) with
ꢀ
o-chlorobenzonitrile (4) in toluene/water using NaOH at 85 C (Scheme 4).
To determine the optimal conditions for this transformation, a range of bidentate
1
6
bisphosphine ligands were investigated, including dppp, dppf, and PCy ꢁHBF . When
3
4
1
mol% Pd(PPh ) was employed for the purpose of this reaction, excellent yields of 3
3 4
were obtained (Table 1, entries 2–4); this is likely due to the electron density on phos-
17–21
phorus facilitating the oxidative insertion of palladium into the Ar-Cl bond.
Finally,
the target product was achieved in high yield using 0.02 mol% Pd(PPh ) and 0.04 mol%
3
4
PCy ꢁHBF (Table 1, entries 5–9).
3
4
ꢀ
Subsequently, the treatment of 3 with H SO in toluene over 24 h at 80 C yielded
2
4
3’,4’,5’-trifluoro-[1,1’-biphenyl]-2-formamide (5) in 98% yield. Finally, 3’,4’,5’-trifluoro-
[
1,1’-biphenyl]-2-amine (1) was prepared by the Hofmann degradation reaction of 5,
ꢀ
whereby the reaction proceeded smoothly using NaClO (7.5 wt%) in ethanol at 0–5 C
over 2 h, followed by stirring at 50 C for an additional 2 h.
ꢀ

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
3
8
Scheme 2. Synthesis of compound 1 based on a radical coupling process.
1
4–15
Scheme 3. Synthesis of compound 1 based on the Suzuki-Miyaura coupling reaction.
In summary, we herein reported a cost-efficient and practical synthetic process for
the key intermediate (1) of Fluxapyroxad using the commercially available (3,4,5-tri-
fluorophenyl) boronic acid (2) as the starting material. This was achieved over three
steps, which included Suzuki-Miyaura reaction/hydrolysis/Hofmann degradation
sequence to afford the final product 1 in 93% yield and 99.79% purity. Furthermore,
the Szuki-miyaura coupling reaction was successfully applied in efficiently constructing
compound 3 using 0.02 mol% Pd(PPh ) , which significantly reduced the cost.
3
4
Experimental section
All solvents and reagents were purchased from commercial sources and used without
further purification unless otherwise indicated. The progress of the reaction was moni-
tored by TLC [stationary phase: silica gel, solvent: hexane/ethyl acetate (10/1)], and
visualized under UV light (254 and 365 nm). Melting points (mp) were determined on a
1
13
€
BUCHI B-540 melting point apparatus and are uncorrected. H and C NMR spectra
were recorded on a Br u€ ker spectrometer at 600 and 150 MHz, respectively. The chem-
ical shifts are reported as d ppm using tetramethylsilane (TMS) as internal standard.
ESI-MS analyses were performed on a Trace DSQ mass spectrometer. The HPLC ana-
lysis data are reported in area %, not adjusted to weight. High-resolution mass spec-
trometry (HRMS) was carried out using an Agilent 6210 TOF LC-MS. Elemental
analyses (EA) were acquired on a Malvern 3000 instrument.

4
Z. LI ET AL.
Scheme 4. Improved scheme for the synthesis of key intermediate 1.
a
Table 1. Optimization of the Suzuki-Miyaura cross-coupling reaction.
b
Entry
Pd(PPh
3
)
4
(mol%)
Ligand
Yield (%)
1
2
3
4
5
6
7
8
9
a
1
1
1
1
0.04
0.03
0.02
0.01
–
75
97
95
99
99
98
98
93
85
dppp
dppf
PCy
PCy
PCy
PCy
PCy
PCy
3
3
3
3
3
3
ꢁHBF
ꢁHBF
ꢁHBF
ꢁHBF
ꢁHBF
ꢁHBF
4
4
4
4
4
4
0.009
Reaction conditions: 2 (0.455 mol), 4 (0.35 mol), NaOH (0.7 mol), TBAB (0.0525 mol), catalyst: ligand (n: n) ¼ 1: 2 for
ꢀ
1
2 h in Tol/H
2
O ¼ 4/1 with N
2
, 85 C.
b
Isolated yield of 3.
3’,4’,5’-Trifluoro-[1,1’-biphenyl]-2-carbonitrile (3)
A 10 L, three-necked, round-bottomed flask containing o-chlorobenzonitrile 4 (275.8 g,
mol) was equipped with a rubber septum. Toluene (4 L) and H O (1 L) were intro-
2
2
duced to the flask. The reaction flask was charged with tetrabutylammonium bromide
96.6 g, 0.3 mol), sodium hydroxide (160.5 g, 4 mol), (3,4,5-trifluorophenyl) boronic acid
(
2
(457.6 g, 2.6 mol), Pd(PPh ) (462 mg), and PCy ꢁHBF (294 mg). The mixture was
3
4
3
4
ꢀ
stirred until reaching complete dissolution, and then heated at reflux (85 C) for 12 h.
After this time, the aqueous layer was extracted with toluene (3 ꢂ 250 mL). The

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
5
combined organic fraction was dried over anhydrous magnesium sulfate, filtered, and
the solvent was then concentrated under reduced pressure. The resulting yellow residue
was recrystallized from ethanol and then filtered to afford pure 3’,4’,5’-trifluoro-[1,1’-
ꢀ
biphenyl]-2-carbonitrile 3 as a white solid (456.7 g, 98%), mp 125-127 C, with 98.07%
1
purity by HPLC. H NMR (600 MHz, CDCl ) d: 7.79 (d, J ¼ 7.8 Hz, 1H), 7.68 (t,
3
13
J ¼ 7.8 Hz, 1H), 7.51 (t, J ¼ 7.8 Hz, 1H), 7.49 (t, J ¼ 7.8 Hz, 1H), 7.19 (m, 2H); C NMR
(
1
150 MHz, CDCl ) d: 152.47, 149.97, 142.25, 141.48, 138.95, 133.93, 133.15, 129.85,
3
þ
28.70, 117.82, 113.31, 111.3; MS-ESI: 256 [M þ Na] . HRMS (ESI): Calcd for
C H F N: 234.0529, Found: 234.0525.
1
3
6 3
Anal. Calcd for C H F N: C, 66.96; H, 2.59. Found: C, 66.81; H, 2.59.
1
3
6 3
HPLC Conditions— Column: Welch Xtimate C18 (250 mm ꢂ 4.6 mm, 5 mm);
Detection: 210 nm; Flow rate: 1.0 mL/min; Temperature: rt; Run time: 10 min; Mobile
phase: acetonitrile/water ¼ 75/25, t : 5.735 min, purity: 98.07%.
R
3’,4’,5’-Trifluoro-[1,1’-biphenyl]-2-carboxamide (5)
Into a 10 L three-necked round-bottomed flask were introduced 3’,4’,5’-trifluoro-[1,1’-
biphenyl]-2-carbonitrile 3 (233.3 g, 1 mol), toluene (160 mL), and concentrated sulfuric
ꢀ
acid (H SO , 163.4 mL, 302.3 g, 3 mol). The resulting mixture was stirred at 80 C for
2
4
2
4 h and then quenched by the addition of cold H O (500 mL). Ethyl acetate (500 mL)
2
was then added followed by a solution of sodium hydroxide (240.3 g, 6 mmol) in H O
2
ꢀ
(
500 g) at 25–30 C. The aqueous layer was extracted with ethyl acetate (3 ꢂ 300 mL).
The combined organic fraction was dried over anhydrous magnesium sulfate, filtered,
and the solvent was then concentrated in vacuo. 3’,4’,5’-Trifluoro-[1,1’-biphenyl]-2-car-
boxamide 5 (245.8 g, 98%) was obtained following crystallization from ethanol, mp 139-
ꢀ
1
1
1
1
41 C, with 99.42% purity by HPLC. H NMR (600 MHz, CDCl ) d: 7.65 (dd, J ¼ 7.8,
3
.2 Hz 1H), 7.51 (td, J ¼ 7.8, 1.2 Hz, 1H), 7.45 (td, J ¼ 7.8, 1.2 Hz, 1H), 7.33 (dd, J ¼ 7.8,
13
.2 Hz, 1H), 7.07 (m, 2H), 5.74 (s, 1H), 5.63 (s, 1H); C NMR (150 MHz, CDCl ) d:
3
1
70.92, 152.28, 149.78, 140.82, 138.31, 137.06, 136.18, 134.89, 130.70, 130.20, 128.41,
þ
112.95. MS (ESI): 250 [M - H] . HRMS (ESI): Calcd for C H F NO: 252.0630,
13
8 3
Found: 252.0631.
Anal. Calcd for C H F NO: C, 62.16; H, 3.21. Found: C, 62.12; H, 3.29.
1
3
8 3
HPLC Conditions— Column: Welch Ultimate XB-Phenyl (250 mm ꢂ 4.6 mm, 5 mm);
Detection: 210 nm; Flow rate: 1.0 mL/min; Temperature: rt; Run time: 15 min; Mobile
phase: acetonitrile/water ¼ 40/60, t : 4.510 min, purity: 99.42%.
R
3’,4’,5’-Trifluoro-[1,1’-biphenyl]-2-amine (1)
Into a 10 L three-necked round-bottomed flask were introduced ethanol (2.5 L), sodium
hydroxide grains (160.2 g, 4 mol) and 3’,4’,5’-trifluoro-[1,1’-biphenyl]-2-carboxamide 5
(
251.3 g, 1 mol). After stirring for 5 min, NaClO (7.5%) (1.5 L, 1.5 mol) was added, and
ꢀ
the mixture was stirred for a futher 2 h at 0-5 C. The reaction was then warmed to
5
ꢀ
0 C for 2 h after which time it was allowed to cool, and extractions with dichlorome-
thane (3 ꢂ 500 mL) were carried out. The organic fraction was dried over anhydrous
magnesium sulfate, filtered and the solvent was recovered by distillation to give the

6
Z. LI ET AL.
ꢀ
14
desired 3’,4’,5’-trifluoro-[1,1’-biphenyl]-2-amine 1 (216.3 g, 97%), mp 56-57 C, lit mp
ꢀ
1
5
7-58 C, 99.79% purity by HPLC. H NMR (600 MHz, CDCl ) d: 7.19 (m, 1H),
3
7
.15–7.08 (m, 2H), 7.07 (dd, J ¼ 7.6, 1.5 Hz, 1H), 6.83 (td, J ¼ 7.5, 1.1 Hz, 1H), 6.77 (dd,
1
3
J ¼ 8.0, 0.9 Hz, 1H), 3.76 (s, 2H); C NMR (150 MHz, CDCl ) d: 152.28, 150.62, 143.35,
3
1
2
39.87, 138.20, 135.75, 130.28, 129.59, 124.53, 119.03, 116.12, 113.35. MS-ESI:
24 [M þ H] .
þ
HPLC Conditions— Column: Welch Welchrom-C18 (250 mm ꢂ 4.6 mm, 5 mm);
Detection: 226 nm; Flow rate: 1.0 mL/min; Temperature: rt; Run time: 15 min; Mobile
phase: acetonitrile/water ¼ 80/20, t : 5.382 min, purity: 99.79%.
R
Copies of the complete NMR, MS, HRMS, EA and HPLC data were submitted for
review and are available from the corresponding author upon request.
Acknowledgment
This work was supported by the National Natural Science Foundation of China (21376221).
ORCID
Zhenhua Li
http://orcid.org/0000-0002-8092-3571
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