Development of a Scalable Process for the Insecticidal Candidate Tyclopyrazoflor. Part 3. A Scalable Synthesis of Methyl 3-((3,3,3-Trifluoropropyl)thio)propanoate via Thiol-Ene Chemistry

Article abstract of DOI:10.1021/acs.oprd.9b00129

Optimization of the thiol-ene reaction for the preparation of methyl 3-((3,3,3-trifluoropropyl)thio)propanoate (4), a key intermediate in the synthesis of the sap-feeding insecticidal candidate tyclopyrazoflor (1), is described. The major challenge with the radical thiol-ene chemistry was control of the regioselectivity between the linear and branched products. Reducing the radical initiation temperature was found to be the key variable in controlling the selectivity. Because of the high cost and storage challenges associated with the use of the room-temperature diazo initiator 2,2′-azobis(4-methoxy-2,4-dimethylvaleronitrile) (V-70), a two-component initiator system consisting of benzoyl peroxide and N,N-dimethylaniline was developed, allowing for radical initiation at temperatures as low as -15 °C. Application of semibatch operation gave 90:1 selectivity favoring the linear product. The overall yield and selectivity of the radical thiol-ene reaction were improved from 78% yield and 11:1 selectivity with azobis(isobutyronitrile) in batch mode to 91% yield and 90:1 selectivity with the two-component system in semibatch mode, further eliminating the need for a fractional distillation purification step.

Full text of DOI:10.1021/acs.oprd.9b00129

Article
pubs.acs.org/OPRD
Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Development of a Scalable Process for the Insecticidal Candidate
Tyclopyrazoflor. Part 3. A Scalable Synthesis of Methyl 3‑((3,3,3-
Trifluoropropyl)thio)propanoate via Thiol−Ene Chemistry
Kaitlyn C. Gray,*,† Patrick Heider,‡ Patrick McGough,† Mark Ondari,§ Jayachandran Devaraj,†
Qiang Yang,† George Frycek,‡ Brian Graham,‡ Joseph Neuman,‡ Beth A. Lorsbach,∥ and Yu Zhang∥
†Product Design and Process R&D, Corteva Agriscience, 9330 Zionsville Road, Indianapolis, Indiana 46268, United States
‡Engineering and Process Sciences, The Dow Chemical Company, 1710 Building, Midland, Michigan 48674, United States
§Global Ag Production Support, Corteva Agriscience, 1710 Building, Midland, Michigan 48674, United States
∥Discovery Chemistry, Corteva Agriscience, 9330 Zionsville Road, Indianapolis, Indiana 46268, United States
ABSTRACT: Optimization of the thiol−ene reaction for the preparation of methyl 3-((3,3,3-trifluoropropyl)thio)propanoate
(4), a key intermediate in the synthesis of the sap-feeding insecticidal candidate tyclopyrazoflor (1), is described. The major
challenge with the radical thiol−ene chemistry was control of the regioselectivity between the linear and branched products.
Reducing the radical initiation temperature was found to be the key variable in controlling the selectivity. Because of the high
cost and storage challenges associated with the use of the room-temperature diazo initiator 2,2′-azobis(4-methoxy-2,4-
dimethylvaleronitrile) (V-70), a two-component initiator system consisting of benzoyl peroxide and N,N-dimethylaniline was
developed, allowing for radical initiation at temperatures as low as −15 °C. Application of semibatch operation gave 90:1
selectivity favoring the linear product. The overall yield and selectivity of the radical thiol−ene reaction were improved from
78% yield and 11:1 selectivity with azobis(isobutyronitrile) in batch mode to 91% yield and 90:1 selectivity with the two-
component system in semibatch mode, further eliminating the need for a fractional distillation purification step.
KEYWORDS: radical reaction, thiol−ene, selectivity, methyl 3-((3,3,3-trifluoropropyl)thio)propanoate, agrochemicals, insecticide
criteria align closely with the 12 principles of green chemistry
proposed by Anastas and Warner.5 To support field efficacy
studies, the product was initially prepared on 100 gram scales
using a simple nucleophilic substitution reaction with 3-halo-
1,1,1-trifluoropropanes (Scheme 2, Route A); however, these
reagents have properties that we attempt to avoid in
manufacturing processes.6 3-Bromo- and 3-chloro-1,1,1-tri-
fluoropropane are known ozone depletors, while the iodide
waste generated from 3-iodo-1,1,1-trifluoropropane poses
waste stream complications. The Michael addition between
methyl acrylate and 3,3,3-trifluoropropane-1-thiol (Scheme 2,
Route B) could be highly selective and atom-efficient, but the
cost of the 3,3,3-trifluoropropane-1-thiol starting material
made this route impractical.7 Switching the addition partners
to 3,3,3-trifluoropropene and methyl 3-mercaptopropionate for
an anti-Markovnikov hydrothiolation (Scheme 2, Route C)
eliminated expensive starting materials and led to the
development of a radical thiol−ene pathway that eliminated
the use of stoichiometric base (Scheme 2, Route D).8 This
report details the development and optimization of the radical
thiol−ene addition of methyl 3-mercaptopropionate (2) to
3,3,3-trifluoropropene (3) to make 4.
INTRODUCTION
■
Pyrazole derivatives have been actively researched over the
past few decades for the development of agrochemicals such as
fungicides, herbicides, and insecticides1 and are also a common
structural motif in pharmaceutical targets.2 Tyclopyrazoflor (1)
(Figure 1), a pyrazole-containing insecticidal candidate with
Figure 1. Structure of tyclopyrazoflor (1).
excellent activities against sap-feeding pests,3 was made via
amidation of advanced pyridinylpyrazole derivative 74 with
acid chloride 6 (Scheme 1). Acid chloride 6 was prepared in
two steps from the key intermediate methyl 3-((3,3,3-
trifluoropropyl)thio)propanoate (4). This report describes
the development of a scalable synthesis of 4.
Tasked with developing a scalable synthesis of 4, we
identified four possible routes (Scheme 2) and evaluated their
viability on the basis of the availability and cost of starting
materials, the regulation of harmful components, and the
inherent selectivity of the reaction being performed. These
Special Issue: Corteva Agriscience
Received: March 22, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.oprd.9b00129
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Scheme 1. Route to Tyclopyrazoflor (1)
Scheme 2. Synthetic Options for the Preparation of 3-((3,3,3-Trifluoropropyl)thio)propanoate Esters and Acids
Scheme 3. Syntheses of 5 via Base-Promoted Anti-Markovnikov Addition and the Radical Thiol−Ene Reaction of 9 and 3
radical with another equivalent of 3 before the internal radical
is quenched, was significantly reduced by decreasing the
amount of 3,3,3-trifluoropropene from 1.8 to 1.0 equiv (entry
2). Switching to a polar aprotic solvent, ethyl acetate (EtOAc),
afforded a good yield but had very little effect on the product
selectivity (entry 3). Finally, a polar protic solvent, methanol
(MeOH), resulted in enhanced selectivity for the single
addition product 5 but a significantly lower yield due to low
conversion (entry 4).
Attempts to purify 5 from the liquid crude product by
fractional distillation were fruitless because of the similar high
boiling points of 5, 12, and 13. It was envisioned that these
obstacles could be overcome by switching to methyl 3-
RESULTS AND DISCUSSION
■
Initial efforts in this research focused on the direct synthesis of
3-((3,3,3-trifluoropropyl)thio)propionic acid (5) to eliminate
one step from the synthesis of acid chloride 6. Starting from
3,3,3-trifluoropropene (3) and 3-mercaptopropionic acid (9),
the anti-Markovnikov addition route did afford a low yield of
the desired product 5 in addition to sulfide 10 and disulfide 11
(Scheme 3). In contrast, the azobis(isobutyronitrile) (AIBN)-
initiated thiol−ene reaction furnished the desired linear
product 5 in good yield with the branched isomer 12 and
double addition adduct 13 as the major side products. (Table
1, entry 1). The yield of the double addition adduct 13, which
results from the reaction of the incipient thiol−ene addition
B
DOI: 10.1021/acs.oprd.9b00129
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Table 1. Optimization of the Radical-Promoted Thiol−Ene Reaction of 9 and 3
a
a
b
entry
solvent
amount of 3 (equiv)
5:12
5:13
yield (%)
1
2
3
4
toluene
toluene
EtOAc
MeOH
1.8
1.0
1.0
1.0
11:1
12:1
11:1
12:1
14:1
43:1
44:1
85:1
NA
74
74
18
a
b
Determined by GC. In-pot yields by quantitative GC analysis. NA: not available.
Table 2. Optimization of the Radical Promoted Thiol−Ene Reaction of 2 and 3
a
b
entry
initiator
AIBN
initiator loading (mol %)
temp. (°C)
4:14
yield (%)
78
1
2
3
4
5
6
7
8
9
2.5
1
5
5
1.75
80
80
35
RT
RT
RT
8
−6
−15
RT
11:1
11:1
22:1
44:1
38:1
31:1
56:1
76:1
95:1
26:1
d
AIBN
DMPA
V-70
68
c
71
77
86
73
86
87
84
71
V-70
e
BP + DMA
BP + DMA
BP + DMA
BP + DMA
BP + TMA
5
5
5
5
e
e
e
f
10
5
a
b
c
d
e
Determined by GC. In-pot yields by quantitative GC analysis. Initiated with a 366 nm light source. The reaction stalled at 91% conversion. 5
f
mol % BP and 5 mol % DMA were used. 5 mol % BP and 5 mol % TMA were used.
mercaptopropionate (2) to generate the more volatile methyl
ester 4.9 The reaction of 2 and 3 with AIBN as the radical
initiator in toluene at 80 °C resulted in an 11:1 mixture of
linear product 4 and branched product 14 (Table 2, entry 1,
virtually identical to that seen for the acid starting material) in
a good yield of 78%. This reaction was ultimately scaled to 5 kg
of methyl ester 2 with no loss in selectivity (11:1 ratio). A
multistage vacuum distillation provided effective separation
from the impurities, including the branched isomer with a
similar boiling point.10 It should be noted that a fast exotherm
of up to 36 °C was observed on the 5 kg scale when the AIBN-
initiated process was run in batch mode with all reagents
present.11
Reducing the radical initiator loading to 1 mol % had little
effect on the reaction selectivity but resulted in somewhat
sluggish reactivity, lower conversion, and consequently a lower
yield of only 68% (Table 2, entry 2). To test the effect of low
temperature on the efficiency and selectivity of the thiol−ene
reaction, we envisioned that a photoinitiator would allow
access to lower-temperature conditions. With the use of 2,2-
dimethoxy-2-phenylacetophenone (DMPA)12 as the initiator
and a reaction temperature of only 35 °C, the reaction
proceeded in good yield (71%) with an improved linear/
branched selectivity of 22:1 (entry 3). Because of the
challenges associated with the scale-up of photochemistry in
the available equipment, alternate low-temperature thermal
initiators were investigated. Reducing the reaction temperature
further to room temperature and using 2,2′-azobis(4-methoxy-
2,4-dimethylvaleronitrile) (V-70)13 as the initiator further
improved the linear/branched product selectivity to 44:1
(entries 4 and 5). While V-70 provided the desired selectivity
and yield, it was less than favorable from a manufacturing
perspective because of its high cost and need for special storage
conditions (it has a short shelf life at 0 °C and must be stored
below −15 °C to extend its lifetime).
The literature suggested that the use of a two-component
initiator system, such as benzoyl peroxide (BP) and N,N-
dimethylaniline (DMA),14 could provide access to radicals at
low temperature while maintaining the stability of the initiators
during storage. Under normal conditions BP has a half-life of
C
DOI: 10.1021/acs.oprd.9b00129
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10 h at 73 °C, but in the presence of DMA, BP can rapidly
decompose at temperatures as low as −15 °C to produce
radicals (Table 2, entries 6−9). Systematic lowering of the
reaction temperature from ambient to −15 °C resulted in a
significant improvement in the linear/branched selectivity
(from 31:1 to 95:1) while affording an excellent yield of 84%
(entry 9).
While the conditions shown in Table 2 achieved high
selectivity, a significant exotherm (estimated at −22 kcal/mol)
was observed during the investigations. Although the heat was
efficiently removed on a small scale (25 g in a 100 mL Parr
reactor), we calculated that >100 min would be required to
remove all of the heat of reaction for a 300 gal glass-lined
vessel, and larger production-scale reactors would require
multiple hours. Switching from a batch process to a semibatch
process would allow for efficient control of heat generation. In
order to enable a semibatch process, a constant supply of
radicals would need to be generated in the reactor. This was
achieved by continuously adding BP to a reactor containing the
aniline activator (Figure 2). Ultimately N,N,4-trimethylaniline
with 50:1 selectivity favoring the desired linear adduct 4. The
purity of the product was acceptable, which obviated the need
for further purification by fractional distillation.
CONCLUSIONS
■
The thiol−ene reaction proved to be an efficient and low-cost
method for the synthesis of methyl 3-((3,3,3-trifluoropropyl)-
thio)propanoate (4). The main side product of this chemistry,
the branched isomer 14, was controlled by reducing the radical
initiation temperature. The two-component initiator system
consisting of BP and DMA or TMA proved to be an efficient
means of accessing radicals at low temperatures and improved
linear/branched selectivity of this reaction while also providing
a low-cost and scalable route. A semibatch process was
successfully developed to afford excellent yield, selectivity, and
effective control of the exotherm, enabling the development of
a scalable process that eliminated the need for a challenging
fractional distillation separation.
EXPERIMENTAL SECTION
■
General. All of the reagents were commercially available
and used as purchased without further purification. H, 13C,
1
and 19F NMR spectra were recorded on a Bruker Ultrashield
400 NMR spectrometer. GC analysis was performed on an
Agilent 7890A GC system with an Agilent DB-5MS column
(30 m × 0.25 mm × 0.25 μm, P/N 122-5532) using the
following conditions: heater, 250 °C; flow rate, 2 mL/min;
injection volume, 1 μL; oven program: 50 °C for 2 min, ramp
to 280 °C at 20 °C/min, hold at 280 °C for 8 min; internal
standard, octanophenone.
Representative Procedure for the Preparation of 4
Using AIBN (Batch Mode). A 10 gal 316 stainless steel (SS)
reactor was charged with methyl 3-mercaptopropionate (5007
g, 41.67 mol), AIBN (170 g, 1.04 mol), and toluene (8410 g)
and cooled to 5 °C. 3,3,3-Trifluoropropene (3843 g, 40.01
mol) was added as a liquefied gas, and the reactor was heated
to 80 °C over 1 h. After 20 h at 80 °C, the pressure was slowly
ramped down to 50 mmHg to remove toluene, giving crude 4
(8200 g, 11:1 linear/branched, 82.2 wt % purity, 78% yield).
Four batches of crude product 4 (31 200 g, 85.6 wt %
purity) were combined and charged to a 10 gal 316 SS reactor
equipped with a 60″ tall, 4″ diameter column packed with
GOODLOE high-efficiency structured packing. The material
was distilled under vacuum (∼5 mmHg at the top of the
column) with a 10:1 reflux ratio. Fractions of desired purity
were combined to give 4 (26 530 g, 95 wt %, 94% recovery).
1H NMR (400 MHz, CDCl3) δ 3.71 (s, 3H), 2.82, (td, J = 7.3,
0.7 Hz, 2H), 2.75−2.68 (m, 2H), 2.63 (td, J = 7.2, 0.6 Hz,
2H), 2.47−2.31 (m, 2H). 13C NMR (101 MHz, CDCl3) δ
Figure 2. Diagram of the semibatch process for the preparation of 4
via radical-initiated thiol−ene reaction.
(TMA) was selected for further optimization as the aniline
activator because it increased the reaction rate by 10-fold,
allowing for shorter semibatch reactions.
A semibatch process was investigated in which TMA (5 mol
%) and 2 were preloaded into a 300 mL autoclave reactor that
was cooled to 0 °C. Two Isco syringe pumps were used to
deliver 315 and a solution of BP in toluene into the reactor over
2 h (Table 3). It was found that increasing the reactant
concentration gave higher conversion, improved the selectivity,
and allowed for reduced BP loadings, with 80 wt % 2 and 3
(1:1.05) being the optimal conditions (entry 3). These
conditions were successfully demonstrated on a 1.5 kg scale
using a 1 gal reactor at −5 °C, affording an in-pot yield of 91%
Table 3. Optimization of the Semibatch Process for the Preparation of 4 via Radical-Initiated Thiol−Ene Reaction
a
b
c
d
entry
reactant concentration (wt %)
BP addition rate (mol %/h)
4:14
conv. (%)
yield (%)
1
2
3
50
60
80
2.5
1
0.5
75:1
87:1
90:1
74
75
99
48
57
91
a
b
c
Combined concentration of 2 and 3 relative to the mass at the end of the additions. Determined by GC. Refers to loss of the starting material 2.
In-pot yields by quantitative GC analysis.
d
D
DOI: 10.1021/acs.oprd.9b00129
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Author Contributions
172.04, 125.93 (q, J = 277.2 Hz), 51.86, 34.68 (q, J = 28.6 Hz),
34.39, 27.06, 24.11 (q, J = 3.3 Hz). 19F NMR (376 MHz,
CDCl3) δ −66.53.
The manuscript was written through contributions of all
authors. All of the authors approved the final version of the
manuscript.
Representative Procedure for the Preparation of 4
Using BP/DMA (Batch Mode). A 2 L autoclave reactor was
charged with methyl 3-mercaptopropionate (376.4 g, 3132.2
mmol), toluene (635.1 g), and benzoyl peroxide (Luperox
A75, 75 wt % BP wet with water, 50.1 g, 155.12 mmol active).
The reactor was sealed and purged with nitrogen, and the
cooling coil was set at −20 °C. 3,3,3-Trifluoropropene (303.0
g, 3154.6 mmol) was added by transfer cylinder, and the
resulting mixture was stirred overnight for effective cooling
prior to reaction initiation. The in-pot temperature reached 1
°C after cooling overnight. Dimethylaniline (19 g) was added
by transfer cylinder. After 1.5 h, more dimethylaniline (18.3 g)
was added, and an exotherm was observed (18 °C temperature
rise). After 19 h, the reactor was emptied, and its contents were
quantified (1353 g, 38.5 wt % active, 520 g active, 77%, 55:1
linear/branched by GC).
The organic layer was divided evenly between two 1 L
reactors, and 10 wt % NaOH was added (170 g each). The
mixtures were stirred at 350 rpm for 2 h and then allowed to
settle. The aqueous layers were removed, and to each reactor
was added 130 g of 2 N HCl, after which the mixtures were
stirred for 20 min. The organic layers were combined and
quantified (1226 g, 42.5 wt %, 521 g active, 77%). The toluene
was distilled off at atmospheric pressure, and the product was
distilled overhead under vacuum (83−88 °C, 6 mmHg), giving
4 as a colorless oil (493 g, 94.4 wt % active, 466 g active, 89%
recovery, 69% yield).
Representative Procedure for the Preparation of 4
Using BP/TMA (Semibatch Mode). Methyl 3-mercaptopro-
pionate (900 g, 7.49 mol) and N,N,4-trimethylaniline (50 g,
0.37 mol) were charged into a 1 gal Hastelloy C reactor with a
peristaltic pump through a 1″ headspace addition port. A 10 wt
% solution of benzoyl peroxide (Benox A-75, 75 wt % BP wet
with water, 27.2 g, 0.084 mol active) in toluene (184 g) was
prepared by mixing for 30 min to dissolve the solids. The
entire mixture was charged into the Isco pump (including the
water phase, which settled to the bottom). The reactor was
inerted with nitrogen and cooled to −5 °C. 3,3,3-
Trifluoropropene (755 g, 7.86 mol) was added at 0.5 equiv/
h with concomitant addition of the benzoyl peroxide solution
at 0.5 mol %/h with the reactor closed (no pressure control on
the reactor or venting during operation). After addition of the
reagents was complete (135 min, BP solution only during the
last 15 min), the feed lines were purged with nitrogen. The
reactor was allowed to mix for 1 h following addition, after
which the jacket set point was changed to 20 °C and the
reactor was left overnight. The mixture was discharged from
the reactor and quantified by GC analysis (1952 g, 75.4 wt %,
91% in-pot yield, 50:1 linear/branched).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Corteva Agriscience is acknowledged for support of this work.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: kaitlyn.gray@corteva.com.
ORCID
Kaitlyn C. Gray: 0000-0001-7564-3703
Qiang Yang: 0000-0003-3762-5015
E
DOI: 10.1021/acs.oprd.9b00129
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(>75 psig) in order to pump 3 as a liquid through an Isco pump.
(5) Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and
Practice; Oxford University Press: New York, 1998.
(6) Leng, R. B.; Emonds, M. V. M.; Hamilton, C. T.; Ringer, J. W.
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́
(7) (a) Nair, D. P.; Podgorski, M.; Chatani, S.; Gong, T.; Xi, W.;
Fenoli, C. R.; Bowman, C. N. The Thiol-Michael Addition Click
Reaction: A Powerful and Widely Used Tool in Materials Chemistry.
Chem. Mater. 2014, 26, 724. (b) Hoyle, C. E.; Lowe, A. B.; Bowman,
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(8) Denes, F.; Pichowicz, M.; Povie, G.; Renaud, P. Thiyl Radicals in
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(9) Methyl ester 4 has a vapor pressure of 10 mmHg at 94.8 °C.
(10) The branched isomer 14 has a boiling point of 90 °C at 10
mmHg, and the branched/linear binary system has a measured
relative volatility of 1.5 from 10−25 mmHg across the composition
range, which is indicative of a separation that is expected to be
difficult and require a large number of equilibrium stages to
significantly purify the linear isomer. At a 27 kg linear isomer scale
(combined batches for distillation), this multistage distillation
removed toluene and unreacted methyl ester as lights with relative
ease and also afforded easy separation from the double addition and
other heavier impurities, but it required a significant number of stages
(10−20 theoretical stages from a 60″ vertical packed column) and a
high reflux ratio (10:1) with a top-of-column pressure of 5 mmHg in
order to separate the linear and branched isomers with reasonable
efficiency. With this distillation system and starting with 85.6% pure
linear isomer with toluene prestripped, 94.3% distillation recovery of
95.0% pure linear isomer was achieved, but the recovery drops to only
67% when 98.0% pure linear isomer is needed.
(11) In this batch-mode reaction, all of the reagents, including the
catalyst, were loaded, and then the reaction contents were heated until
the radical reaction initiated, which occurred at around 65 °C. Upon
initiation, the vessel jacket was switched to full cooling, but the
reaction still proceeded quickly, with the exotherm rising within 5 to 7
min to the maximum observed temperature before the system could
be cooled back to the desired aging temperature of 80 °C. These 5 kg-
scale reactions occurred in a well-stirred 10 gal stainless steel reactor
with external jacket services. Upon scale-up of this process to larger
scales with lower heat transfer area-to-volume ratios in stirred tank
reactors, this approach would be expected to produce larger observed
exotherms. Reducing the temperature of initiation and/or determin-
ing a way to run this reaction in semibatch mode to extend the
exotherm were both identified as project goals following these scale-
up batches.
(12) (a) Kottari, N.; Chabre, Y. M.; Shiao, T. C.; Rej, R.; Roy, R.
Efficient and accelerated growth of multifunctional dendrimers using
orthogonal thiol-ene and SN2 reactions. Chem. Commun. 2014, 50,
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dioxynaphthalene[38]crown-10 macrocycles: Synthesis, self-assembly,
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(fluoroalkylthio)acetic acid ester. US20120101294A1, 2012.
(14) Sideridou, I. D.; Achilias, D. S.; Karava, O. Reactivity of
Benzoyl Peroxide/Amine System as an Initiator for the Free Radical
Polymerization of Dental and OrthopaedicDimethacrylate Mono-
F
DOI: 10.1021/acs.oprd.9b00129
Org. Process Res. Dev. XXXX, XXX, XXX−XXX