Development of a Scalable Process for the Insecticidal Candidate Tyclopyrazoflor. Part 1. Evaluation of [3 + 2] Cyclization Strategies to 3-(3-Chloro-1 H-pyrazol-1-yl)pyridine

Article abstract of DOI:10.1021/acs.oprd.9b00127

The evaluation of [3 + 2] cyclization strategies to prepare a key intermediate, 3-(3-chloro-1H-pyrazol-1-yl)pyridine, for the insecticidal candidate tyclopyrazoflor (1) is described. Among the validated strategies, the route involving [3 + 2] cyclization of 3-hydrazinopyridine·2HCl with methyl acrylate was selected for further optimization. This route provided ready access to 3-(3-chloro-1H-pyrazol-1-yl)pyridine in three steps via cyclization, chlorination, and oxidation. Further functionalization of 3-(3-chloro-1H-pyrazol-1-yl)pyridine via nitration, reduction, and amide formation with 3-((3,3,3-trifluoropropyl)thio)propanoic acid followed by ethylation rendered 1 in a total of seven steps.

Full text of DOI:10.1021/acs.oprd.9b00127

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 1. Evaluation of [3 + 2] Cyclization Strategies to
3‑(3-Chloro‑1H‑pyrazol-1-yl)pyridine
Qiang Yang,*,† Xiaoyong Li,† Beth A. Lorsbach,‡ Gary Roth,† David E. Podhorez,† Ronald Ross, Jr.,‡
Noormohamed Niyaz,‡ Ann Buysse,‡ Daniel Knueppel,† and Jeffrey Nissen†
†Product Design & Process R&D, Corteva Agriscience, 9330 Zionsville Road, Indianapolis, Indiana 46268, United States
‡Discovery Chemistry, Corteva Agriscience, 9330 Zionsville Road, Indianapolis, Indiana 46268, United States
ABSTRACT: The evaluation of [3 + 2] cyclization strategies to prepare a key intermediate, 3-(3-chloro-1H-pyrazol-1-
yl)pyridine, for the insecticidal candidate tyclopyrazoflor (1) is described. Among the validated strategies, the route involving [3
+ 2] cyclization of 3-hydrazinopyridine·2HCl with methyl acrylate was selected for further optimization. This route provided
ready access to 3-(3-chloro-1H-pyrazol-1-yl)pyridine in three steps via cyclization, chlorination, and oxidation. Further
functionalization of 3-(3-chloro-1H-pyrazol-1-yl)pyridine via nitration, reduction, and amide formation with 3-((3,3,3-
trifluoropropyl)thio)propanoic acid followed by ethylation rendered 1 in a total of seven steps.
KEYWORDS: pyrazole, 3-(3-chloro-1H-pyrazol-1-yl)pyridine, [3 + 2] cyclization, 3-hydrazinopyridine·2HCl, methyl acrylate,
agrochemicals
indicated that 3-(3-chloro-1H-pyrazol-1-yl)pyridine (2) could
serve as a key intermediate for the synthesis of tyclopyrazoflor
(1). This intermediate could potentially be obtained via the [3
+ 2] cyclization of 3-hydrazinopyridine·2HCl (3) or its
derivatives with a variety of commercially available α,β-
unsaturated electrophiles such as acrylates, acrylonitriles, and
maleates (Scheme 1). It was envisioned that this intermediate
could be readily converted to 1 via selective nitration,
reduction, and amide formation with 3-((3,3,3-
trifluoropropyl)thio)propanoic acid followed by ethylation.
Routes 1 and 2: [3 + 2] Cyclization of 3-
Hydrazinopyridine·2HCl with Acrylonitriles. Acryloni-
triles have been frequently used for the synthesis of pyrazoles
via [3 + 2] cyclization with hydrazines.6 In our preliminary
investigations, 3-amino-4,5-dihydropyrazole 5 was obtained in
74% yield when 3 was treated with acrylonitrile (4) in the
presence of 3.0 equiv of sodium ethoxide (NaOEt) in ethanol
(EtOH). Compound 5 was then oxidized with manganese
dioxide (MnO2) in acetonitrile (MeCN) at 60 °C for 18 h to
give 7 in 69% yield after column chromatographic purification
(Scheme 2).7 Alternatively, compound 7 was obtained in 84%
yield in one step when readily available 3-ethoxyacrylonitrile
(6) was treated with 3 in the presence of 3.0 equiv of NaOEt
in EtOH. The desired product was easily isolated by filtration
INTRODUCTION
■
To address the food security needs of the growing world
population, modern agriculture must continually develop
technologies that increase production.1 Especially with the
continuing decrease of arable land, it is crucial to minimize
crop losses due to damage from pests.2 Over the past decades,
pyrazole derivatives have been actively researched for the
development of agrochemicals such as fungicides, herbicides,
and insecticides.3 Pyrazoles are also a common structural motif
in a variety of pharmaceutical targets.4 Tyclopyrazoflor (1), a
pyridinylpyrazole derivative (Figure 1), was discovered to have
Figure 1. Structure of tyclopyrazoflor (1)
excellent activities against sap-feeding pests.5 To support
further evaluation of this compound, the identification and
optimization of scalable and cost-effective routes were keys to
success of this exciting new opportunity. This report details the
evaluation of several [3 + 2] cyclization strategies to prepare
the key intermediate, 3-(3-chloro-1H-pyrazol-1-yl)pyridine
(2).
1
as a white solid with high purity (>95 wt % by H NMR
analysis) because of its low solubility in ethyl acetate
(EtOAc).8
Compound 7 was subsequently converted to diazonium salt
8 by treatment with sodium nitrite (NaNO2) in hydrochloric
RESULTS AND DISCUSSION
■
Special Issue: Corteva Agriscience
Received: March 22, 2019
The [3 + 2] cyclization of hydrazines with α,β-unsaturated
electrophiles is undeniably one of the most powerful strategies
for the construction of pyrazole rings.6 Retrosynthetic analysis
© XXXX American Chemical Society
A
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Scheme 1. Retrosynthetic Analysis
Scheme 2. Synthesis of 2 via [3 + 2] Cyclization of Hydrazinopyridine with Acrylonitriles
acid (HCl) between −5 and 0 °C. Diazonium salt 8 was
directly added into a suspension of 1.2 equiv of copper(I)
chloride (CuCl) in toluene at room temperature, which after
standard aqueous workup and purification by column
chromatography afforded 2 as a yellow solid in 68% yield
(Scheme 2).7,8 It is worthwhile to note that no significant
foaming or exotherm was observed. The major impurity was
determined to be 3-(1H-pyrazol-1-yl)pyridine at 10.8% (area
under the curve, AUC) by HPLC analysis. Although these
strategies afforded the desired product 2 in two or three steps
in good overall yields, they were less appealing for large-scale
practice because of the involvement of hazardous diazonium
chemistry.
Route 3: [3 + 2] Cyclization of (E)-2-(2-(Pyridin-3-
yl)hydrazono)acetic Acid·HCl (10) with Acrylonitrile and
Methyl Acrylate. (E)-2-(2-Phenylhydrazono)acetic acid,
B
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Scheme 3. Synthesis of 2 via [3 + 2] Cyclization of 10 with Acrylonitrile or Methyl Acrylate
Scheme 4. Synthesis of 2 from Diethyl Maleate
prepared from the reaction of phenylhydrazine with glyoxylic
acid (9) in 20 wt % HCl, has been reported for the preparation
of 2-bromopyrazole derivatives via [3 + 2] cyclization with α,β-
unsaturated electrophiles such as acrylonitrile and acrylates.9 It
was envisioned that the corresponding 3-chloropyrazole
derivatives could also be obtained following this methodology
and then converted to the desired product 2 after additional
modification. To this end, 3-chloro-1-(pyridin-3-yl)-4,5-dihy-
dro-1H-pyrazole-5-carbonitrile (11) was obtained in 58% yield
after column chromatographic purification when 10 was
treated with 3.0 equiv of 4 in the presence of 2.0 equiv of
N-chlorosuccinimide (NCS), 3.0 equiv of potassium bicar-
bonate (KHCO3), and a catalytic amount of water in EtOAc.
Treatment of 11 with 1.5 equiv of 1,5-diazabicyclo[5.4.0]-
undec-5-ene (DBU) in N,N-dimethylformamide (DMF)
successfully afforded compound 2 in 93% yield (Scheme
3).10 It is worth noting that an uncontrollable exotherm was
observed upon the addition of NCS to the mixture of
compound 10, acrylonitrile, KHCO3, and a catalytic amount of
water in EtOAc, probably caused by the polymerization of
acrylonitrile.
aqueous lithium hydroxide (LiOH) to give acid 15, followed
by decarboxylation with 0.2 equiv of copper(II) oxide (CuO)
in DMF, afforded the desired product 2 in 64% yield over two
steps.10 However, these routes were not further pursued
because of the uncontrollable exotherms observed in the
reactions of 10 with acrylonitrile and methyl acrylate in the
presence of NCS.
Route 4: [3 + 2] Cyclization of 3-Hydrazinopyridine·
2HCl with Diethyl Maleate. Because of their low cost and
ready availability, maleates are also very attractive starting
materials for the synthesis of pyrazole analogues via cyclization
with hydrazines.11 Condensation of 3 with diethyl maleate
(16) in the presence of 3.5 equiv of NaOEt afforded
pyrazolidinone 17 in 51% yield; 17 was then treated with
1.2 equiv of phosphoryl chloride (POCl3) in MeCN at 60 °C
to give 18 in 79% yield. Oxidation of 18 using 5.0 equiv of
MnO2 in MeCN at 60 °C afforded 19 in 93% yield. Similar to
the modifications of 14 in Scheme 3, hydrolysis of 19 followed
by decarboxylation of the resulting acid 15 with CuO in DMF
afforded the desired product 2 in 70% yield over two steps
(Scheme 4).12 While this route successfully delivered the
desired intermediate 2, we continued our investigation to
identify a more concise, economical, and process-friendly
route.
Through a similar mechanism, compound 13 was obtained
in 63% yield by treating 10 with methyl acrylate in the
presence of NCS, KHCO3, and a catalytic amount of water in
EtOAc. Oxidation of 13 with 2.5 equiv of ceric ammonium
nitrate (CAN) in a mixture of tetrahydrofuran (THF) and
water afforded 14 in 52% yield. Saponification of 14 with
Route 5: [3 + 2] Cyclization of 3-Hydrazinopyridine·
2HCl with 2-Methylenemalonate. Initially we planned to
prepare diethyl 2-methylenemalonate (21) from diethyl
C
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Scheme 5. Attempted Synthesis of 2 via [3 + 2] Cyclization with 2-Methylenemalonate 21
Scheme 6. Synthesis of 2 via [3 + 2] Cyclization with Methyl Methacrylate (26)
malonate (20)13 and then treat it with 3 to construct the
pyrazolidinone moiety 22. Subsequent chlorination, oxidation,
hydrolysis, and decarboxylation would then lead to the key
intermediate 2 (Scheme 5). However, initial attempts to
synthesize compound 21 resulted in low yields and difficult
separation caused by the unstable nature of 21. In addition,
literature precedent indicated that the purification of 21
required a nonscalable fractional distillation of this highly
reactive compound from a mixture of oligomeric side products
under high vacuum (<1 mmHg at 80 °C).13a Therefore, we
decided to turn our attention to a more process-friendly route
using inexpensive methyl methacrylate as the starting material
(Scheme 6).
Route 6: [3 + 2] Cyclization of 3-Hydrazinopyridine·
2HCl with Methyl Methacrylate. Methyl methacrylate (26)
readily cyclized with 3 in the presence of 3.0 equiv of NaOEt in
EtOH to give pyrazolidinone 27 (Scheme 6). The reaction was
fast and achieved full conversion after 4 h at 50 °C as
determined by HPLC analysis. At the end of the reaction, HCl
was added to neutralize the excess base to pH 7−8. The
resultant light-brown suspension was concentrated to afford a
brown solid. The high water solubility of the product
precluded aqueous workup to remove the inorganic salt
(NaCl). The crude product 27 was therefore suspended in
MeCN and treated with 1.5 equiv of POCl3 at 75 °C for 1 h to
give full conversion to the chlorinated product 28. The
reaction mixture was quenched with aqueous sodium
hydroxide (NaOH) and extracted with EtOAc to afford the
crude product after concentration of the organic layer. The
crude product was used directly in the next step without
further purification.14
Conversion of 4,5-dihydropyrazole 28 to pyrazole 29 was
initially performed using 3.0 equiv of MnO2 in MeCN. This
was a slow reaction because of the heterogeneous nature of the
reaction mixture and required an additional 1.0 equiv of MnO2
to achieve >95% conversion after 21 h of stirring at 40 °C.
Typically the desired product 29 was obtained as a light-yellow
solid in >95% yield with ∼98% (AUC) purity after filtration
over a pad of Celite followed by removal of solvents.14
Initial attempts to oxidize the 4-methyl group of 29 to the
corresponding carboxylic acid using 2.5 equiv of sodium
permanganate (NaMnO4) in 20:1 water/tert-butyl alcohol (t-
BuOH) at 70 °C did not afford the desired product after 24 h.
We propose that this was caused by the low solubility of
starting material 29 in the solvent system. When the reaction
was performed using 4.0 equiv of NaMnO4 in 5:1 water/t-
BuOH at 80 °C, the desired product 25 was observed, but the
oxidation stalled at <50% conversion. It is worth noting that
the addition of NaMnO4 was highly exothermic, resulting in a
temperature increase from 20 to ∼80 °C over a 20 min
addition on a 2 g scale. The reaction mixture was extracted
with EtOAc to remove the starting material and acidified with
HCl to pH 5 to afford the desired product 25 in 46% yield
with 97% (AUC) purity. Decarboxylation of 25 was achieved
D
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Scheme 7. Synthesis of 2 via [3 + 2] Cyclization with Methyl Acrylate
Scheme 8. Attempted Synthesis of 2 from 34
in the presence of 10 wt % copper(I) oxide (Cu2O) in N,N-
dimethylacetamide (DMAc) at 125 °C for 6 h to afford the
desired product 2 in 69% solution yield by HPLC analysis
using di-n-propyl phthalate as the internal standard.14,15
Although the desired intermediate 2 was obtained, this five-
step route involved many conditions that would likely generate
large amounts of waste and was thus deprioritized.
Oxidation of 33 was first attempted following a literature
procedure using sodium persulfate (Na2S2O8) in the presence
of sulfuric acid (H2SO4) in MeCN and water.17 Although the
desired product was observed, it was accompanied by many
impurities, and as a result the isolated yield was only <30%.
Preliminary screening of alternative oxidation conditions
indicated that the isolated yield could be improved to 54%
using 1.5 equiv of Na2S2O8 in DMF on a small scale.10
However, this reaction led to an uncontrollable exotherm
caused by the incompatibility of DMF with Na2S2O8. This
served as a proof-of-concept for this route, and further
investigations identified many safer and scalable conditions
for this conversion.18
While oxidation of 32 using MnO2 in MeCN afforded 34,
attempts to convert 34 to 2 with POCl3 failed to afford the
desired product (Scheme 8). The two major products formed
in this reaction after quenching were 35 and 36, caused by
preferential reaction of POCl3 with N2 of 34.19
Route Selection. This report details the evaluation of
several [3 + 2] cyclization strategies to prepare the key
intermediate 3-(3-chloro-1H-pyrazol-1-yl)pyridine (2). Of the
potential routes that were explored, all of the routes except for
Route 5 successfully led to the desired product 2.
Consideration of reactive chemical hazards led to the
elimination of three of these routes. Routes 1 and 2 were
not pursued for further optimization because of potential safety
hazards associated with diazonium salt generation, and Route 3
Route 7: [3 + 2] Cyclization of 3-Hydrazinopyridine·
2HCl with Methyl Acrylate. Condensation of a hydrazine
with an acrylate to give a dihydropyrazole is well-documented
in the literature.11,16 Compound 2 was obtained in 49% yield
over two steps by treatment of 3 with methyl 2-
acetamidoacrylate (30) in the presence of 4.0 equiv of
NaOEt followed by treatment of 31 with 7.0 equiv of POCl3
(Scheme 7). Although oxidation of the dihydropyrazole was
avoided, this route was not pursued further because of the
relatively high cost of 30. Alternatively, 3 was treated with
methyl acrylate (12) in the presence of 4.0 equiv of NaOEt in
EtOH to provide the corresponding pyrazolidinone 32
(Scheme 7). Initial attempts to isolate this compound without
quenching the reaction mixture resulted in decomposition of
the product. It was later found that the product was stable after
the reaction mixture was neutralized with anhydrous HCl in
1,4-dioxane upon reaction completion. Treatment of the
resulting crude 32 with 6.0 equiv of POCl3 afforded 3-
chloro-4,5-dihydropyrazole 33 in 66% yield over two steps.10
E
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Scheme 9. Route to Tyclopyrazoflor (1) Selected for Optimization
was not selected because of the uncontrolled exotherm during
the cyclization of 10. Although Routes 4 and 6 both were
validated to afford the desired product 2, these routes were two
steps longer than Route 7 and would likely have led to a lower
overall yield. Separate studies showed that compound 2 is a
viable intermediate for tyclopyrazoflor. Nitration of compound
2 using nitric acid (HNO3) in the presence of H2SO4 afforded
the desired nitropyrazole derivative 37 in 65% yield; 37 was
converted to 38 in 75% yield via hydrogenation in the presence
of a catalytic amount of Pd/C. Treatment of 38 with 3-((3,3,3-
trifluoropropyl)thio)propanoic acid (39)20 using N-ethyl-N′-
(3-(dimethylamino)propyl)carbodiimide hydrochloride
(EDCI) as the coupling reagent in the presence of 4-
dimethylaminopyridine (DMAP) afforded 40 in 90% yield
after column chromatographic purification. Preliminary inves-
tigations revealed that ethylation of 40 using ethyl bromide
(EtBr) or ethyl iodide (EtI) in the presence of a base such as
potassium carbonate or cesium carbonate (Cs2CO3) in polar
aprotic solvents successfully afforded the final product 1.
However, the desired product was isolated in low yield after
acid followed by ethylation rendered 1 in a total of seven steps.
This route represents a solid foundation for further develop-
ment of a cost-effective process for large-scale production.
EXPERIMENTAL SECTION
■
General. All of the reagents were commercially available
and used as purchased without further purification. Unless
otherwise noted, all of the reactions were performed in round-
1
bottom or jacketed cylindrical flasks under nitrogen. H NMR
spectra were recorded on a Bruker Ultrashield 400 NMR
spectrometer. Mass spectra were obtained using a Waters
Micromass ZQ mass spectrometer. HPLC analysis was
performed on an Agilent 1260 chromatograph with a
ZORBAX SB-C8 column (3 mm × 150 mm, 3.5 μm, P/N
863954-306) using the following conditions: mobile phase A,
water (0.1% formic acid); mobile phase B, MeCN (0.1%
formic acid); gradient, 5 to 100% MeCN over 15 min; postrun
equilibration for 5 min; flow rate, 1.0 mL/min; column
temperature, 40 °C; injection volume, 3 μL; UV detection, 230
nm.
column chromatographic purification because of the formation
of undesired side products. On the basis of the above
considerations, the seven-step route outlined in Scheme 9
was selected for further optimization. Special consideration was
given to the safety concerns associated with the oxidation of
33. Details of the optimization work are reported in the
accompanying paper.18
Preparation of 5. To a 250 mL four-neck round-bottom
flask was charged NaOEt (21 wt % in EtOH, 32.0 mL, 85.4
mmol). 3-Hydrazinopyridine·2HCl (3) (5.0 g, 27.5 mmol) was
added, causing an exotherm from 20 to 58 °C. The mixture
was allowed to cool to 20 °C, and acrylonitrile (2.9 g, 54.9
mmol) was added. The reaction mixture was heated at 60 °C
for 5 h, allowed to cool to 20 °C, and quenched with 4 N HCl
in dioxane (6.90 mL, 27.5 mmol) at <20 °C. The mixture was
adsorbed on silica gel (10.0 g) and purified by column
chromatography (silica, 120 g) using 0−10% MeOH/DCM as
the eluent. The fractions containing pure product were
concentrated to dryness to afford a yellow solid (3.3 g, 74%
CONCLUSIONS
■
A variety of [3 + 2] cyclization strategies to prepare 3-(3-
chloro-1H-pyrazol-1-yl)pyridine (2), a key intermediate for the
insecticidal candidate tyclopyrazoflor (1), were evaluated.
Selection of the cyclization route to 2 using methyl acrylate
followed by chlorination and oxidation was based largely on
reactive chemical concerns of the other demonstrated routes.
Further functionalization of 2 via nitration, reduction, and
amide formation with 3-((3,3,3-trifluoropropyl)thio)propanoic
1
yield). Mp 156−160 °C. H NMR (400 MHz, CDCl3) δ 8.24
(dd, J = 2.8, 0.8 Hz, 1H), 8.01 (dd, J = 4.6, 1.4 Hz, 1H), 7.22
(ddd, J = 8.4, 2.8, 1.5 Hz, 1H), 7.12 (ddd, J = 8.4, 4.6, 0.8 Hz,
1H), 4.20 (s, 2H), 3.70 (t, J = 9.3 Hz, 2H), 2.92 (t, J = 9.3 Hz,
F
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2H). 13C NMR (101 MHz, CDCl3) δ 154.23, 144.78, 139.22,
135.08, 123.44, 119.44, 49.23, 32.74. MS m/z 163.2 [M + H]+.
Preparation of 7 from 5. To a 100 mL three-neck round-
bottom flask were charged compound 5 (1.00 g, 6.17 mmol)
and MeCN (20 mL). MnO2 (2.70 g, 30.8 mmol) was added,
causing an exotherm from 20 to 25 °C. The reaction mixture
was stirred at 60 °C for 18 h and then filtered through a Celite
pad, and the pad was rinsed with MeCN (20 mL). Water (20
mL) was added to the combined filtrates, and the resulting
mixture was concentrated to ∼10 mL. A second charge of
water (20 mL) was added, and the resulting mixture was again
concentrated to 10 mL. The resulting suspension was stirred at
20 °C for 18 h and filtered. The filter cake was rinsed with
water (2 × 5 mL) and dried under vacuum to afford a brown
as a white solid (3.8 g, 68% yield). Mp 104−106 °C. 1H NMR
(400 MHz, CDCl3) δ 8.93 (d, J = 27 Hz, 1H), 8.57 (dd, J =
4.8, 1.4 Hz, 1H), 8.02 (ddd, J = 8.3, 2.7, 1.5 Hz, 1H), 7.91 (d, J
= 2.6 Hz, 1H), 7.47−7.34 (m, 1H), 6.45 (d, J = 2.6 Hz, 1H).
13C NMR (101 MHz, CDCl3) δ 148.01, 142.72, 140.12,
135.99, 128.64, 126.41, 124.01, 108.08. MS m/z 180 [M +
H]+.
Preparation of 10. Glyoxylic acid (54.5 mL, 494 mmol, 50
wt % in water) and 1 N HCl (100 mL) were added to 3 (60.0
g, 330 mmol). The reaction mixture was stirred at ambient
temperature for 2 h, at which point a solid started to
precipitate. The reaction mixture was stirred for an additional
24 h and then diluted with MeCN (1 L). The mixture was
azotropically distilled under vacuum using MeCN (3 × 1 L).
The resulting suspension in 1 L of MeCN was filtered to afford
a green solid, which was vacuum-dried at 40 °C to afford the
desired product (E)-2-(2-(pyridin-3-yl)hydrazono)acetic acid·
HCl (10) as a green solid (68.3 g, 98% yield). Mp 173−174
1
solid (0.68 g, 69% yield). H NMR (400 MHz, DMSO-d6): δ
8.93 (d, J = 2.4 Hz, 1H), 8.33 (dd, J = 4.8, 1.2 Hz, 1H), 8.23
(d, J = 2.4 Hz, 1H), 8.01 (ddd, J = 8.4, 2.8, 1.2 Hz, 1H), 7.42
(dd, J = 8.4, 4.8 Hz, 1H), 5.80 (d, J = 2.4 Hz, 1H), 5.19 (br s,
2H). 13C NMR (101 MHz, DMSO-d6) δ 157.66, 144.68,
138.00, 136.19, 128.30, 123.92, 123.19, 97.09. MS m/z 160.
Preparation of 7 from 3. To a 50 mL three-neck round-
bottom flask equipped with a reflux condenser and a N2 inlet
were introduced 3 (1.80 g, 10.0 mmol) and anhydrous EtOH
(10 mL). NaOEt (21 wt % in EtOH, 11.8 mL, 31.5 mmol) was
added over 5 min, causing the internal temperature to increase
from 23 to 30 °C. The resulting light-brown slurry was stirred
for 10 min, resulting in a light-pink color. 3-Ethoxyacrylonitrile
6 (2.10 mL, 20.0 mmol) was added over 5 min at 30 °C. The
yellow mixture was stirred at 78 °C for 5 h and then cooled to
15 °C. HCl solution in dixoane (4 N, 2.9 mL) was added
slowly to quench excess base, giving a light-brown suspension.
The mixture was concentrated under reduced pressure to
afford a brown solid. The solid was partitioned between water
(30 mL) and EtOAc (50 mL). The insoluble light-brown solid
was collected by filtration to afford the first portion of the
desired product (340 mg, >95 wt % by 1H NMR analysis). The
aqueous layer was extracted with EtOAc (3 × 50 mL), and the
combined organic extracts were concentrated to afford a dark-
brown solid. The solid was suspended in EtOAc (10 mL),
filtered, and washed with heptane (20 mL) to afford a second
portion of the desired product as a brown solid (1.00 g, >95 wt
% by 1H NMR analysis). The combined yield was 83.8%. The
analytical data were consistent with the previously reported
data.
Preparation of 2 from 7. To a 250 mL three-neck round-
bottom flask were charged 7 (5.00 g, 31.2 mmol) and HCl (37
wt %, 15 mL). The mixture was cooled to 0 °C, and a solution
of NaNO2 (4.31 g, 62.4 mmol) in water (15 mL) was added in
portions at <1 °C. The resulting yellow suspension was stirred
at <0 °C for 2 h. To a separate 250 mL three-neck round-
bottom flask were charged CuCl (5.04 g, 37.5 mmol) and
toluene (30 mL). It was cooled to 0 °C, and the resulting
yellow diazomium suspension was added to the CuCl
suspension in portions over 15 min at <1 °C. The reaction
mixture was allowed to warm to 20 °C, stirred for 18 h, and
basified with 50 wt % NaOH to pH ∼10, and Celite (10 g) was
charged. The suspension was filtered, and the filter cake was
rinsed with EtOAc (2 × 50 mL). The layers were separated,
and the aqueous layer was extracted with EtOAc (100 mL).
The organic layers were concentrated to dryness, and the
residue was purified by column chromatography using 0−60%
EtOAc/hexanes as the eluent. The fractions containing the
desired product were concentrated to give the desired product
1
°C. H NMR (400 MHz, DMSO-d6) δ 12.55 (d, J = 1.2 Hz,
1H), 8.61 (d, J = 2.5 Hz, 1H), 8.40 (dt, J = 5.4, 0.9 Hz, 1H),
8.14 (ddd, J = 8.7, 2.6, 1.2 Hz, 1H), 7.91 (dd, J = 8.7, 5.4 Hz,
1H), 7.43 (d, J = 1.0 Hz, 1H). 13C NMR (101 MHz, DMSO-
d6) δ 164.30, 143.17, 133.16, 131.86, 127.99, 127.63, 126.31.
MS m/z 165 [M − H]−.
Preparation of 11. Compound 10 (2.00 g, 9.42 mmol)
was stirred in EtOAc (47 mL). NCS (2.63 g, 19.32 mmol),
acrylonitrile (1.85 mL, 28.3 mmol), and KHCO3 (2.86 g, 28.3
mmol) were added (Exothermic!). One drop of water was
added, and the mixture was stirred at ambient temperature for
18 h. Brine (50 mL) was added, and the mixture was filtered
through a Celite pad. The filter cake was washed with EtOAc,
and the layers were separated. The organic layer was dried over
anhydrous Na2SO4 and concentrated to afford a residue, which
was purified by column chromatography (silica, 80 g) using
80−100% EtOAc/hexanes as the eluent to afford the desired
1
product 11 as an orange solid (1.40 g, 58% yield). H NMR
(400 MHz, CDCl3) δ 8.51 (dd, J = 2.9, 0.7 Hz, 1H), 8.33 (dd,
J = 4.7, 1.4 Hz, 1H), 7.51 (ddd, J = 8.4, 2.9, 1.4 Hz, 1H),
7.39−7.22 (m, 1H), 5.06 (dd, J = 11.3, 5.9 Hz, 1H), 3.64 (dd, J
= 17.4, 11.3 Hz, 1H), 3.51 (dd, J = 17.4, 5.9 Hz, 1H). 13C
NMR (101 MHz, CDCl3) δ 143.35, 142.80, 140.12, 136.17,
123.93, 121.95, 115.81, 51.39, 43.04. MS m/z 207 [M + H]+.
Preparation of 2 from 11. To a solution of compound 11
(0.5 g, 2.42 mmol) in DMF (6.0 mL) was charged DBU (0.54
mL, 3.63 mmol), and the dark mixture was stirred at ambient
temperature overnight. The mixture was concentrated, and the
resulting dark oil was dissolved in EtOAc and washed with 15
wt % aqueous LiCl and brine. The organic layer was dried over
anhydrous Na2SO4 and concentrated. The residue was purified
by column chromatography (silica, 80 g) using EtOAc as the
eluent. The fractions containing the pure product were
concentrated, and the residue was vacuum-dried at 45 °C to
provide the desired product 2 as a white solid (0.45 g, 93%
yield). The analytical data of the isolated product were
consistent with those of the previously prepared sample.
Preparation of 13. To a suspension of 10 (13.6 g, 64.1
mmol) in EtOAc (250 mL) was added NCS (17.9 g, 131
mmol), and the mixture stirred for 10 min. Methyl acrylate
(12) (35.2 mL, 385 mmol) was added (Exothermic!),
followed by KHCO3 (19.4 g, 192 mmol). One drop of water
was added, and the mixture was stirred at ambient temperature
for 21 h. Water (300 mL) and saturated aqueous Na2CO3
solution (100 mL) were added. The mixture was filtered
G
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through a Celite pad, and the filtrate was extracted with EtOAc
(2 × 500 mL). The organic layers were dried over anhydrous
Na2SO4 and concentrated under reduced pressure. The residue
was purified by column chromatography (silica, 330 g) using
50−100% EtOAc/hexanes as the eluent to afford the desired
product 13 as an orange oil (10.1 g, 63% yield). 1H NMR (400
MHz, CDCl3) δ 8.30 (dd, J = 2.9, 0.7 Hz, 1H), 8.18 (dd, J =
4.7, 1.4 Hz, 1H), 7.38 (ddd, J = 8.4, 2.9, 1.4 Hz, 1H), 7.19
(ddd, J = 8.5, 4.7, 0.7 Hz, 1H), 4.81 (dd, J = 12.4, 6.9 Hz, 1H),
3.79 (s, 3H), 3.56 (dd, J = 17.8, 12.4 Hz, 1H), 3.34 (dd, J =
17.8, 6.9 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 170.17,
141.71, 141.08, 134.86, 123.67, 120.43, 62.64, 53.17, 42.43,
29.69. MS m/z 240 [M + H]+.
mixture was allowed to cool to 20 °C, and diethyl maleate
(13.4 mL, 82.0 mmol) was added. The reaction mixture was
heated at 60 °C for 3 h, at which point TLC analysis (eluent:
EtOAc) indicated that a major product had formed. The
reaction mixture was cooled to 20 °C and quenched with
AcOH (1.5 equiv). The resulting mixture was diluted with
water (100 mL) and extracted with EtOAc (3 × 100 mL). The
combined organics were concentrated to dryness, and the
residue was purified by column chromatography (silica, 220 g)
using EtOAc as the eluent. The pure fractions were
concentrated to dryness to afford the desired product 17 as
a blue oil (6.6 g, 51% yield). 1H NMR (400 MHz, DMSO-d6)
δ 10.40 (s, 1H), 8.40−8.26 (m, 1H), 8.19 (dd, J = 4.4, 1.6 Hz,
1H), 7.47−7.21 (m, 2H), 4.77 (dd, J = 9.8, 2.1 Hz, 1H), 4.22
(qd, J = 7.1, 1.7 Hz, 2H), 3.05 (dd, J = 17.0, 9.8 Hz, 1H), 1.99
(s, 1H), 1.25 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz,
DMSO) δ 170.37, 146.60, 142.60, 137.28, 123.54, 121.94,
65.49, 61.32, 32.15, 20.72, 13.94. MS m/z 236.2 [M + H]+.
Preparation of 18. To a 100 mL three-neck round-bottom
flask were charged 17 (8.50 g, 36.1 mmol) and MeCN (40.0
mL). POCl3 (4.10 mL, 43.4 mmol) was charged, and the
reaction mixture was heated at 60 °C for 2 h, at which point
HPLC analysis indicated that the starting material had
disappeared and a major product had formed. The reaction
mixture was cooled to 20 °C, and water (100 mL) was added
(Exothermic!). Na2CO3 was added to adjust the pH to ∼8,
and the mixture was extracted with EtOAc (3 × 100 mL). The
organics were concentrated to dryness, and the residue was
purified by column chromatography (silica, 220 g) using 30−
80% EtOAc/hexanes as the eluent. The pure fractions were
concentrated to dryness to afford the desired product 18 as a
Preparation of 14. To a solution of 13 (2.63 g, 11.0
mmol) in 1:1 THF/water (50 mL) was added CAN (15.0 g,
27.4 mmol) in portions at 0 °C. The reaction mixture was
stirred at ambient temperature for 18 h. The mixture was
extracted with EtOAc (2 × 300 mL), and the organic layers
were dried over anhydrous Na2SO4 and concentrated. The
residue was purified by column chromatography (silica, 80 g)
using 50−100% EtOAc/hexanes as the eluent. The fractions
containing pure product were concentrated to provide the
desired product 14 as a yellow solid (1.50 g, 52% yield). Mp
1
99−102 °C. H NMR (400 MHz, DMSO-d6) δ 9.00 (dd, J =
2.5, 0.7 Hz, 1H), 8.83 (dd, J = 5.2, 1.5 Hz, 1H), 8.35 (ddd, J =
8.3, 2.5, 1.4 Hz, 1H), 7.83 (ddd, J = 8.3, 5.2, 0.7 Hz, 1H), 7.35
(s, 1H), 3.78 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 158.36,
149.91, 146.90, 141.42, 136.11, 134.80, 133.33, 123.17, 112.03,
52.55. MS m/z 238 [M + H]+.
Preparation of 15. To a suspension of 14 (3.80 g, 16.1
mmol) in dioxane (54 mL) was added a solution of LiOH·
H2O (1.00 g, 24.2 mmol) in water (27 mL) to afford a dark-
red solution. The reaction mixture was stirred at ambient
temperature for 1 h and concentrated to dryness. The residue
was suspended in 4 N HCl in dioxane (100 mL), and the
suspension was heated at reflux for 1 h and allowed to cool to
ambient temperature. The resulting suspension was filtered,
and the filter cake was rinsed with dioxane. The solid was
vacuum-dried at 50 °C to afford the desired product 15 as a
1
yellow oil (7.3 g, 79% yield). H NMR (400 MHz, CDCl3) δ
8.30 (dd, J = 2.9, 0.8 Hz, 1H), 8.17 (dd, J = 4.7, 1.4 Hz, 1H),
7.38 (ddd, J = 8.4, 2.8, 1.4 Hz, 1H), 7.18 (ddd, J = 8.4, 4.7, 0.7
Hz, 1H), 4.79 (dd, J = 12.4, 6.9 Hz, 1H), 4.24 (qd, J = 7.1, 1.1
Hz, 2H), 3.55 (dd, J = 17.7, 12.4 Hz, 1H), 3.33 (dd, J = 17.8,
6.9 Hz, 1H), 1.25 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz,
CDCl3) δ 169.65, 141.90, 141.33, 141.09, 135.13, 123.53,
120.37, 62.89, 62.35, 42.45, 14.03. MS m/z 254.2 [M + H]+.
Preparation of 19. To a 100 mL three-neck round-bottom
flask were charged 18 (2.00 g, 7.88 mmol) and MeCN (20
mL). MnO2 (3.4 g, 39.4 mmol) was added, and the reaction
mixture was stirred at 60 °C for 18 h, at which point TLC
analysis (eluent: EtOAc) indicated that the reaction was
incomplete. Additional MnO2 (3.43 g, 39.4 mmol) was added,
and the reaction mixture was stirred at 80 °C for 6 h, at which
time TLC analysis indicated that only a trace of starting
material remained. The mixture was filtered through a Celite
pad, and the pad was rinsed with EtOAc (20 mL). The
combined filtrates were concentrated to dryness, and the
residue was purified by column chromatography (silica, 80 g)
using 10−60% EtOAc/hexanes as the eluent. The pure
fractions were concentrated to dryness to afford the desired
product as a white solid after drying (1.8 g, 93% yield). Mp
1
white solid (4.0 g, 91% yield). Mp 244−246 °C. H NMR
(400 MHz, DMSO-d6) δ 9.00 (dd, J = 2.5, 0.7 Hz, 1H), 8.82
(dd, J = 5.2, 1.4 Hz, 1H), 8.35 (ddd, J = 8.3, 2.4, 1.4 Hz, 1H),
7.85 (ddd, J = 8.3, 5.2, 0.7 Hz, 1H), 7.25 (s, 1H). 13C NMR
(101 MHz, DMSO) δ 158.60, 146.43, 143.77, 140.23, 137.14,
136.87, 136.83, 125.02, 111.58. MS m/z 224 [M + H]+.
Preparation of 2 from 15. To a solution of 15 (1.00 g,
3.65 mmol) in DMF (10 mL) was added CuO (0.058 g, 0.70
mmol), and the reaction mixture was heated at 120 °C for 16
h, at which point only ∼20% conversion was observed.
Additional CuO (112 mg, 1.4 mmol) was added, and the
reaction mixture was stirred for 5 h, at which point the reaction
was complete by TLC (eluent: EtOAc). The mixture was
diluted with NH4OH and water and extracted with EtOAc.
The organic layer was washed with 15% LiCl and concentrated
to provide an orange solid. The residue was purified by column
chromatography (silica, 40 g) using EtOAc as the eluent, and
the pure fractions were concentrated to afford the desired
product 15 as a white solid (0.48 g, 70% yield). The analytical
data of the isolated product were consistent with those of the
previously prepared sample.
1
88−91 °C. H NMR (400 MHz, CDCl3) δ 8.75−8.64 (m,
2H), 7.79 (ddd, J = 8.2, 2.6, 1.5 Hz, 1H), 7.42 (ddd, J = 8.2,
4.8, 0.8 Hz, 1H), 6.98 (s, 1H), 4.27 (q, J = 7.1 Hz, 2H), 1.27
(t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 157.90,
149.88, 147.01, 141.41, 136.24, 135.27, 133.34, 123.11, 111.97,
61.87, 13.98. MS m/z 252.2 [M + H]+.
Preparation of 17. To a 21 wt % solution of NaOEt in
EtOH (56.0 mL, 192 mmol) was charged 3 (10.0 g, 55 mmol)
in portions, causing an exotherm from 20 to 32 °C. The
Preparation of 15 from 19. To a 100 mL three-neck
round-bottom flask were charged 19 (0.20 g, 0.80 mmol) and
37 wt % HCl (4.0 mL). The reaction mixture was heated at 90
H
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°C for 18 h and allowed to cool to 20 °C. A second charge of
dioxane (5 mL) was added, and the suspension was
concentrated to afford a white solid. Dioxane (5 mL) was
added, and the resulting suspension was stirred for 1 h at 20
°C. The suspension was filtered, and the solid was rinsed with
dioxane (2 mL). The filter cake was dried under vacuum at 20
°C to afford the desired product 15 as a white solid (0.22 g,
quantitative yield). The analytical data of the isolated product
were consistent with those of the previously obtained sample.
Preparation of 28. To a 250 mL three-neck round-bottom
flask equipped with a reflux condenser and a nitrogen inlet was
charged 3 (15.0 g, 82.4 mmol). NaOEt (21 wt % in EtOH,
92.3 mL, 247 mmol) was added over 5 min, causing the
internal temperature to increase from 23 to 38 °C. The
resultant light-brown slurry was stirred for 10 min, and methyl
methacrylate (17.7 mL, 165 mmol) was added at 38 °C over
15 min. The yellow mixture was stirred at 50 °C for 4 h, at
which point HPLC analysis indicated full conversion. The
mixture was cooled to 10 °C, and 4 N HCl solution in dioxane
(20.6 mL, 82.4 mmol) was added slowly to quench the excess
base, resulting in a light-brown suspension. The mixture was
concentrated under reduced pressure to afford crude 27 as a
brown solid.
139.53, 135.90, 126.53, 125.69, 123.84, 116.86, 22.47. MS m/z
193 [M]+.
Preparation of 25. To a mixture of 29 (2.00 g, 10.0
mmol) in water (10 mL) and t-BuOH (5 mL) was added a
solution of NaMnO4 (5.00 g, 35.0 mmol) in water (15 mL)
over 20 min. The mixture was heated at 80 °C for 16 h, at
which point HPLC analysis indicated that the reaction was
incomplete. Additional NaMnO4 solution (0.7 g, 5.0 mmol) in
water (2.0 mL) was added, and the mixture was stirred for an
additional 4 h. The dark mixture was filtered through a Celite
pad, and the pad was rinsed with water (5.00 mL) and EtOAc
(3 × 15 mL). The organic layer was separated, and the
aqueous layer was extracted with EtOAc (25.0 mL). The
aqueous layer was acidified with HCl (37 wt %) to pH 5,
resulting in a white suspension. The suspension was filtered,
and the filtrate was concentrated to give a white suspension;
this suspension was filtered, and the solid was washed with
water (2 mL). The combined solids were dried under vacuum
to afford 25 as a white solid (1.0 g, 46.0% yield, 97% purity by
HPLC). 1H NMR (400 MHz, DMSO-d6) δ 9.11 (s, 2H), 8.59
(d, J = 4.7, 1H), 8.28 (ddd, J = 8.4, 2.7, 1.4 Hz, 1H), 7.58 (dd,
J = 8.0, 4.4 Hz, 1H). 13C NMR (101 MHz, DMSO-d6) δ
162.24, 148.35, 141.46, 140.21, 135.01, 134.01, 126.45, 124.23,
115.34. MS m/z 224 [M + H]+.
To a suspension of the above crude 27 in MeCN (100 mL)
was added POCl3 (11.6 mL, 124 mmol) slowly. The resulting
yellow slurry was stirred at 75 °C for 1 h, at which point HPLC
indicated complete consumption of 27. The mixture was
cooled to ambient temperature and concentrated under
reduced pressure. The brown residue was carefully quenched
with water (120 mL) and basified with 50 wt % NaOH to pH
10 (Exothermic!) while the temperature was maintained
below 60 °C. The mixture was then extracted with EtOAc (3 ×
150 mL). The combined organic layers were washed with
water (80 mL) and concentrated under reduced pressure to
afford the crude product 28 as a dark-purple oil. The crude
product was purified by column chromatography (silica, 220 g)
using 0−70% EtOAc/hexanes as the eluent to afford 28 as a
brown oil (12.3 g, 76% yield over two steps, 96% purity by
HPLC). 1H NMR (400 MHz, CDCl3) δ 8.27 (dd, J = 2.8, 0.7
Hz, 1H), 8.15 (dd, J = 4.6, 1.4 Hz, 1H), 7.38 (ddd, J = 8.4, 2.9,
1.4 Hz, 1H), 7.18 (ddd, J = 8.4, 4.7, 0.7 Hz, 1H), 4.17−4.06
(m, 1H), 3.47 (t, J = 8.9 Hz, 1H), 3.44−3.34 (m, 1H), 1.37 (d,
J = 6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 148.17,
142.07, 141.10, 134.74, 123.39, 119.92, 56.62, 43.62, 16.16.
MS m/z 195 [M]+.
Preparation of 2 from 25. To a mixture of 25 (0.22 g, 1.0
mmol) in DMAc (3 mL) was added Cu2O (22.3 mg, 10 wt %).
The mixture was heated at 125 °C for 6 h, at which point
HPLC analysis indicated complete consumption of 25. The
brown mixture was filtered through a Celite pad, and the pad
was rinsed with DMAc (1 mL) and MeCN (2 × 2 mL). The
light-yellow filtrate (8.54 g) was analyzed by HPLC using di-n-
propyl phthalate as an internal standard, which indicated 124
mg of product (69% solution yield).
Preparation of 2 via [3 + 2] Cyclization of 3 and 30. A
250 mL three-neck round-bottom flask was charged with
methyl 2-acetamidoacrylate (30) (4.90 g, 34.3 mmol) and
EtOH (40 mL). 3 (5.00 g, 27.5 mmol) was added, followed by
NaOEt (7.50 g, 110 mmol). The reaction mixture was stirred
at 60 °C for 6 h, at which point TLC analysis (eluent: 10%
MeOH/DCM) indicated that the starting material had been
consumed and a major product had formed. The reaction
mixture was allowed to cool to ambient temperature and
concentrated to afford a yellow solid. The resulting solid was
slowly charged with POCl3 (29.2 g, 191 mmol), and the
reaction mixture was stirred at 60 °C for 3 h, at which point
HPLC analysis indicated that the reaction was complete. The
reaction mixture was concentrated at 40 °C to remove POCl3,
and the residue was slowly quenched with water (40 mL) at
<30 °C (Exothermic!). The resulting solution was basified
with 50 wt % NaOH solution, and the resulting suspension was
extracted with EtOAc (3 × 50 mL). The organic layers were
concentrated to dryness, and the residue was purified by
column chromatography (silica, 80 g) using 40−50% EtOAc/
hexanes as the eluent. The fractions containing the pure
product were concentrated to dryness, and the solid was
further dried under vacuum at ambient temperature to afford
the desired product 2 as a white solid (2.4 g, 49% yield over
two steps). The analytical data of the isolated product were
consistent with those of the previously prepared sample.
Preparation of 33. A 500 mL three-neck round-bottom
flask was charged with 12 (18.9 g, 220 mmol) and EtOH (110
mL). Compound 3 (20.0 g, 110 mmol) was added, followed by
NaOEt (29.9 g, 439 mmol) in portions. The reaction mixture
Preparation of 29. To a solution of 28 (1.00 g, 5.00
mmol) in MeCN (10.0 mL) was added MnO2 (1.30 g, 15.0
mmol) portionwise over 10 min at 0 °C. The mixture was
heated at 40 °C for 1 h, at which point HPLC analysis
indicated 43.0% conversion. The mixture was stirred at 40 °C
for an additional 20 h. Additional MnO2 (0.40 g, 5.0 mmol)
was added in one portion, and the mixture was stirred for
another 1 h, at which point HPLC analysis indicated complete
consumption of 28. The mixture was cooled to ambient
temperature and filtered. The filter cake was washed with
MeCN (3 × 15 mL). The filtrate was dried over anhydrous
Na2SO4 and concentrated to afford 29 as a light-yellow solid
1
(0.92 g, 95% yield, 98% purity by HPLC). H NMR (400
MHz, CDCl3) δ 8.90 (dd, J = 2.6, 0.8 Hz, 1H), 8.52 (dd, J =
4.8, 1.5 Hz, 1H), 7.99 (ddd, J = 8.3, 2.7, 1.4 Hz, 1H), 7.74 (q, J
= 0.9 Hz, 1H), 7.39 (ddd, J = 8.3, 4.8, 0.8 Hz, 1H), 2.13 (d, J =
0.9 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 147.26, 142.87,
I
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People. Science 2010, 327, 812. (b) Foley, J. A.; Ramankutty, N.;
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(eluent: 10% MeOH/DCM) indicated that starting material
had been consumed and a major product had formed. The
reaction mixture was allowed to cool to 20 °C and
concentrated to afford a yellow solid.
̈
M.; Carpenter, S. R.; Hill, J.; Monfreda, C.; Polasky, S.; Rockstrom, J.;
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The resulting solid was charged with POCl3 (100 g, 654
mmol), and the mixture was stirred at 60 °C for 3 h, at which
point TLC analysis (eluent: EtOAc) indicated that the reaction
was complete. The reaction mixture was slowly quenched into
water (400 mL) at <30 °C (Exothermic!), and the resulting
solution was basified with 50 wt % NaOH solution to pH >10.
The resulting solution was extracted with EtOAc (3 × 200
mL), and the organic layers were combined and concentrated
to dryness. The residue was purified by column chromatog-
raphy (silica, 330 g) using 50−80% EtOAc/hexanes as the
eluent. The fractions containing pure product were concen-
trated to dryness, and the resulting yellow solid was dried
under vacuum to afford the desired product 33 as a yellow
(2) Gianessi, L. P. The increasing importance of herbicids in
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J.; Ma, S.; Fandrick, D. R.; Grinberg, N.; Lee, H.; Bosanac, T.;
Takahashi, H.; Chen, Z.; Bartolozzi, A.; Nemoto, P.; Busacca, C. A.;
Song, J. J.; Yee, N. K.; Mahaney, P. E.; Senanayake, C. H. Early
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1
solid (11.3 g, 66% yield over two steps). Mp 66−68 °C. H
NMR (400 MHz, DMSO-d6) δ 8.28 (d, J = 2.8 Hz, 1H), 8.07
(dd, J = 4.5, 1.5 Hz, 1H), 7.32 (ddd, J = 8.4, 2.9, 1.6 Hz, 1H),
7.26 (dd, J = 8.4, 4.5 Hz, 1H), 3.93 (t, J = 10.2 Hz, 2H), 3.23
(t, J = 10.2 Hz, 2H). 13C NMR (101 MHz, DMSO-d6) δ
144.37, 142.05, 140.50, 134.64, 123.65, 119.31, 49.63, 36.90.
MS m/z 181 [M]+.
Preparation of 2 from 33. A 100 mL three-neck round-
bottom flask was charged with 33 (3.00 g, 16.6 mmol) and
DMF (15 mL). K2S2O8 (6.70 g, 24.8 mmol) was added, and
the reaction mixture was heated at 80 °C for 3 h. An exotherm
to ∼110 °C was observed during heating (Highly
exothermic!). The mixture was allowed to cool to 80 °C,
stirred for 3 h, and then cooled to 20 °C. The reaction mixture
was diluted with water (50 mL) and basified with 50 wt %
NaOH. The resulting mixture was extracted with EtOAc (4 ×
30 mL), and the combined organic layers were concentrated.
The residue was purified by column chromatography (silica, 80
g) using 30% EtOAc/hexanes as the eluent. The pure fractions
were concentrated to dryness to afford 2 as a white solid (1.60
g, 54% yield). The analytical data of the isolated product were
consistent with those of the previously prepared sample.
AUTHOR INFORMATION
Corresponding Author
*E-mail: qiang.yang@corteva.com.
̈
(h) Karlsson, S.; Bergman, R.; Broddefalk, J.; Lofberg, C.; Moore,
■
̈
P. R.; Stark, A.; Emtenas, H. A Practical Telescoped Three-Step
Sequence for the Preparation of (1R,2R)-2-(4-Bromobenzoyl)-
cyclohexanecarboxylic Acid: A Key Building Block Used in One of
Our Drug Development Projects. Org. Process Res. Dev. 2018, 22, 618.
(i) Li, B.; Barnhart, R. W.; Hoffman, J. E.; Nematalla, A.; Raggon, J.;
Richardson, R.; Sach, N.; Weaver, J. Exploratory Process Develop-
ment of Lorlatinib. Org. Process Res. Dev. 2018, 22, 1289.
ORCID
Qiang Yang: 0000-0003-3762-5015
Xiaoyong Li: 0000-0002-3518-3746
Author Contributions
(5) (a) Buysse, A. M.; Niyaz, N. M.; Zhang, Y.; Walsh, M. J.;
Kubota, A.; Hunter, R.; Trullinger, T. K.; Lowe, C. T.; Knueppel, D.;
Demeter, D. A.; Patny, A.; Garizi, N.; LePlae, P. R.; Wessels, F.
Preparation of pyridinylpyrazolamine derivatives as pesticides and
their pesticidal compositions. WO 2013162715, 2013. (b) Buysse, A.
M.; Niyaz, N. M.; Demeter, D. A.; Zhang, Y.; Walsh, M. J.; Kubota,
A.; Hunter, R.; Trullinger, T. K.; Lowe, C. T.; Knueppel, D.; Patny,
A.; Garizi, N.; LePlae, P. R.; Wessels, F.; Ross, R.; Deamicis, C.;
Borromeo, P. WO 2013162716, 2013.
(6) (a) Smith, R. F.; Brophy, K. A.; Rodriguez, G.; Dennis, L. A.;
Ryan, W. J. Amidrazones. 13. A convenient method for the
preparation of 1-alkyl-1-methylhydrazines. Synth. Commun. 1990,
20, 183. (b) Rademacher, P. Product class 7: hydrazines and
hydrazinium salts. Sci. Synth. 2009, 40b, 1133. (c) Bagley, M. C.;
Baashen, M.; Paddock, V. L.; Kipling, D.; Davis, T. Regiocontrolled
synthesis of 3- and 5-aminopyrazoles, pyrazolo[3,4-d]pyrimidines,
The manuscript was written through contributions of all
authors. All of the authors approved the final version of the
manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors thank Dr. Gregory T. Whiteker and Dr. Carl
DeAmicis for helpful discussions throughout this project.
■
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