Two-Step Continuous-Flow Synthesis of Fungicide Metalaxyl through Catalytic C?N Bond-Formation Processes

Article abstract of DOI:10.1002/adsc.202100898

Metalaxyl, an acylalanine fungicide, was synthesized through catalytic continuous sequential-flow reactions. Commonly used syntheses of this compound use batch systems and suffer from problems such as coproduction of halogen-containing by-products derived from acyl and alkyl halides in the substitution reactions of 2,6-dimethylaniline. To minimize waste and enhance efficiency, a halide-free approach including two continuous-flow catalytic processes, heterogeneous Pt-catalyzed reductive alkylation and homogeneous acid-catalyzed amidation with an acid anhydride, was developed. Systematic examination of the two reactions in flow mode enabled a high-yielding, two-step sequential continuous-flow process to be achieved. (Figure presented.).

Full text of DOI:10.1002/adsc.202100898

COMMUNICATIONS
doi.org/10.1002/adsc.202100898
Very Important Publication
Two-Step Continuous-Flow Synthesis of Fungicide Metalaxyl
through Catalytic CÀ N Bond-Formation Processes
Haruro Ishitani,a,* Zhibo Yu,b Tomohiro Ichitsuka,c, d Nagatoshi Koumura,d
Shun-ya Onozawa,d Kazuhiko Sato,d and Shū Kobayashia, b, d,
*
a
Green & Sustainable Chemistry Social Cooperation Laboratory
Graduate School of Science
The University of Tokyo
Hongo, Bunkyo-ku, Tokyo 133-0033 (Japan)
Phone: +81-3-5841-8343
E-mail: hishitani@chem.s.u-tokyo.ac.jp
Department of Chemistry, School of Science
b
The University of Tokyo
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
Phone: +81-3-5841-4790
E-mail: shu_kobayashi@chem.s.u-tokyo.ac.jp
Research Institute of Chemical Process Technology
c
National Institute of Advanced Industrial Science and Technology
Nigatake 4-2-1, Sendai, Miyagi 983-8551 (Japan)
Interdisciplinary Research Center for Catalytic Chemistry
d
National Institute of Advanced Industrial Science and Technology
Central 5, Higashi 1-1-1, Tsukuba, Ibaraki 305-8565 (Japan)
Manuscript received: July 19, 2021; Revised manuscript received: August 13, 2021;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100898
Although a highly controversial issue, the use of
pesticides is still important for securing efficient and
Abstract: Metalaxyl, an acylalanine fungicide, was
synthesized through catalytic continuous sequential-
reliable supplies of crops and foods worldwide. To
flow reactions. Commonly used syntheses of this
reduce the environmental impact associated with
compound use batch systems and suffer from
pesticide use, harmful processes associated with their
problems such as coproduction of halogen-contain-
manufacture must be minimized and efficient technol-
ing by-products derived from acyl and alkyl halides
ogies in this field are in high demand. A series of acyl
in the substitution reactions of 2,6-dimethylaniline.
alanine-type pesticides such as metalaxyl (1), benalax-
To minimize waste and enhance efficiency, a halide-
free approach including two continuous-flow cata-
lytic processes, heterogeneous Pt-catalyzed reduc-
yl (2), furalaxyl (3), and ofurace (4) are common,
commercially available phenylamide fungicides (PAFs;
Scheme 1(a)).[1] PAFs affect mitosis and cell division
tive alkylation and homogeneous acid-catalyzed
in fungi, and are widely used on a preventive basis for
amidation with an acid anhydride, was developed.
plant diseases. An easily visualized and reliable
Systematic examination of the two reactions in flow
method for preparing these PAFs as racemates includes
mode enabled a high-yielding, two-step sequential
alkylation and acylation (amidation) of the nitrogen
continuous-flow process to be achieved.
atom of 2,6-dimethylaniline (5), as shown in
Scheme 1(b).[2] Typical methods that are used for these
two transformations require organic halides with
Keywords: sequential continuous-flow; reductive al-
stoichiometric amounts of base; however, such ap-
kylation; heterogeneous catalyst; amidation; metal-
proaches produce large amounts of waste organic
axyl
halides. The structural features of these PAFs demand
harsh conditions to achieve substitution reactions at the
nitrogen atom of sterically hindered 2,6-dimeth-
ylaniline. Likewise, the conjunction of the two frag-
Adv. Synth. Catal. 2021, 363, 1–7
1
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

COMMUNICATIONS
asc.wiley-vch.de
construct N-(2,6-xylyl)alanine methyl ester (7), the
common intermediate of PAFs. Based on our experi-
ence gained in the previous studies on reductive C–N
bond formation, we first chose a heterogeneous
platinum catalyst (Pt/C) as a candidate for the reaction.
Our basic continuous-flow hydrogenation system is
illustrated in Scheme 2. The system included Reservoir
A, containing a solution of 5 and 6 in toluene, which
was pumped into a 10 mm×100 mm stainless-steel
column reactor equipped with a double-inlet-type
column head. A back-pressure regulator (BPR) was
included in the outlet line to maintain the pressure of
the reactor at 0.1–0.5 MPa. Although consumption of 6
was rapid under the conditions given in Table 1,
Entry 1, conversion of 5 and the yield of the desired
product 7 were poor (Entries 1 and 2). The use of Pt/
Al2O3 as a catalyst gave similar results (Entry 3). The
main product obtained by catalysis with Pt/C under the
conditions given in Entry 2 was found to be methyl
lactate 8 (>95% based on 6), a reduced alcohol
product of pyruvate 6. This indicated that hydro-
genation of the carbonyl group in methyl pyruvate (6)
was faster than the imine or its intermediate formation
by the reaction between 6 and aniline 5 due to the
steric hindrance of 5. To suppress the rapid hydro-
genation of the activated ketone moiety, we inves-
tigated the use of poisoned catalysts and found that a
commercially available Pt on sulfided carbon (Pt/s-C)
Scheme 1. (a) Structures of commercial PAFs. (b) Typical syn-
thetic route to PAFs. (c) This work.
ments requires appropriate separation and purification provided a moderate yield, although lactate 8 was still
steps to remove by-products. Such waste-generating seen in the output (Entry 4). Notably, although high-
processes should be avoided in industry to decrease the pressure conditions such as 5 to 8 MPa were normally
amount of environmental pollutants. To address these required to accomplish the reaction in conventional
issues, the use of catalytic processes with environ- batch systems,[9] lower back pressure of 0.2 MPaG was
mentally benign reagents for the two modifications on sufficient for the present flow system. We further
the nitrogen atom is highly desirable.
investigated flow conditions to attain high yield and to
We previously reported a continuous-flow process gain more information on catalyst performance to
of reductive amination of carbonyl compounds with increase productivity. A high Pt loading slightly
hydrogen as a surrogate for a conventional substitution improved the yield, and the use of 2 equiv. of pyruvate
reaction on the amine.[3,4] In this context, and to 6, to accelerate the reaction between 5 and 6, gave the
demonstrate the efficiency of the flow reductive desired N-(2,6-xylyl)alanine in 93% yield (Entries 5
amination as a waste-free N-alkylation process for the and 6). With the same Pt loading, 0.2 mmol in
synthesis of useful compounds, we designed a novel
two-step sequential-flow synthesis of metalaxyl, in-
cluding catalytic amidation as a second step (Sche-
me 1(c)). Multistep continuous-flow synthesis is now
widely recognized as an enabling technology for the
synthesis of fine chemicals, pharmaceuticals, and
agrochemicals,[5] with many reports and reviews
addressing its applications.[6,7] The true potential of
continuous-flow synthesis as a next-generation tech-
nology for chemical processes can be met when a flow
reaction is performed using fully catalytic processes
with high productivity.[8] In this paper, we describe the
synthesis of metalaxyl in a two-step catalytic sequen-
tial-flow manner.
We first investigated reductive alkylation of 2,6-
dimethylaniline (5) with methyl pyruvate (6) to
Scheme 2. Reaction setup for continuous-flow reductive alkyla-
tion.
Adv. Synth. Catal. 2021, 363, 1–7
2
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

COMMUNICATIONS
asc.wiley-vch.de
Table 1. Continuous-flow reductive alkylation of 5.
Entry
Catalyst[a]
5/6 (M/M)
SVmol (hÀ 1)
Conv. 5 (%)[b]
Yield 7 (%)[b]
1
2
Pt/C
0.1/0.12
0.1/0.2
0.1/0.12
0.1/0.12
0.1/0.12
0.1/0.2
10
6
10
10
10
6
6
17
6
55
74
94
<5
10
<5
51
73
93
Pt/C[c]
Pt/Al2O3
Pt/s-C
Pt/s-C
Pt/s-Cc
3
4[d]
5
6
[a]
0.12 mmol Pt was used.
Determined using GC analysis.
0.2 mmol Pt was used.
[b]
[c]
[d]
Without back pressure.
reactor I, we examined the effect of substrate concen- maintained from SVmol of 3 to 36 hÀ 1; even at
tration to attain high productivity. The mole ratio of SVmol=36 hÀ 1 using a 0.6 M solution of 5, a yield of
the two reactants and the flow rate of the solution were 87% was obtained, indicating 6.5 g of N-(2,6-xylyl)
fixed at 5/6=1:2 and 0.2 mL/min, respectively, and alanine methyl ester 7 was obtained per 1 mmol of Pt
the yields of the desired 7 are plotted in Figure 1 as a within an hour. Higher SVmol conditions using a
function of substance amount (moles)-based space 0.8 M solution at SVmol=48 hÀ 1 strongly affected the
velocity (SVmol), meaning the amount of 5 supplied performance of the catalyst, and the yield of 7
for Pt in a reactor in an hour. Around 90% yields were decreased to 29%. Further investigations to establish
the catalysis turnover were performed in a long-run
experiment. Figure 2 shows the change in yield of 7
over the running time. The SVmol value was set to
10 hÀ 1 for this experiment. Yields of 97–94% were
attained in the initial 18–26 h, and the high yields were
maintained for >74 h. In addition, a lead time until
reaching a steady state was estimated to be ca. 4 h. The
upper scale in Figure 2 indicates the total amount of 5
supplied per Pt atom in reactor I; the turnover number
for Pt with the present catalyst for 0–74 h was
estimated to be 680, based on the average 92% yield.
The productivity in this reductive alkylation step
during the period of 18–74 h was calculated to be ca.
12.8 g.
We then focused on the acylation of N-(2,6-xylyl)
Figure 1. Dependence of the yield on SVmol value; Conditions:
Pt/s-C, 0.2 mmol (Pt); 5, 0.1 M; 6, 0.2 M; vsub =0.2 mL/min,
°
Reactor Temp., 120 C; Back pressure, 0.2 MPaG. The open
circle indicates the result using 5/6=1:1.2 solution (Table 1,
Entry 5).
alanine methyl ester 7. We chose the corresponding
acid anhydride, methoxyacetic acid anhydride (9), as
an acylating agent and surveyed the use of acid
catalysis for this amidation. Table 2 summarizes
selected results of batch experiments for this catalytic
amidation with anhydride 9. Among the variety of
acids studied, solid acids bis(trifluoromethanesulfonyl)
imide (Tf2NH) and Fe(OTf)3 showed promising activ-
ities and gave the corresponding amide in 67 and 80%
yield, respectively (see also Table S5). Moving on to
continuous-flow experiments, we faced an issue of
solvent choice; we initially wanted to use a toluene
solution of 7 in a sequential continuous-flow system.
However, requirements of both higher reaction temper-
ature and solubility for Tf2NH and Fe(OTf)3 prevented
the use of toluene as a sole solvent. Furthermore,
especially for iron-based Lewis acids, the use of polar
solvents proved disappointing and suppressed the
reaction. We then examined a range of solvents
Figure 2. Long-run experiment on reductive alkylation; Con-
ditions: Pt/s-C, 0.12 mmol (Pt); 5, 0.1 M; 6, 0.2 M; vsub
=
°
0.2 mL/min, Reactor temp., 120 C; Back pressure, 0.2 MPaG.
Adv. Synth. Catal. 2021, 363, 1–7
3
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

COMMUNICATIONS
asc.wiley-vch.de
(with a void space for liquid of 7.14 mL) was
estimated to be 42 min based on 0.17 mL/min total
flow rate.
Table 2. Effect of catalyst on amidation.
Finally, we combined the above two flow processes
as shown in Scheme 4 to achieve sequential-flow
synthesis. A 0.1 M and 0.2 M mixed solution of aniline
5 and pyruvate 6 in Reservoir A was flowed into
packed catalyst reactor I of 3% Pt/s-C (Pt: 0.2 mmol)
at a flow rate of 0.1 mL/min with hydrogen gas. The
outlet flow was cooled to prevent evaporation of the
solvent, and passed through a BPR and received in
Reservoir B. The resulting solution of 7 was pumped
into amidation reactor II with the anhydride flow and
the Tf2NH flow. The outlet solution from reactor II
was cooled in an ice bath and collected. The desired
metalaxyl 1 was obtained in 89% yield (1H NMR) after
basic work-up, which corresponds to be 0.14 g/h of
productivity. Further purification by column chroma-
°
Entry Catalyst
Temp./ C Yield/%[a]
1
2
3
4
5
6
β-zeolite 200 mg/mmol7 110
Y-zeolite 200 mg/mmol7 110
Sc(OTf)3 10 mol%
Fe(OTf)3 10 mol%
AcOH
Tf2NH
9
6
110
110
140
140
22
80
30
67
50 mol%
25 mol%
[a]
Determined using 1H NMR analysis.
together with Tf2NH (Table S6) and decided to use o- tography gave pure 1 in 85% isolated yield.
dichlorobenzene (o-DCB) as the solvent for 9, which In conclusion, we have developed a two-step
allowed a stable flow to be maintained in the reaction sequential continuous-flow synthesis of phenylalanine
at the required high temperature, and DMF as the fungicide metalaxyl without using organic halides. It
solvent for Tf2NH, to make the solution homogeneous. was found that Pt on a poisoned carbon support was an
With these solvents, we examined several continuous- efficient catalyst for selective reductive alkylation of
flow conditions as illustrated in Scheme 3. Solutions of sterically hindered 2,6-dimethylaniline with pyruvate
pure intermediate 7 in toluene and anhydride 9 in o- under continuous-flow conditions with hydrogen gas.
DCB were separately supplied at flow rates of 0.1 and
0.05 mL/min, respectively, and a Tf2NH solution in
DMF was assembled before mixing and flow onto a
reactor heating area. We used a 10 mm×200 mm
stainless-steel plug flow reactor filled with Celite,
which provided a higher mixing efficiency than PTEF
or SUS coil reactors.[10] A 97% yield of the desired
1
metalaxyl 1 was determined using H NMR analysis
when 1.5 equiv. of anhydride 9 was employed and the
°
reaction was performed at 140 C. Under these con-
ditions, 25 mol% Tf2NH was employed for the reaction
and the residence time for the Celite-packed reactor
Scheme 3. Continuous-flow catalytic amidation.
Scheme 4. Two-step sequential-flow synthesis of metalaxyl (1).
Adv. Synth. Catal. 2021, 363, 1–7
4
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

COMMUNICATIONS
asc.wiley-vch.de
In the sequential process, we have combined the
reductive alkylation process with the amidation process
by assembling the first stream with the anhydride and
Tf2NH streams, giving the desired fungicide in high
overall yield.
References
[1] K. Scott, M. Eyre, D. McDuffee, A. E. Dorrance, Plant
Dis. 2020, 104, 1421–1432.
[2] a) H. Du, H. Peng, Faming Zhuanli Shenqing CN
111471237, 2020; b) L. Zheng, S. Zhang, Y. Xie, Z.
Ding, X. Zhu, Faming Zhuanli Shenqing Gongkai
Shuomingshu CN 101088986, 2007; c) A. S. Agnihotri,
R. S. Deshpande, B. Shanker, Indian IN 182815, 1999;
d) L. Nagy, J. Pelyva, P. Agocs, C. Soptei, Z. Kolonics,
J. Benczik, S. Balini, D. Sebok, J. Cseke, PCT Int. Appl.
WO 9320041, 1993.
Experimental Section
Continuous-Flow Reductive Alkylation
A 10 mm×100 mm stainless-steel column (Reactor I) was
packed with heterogeneous Pt catalyst, such as Pt/s-C (3% Pt on
sulfided carbon, AC-1304 purchased from N.E. CHEMCAT,
0.12 or 0.2 mmol for Pt) with 2.0–4.1 g of Celite as a diluent.
On the head part of the column, a double-inlet-type column
head was equipped to charge gas and liquid into the catalyst
phase separately. The catalyst reactor was first treated with
toluene, and then a stock solution of aniline 5 and methyl
pyruvate (6) was flowed through. Reactor I was heated to
[3] B. Laroche, H. Ishitani, S. Kobayashi, Adv. Synth. Catal.
2018, 360, 4699–4704.
[4] a) E. A. Artiukha, A. L. Nuzhdin, G. A. Bukhtiyarova,
S. Y. Zaytsev, P. E. Plyusnin, Y. V. Shubin, V. I. Bukh-
tiyarov, Catal. Sci. Technol. 2015, 5, 4741–4745; b) G.
Chieffi, M. Braun, D. Esposito, ChemSusChem 2015, 8,
3590–3594; c) C. Zor, H. A. Reeve, J. Quinson, L. A.
Thompson, T. H. Lonsdale, F. Dillon, N. Grobert, K. A.
Vincent, Chem. Commun. 2017, 53, 9839–9841;
d) H. W. Kim, S. Byun, S. M. Kim, H. J. Kim, C. Lei,
D. Y. Kang, B. M. Kim, J. K. Park, Catal. Sci. Technol.
2020, 10, 944–949.
[5] a) B. Gutmann, D. Cantillo, C. O. Kappe, Angew. Chem.
Int. Ed. 2015, 54, 6688–6728; Angew. Chem. 2015, 127,
6788–6832; b) R. Porta, M. Benaglia, A. Puglisi, Org.
Process Res. Dev. 2016, 20, 2–25; c) M. B. Plutschack,
B. Pieber, K. Gilmore, P. H. Seeberger, Chem. Rev. 2017,
117, 11796–11893; d) F. M. Akwi, P. Watts, Chem.
Commun. 2018, 54, 13894–13928; e) B. R. L. J. Bloe-
mendal, M. A. C. H. Janssen, J. C. M. van Hest, F. P. J. T.
Rutjes, React. Chem. Eng. 2020, 5, 1186–1197; f) F.
Ferlin, D. Lanari, L. Vaccaro, Green Chem. 2020, 22,
5937–5955; g) A. I. Alfano, M. Brindisi, H. Lange,
Green Chem. 2021, 23, 2233–2292; h) J. Jiao, W. Nie, T.
Yu, F. Yang, Q. Zhang, F. Aihemaiti, T. Yang, X. Liu, J.
Wang, P. Li, Chem. Eur. J. 2021, 27, 4817–4838.
°
110 C with a column heater. During these processes, a BPR
was needed to stabilize the pressure at 0.2 MPaG. Hydrogen
gas was introduced, and the system was kept at the same
pressure. The solution was flowed for 2 h to stabilize the flow
system, and then samples were collected at appropriate time
intervals. Except for the long-run experiment, at least eight
samples were collected to reduce the error margin. The yields
and conversions of products and substrates were determined
using 1H NMR spectroscopic (using 1,1,2,2-tetrachloroethane as
internal standard) or GC (using mesitylene as internal standard)
analyses.
Sequential-Flow Synthesis of Metalaxyl
The first step for the flow synthesis of N-(2,6-xylyl)alanine (7)
was conducted as described above, and the resulting solution
was collected in a flask (Reservoir B) to release H2 gas. The
crude solution in Reservoir B was pumped at a flow rate of
0.1 mL/min, and combined with a stream of methoxyacetic
anhydride (0.3 M in o-DCB), provided from another pump at a
flow rate of 0.05 mL/min, using a T-shaped connector. A
solution of Tf2NH (0.125 M in DMF) was pumped at a flow
rate of 0.02 mL/min and the streams were combined and flowed
into a 10 mm×200 mm stainless-steel column packed with
[6] a) N. G. Anderson, Org. Process Res. Dev. 2012, 16,
852–869; b) D. Dallinger, C. O. Kappe, Curr. Opin.
Green Sustain. Chem. 2017, 7, 6–12; c) L. Rogers, K. F.
Jensen, Green Chem. 2019, 21, 3481–3498.
°
8.2 g of Celite (Reactor II) heated at 140 C. The product
[7] Recent achievements in multistep continuous-flow re-
search from other groups: a) S. B. Otvös, M. A. Pericas,
C. O. Kappe, Chem. Sci. 2019, 10, 11141–11146; b) V.-
E. H. Kassin, R. Gérardy, T. Toupy, D. Collin, E.
Salvadeo, F. Toussain, K. Van Hecke, J.-C. M. Monbaliu,
Green Chem. 2019, 21, 2839–3202; c) M. G. Russell,
T. F. Jamison, Angew. Chem. Int. Ed. 2019, 58, 7678–
7681; Angew. Chem. 2019, 131, 7760–7763; d) K.
Hiebler, C. Dertnig, S. Soritz, M. C. Maier, T. R.
Hörmann, B. Grabner, H. Gruber-Woelfler, J. Flow
Chem. 2020, 10, 259–270; e) S. Chatterjee, M. Giudi,
P. H. Seeberger, K. Gilmore, Nature 2020, 579, 379–384;
f) S. B. Otvös, P. Llanes, M. A. Pericas, C. O. Kappe,
Org. Lett. 2020, 22, 8122–8126.
solution was obtained from the outlet of the ice-cooled loop
with a global flow rate of 0.17 mL/min and collected in test
tubes kept at room temperature. To check the yield of the
product, we usually start a sample collection from an outlet
solution after 1 h when the second flow attains a steady state.
The yields were determined using 1H NMR analysis with
1,1,2,2-tetrachloroethane as internal standard after basic work-
up. Further purification with silica gel column chromatography
gave pure metalaxyl.
Acknowledgements
This work was supported in part by a Grant-in-Aid for Scientific
Research from the New Energy and Industrial Technology
Development Organization (NEDO) project, Japan.
[8] a) S. Kobayashi, Chem. Asian J. 2016, 11, 425–436;
b) K. Masuda, T. Ichitsuka, N. Koumura, K. Sato, S.
Adv. Synth. Catal. 2021, 363, 1–7
5
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

COMMUNICATIONS
asc.wiley-vch.de
Kobayashi, Tetrahedron 2018, 74, 1705–1730; c) H.
Ishitani, Y. Saito, B. Laroche, X. Rao, S. Kobayashi, In
Milenkovic, M. Lemaire, Tetrahedron 1996, 52, 9777–
9784.
Flow Chemistry: Integrated Approaches for Practical [10] For example, when a 0.1 M toluene solution of 7
Applications Luis, S. V., Garcia-Verdugo, E. Eds., RSC
Publishing, Cambridge, 2020, pp 1–49; d) W.-J. Yoo, H.
Ishitani, Y. Saito, B. Laroche, S. Kobayashi, J. Org.
Chem. 2020, 85, 5132–5145.
(0.1 mL/min), a 1.2 M DMF solution of 9 (0.01 mL/
min), and a 0.25 MDMF solution of Tf2NH (0.01 mL/
min) were flowed into a 1/16 inch×4 m SUS coil reactor
°
at 140 C, the yield of 1 in the resulting solution was
[9] a) X. Hu, X. Hu, Faming Zhuanli Shenqing CN
111285770, 2020; b) X. Hu, X. Hu, Faming Zhuanli
Shenqing CN 110551035, 2019; c) F. Fache, F. Valot, A.
44%. The residence time for this SUS coil reactor was
estimated to be 16 min, however, the flow was relatively
unstable and a long lead time was sometimes required.
Adv. Synth. Catal. 2021, 363, 1–7
6
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

COMMUNICATIONS
Two-Step Continuous-Flow Synthesis of Fungicide Metalaxyl
through Catalytic CÀ N Bond-Formation Processes
Adv. Synth. Catal. 2021, 363, 1–7
H. Ishitani*, Z. Yu, T. Ichitsuka, N. Koumura, S.-y. Onozawa,
K. Sato, S. Kobayashi*