Strategy to Prepare 3-Bromo- and 3-Chloropyrazoles

Article abstract of DOI:10.1021/acs.joc.7b03282

A general strategy to prepare substituted 3-bromo- and 3-chloropyrazoles is described. The three-step method involves condensation of crotonates or β-chloro carboxylic acids with hydrazines, followed by halogenation and oxidation. Several condensation and oxidation protocols were developed to enable preparation of a wide variety of 3-halopyrazoles with good to excellent yields and regiocontrol.

Full text of DOI:10.1021/acs.joc.7b03282

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Article
Strategy to Prepare 3-Bromo and 3-Chloropyrazoles
Richard J. Fox, Michael A. Schmidt, and Martin D. Eastgate
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b03282 • Publication Date (Web): 11 Feb 2018
Downloaded from http://pubs.acs.org on February 11, 2018
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The Journal of Organic Chemistry
Strategy to Prepare 3-Bromo and 3-Chloropyrazoles
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Richard J. Fox,* Michael A. Schmidt, and Martin D. Eastgate
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Chemical & Synthetic Development, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, New Jersey 08903, United States
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ABSTRACT
A general strategy to prepare substituted 3-bromo and 3-chloropyrazoles is described. The 3-step method involves condensation of
crotonates or β-chloro carboxylic acids with hydrazines, followed by halogenation and oxidation. Several condensation and oxidation
protocols were developed to enable preparation of a wide-variety of 3-halopyrazoles with good to excellent yields and regiocontrol.
INTRODUCTION
3-Bromo and 3-chloropyrazoles represent an important class of heterocyclic compounds due to their presence in a variety of biologically
active compounds,1 as well as their synthetic utility as starting materials for further functionalization.2 Multiple methodologies have
been reported to prepare 3-halopyrazoles, including: (1) electrophilic halogenation, (2) dehydroxyhalogenation, (3) Sandmeyer
halogenodediazoniation, (4) cycloaddition, (5) N1 alkylation, and (5) palladium-catalyzed halogenation.3 While successful in many
cases, these methodologies often require harsh reaction conditions, leverage intermediates with genotoxicity concerns (e.g., use of
aminopyrazole derivatives), or have limited substrate scope.
As part of a recent program that required kilogram quantities of a 3-bromopyrazole, we were attracted to an additional disconnection
strategy involving sequential halogenation and oxidation of a starting pyrazolidin-3-one (Scheme 1a). While some examples of this
strategy have been reported, the substrate scope was limited to aromatic side-chains.4 In the few examples in which R1 was alkyl, R2
remained electron-withdrawing,5 and when R2 was not electron withdrawing, R1 remained aromatic.6 Our report describing the
preparation of >150 kg 3 was the first example to sequentially halogenate/oxidize a pyrazolidin-3-one to prepare a 3-bromopyrazole
with alkyl substitution at both R1 and R2 (Scheme 1b).7,8 Interestingly, during our initial studies we observed competitive endo- versus
exocyclic proton-elimination during oxidation (i.e., Ha versus Hb in 5, Scheme 1), leading to 3 and des-methyl pyrazole 4, respectively.
This regioselectivity challenge supported why previous reports to prepare 3-halopyrazoles utilizing this methodology were focused on
substrates that either lacked Hb protons (e.g., R1 = aromatic), or contained electron-withdrawing groups at C(5) (e.g., R2) to favor Ha
elimination.
Herein, we report the first systematic study to examine the impact of substitution on the sequential condensation of crotonates
or β−chloro carboxylic acids with hydrazines, followed by halogenation and oxidation of the resulting pyrazolidin-3-ones, to prepare 3-
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halopyrazoles (Scheme 1c). We describe the utilization of both direct condensation and regioselective reductive amination conditions
to prepare the requisite pyrazolidin-3-ones, along with multiple oxidation protocols to, for the first time, prepare a wide variety of 3-
bromo- and 3-chloropyrazoles with good to excellent yields and excellent regiochemical control, utilizing a single synthetic strategy.
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SCHEME 1
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RESULTS AND DISCUSSION
Our efforts began by investigating the condensation of a variety of crotonates with various hydrazine derivatives. As shown in Scheme
2, using the conditions developed to prepare 3, direct condensation (Method A) between methyl hydrazine (R1 = Me), hydrazine
monohydrate (R1=H) or phenyl hydrazine (R1=Ph), and either methyl crotonate (R=R2=Me; R3=H), methyl methacrylate
(R=R3=Me;R2=H), or methyl acrylate (R=Me;R2=R3=H) proceeded with good (>10:1 crude) regioselectivity and high isolated yields
(IY) as single regioisomers (6a, 6b, 6d, 6h, 6i). Excellent regioselectivities were also observed with Method A using methylhydrazine
to prepare the more electron–deficient crotonates 6f (R2=CF3, R3=H,) and 6g (R2=CO2Me, R3=H). However, the regioselectivity dropped
upon increasing the steric bulk of the R2 substituent. For example, when R2= Et, R3=H, the selectivity decreased to 5:1 (6c) and when
R2 = Ph, R3 =H, the selectivity was only 2:1 (6e).9 Despite the lower regioselectivities for these substrates, both 6c and 6e were isolated
in good yields as single isomers after purification.
SCHEME 2. Condensation Approaches
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Me
Me
Me
Me
N
N
N
HN
N
HN
HN
HN
Me
*HBr
Et
*HBr
*HBr
Me
O
O
O
O
6a
method A
crude: 6:7 >10:1
IY*: 90% (1 isomer)
6b
method A
crude: 6:7 >20:1
6c
6d
method A
crude: 6:7 5:1
method A
crude: 6:7 >10:1
IY: 88% (1 isomer) IY: 75% (1 isomer) IY: 87% (1 isomer)
Me
Me
Me
H
N
N
HN
N
N
HN
HN
HN
Ph
CF3
CO2Me
*HBr
6g
Me
O
O
O
O
*HBr
6e
method A
crude: 6:7 2:1
6f
method A
crude: 6:7 >10:1
6h
method A
method A
crude: only 6
crude: 6:7 >10:1
IY: 87% (1 isomer)
IY: 57% (1 isomer) IY: 75% (1 isomer) IY: 99% (1 isomer)
Me
Et
Ph
N
N
N
HN
HN
HN
i-Pr
Me
*HBr
Me
*HBr
O
O
O
6i
method A
crude: 6:7 >20:1
6j
6k
method A; 6:7 2.5:1
method B: only 6
IY: 74% (1 isomer)
method A; 6:7 1:1
method B: only 6
IY: 79% (1 isomer)
IY: 71% (1 isomer)
t-Bu
Bn
c-hex
N
N
N
HN
HN
HN
Me
Me
*HBr
Me
*HBr
O
O
O
6l
6m
6n
method C
only 6
method A: only 7
method B: only 6
IY: 79% (1 isomer)
method A; 6:7 1:1.7
method B: only 6
IY: 73% (1 isomer)
IY: 69% (1 isomer)
*IY = isolated yield
As the size of either the N-R1 or R2 substituent increased further, the regioselectivities using Method A remained poor (6j and 6k); and
use of benzylhydrazine or cyclohexylhydrazine (6l and 6m), favored the undesired regioisomer. Thus, to prepare substrates 6j-6m, we
developed a modified 2-step telescope (Method B) in which the crotonate esters were first condensed with hydrazine monohydrate,
followed by regioselective reductive amination in the presence of NaBH(OAc)3 and the requisite aldehydes.10 Starting from isopropyl
4-methyl-2-pentenoate,9 condensation with hydrazine monohydrate, followed by reductive amination with aqueous formaldehyde led to
6j in 74% yield (2-steps) as a single regioisomer. Starting from hydrazine monohydrate and methyl crotonate, and using either
acetaldehyde, benzaldehyde or cyclohexanone, led to 6k-6m, respectively, in good yields as single regioisomers.11 Lastly, to generate
the t-butyl hydrazine derived substrate with the desired regioselectivity, we developed a third protocol (Method C) that involved initial
amidation between t-butyl hydrazine and 3-chlorobutyric acid, followed by intramolecular chloride displacement to afford 6n in 69%
overall yield. While not shown in Scheme 1, methyl tiglate (i.e., R=R2=R3=Me) was unreactive with methyl hydrazine, and did not lead
to significant product upon reaction with hydrazine hydrate.
SCHEME 3. Bromination and Oxidation Conditions
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Continuing with the halogenation, with the exception of pyrazolidin-3-one 6h12 (R1=R3=H, R2=Me), the bromination of substrates 6a-
6n with POBr3 and Et4NBr in DCM all proceeded in good to excellent yields (Scheme 3).13 Following aqueous workup, the DCM
solutions of 3-bromo dihydropyrazoles 8a-n were quantified by 1H NMR to obtain the reported in-process assay yields (AY).
As previously disclosed (Scheme 1b),7 the oxidation of 8a using NaOCl/KBr14 and K3PO4 under biphasic DCM/water conditions led to
a 2.1:1 crude ratio of 9a:10a. Following workup and purification, 9a was isolated in 58% yield as a single compound. Comparable
crude ratios of 9:10 (i.e., 1.6-2.5:1), and isolated yields, were observed starting from 8b (R1=R3=Me, R2=H) and 8c (R1=Me, R2=Et,
R3=H), as well as when the C(5) substituent was changed from methyl to i-Pr (8j, R1=Me, R2=i-Pr, R3=H). On the other hand, when the
C(5) methyl substituent was replaced with hydrogen (i.e., 8d, R1=Me, R2=R3=H) or phenyl (i.e., 8e, R1=Me, R2=Ph, R3=H), the crude
ratio of 9d:10d increased to approximately 5:1. Taken together, these results supported the hypothesis that increasing the accessibility
and/or acidity of the C(5) proton favored the desired elimination of the activated N-halo intermediate (i.e., Ha vs Hb 5, Scheme 1). This
was further reinforced in the excellent selectivities observed using C(5) electron deficient compounds 8f (R1=Me, R2=CF3, R3=H) and
8g (R1=Me, R2=CO2Me, R3=H). With 8g, the crude ratio of 9g:10g was >20:1, and 9g was isolated in 80% yield. Substrate 8f proved
too electron deficient to react with NaOCl, but oxidation with NBS afforded 9f in 55% yield, and 10b was not detected.15 As expected,
increasing the steric bulk of the N-substituent from N-methyl to N-cyclohexyl also led to a significantly improved crude ratio of 9m:10m
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(>20:1), and 9m (R1= c-hex, R2=Me, R3=H) was isolated in 71% yield. For N-t-Bu substrate 8n, which lacked competing protons for
elimination, 9n (R1=t-Bu, R2=Me, R3=H) was isolated in 94% yield. On the contrary, N-benzyl substrate 8l (R1=Bn, R2=Me, R3=H) led
to a crude 1:10 ratio of 9l:10l, presumably due to the phenyl ring increasing the acidity of the exocyclic benzylic protons and favoring
debenzylation. For 8l, alternative MnO2 oxidation conditions were utilized to isolate 9l in 49% yield. Interestingly, under the MnO2
conditions, des-benzyl impurity 10l was not observed. The MnO2 oxidation conditions were also utilized for substrates 8i and 8k,
possessing either an N-phenyl or N-ethyl substituent, as the corresponding oxidations with NaOCl failed to yield the desired product (9i,
R1=Ph, R2=Me, R3=H), or produced a complex reaction mixture (9k, R1=Et, R2=Me, R3=H). With MnO2, 9i and 9k were isolated in
56% and 42% yield, respectively.
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In addition to 3-bromopyrazoles, we also investigated application of this methodology to the preparation of 3-chloro derivatives,
(Scheme 4) and while successful, we observed some important differences. The chlorinations of pyrazolidin-3-ones 6e,i,o,p with POCl3
were far slower than the corresponding brominations, necessitating a change of solvent to 1,2-dichloroethane (DCE) and a temperature
increase to 60 °C (vs 30 °C). The subsequent oxidations to the pyrazoles were also ineffective (no reaction) under the NaOCl conditions,
while utilization of potassium persulfate led to decomposition, DBU/NCS to no reaction, and DDQ to slow and complex reaction
mixtures. The optimal oxidation reagents were found to be excess MnO2, and in the case of highly electron-deficient substrate 6p, NCS.
Finally, the product 3-chloropyrazoles were inherently more volatile than the bromopyrazoles. For example, while the analogous C3-
chloropyrazole of 9a (R1=R2=Me, R3=-H) was effectively prepared by the conditions in Scheme 4, it was isolated in only 20% yield due
to losses during concentration. Based on this observation, we opted to prepare the higher molecular weight analogues 11c and 11d
bearing an n-hexyl (vs Me) substituent. Despite these differences, in analogy to the 3-bromo series, 3-chloropyrazoles containing both
alkyl and phenyl substituents at both N(1) and C(5) were prepared in moderate to good yields (11a-c), as well as a C(5) –CF3 group
(11d).
SCHEME 4. Application to 3-Chloropyrazoles
CONCLUSION
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In summary, we have disclosed a systematic study of the impact of substitution on a general 3-step approach to prepare substituted 3-
bromo- or 3-chloropyrazoles based on the condensation of either crotonate esters or β-chloro carboxylic acids with substituted
hydrazines, followed by sequential halogenation and oxidation. Most importantly, we identified multiple condensation and oxidation
protocols to enable the preparation of a wide-variety of substituted products utilizing a single synthetic strategy, which would have been
difficult to achieve with previously published methodologies.
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EXPERIMENTAL SECTION
General. The reactions were performed under a nitrogen atmosphere. All reagents were commercially available and used as received.
MnO2 (activated, ~85%, <5 μm) was purchased from Sigma-Aldrich and used without further activation. Commercial
tetraethylammonium chloride was dried in a 110 °C oven for 24 h, cooled to room temperature and ground to a fine powder before use.
TLC or HPLC was used to monitor reaction progress. SiO2 purification was performed using either traditional columns (100-200 mesh)
or a Teledyne ISCO purification system. NMR analysis was performed on a Bruker DRX-400 or DRX-500 instrument, and all 13
spectra were proton-decoupled L/kg refer to liters of solvent charged per kg of the limiting reagent in each experiment.
C
General Condensation Procedure to Prepare Pyrazolidin-3-one HBr Salts. 1,5-Dimethylpyrazolidin-3-one hydrobromide (6a). To
a mixture of isopropanol (4.7 mL, 2.3 L/kg), and KOH (0.12 g, 2.14 mmoles, 0.05 equiv) at 20-25 °C was charged methyl hydrazine
(2.02 g, 43.8 mmoles, 1.0 equiv). The reaction mass was then heated to 60-65 °C and visually checked to confirm all KOH had dissolved.
The reaction mass was then cooled to 5-10 °C and slowly charged with trans-methyl crotonate (4.83 g, 48.2 mmoles, 1.10 equiv),
maintaining the internal temperature <25 °C. Note: strong exotherm observed. The reaction mixture was then agitated at 20-25 °C for
5 h. To a second RBF containing isopropanol (18.8 mL, 9.3 L/kg) at 0-5°C was slowly charged acetyl bromide (5.93 g, 48.2 mmoles,
1.1 equiv) over ~30 min., maintaining the internal temperature < 25 °C. Note: strong exotherm observed. The HBr/IPA solution was
then charged to reaction mixture over ~2 h, maintaining the internal temperature between 20‐25 °C. The RBF containing the HBr/IPA
solution was then rinsed with isopropanol (1.0 mL, 0.5 L/kg) and transferred to reaction mixture. The resulting slurry was then aged at
20‐25 °C for 2 h. The slurry was then filtered, sequentially washed cake with isopropanol (16.2 mL, 8.0 L/kg) and MTBE (2 x 16.2
mL, 2 x 8.0 L/kg), and dried under vacuum at 40 °C to afford 7.69 g (99.9 LCAP, 99.8 wt%) of 6a as a white solid in 90% yield; mp =
150-160oC; 1H NMR (400 MHz, D2O) δ 4.15 (m, 1 H), 3.15 (s, 3 H), 3.06 (dd, J=8.0, 16.0 Hz, 1 H), 2.63 (dd, J= 8.0, 16.0 Hz, 1 H),
1.52 (d, J= 4.0 Hz, 3 H); 13C NMR (100 MHz, D2O) δ 174.2, 65.9, 43.5, 36.0, 15.0; HRMS-ESI (m/z) calcd for C5H11ON2 [M + H]+
115.0866, found 115.0869.
1,4-Dimethylpyrazolidin-3-one hydrobromide (6b). Starting from methyl hydrazine (4.00 g, 85.1 mmoles, 1.0 equiv) and methyl
methacrylate (9.46 g, 93.5 mmoles, 1.10 equiv), with 20 h reaction time, isolated 14.7 g of 6b as a white solid in 88% yield; mp = 185-
188oC; 1H NMR (500 MHz, D2O, 1:1 mixture of rotamers) δ 4.42 (app t, J = 10 Hz, 1 H), 3.96-3.90 (m, 1 H), 3.89-3.82 (m, 1 H), 3.39
(app t, J= 10 Hz, 1 H), 3.27-3.17 (m , 1 H), 3.19 (d, J= 10 Hz, 3 H), 3.13-3.07 (m, 1 H), 1.24 (d, J= 4.0 Hz, 3 H); 13C NMR (125 MHz,
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D2O, 1:1 mixture of rotamers) δ 177.3, 60.9, 60.4, 45.7, 45.2, 35.8, 34.0, 12.9, 12.3; HRMS-ESI (m/z) calcd for C5H11N2O [M + H]+
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115.0866, found 115.0867.
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5-Ethyl-1-methylpyrazolidin-3-one hydrobromide (6c). Starting from methyl hydrazine (4.00 g, 85.1 mmoles, 1.0 equiv) and methyl 2-
pentenoate (10.9 g, 93.5 mmoles, 1.10 equiv), with 23 h reaction time, isolated 13.3 g of 6c as a white solid in 75% yield; mp = 155-
157oC; 1H NMR (500 MHz, D2O) δ 4.10−4.00 (m, 1 H), 3.18 (s, 3 H), 3.09 (dd, J= 5.0, 15 Hz, 1 H), 2.69 (dd, J = 5.0, 15 Hz, 1 H), 2.09-
1.97 (m, 1 H), 1.83-1.77 (m, 1 H), 0.97 (t, J= 10 Hz, 3 H); 13C NMR (125 MHz, D2O) δ 174.2, 70.8, 44.5, 34.1, 23.4, 9.2; HRMS-ESI
(m/z) calcd for C6H13N2O [M + H]+ 129.1022, found 129.1022.
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Methyl 2-methyl-5-oxopyrazolidine-3-carboxylate hydrobromide (6g). Starting from methyl hydrazine (4.00 g, 85.1 mmoles, 1.0 equiv)
and dimethyl maleate (13.6 g, 93.5 mmoles, 1.10 equiv), with 16 h reaction time, isolated 20.2 g of 6g as a white solid in 99% yield; mp
= 193-195oC; 1H NMR (500 MHz, D2O) δ 4.51 (dd, J= 5.0, 10.0 Hz, 1 H), 3.76 (s, 3 H), 3.21 (dd, J= 10.0, 15.0 Hz, 1 H), 2.94 (s, 3 H),
2.88 (dd, J= 5.0, 15.0 Hz, 1 H); 13C NMR (125 MHz, D2O) δ 172.5, 168.1, 66.6, 54.2, 46.2, 32.1; HRMS-ESI (m/z) calcd for C6H11N2O3
[M + H]+ 159.0764, found 159.0763.
5-Methylpyrazolidin-3-one hydrobromide (6h). To a solution of methanol (100 mL, 2.3 L/kg), and hydrazine hydrate (5.26 g, 64 wt%,
105 mmoles, 1.0 equiv) at 20-25 °C was charged trans-methyl crotonate (11.3 g, 110 mmoles, 1.05 equiv). The reaction mixture was
then heated to reflux, and after 5 h, concentrated to dryness, followed by charging with isopropanol (13 mL, 2.5 L/kg). Analogous
isolation as 6a afforded 16.5 g of 6h as a white solid in 87% yield; mp = 195-198oC; 1H NMR (500 MHz, D2O) δ 4.43-4.35 (m, 1 H),
2.96 (dd, J= 10.0, 15.0 Hz, 1 H), 2.56 (dd, J= 5.0, 15.0 Hz, 1 H), 1.50 (d, J= 10.0 Hz, 3 H); 13C NMR (125 MHz, D2O) δ 175.7, 55.5,
35.6, 16.2; HRMS-ESI (m/z) calcd for C4H9N2O [M + H]+ 101.0709, found 101.0713.
General Condensation Procedure to Prepare Pyrazolidin-3-one Freebase. 1-Methylpyrazolidin-3-one (6d). To a mixture of
isopropanol (85 mL, 3.8 L/kg), and KOH (0.84 g, 13.0 mmoles, 0.05 equiv) at 20-25 °C was charged methyl hydrazine (15.58 g, 331.4
mmoles, 1.3 equiv). The reaction mass was then heated to 60-65 °C and visually checked to confirm all KOH had dissolved. The
reaction mass was then cooled to 5-10 °C and slowly charged methyl acrylate (22.2 g, 255 mmoles, 1.0 equiv), maintaining the internal
temperature <25 °C. Note: strong exotherm observed. The reaction mixture was then agitated at 20-25 °C for 16 h. The reaction mixture
was then concentrated to dryness, charged with toluene (2 x 50 mL, 2 x 2.3 L/kg), concentrating after each charge. Purification by ISCO
chromatography (330 g column, flow rate 200 mL/min, gradient 0% MeOH in EtOAc for 1 CV, then to 25% MeOH over 1 CV and
25% till end, collected 25 mL fractions) afforded 22.3 g of 6d as a pale yellow oil in 87% yield . Rf = 0.20 (20% MeOH in EtOAc); 1H
NMR (500 MHz, CDCl3) δ 7.58 (br s, 1 H), 3.50-3.00 (m, 2 H), 2.61 (s, 3 H), 2.62-2.50 (m, 2 H); 13C NMR (125 MHz, CDCl3) δ 174.2,
53.7, 46.5, 30.2; HRMS-ESI (m/z) calcd for C4H9N2O [M + H]+ 101.0709, found 101.0712.
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1-Methyl-5-phenylpyrazolidin-3-one (6e). Starting from isopropanol (30 mL, 1.2 L/kg), KOH (0.365 g, 6.44 mmoles, 0.05 equiv), methyl
hydrazine (9.08 g, 193 mmoles, 1.5 equiv) and isopropyl cinnamate (25.0 g, 129 mmoles, 1.0 equiv), with 3.5 day reaction time at 65
oC, isolated 12.9 g of 6e as a white solid in 57% yield after ISCO purification (330 g column, flow rate 200 mL/min, gradient 100%
EtOAc for 5 CV, then to 10% MeOH in EtOAc over 2 CV, collected 25 mL fractions). Rf = 0.30 (100% EtOAc); mp = 118-120oC; 1H
NMR (500 MHz, CDCl3) δ 7.45-7.30 (m, 5 H), 3.96 (m, 1 H), 2.96 (dd, J= 7.5, 15.0 Hz, 1 H), 2.65 (dd, J= 10.0, 15.0 Hz, 1 H), 2.56 (s,
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3 H); 13C NMR (125 MHz, CDCl3) δ 177.2, 138.7, 128.7, 128.2, 127.3, 70.0, 44.7, 40.1; HRMS-ESI (m/z) calcd for C10H13N2O [M +
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H]+ 177.1022, found 177.1022.
1-Methyl-5-(trifluoromethyl)pyrazolidin-3-one (6f). Starting with isopropanol (11.5 mL, 2.3 L/kg), KOH (0.301 g, 5.31 mmoles, 0.05
equiv), methyl hydrazine (5.00 g, 106 mmoles, 1.0 equiv) and 4,4,4-trifluorocrotonate (18.1 g, 112 mmoles, 1.05 equiv), with 0.5 h
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reaction time at 20-25 C, isolated 14.1 g of 6f as a white solid in 75% yield after ISCO purification (330 g column, flow rate 200
mL/min, gradient 100% hexanes for 1 CV, then to 100% EtOAc over 1 CV, collected 25 mL fractions). Rf = 0.25 (6:1 EtOAc:hexanes);
mp = 95-97oC; 1H NMR (500 MHz, CDCl3) δ 3.65-3.45 (m, 1 H), 3.07 (dd, J= 10.0, 15.0 Hz, 1 H), 2.74 (s, 3 H), 2.56 (dd, J= 5.0, 15.0
Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ 171.0, 124.2 (q, J= 278 Hz), 64.4 (q, J= 31 Hz), 48.3, 29.5; HRMS-ESI (m/z) calcd for
C5H8F3N2O [M + H]+ 169.0583, found 169.0582.
5-Hexyl-1-methylpyrazolidin-3-one (6o). Starting with methanol (4.6 mL, 2.3 L/kg), KOH (32 mg, 0.58 mmoles, 0.05 equiv), methyl
hydrazine (671 uL, 12.7 mmoles, 1.10 equiv) and methyl 2-nonenoate (2.00 g, 11.50 mmoles, 1.00 equiv.), with 24 h reaction time at
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isopropanol in dichloromethane); H NMR (400 MHz, CDCl3) δ 8.93 (br s, 1 H), 2.90 (quintet, J = 6.9 Hz, 1 H), 2.74 (dd, J = 8.1, 16.4
Hz, 1 H), 2.53 (s, 3 H), 2.07 (dd, J = 3.8, 16.7 Hz, 1 H), 1.53-1.69 (m, 9 H), 0.83 (app t, J = 6.8 Hz, 3 H); 13C NMR (100 MHz, CDCl3)
δ 173.7; 65.5, 45.9, 35.7, 33.7, 31.6, 29.0, 25.9, 22.4, 13.9; HRMS-ESI (m/z) calcd for C10H21N2O [M + H]+ 185.1648, found 185.1647.
5-Methyl-1-phenylpyrazolidin-3-one (6i). To a 0-5 oC solution of toluene (202 mL, 13.5 L/kg), phenylhydrazine (15.0 g, 135 mmoles,
1.0 equiv) and methyl crotonate (17.9 g, 175 mmoles, 1.3 equiv) was charged potassium t-butoxide (20 wt% in THF, 75.5 g, 135 mmoles,
1.0 equiv) over ~1 h. After 7.5 h, added kicker charge of potassium t-butoxide (20 wt% in THF, 7.55 g, 135 mmoles, 0.1 equiv). The
reaction mixture was then warmed to 20-25 oC, and after 14 h, charged with acetic acid (~7 mL) until apparent pH = 7. Water (100 mL,
6.7 L/kg) was then added, followed by an additional ~3 mL AcOH to adjust pH to 7. The layers were separated, and the organic layer
was dried over MgSO4, filtered and concentrated to dryness to afford 24 g of a crude solid. The solids were then charged with MTBE
(25 mL), agitated for 2.5 h and filtered. The solids were then washed with MTBE (2 x 25 mL), and dried in vacuum oven at 45 oC to
afford 16.8 g of 6i as a pale yellow solid in 71% yield; mp = 123-125oC; H NMR (500 MHz, CDCl3) δ 9.00 (br s, 1 H), 7.33-7.27 (m,
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2 H), 7.08-7.03 (m, 3 H), 4.02-3.96 (m, 1 H), 2.91 (dd, J= 5.0, 15.0 Hz, 1 H), 2.03 (app d, J= 15.0 Hz, 1 H), 1.46 (d, J= 5.0 Hz, 3 H);
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13C NMR (125 MHz, CDCl3) δ 174.8, 151.0, 129.1, 123.0, 116.7, 63.5, 36.3, 21.4; HRMS-ESI (m/z) calcd for C10H13N2O [M + H]+
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General 2-Step Condensation/Reductive Amination Procedure. 5-Isopropyl-1-methylpyrazolidin-3-one hydrobromide (6j). To a 20-
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25 C solution of isopropanol (76 mL, 15.8 L/kg) and hydrazine hydrate (4.80 g, 50.5 wt%, 75.6 mmoles, 1.0 equiv) was charged
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isopropyl 4-methyl-2-pentenoate (13.0 g, 83.2 mmoles, 1.10 equiv). The reaction mixture was then heated to 80 C, and after 40 h,
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concentrated to dryness, followed by charging 1,2-dichloroethane (~40 mL) and reconcentrating to dryness to remove residual IPA.
Residue was then charged with 1,2-dichloroethane (151 mL, 31.5 L/kg) and formaldehyde (37 wt% in water, 6.80 g, 83.8 mmoles, 1.10
equiv). Reaction mixture was then placed in a cold water bath and charged sodium triacetoxyborohydride (67.5 g, 303 mmoles, 4.0
equiv) to control exotherm to <35 oC. Gas evolution also observed. The thick reaction mixture was then warmed to 20-25 oC, and after
1 h 45 min, charged with DCM (100 mL) and saturated aqueous NaHCO3 (100 mL). Gas evolution observed. Charged 5 N NaOH (~50
mL) to adjust pH to 8-9. Split layers and washed aqueous layer with DCM (3 x 50 mL). The combined organic layers were then dried
over MgSO4, filtered, concentrated to dryness, and charged isopropanol (10 mL, 2.1 L/kg). To a second RBF containing isopropanol
(34 mL, 7.1 L/kg), at 0-5°C was slowly charged acetyl bromide (10.3 g, 82.9 mmoles, 1.1 equiv) over ~10 min., maintaining the internal
temperature <25 °C. Note: strong exotherm observed. The HBr/IPA solution was then charged to reaction solution over ~1 h,
maintaining the internal temperature between 20‐25 °C. The RBF containing the HBr/IPA solution was then rinsed with isopropanol
(4.0 mL, 0.8 L/kg) and transferred to reaction mixture. The resulting slurry was then aged at 20‐25 °C for 1.5 h, filtered, sequentially
washed with isopropanol (18 mL, 3.8 L/kg) and MTBE (2 x 18 mL, 2 x 3.8 L/kg) and dried under vacuum at 50 °C to afford 12.4 g of
6j as a white solid in 74% yield (2-steps); mp =159-161oC; 1H NMR (500 MHz, D2O) δ 4.12-4.07 (m, 1 H), 3.22 (s, 3 H), 3.15-3.05 (m,
1 H), 2.83-2.73 (m, 1 H), 2.85-2.70 (m, 1 H), 1.02 (d, J= 5.0 Hz, 3 H), 0.97 (d, J= 5.0 Hz, 3 H); 13C NMR (125 MHz, D2O) δ 174.2,
74.6, 46.4, 31.2, 29.3, 18.2, 16.3; HRMS-ESI (m/z) calcd for C7H15N2O [M + H]+ 143.1179, found 143.1179.
1-Ethyl-5-methylpyrazolidin-3-one hydrobromide (6k). Starting with methanol (72 mL, 2.3 L/kg), hydrazine hydrate (3.79 g, 64 wt%,
75.8 mmoles, 1.0 equiv) and trans-methyl crotonate (8.52 g, 83.4 mmoles, 1.10 equiv), with 5 h reaction time at reflux, followed by 1,2-
dichloroethane (152 mL, 40.1 L/kg), acetaldehyde (8.15 g, 182 mmoles, 2.4 equiv) and sodium triacetoxyborohydride (25.4 g, 114
mmoles, 1.5 equiv), with 3 h reaction time at 20-25 oC and then additional acetaldehyde (2.8 g, 63 mmoles, 0.8 equiv). and 1 h reaction
time, along with 15 x 75 mL DCM washed during workup to fully back extract product, isolated 12.5 g of 6k as a white solid in 79%
yield (2-steps) after HBr salt formation; mp = 158-160oC; 1H NMR (500 MHz, D2O) δ 4.34-4.27 (m, 1 H), 3.63-3.56 (m, 1 H), 3.45-
3.38 (m, 1 H), 3.11 (dd, J= 10.0, 15.0 Hz, 1 H), 2.59 (dd, J = 5.0, 15.0 Hz, 1 H), 1.52 (d, J= 5.0 Hz, 3 H), 1.30 (t, J = 5.0 Hz, 3 H); 13
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NMR (125 MHz, D2O) δ 174.6, 63.4, 53.5, 35.7, 16.3, 8.5; HRMS-ESI (m/z) calcd for C6H13N2O [M + H]+ 129.1022, found 129.1023.
1-Benzyl-5-methylpyrazolidin-3-one hydrobromide (6l). Started with methanol (95 mL, 2.3 L/kg), hydrazine hydrate (5.00 g, 64 wt%,
99.9 mmoles, 1.0 equiv) and trans-methyl crotonate (11.2 g, 110 mmoles, 1.10 equiv), with 5 h reaction time at reflux, followed by 1,2-
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dichloroethane (200 mL, 40 L/kg), benzaldehyde [11.7 g, 110 mmoles, 1.1 equiv, age 8 h before adding NaBH(OAc)3] and sodium
triacetoxyborohydride (33.4 g, 150 mmoles, 1.5 equiv), with 17 h reaction time at 20-25 oC. Benzaldehyde [21.07 g, 10.0 mmoles, 0.10
equiv, age 8 h before NaBH(OAc)3 kicker] and sodium triacetoxyborohydride (33.4 g, 150 mmoles, 1.5 equiv) kickers were then added,
and after an additional 17 h, charged additional benzaldehyde (21.07 g, 10.0 mmoles, 0.10 equiv), aged 2 h, and sodium
triacetoxyborohydride (33.4 g, 150 mmoles, 1.5 equiv). After 20 h, added additional sodium triacetoxyborohydride (4.46 g, 20 mmoles,
0.2 equiv). After an additional 21 h, completed workup to afford 19.8 g of 6l as a white solid in 73% yield (2-steps) after HBr salt
formation; mp = 184-186oC; 1H NMR (500 MHz, D2O) δ 7.5-7.25 (m, 5 H), 4.68-4.50 (m, 1 H), 4.50-4.40 (m, 1 H), 4.40-4.25 (m, 1 H),
2.80-2.70 (m, 1 H), 2.45-2.35 (m, 1 H), 1.45-1.30 (m, 3 H); 13C NMR (125 MHz, D2O) δ 174.5, 131.6, 130.0, 129.5, 127.3, 62.9, 61.5,
35.6, 16.6; HRMS-ESI (m/z) calcd for C11H15N2O [M + H]+ 191.1179, found 191.1177.
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1-Cyclohexyl-5-methylpyrazolidin-3-one hydrobromide (6m). Starting with methanol (72 mL, 2.3 L/kg), hydrazine hydrate (3.79 g, 64
wt%, 75.8 mmoles, 1.0 equiv) and trans-methyl crotonate (8.52 g, 83.4 mmoles, 1.10 equiv), with 5 h reaction time at reflux, followed
by 1,2-dichloroethane (152 mL, 40.1 L/kg), cyclohexanone (8.36 g, 83.5 mmoles, 1.1 equiv) and sodium triacetoxyborohydride (25.4
g, 114 mmoles, 1.5 equiv), with 6.5 h reaction time at 20-25 oC, isolated 15.7 g of 6m as a white solid in 79% yield (2-steps) after HBr
salt formation; mp = 189-191oC; 1H NMR (500 MHz, D2O) δ 4.56-4.49 (m, 1 H), 3.57-3.28 (m, 1 H), 3.12 (dd, J= 10.0, 15.0 Hz, 1 H),
2.53 (dd, J= 5.0, 20.0 Hz, 1 H), 2.06-2.00 (m, 2 H), 1.87-1.84 (m, 2 H), 1.64-1.61 (m, 1 H),1.52 (d, J= 5.0 Hz, 3 H), 1.45-1.25 (m, 4 H),
1.15-1.07 (m, 1 H); 13C NMR (125 MHz, D2O) δ 174.5, 67.7, 60.6, 36.7, 26.9, 25.7, 24.3, 24.1, 23.9, 17.8; HRMS-ESI (m/z) calcd for
C10H19N2O [M + H]+ 183.1492, found 183.1491.
1-Hexyl-5-(trifluoromethyl)pyrazolidin-3-one (6p). Starting with methanol (20 mL), hydrazine monohydrate (658 µL, 13.60 mmoles,
1.10 equiv) and methyl 4,4,4-trifluorocrotonate (1.62 mL, 12.30 mmoles, 1.00 equiv), with 0.5 h reaction time at 20-25oC, followed by
1,2-dichloroethane (20 mL), hexanal [2.25 mL, 18.50 mmoles, 1.50 equiv, aged 2.5 h before adding NaBH(OAc)3] and sodium
triacetoxyborohydride (4.71 g, 21.60 mmoles, 1.75 equiv), with 15 h reaction time at 20-25 oC, isolated 2.68 g of 6p as a thick oil that
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NMR (400 MHz, CDCl3) δ 8.07 (br s, 1 H), 3.64 (dqd, J = 2.9, 7.4, 10.2 Hz, 1 H), 3.04 (dd, J = 9.9, 17.7 Hz, 1 H), 2.83 (t, J = 7.6 Hz,
2 H), 2.50 (dd, J = 2.9, 17.8 Hz, 1 H), 1.46-1.59 (m, 2 H), 1.26-1.42 (m, 6 H), 0.90 (app t, J = 7.0 Hz, 3 H); 13C NMR (100 MHz, CDCl3)
δ 171.8, 124.6 (q, J = 279.6 Hz), 62.5 (q, J = 31.0 Hz), 61.1, 31.4, 29.2, 26.8, 26.3, 22.5, 13.9; HRMS-ESI (m/z) calcd for C10H18F3N2O
[M + H]+ 239.1366, found 239.1364.
Method for 2-Step Amidation/Cyclization Route. 1-tert-Butyl-5-methylpyrazolidin-3-one (6n). To a solution of DCM (41 mL, 8.2
L/kg) and 3-chlorobutyricacid (5.00 g, 40.8 mmoles, 1.0 equiv) was charged 1 drop of DMF. Cooled solution to 0-5 oC and charged
oxalyl chloride (4.3 mL, 50 mmoles, 1.2 equiv) over 1 min. Allowed reaction mixture to warm to 20-25 oC during which time slow gas
evolution was observed. After 8 h, concentrated to dryness, followed by charging and reconcentrating with DCM (2 x 40 mL). Charged
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residue with DCM (41 mL, 8.2 L/kg) and quantified by 1H NMR using 1,2-dichloroethane as internal standard to verify in-process DCM
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solution contained 7.88 wt% acid chloride intermediate. Based on solution mass = 59.61 g, solution yield = 82%. H NMR of acid
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chloride (400 MHz, CDCl3) δ 4.46-4.37 (m, 1 H), 3.30 (app dddd, J= 7.8, 17.2, 17.2, 17.2 Hz, 2 H), 1.58 (d, J= 6.6 Hz, 3 H); To t-
butylhydrazine hydrochloride (5.29 g, 42.5 mmoles, 2.0 equiv) and sodium bicarbonate (3.57 g, 42.5 mmoles, 2.0 equiv) was charged
DCM (38 mL, 1 L/kg) and water (38 mL, 1 L/kg). After aging at 20-25 oC for 5 min, during which time minor gas evolution was slowly
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pump over 3.5 h. After an additional 15 min., warmed reaction mixture to 40 oC, and after an additional 24 h, cooled to 20-25 oC. Split
layers (pH aq layer = 2; saved product rich aqueous layer) and washed DCM layer with 0.5 M aqueous H3PO4 (2 x 15 mL). To the
combined aqueous layers, charged DCM (20 mL), followed by the slow addition of 45 wt% aqueous KOH (9.5 mL), keeping internal
temperature <28 oC, to increase pH to 12. Split layers, and washed aqueous layer with DCM (4 x 20 mL). Dried combined product-
rich DCM layers over MgSO4, filtered, concentrated to dryness and purified by ISCO chromatography (80 g column, flow rate 60
mL/min, gradient 100% DCM for 1 CV, then to 10% MeOH over 6 CV) to afford 2.80 g of 6n as a white solid in 84% yield; Rf = 0.44
(10% MeOH in DCM); mp = 84-86oC; 1H NMR (400 MHz, CDCl3) δ 8.87 (br s, 1 H), 3.55-3.47 (m, 1 H), 2.81 (dd, J= 9.1, 17.0 Hz, 1
H), 1.86 (dd, J= 1.8, 17.0 Hz, 1 H), 1.17 (d, J= 6.6 Hz, 3 H), 1.05 (s, 9 H); 13C NMR (100 MHz, CDCl3) δ 174.6, 58.7, 51.3, 37.9, 25.3,
23.6; HRMS-ESI (m/z) calcd for C8H17N2O [M + H]+ 157.1335, found 157.1335.
General Method for Halogenation. 3-Bromo-1,5-dimethyl-4,5-dihydro-1H-pyrazole (8a). To a mixture of 6a (10.00 g, 50.73 mmoles,
1.0 equiv) and tetraethylammonium bromide (3.20 g, 15.2 mmoles, 0.3 equiv) in dichloromethane (30 mL, 3.0 L/kg) at 20‐25 °C was
charged triethylamine (4.62 g, 45.7 mmoles, 0.90 equiv) over 2-3 minutes, maintaining the internal temperature <35 °C. The resulting
reaction mixture was then cooled to 0‐5 °C and charged with a solution of POBr3 in dichloromethane [prepared with 18.9 g (65.9
mmoles, 1.3 equiv) POBr3 and 20 mL (2.0 L/kg) dichloromethane] over 5-10 minutes, maintaining the internal temperature <20 °C.
The reaction mixture was then warmed to 30 °C and agitated for 5 h. In a separate reactor containing a 0-5 °C solution of water (190
mL, 3.7 L/mole) and NaOH (9.14 g, 228 mmoles, 4.5 equiv) was slowly charged the bulk reaction mixture, maintaining the internal
temperature <20 °C, followed by a dichloromethane rinse (5 mL, 0.1 L/mole). The resulting biphasic mixture was then warmed to 20‐
25 °C, agitated for 0.5 h, and the aqueous layer checked by pH. Target: 4 < pH < 5. If pH <4, adjusted with 2 N aqueous NaOH; if pH
>5, adjusted with 2 N aqueous H3PO4. Split layers, and washed lower product-rich organic layer sequentially with 0.1 M NaH2PO4 (50
mL, 0.975 L/mole) and water (50 mL, 0.975 L/mole). Isolated 91.36 g of final 8a/DCM solution. Quantified wt% by 1H QNMR (d1 =
5 sec) using 1,2-dichloroethane as internal standard. For 10 g scale batch, final 8a/DCM solution = 8.78 wt% and in‐process yield =
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89%. H NMR (500 MHz, CDCl3) δ 3.16-3.07 (m, 1 H), 2.93 (dd, J= 9.4, 16.4 Hz, 1 H), 2.30 (s, 3 H), 2.62 (dd, J= 13.9, 16.1 Hz, 1 H),
1.27 (d, J= 6.3 Hz, 3 H).
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3-Bromo-1,4-dimethyl-4,5-dihydro-1H-pyrazole (8b). Starting from 6b (10.00 g, 51.27 mmoles, 1.0 equiv), tetraethylammonium
bromide (3.23 g, 15.4 mmoles, 0.3 equiv), triethylamine (4.67 g, 46.2 mmoles, 0.90 equiv), DCM (30 mL, 3 L/kg), and POBr3 (19.11
g, 66.66 mmoles, 1.3 equiv) in DCM (20 mL, 2 L/kg), with a DCM (10 mL, 1 L/kg) rinse, 7 h reaction time, and aqueous workup,
isolated 95.25 g of final 8b/DCM solution. Final 8b/DCM solution = 8.06 wt% and in‐process yield = 85%. 1H NMR (500 MHz,
CDCl3) δ 3.37 (dd, J= 10.0, 10.0 Hz, 1 H), 3.16-3.08 (m, 1 H), 2.75 (s, 3 H), 2.61 (dd, J= 10.0, 10.0 Hz, 1 H), 1.16 (d, J = 5.0 Hz, 3 H).
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3-Bromo-5-ethyl-1-methyl-4,5-dihydro-1H-pyrazole (8c). Starting from 6c (10.72 g, 51.27 mmoles, 1.0 equiv), tetraethylammonium
bromide (3.23 g, 15.4 mmoles, 0.3 equiv), triethylamine (4.67 g, 46.2 mmoles, 0.90 equiv), DCM (30 mL, 2.8 L/kg), and POBr3 (19.11
g, 66.66 mmoles, 1.3 equiv) in DCM (20 mL, 1.9 L/kg), with a DCM (10 mL, 0.93 L/kg) rinse, 4 h reaction time, and aqueous workup,
isolated 100.58 g of final 8c/DCM solution. Final 8c/DCM solution = 9.45 wt% and in‐process yield = 97%. 1H NMR (500 MHz,
CDCl3) δ 3.01-2.90 (m, 2 H), 2.73 (s, 3 H), 2.65 (dd, J= 15.0, 15.0 Hz, 1 H), 1.80-1.73 (m, 1 H), 1.56-1.47 (m, 1 H), 0.89 (t, J= 10.0
Hz, 3 H).
3-Bromo-5-isopropyl-1-methyl-4,5-dihydro-1H-pyrazole (8j). Starting from 6j (10.04 g, 45.00 mmoles, 1.0 equiv), tetraethylammonium
bromide (2.84 g, 13.5 mmoles, 0.3 equiv), triethylamine (4.09 g, 40.04 mmoles, 0.90 equiv), DCM (27 mL, 2.7 L/kg), and POBr3 (16.78
g, 58.53 mmoles, 1.3 equiv) in DCM (18 mL, 1.8 L/kg), with a DCM (9 mL, 0.89 L/kg) rinse, 3.5 h reaction time, and aqueous workup,
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isolated 92.85 g of final 8j/DCM solution. Final 8j/DCM solution = 9.88 wt% and in‐process yield = 99%. H NMR (500 MHz, CDCl3)
δ 3.02-2.97 (m, 1 H), 2.82-2.70 (m, 2 H), 2.74 (s, 3 H), 1.97-1.91 (m, 1 H), 0.91 (d, J= 6.9 Hz, 3 H), 0.87 (d, J= 6.7 Hz, 3 H).
3-Bromo-1-ethyl-5-methyl-4,5-dihydro-1H-pyrazole (8k). Starting from 6k (10.72 g, 51.27 mmoles, 1.0 equiv), tetraethylammonium
bromide (3.23 g, 15.4 mmoles, 0.3 equiv), triethylamine (4.67 g, 46.2 mmoles, 0.90 equiv), DCM (30 mL, 2.8 L/kg), and POBr3 (19.11
g, 66.66 mmoles, 1.3 equiv) in DCM (20 mL, 1.9 L/kg), with a DCM (10 mL, 0.93 L/kg) rinse, 3 h reaction time, and aqueous workup,
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isolated 110.07 g of final 8k/DCM solution. Final 8k/DCM solution = 8.72 wt% and in‐process yield = 98%. H NMR (500 MHz,
CDCl3) δ 3.35-3.22 (m, 1 H), 3.05-2.92 (m, 2 H), 2.76-2.70 (m, 1 H), 2.61 (dd, J= 10.0, 15.0 Hz, 1 H), 1.26 (d, J= 5.0 Hz, 3 H), 1.21 (t,
J= 10.0 Hz, 3 H).
1-Benzyl-3-bromo-5-methyl-4,5-dihydro-1H-pyrazole (8l). Starting from 6l (10.00 g, 36.88 mmoles, 1.0 equiv), tetraethylammonium
bromide (2.33 g, 11.1 mmoles, 0.3 equiv), triethylamine (3.36 g, 33.2 mmoles, 0.90 equiv), DCM (22 mL, 2.2 L/kg), and POBr3 (13.75
g, 47.96 mmoles, 1.3 equiv) in DCM (14.4 mL, 1.4 L/kg), with a DCM (8 mL, 0.8 L/kg) rinse, 3 h reaction time, and aqueous workup,
isolated 79.67 g of final 8l/DCM solution. Final 8l/DCM solution = 10.77 wt% and in‐process yield = 92%. 1H NMR (500 MHz,
CDCl3) δ 7.28−7.20 (m, 5 H), 3.58 (ABq, 2 H, ΔδAB = 67.5, JAB = 12.5 Hz), 3.31-3.23 (m, 1 H), 2.88 (dd, J= 10.0, 15.09 Hz, 1 H), 2.58
(dd, J= 15.0, 16.0 Hz, 1 H), 1.16 (d, J= 5.0 Hz, 3 H).
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3-Bromo-1-cyclohexyl-5-methyl-4,5-dihydro-1H-pyrazole (8m). Starting from 6m (10.00 g, 38.00 mmoles, 1.0 equiv),
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tetraethylammonium bromide (2.40 g, 11.4 mmoles, 0.3 equiv), triethylamine (3.46 g, 34.2 mmoles, 0.90 equiv), DCM (22 mL, 2.2
L/kg), and POBr3 (14.20 g, 49.53 mmoles, 1.3 equiv) in DCM (15 mL, 1.5 L/kg), with a DCM (8 mL, 0.8 L/kg) rinse, 3 h reaction time,
and aqueous workup, isolated 74.11 g of final 8m/DCM solution. Final 8m/DCM solution = 12.54 wt% and in‐process yield = 99%.
1H NMR (500 MHz, CDCl3) δ 3.64-3.56 (m, 1 H), 2.96 (dd, J= 10.0, 20.0 Hz, 1 H), 2.72-2.65 (m, 1 H), 2.57 (dd, J= 12.5, 17.5 Hz, 1
H), 1.87-1.77 (m, 4 H), 1.66-1.58 (m, 2 H), 1.31-1.20 (m, 1 H), 1.24 (d, J= 5.0 Hz, 3 H), 1.20-1.09 (m, 3 H).
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Methyl 3-bromo-1-methyl-4,5-dihydro-1H-pyrazole-5-carboxylate (8g). Starting from 6g (10.00 g, 92 wt%, 38.48 mmoles, 1.0 equiv),
tetraethylammonium bromide (2.43 g, 11.6 mmoles, 0.3 equiv), triethylamine (8.96 g, 88.5 mmoles, 2.3 equiv), DCM (22.5 mL, 2.25
L/kg), and POBr3 (14.34 g, 50.02 mmoles, 1.3 equiv) in DCM (15 mL, 1.5 L/kg), with a DCM (8 mL, 0.8 L/kg) rinse, 3 h reaction time,
and aqueous workup, isolated 82.12 g of final 8g/DCM solution. Final 8g/DCM solution = 5.08 wt% and in‐process yield = 49%. ~10%
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oxidized product 9g was also observed by HPLC. H NMR (400 MHz, CDCl3) δ 3.72 (s, 3 H), 3.69-3.66 (m, 1 H), 3.27 (dd, J= 12.6,
16.9 Hz, 1 H), 3.13 (dd, J= 11.1, 16.9 Hz, 1 H), 2.85 (s, 3 H).
3-Bromo-1-methyl-4,5-dihydro-1H-pyrazole (8d). Starting from 6d (7.91 g, 79.0 mmoles, 1.0 equiv), tetraethylammonium bromide
(4.98 g, 23.7 mmoles, 0.3 equiv), DCM (57 mL, 7.2 L/kg), and POBr3 (29.4 g, 103 mmoles, 1.3 equiv) in DCM (29 mL, 3.7 L/kg), 19
h reaction time, and analogous aqueous workup as 8a but using water (273 mL, 34.5 L/kg) and 85% KOH (23.5 g, 356 mmoles, 4.5
equiv), keeping pH >10 to prevent product decomposition, isolated 147.87 g of final 8d/DCM solution. Final 8d/DCM solution = 4.42
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wt% and in‐process yield = 51%. H NMR (500 MHz, CDCl3) δ 3.34-3.16 (m, 2 H), 3.06-2.95 (m, 2 H), 2.87 (br s, 3 H).
3-Bromo-1-methyl-5-phenyl-4,5-dihydro-1H-pyrazole (8e). Starting from 6e (5.02 g, 28.5 mmoles, 1.0 equiv), tetraethylammonium
bromide (1.80 g, 8.56 mmoles, 0.3 equiv), DCM (17 mL, 3.4 L/kg), and POBr3 (10.60 g, 36.97 mmoles, 1.3 equiv) in DCM (11 mL, 2.2
L/kg), 2 h reaction time, and analogous aqueous workup as 8a, but using water (106 mL, 21.1 L/kg) and NaOH (6.27 g, 157 mmoles,
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5.5 equiv) isolated 58.78 g of final 8e/DCM solution. Final 8e/DCM solution = 10.9 wt% and in‐process yield = 94%. H NMR (500
MHz, CDCl3) δ 7.41-7.27 (m, 5 H), 4.05 (dd, J= 10.0, 15.0 Hz, 1 H), 3.21 (dd, J= 10.0, 15.0 Hz, 1 H), 3.00 (dd, J= 15.0, 15.0 Hz, 1 H),
2.70 (s, 3 H).
3-Bromo-1-methyl-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazole (8f). Starting from 6f (5.00 g, 29.7 mmoles, 1.0 equiv),
tetraethylammonium bromide (1.90 g, 9.04 mmoles, 0.3 equiv), DCM (30 mL, 6 L/kg), and POBr3 (11.10 g, 38.72 mmoles, 1.3 equiv)
in DCM (15 mL, 3 L/kg), 9 h reaction time, and analogous aqueous workup as 8a, but using water (95 mL, 19 L/kg), NaOH (4.16 g,
104 mmoles, 3.5 equiv) and adding aqueous NaOH to reaction mixture, isolated 103.38 g of final 8f/DCM solution. Final 8f/DCM
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solution = 5.45 wt% and in‐process yield = 82%. H NMR (500 MHz, CDCl3) δ 3.69-3.62 (m, 1 H), 3.25 (dd, J = 11.4, 17.5, Hz, 1 H),
3.15 (dd, J= 11.7, 17.5 Hz, 1 H), 2.92 (br s, 3 H).
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3-Bromo-5-methyl-1-phenyl-4,5-dihydro-1H-pyrazole (8i). Starting from 6i (10.00 g, 56.75 mmoles, 1.0 equiv), tetraethylammonium
bromide (3.20 g, 15.2 mmoles, 0.3 equiv), DCM (57 mL, 5.7 L/kg), triethylamine (5.22 g, 51.1 mmoles, 0.9 equiv) and POBr3 (21.2 g,
73.9 mmoles, 1.3 equiv) in DCM (29 mL, 2.9 L/kg), 8 h reaction time at 0-5 oC, and aqueous workup, isolated 493.40 g of final 8i/DCM
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solution, containing some other minor byproducts. Final 8i/DCM solution = 1.80 wt% and in‐process yield = 65%. H NMR (500 MHz,
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CDCl3) δ 7.27 (app br s, 2 H), 7.04 (app br s, 2 H), 6.88 (app br s, 1 H), 4.38 (app br s, 1 H), 3.42 (app br s, 1 H), 2.82 (app br s, 1 H),
1.32 (app br s, 3 H).
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3-Bromo-1-tert-butyl-5-methyl-4,5-dihydro-1H-pyrazole (8n). Starting from 6n (2.40 g, 15.4 mmoles, 1.0 equiv), tetraethylammonium
bromide (0.97 g, 4.6 mmoles, 0.3 equiv), DCM (16 mL, 6.7 L/kg), and POBr3 (5.75 g, 20.1 mmoles, 1.3 equiv) in DCM (8 mL, 3.3
L/kg), 4.5 h reaction time, and analogous aqueous workup as 8a, but using water (48 mL, 20 L/kg) and NaOH (2.15 g, 53.7 mmoles,
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3.5 equiv), isolated 41.36 g of final 8n/DCM solution. Final 8n/DCM solution = 7.37 wt% and in‐process yield = 91%. H NMR (500
MHz, CDCl3) δ 3.69-3.61 (m, 1 H), 3.18 (dd, J= 11.4, 17.3 Hz, 1 H), 2.59 (dd, J= 9.6, 17.3 Hz, 1 H), 1.30 (d, J= 6.0 Hz, 3 H), 1.16 (s,
9 H).
General Method for Oxidation using NaOCl/KBr. 3-Bromo-1,5-dimethyl-1H-pyrazole (9a). To a 0‐5 °C solution of potassium
phosphate tribasic (9.52 g, 44.8 mmoles, 2.0 equiv), potassium bromide (1.33 g, 11.2 mmoles, 0.5 equiv) and water (45 mL, 2.0 L/mole
8a) was charged crude 8a/DCM solution (44.20 g solution, 8.78 wt% 8a in DCM, 21.9 mmoles, 1.0 equiv). Aqueous bleach (27.2 g,
10.5 wt% in water, 38.4 mmoles, 1.75 equiv) was then added via syringe pump subsurface using a Teflon tube as the needle over 2.5-3
h, maintaining reaction mixture at 0‐5 °C. The reaction mixture was then agitated at 0-5 °C for an additional 2.5 h before charging water
(8 mL, 0.36 L/mole 8a) to fully dissolve solids. Split layers, and the lower organic phase was charged into a 0-5 °C solution of 0.1 M
aqueous sodium thiosulfate (45 mL, 2.0 L/mole 8a), maintaining the internal temperature between 0-5 °C. Split layers, and the lower
DCM phase was charged with triethylamine (1.12 g, 11.0 mmoles, 0.5 equiv), warmed to 30-35 °C, and after 15.5 h, cooled to 20‐25
°C, dried over MgSO4, filtered and concentrated to dryness. Purified residue (2.1 : 1 9a:10a) by SiO2 (5 cm diameter column, 6 in SiO2,
flow rate = 1 in/min, gradient = 8:1 hex:EtOAc for 1 CV then 4:1 for 4 CV) to afford 2.22 g of 9a as a colorless oil in 58% yield which
solidified upon standing; Rf 9a = 0.15 (10% EtOAc in hexanes); mp = 35-38oC; 1H NMR (500 MHz, CDCl3) δ 6.02 (s, 1 H), 3.74 (s, 3
H), 2.25 (s, 3 H); 13C NMR (125 MHz, CDCl3) δ140.7, 124.0, 107.6, 36.2, 10.9; HRMS-ESI (m/z) calcd for C5H8BrN2 [M + H]+
174.9865, found 174.9864.
3-Bromo-1,4-dimethyl-1H-pyrazole (9b). Starting from potassium phosphate tribasic (9.08 g, 42.8 mmoles, 2.0 equiv), potassium
bromide (1.27 g, 10.7 mmoles, 0.5 equiv), water (43 mL, 2.0 L/mole 8b), 8b/DCM solution (47.00 g solution, 8.06 wt% 8b in DCM,
21.4 mmoles, 1.0 equiv), aqueous bleach (26.5 g, 10.5 wt% in water, 37.4 mmoles, 1.75 equiv added over 3 h, then after an additional
2 h, 1.53 g, 2.16 mmoles, 0.10 equiv kicker added over 12 min and 1 h further reaction time), and triethylamine (1.08 g, 10.6 mmoles,
0.5 equiv with 14 h @ 30-35 oC), isolated 1.86 g of 9b as a colorless oil in 50% yield after SiO2 purification (5 cm diameter column, 9
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in SiO2, flow rate = 1 in/min, gradient = 8:1 hex:EtOAc for 1 CV, 4:1 for 4 CV, 1:1 till end); Rf 9b = 0.18 (10% EtOAc in hexanes);
1H NMR (500 MHz, CDCl3) δ 7.09 (s, 1 H), 3.82 (s, 3 H), 2.00 (s, 3 H); 13C NMR (125 MHz, CDCl3) δ 130.0, 126.9, 116.4, 39.2, 8.9;
HRMS-ESI (m/z) calcd for C5H8BrN2 [M + H]+ 174.9865, found 174.9865.
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3-Bromo-5-ethyl-1-methyl-1H-pyrazole (9c). Starting from potassium phosphate tribasic (9.09 g, 42.8 mmoles, 2.0 equiv), potassium
bromide (1.27 g, 10.7 mmoles, 0.5 equiv), water (43 mL, 2.0 L/mole 8c), 8c/DCM solution (43.30 g solution, 9.45 wt% 8c in DCM,
21.4 mmoles, 1.0 equiv), aqueous bleach (25.0 g, 10.5 wt% in water, 35.3 mmoles, 1.65 equiv added over 3 h, then after an additional
2 h, 1.53 g, 2.16 mmoles, 0.10 equiv kicker added over 5 min and 1 h further reaction time), and triethylamine (1.09 g, 10.7 mmoles,
0.5 equiv with 30 h @ 30-35 oC), isolated 2.20 g of 9c as a colorless oil in 54% yield after SiO2 purification (6.5 cm diameter column,
9 in SiO2, flow rate = 1 in/min, gradient = 8:1 hex:EtOAc for 1 CV, 4:1 for 3.5 CV, 1:1 till end); Rf 9c = 0.21 (10% EtOAc in hexanes);
1H NMR (500 MHz, CDCl3) δ 5.99 (s, 1 H), 3.70 (s, 3 H), 2.55 (q, J= 7.5 Hz, 2 H), 1.21 (t, J= 7.5 Hz, 3 H); 13C NMR (125 MHz,
CDCl3) δ 146.8, 124.0, 105.9, 36.1, 18.7, 12.3; HRMS-ESI (m/z) calcd for C6H10BrN2 [M + H]+ 189.0022, found 189.0021.
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3-Bromo-1-methyl-1H-pyrazole (9d). Starting from potassium phosphate tribasic (4.90 g, 23.1 mmoles, 2.0 equiv), potassium bromide
(0.69 g, 5.8 mmoles, 0.5 equiv), water (23 mL, 2.0 L/mole 8d), 8d/DCM solution (90.00 g solution, 2.09 wt% 8d in DCM, 11.5 mmoles,
1.0 equiv), aqueous bleach (11.1 g, 10.8 wt% in water, 16.1 mmoles, 1.4 equiv added over 3 h, then after an additional 1.5 h, 1.6 g, 2.3
mmoles, 0.20 equiv kicker added over 25 min, then after an additional 0.5 h, 2.0 g, 2.9 mmoles, 0.25 equiv kicker added over 20 min,
then after an additional 1 h, 1.6 g, 2.3 mmoles, 0.20 equiv kicker added over 1 min, then after an additional 1 h, 1.6 g, 2.3 mmoles, 0.20
equiv kicker added in one portion and 30 min further reaction time), and triethylamine (0.590 g, 5.77 mmoles, 0.5 equiv with 14 h @
30-35 oC), isolated 1.38 g of 9d as a pale orange oil in 74% yield after ISCO purification (120 g column, flow rate 85 mL/min, gradient
100% hexanes for 1 CV, then to 10% EtOAc over 1 CV, 10% EtOAc for 1 CV then to 20% EtOAc over 1 CV, 20% EtOAc for 4 CV,
then to 35% EtOAc over 1 CV, 35% EtOAc for 4 CV then to 65% EtOAc over 1 CV); Rf 9d = 0.15 (10% EtOAc in hexanes); 1H NMR
(500 MHz, CDCl3) δ 7.24 (d, J= 5.0 Hz, 1 H), 6.21 (d, J= 5.09 Hz, 1 H), 3.85 (s, 3 H); 13C NMR (125 MHz, CDCl3) δ 132.0, 124.9,
108.4, 39.3; HRMS-ESI (m/z) calcd for C4H6BrN2 [M + H]+ 160.9709, found 160.9708.
3-Bromo-1-methyl-5-phenyl-1H-pyrazole (9e). Starting from potassium phosphate tribasic (9.09 g, 42.8 mmoles, 2.0 equiv), potassium
bromide (1.27 g, 10.7 mmoles, 0.5 equiv), water (43 mL, 2.0 L/mole 8e), 8e/DCM solution (48.9 g solution, 10.46 wt% 8e in DCM,
21.4 mmoles, 1.0 equiv), aqueous bleach (22.8 g, 10.5 wt% in water, 32.2 mmoles, 1.5 equiv added over 3 h, then after an additional
2.5 h, 3.79 g, 5.35 mmoles, 0.25 equiv kicker added over 15-20 min, and 30 min further reaction time), and triethylamine (1.09 g, 10.7
mmoles, 0.5 equiv with 16 h @ 30-35 oC), isolated 3.54 g of 9e as a pale yellow oil in 70% yield after ISCO purification (220 g column,
flow rate 150 mL/min, gradient 100% hexanes for 1 CV, then to 10% EtOAc over 1 CV, 10% EtOAc for 3.5 CV then to 100% EtOAc
over 15 CV); Rf 9e = 0.30 (10% EtOAc in hexanes); 1H NMR (500 MHz, CDCl3) δ 7.49-7.38 (m, 5 H), 6.32 (s, 1 H), 3.86 (s, 3 H); 13
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NMR (125 MHz, CDCl3) δ 145.8, 129.3, 129.0, 128.8, 128.7, 124.8, 108.3, 37.6; HRMS-ESI (m/z) calcd for C10H10BrN2 [M + H]+
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Methyl 3-bromo-1-methyl-1H-pyrazole-5-carboxylate (9g). Starting from potassium phosphate tribasic (6.34 g, 29.9 mmoles, 2.0
equiv), potassium bromide (0.89 g, 7.5 mmoles, 0.5 equiv), water (30 mL, 2.0 L/mole 8g), 8g/DCM solution (65.0 g solution, 5.08 wt%
8g in DCM, 14.9 mmoles, 1.0 equiv), aqueous bleach (12.4 g, 10.8 wt% in water, 18.0 mmoles, 1.2 equiv added over 3 h, with no
additional age time required), and triethylamine (0.76 g, 7.5 mmoles, 0.5 equiv with 17 h @ 30-35 oC), isolated 2.63 g of 9g as a colorless
oil in 80% yield after ISCO purification (120 g column, flow rate 85 mL/min, gradient 100% hexanes for 1 CV, then to 50% DCM over
1 CV, 50% DCM for 4 CV then to 65% DCM over 1 CV); Rf 9g = 0.26 (50% DCM in hexanes); 1H NMR (400 MHz, CDCl3) δ 6.80
(s, 1 H), 4.14 (s, 3 H), 3.88 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 159.1, 134.0, 124.1, 113.3, 52.2, 39.8; HRMS-ESI (m/z) calcd for
C6H8BrN2O2 [M + H]+ 218.9764, found 218.9760.
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3-Bromo-5-isopropyl-1-methyl-1H-pyrazole (9j). Starting from potassium phosphate tribasic (9.09 g, 42.8 mmoles, 2.0 equiv),
potassium bromide (1.27 g, 10.7 mmoles, 0.5 equiv), water (43 mL, 2.0 L/mole 8j), 8j/DCM solution (44.4 g solution, 9.88 wt% 8j in
DCM, 21.4 mmoles, 1.0 equiv), aqueous bleach (26.6 g, 10.5 wt% in water, 37.5 mmoles, 1.75 equiv added over 3 h, with 1 h additional
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age time), and triethylamine (1.09 g, 10.7 mmoles, 0.5 equiv with 7 days @ 35-40 C), isolated 2.64 g of 9j as an orange oil in 61%
yield after ISCO purification (220 g column, flow rate 150 mL/min, gradient 100% hexanes for 1 CV, then to 10% EtOAc over 1.5 CV,
10% EtOAc for 3 CV then to 100% EtOAc over 10 CV); Rf 9j = 0.31 (4:1 hex:EtOAc); 1H NMR (500 MHz, CDCl3) δ 5.99 (s, 1 H),
3.73 (s, 3 H), 2.88 (sept, J= 10.0 Hz, 1 H), 1.20 (d, J= 10.0 Hz, 6 H); 13C NMR (125 MHz, CDCl3) δ 151.5, 124.1, 104.4, 36.2, 25.3,
21.9; HRMS-ESI (m/z) calcd for C7H12BrN2 [M + H]+ 203.0178, found 203.0177.
3-Bromo-1-cyclohexyl-5-methyl-1H-pyrazole (9m). Starting from potassium phosphate tribasic (5.43 g, 25.6 mmoles, 2.0 equiv),
potassium bromide (0.76 g, 6.39 mmoles, 0.5 equiv), water (26 mL, 2.0 L/mole 8m), 8m/DCM solution (25.00 g solution, 12.54 wt%
8m in DCM, 12.79 mmoles, 1.0 equiv), and aqueous bleach (13.6 g, 10.5 wt% in water, 19.2 mmoles, 1.5 equiv added over 3 h, with
no additional age time), isolated 2.20 g of 9m as a colorless oil in 71% yield after ISCO purification (120 g column, flow rate 85 mL/min,
gradient 100% hexanes for 2 CV, then to 10% EtOAc over 3 CV, 10% EtOAc for 4 CV then to 20% EtOAc over 3 CV). Note:
triethylamine treatment was not performed with this substrate; Rf 9m = 0.39 (10:1 hex:EtOAc); 1H NMR (400 MHz, CDCl3) δ 5.96 (s,
1 H), 3.93-3.85 (m, 1 H), 2.24 (s, 3 H), 1.98-1.84 (m, 6 H), 1.70-1.68 (m, 1 H), 1.41-1.22 (m, 3 H); 13C NMR (100 MHz, CDCl3) δ 139.3,
124.1, 107.2, 57.9, 32.6, 25.6, 25.0, 10.9; HRMS-ESI (m/z) calcd for C10H16BrN2 [M + H]+ 243.0491, found 243.0488.
3-Bromo-1-tert-butyl-5-methyl-1H-pyrazole (9n). Starting from potassium phosphate tribasic (5.00 g, 23.6 mmoles, 2.0 equiv),
potassium bromide (0.700 g, 5.88 mmoles, 0.5 equiv), water (23.5 mL, 2.0 L/mole 8n), 8n/DCM solution (35.0 g solution, 7.37 wt% 8n
in DCM, 11.8 mmoles, 1.0 equiv), and aqueous bleach (10.7 g, 9.80 wt% in water, 14.1 mmoles, 1.2 equiv added over 3 h, with 2 h
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additional age time), and triethylamine (0.60 g, 5.9 mmoles, 0.5 equiv with 15 h @ 30-35 oC), isolated 2.40 g of 9n as a pale yellow oil
in 94% yield after ISCO purification (80 g column, flow rate 50 mL/min, gradient 100% hexanes for 1 CV, then to 5% MeOH over 4
CV, 5% MeOH for 4 CV then to 20% MeOH); Rf 9n = 0.58 (5% MeOH in hex); 1H NMR (400 MHz, CDCl3) δ 6.01 (s, 1 H), 2.41 (s,
3 H), 1.61 (s, 9 H); 13C NMR (100 MHz, CDCl3) δ140.2, 122.5, 110.3, 60.7, 30.0, 14.5; HRMS-ESI (m/z) calcd for C8H14BrN2 [M +
H]+ 217.0335, found 217.0334.
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Oxidation using NBS. 3-Bromo-1-methyl-5-(trifluoromethyl)-1H-pyrazole (9f). To a 0‐5 °C solution of crude 8f/DCM solution (41.2
g solution, 7.11 wt% 8f in DCM, 12.7 mmoles, 1.0 equiv) was charged N-bromosuccinimide (1.48 g, 8.26 mmoles, 0.65 equiv). After
30 min, charged additional N-bromosuccinimide (1.48 g, 8.26 mmoles, 0.65 equiv). After 4 h, charged additional N-bromosuccinimide
(0.46 g, 2.6 mmoles, 0.20 equiv). After 17 h, charged 0.1 M aqueous Na2S2O3 (30 mL, 2.4 L/mole 8f) in 5 mL aliquots, maintaining
internal temperature <10 oC, followed by additional solid Na2S2O3 (2 g in 2 x 1 g portions). Charged 5 N NaOH (3 mL) to adjust pH to
10, followed by water (30 mL, 2.4 L/mole 8f). Split layers, washed lower DCM layer with saturated aqueous NaHCO3 (20 mL, 1.6
L/mole 8f), dried over MgSO4, filtered, concentrated and purified by ISCO chromatography (80 g column, flow rate 60 mL/min, gradient
100% hexanes for 2 CV, then to 10% EtOAc over 4 CV, 10% EtOAc till end) to afford 1.59 g of 9f as a colorless oil in 55% yield; Rf =
0.30 (10% EtOAc in hexanes); 1H NMR (400 MHz, CDCl3) δ 6.62 (s, 1 H), 3.97 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 133.8 (q, J=
40 Hz), 124.5, 119.0 (q, J= 268 Hz), 110.0, 38.4; HRMS-ESI (m/z) calcd for C5H5BrF3N2 [M + H]+ 228.9583, found 228.9582.
General Method for Oxidation using MnO2. 3-Bromo-5-methyl-1-phenyl-1H-pyrazole (9i). The crude 8i/DCM solution (250 g
solution, 1.80 wt% 8i in DCM, 18.8 mmoles, 1.0 equiv) was concentrated to dryness, charged toluene (65 mL, 3.5 L/mole 8i) and
o
manganese dioxide (16.4 g, 189 mmoles, 10.0 equiv), and warmed to 100-105 C. After 5 days, cooled to 20-25 oC filtered reaction
mixture through a pad of celite (16 g, 0.85 g/mole 8i) wetted with 1:1 DCM:2-propanol and washed with 1:1 DCM:2-propanol (3 x 50
mL portions). Combined filtrate was then further polish filtered, rinsing with 1:1 DCM:2-propanol (50 mL), and concentrated to dryness.
Purification by ISCO chromatography (220 g column, flow rate 150 mL/min, gradient 100% hexanes for 1 CV, then to 20% EtOAc
over 4 CV, 20% EtOAc for 4 CV then to 35% EtOAc over 2 CV) led to 2.51 g of 9i as an orange oil in 56% yield; Rf = 0.42 (5:1
hex:EtOAc); 1H NMR (500 MHz, CDCl3) δ 7.50-7.35 (m, 5 H), 6.22 (s, 1 H), 2.31 (s, 3 H); 13C NMR (125 MHz, CDCl3) δ 141.1, 138.9,
129.0, 128.0, 126.9, 124.8, 109.4, 12.2; HRMS-ESI (m/z) calcd for C10H10BrN2 [M + H]+ 237.0022, found 237.0019.
3-Bromo-1-ethyl-5-methyl-1H-pyrazole (9k). Starting from crude 8k/DCM solution (40.17 g solution, 8.72 wt% 8k in DCM, 18.3
mmoles, 1.0 equiv), toluene (30 mL, 1.64 L/mole 8k) and manganese dioxide (19.0 g, 219 mmoles, 12.0 equiv), with a manganese
dioxide (3.20 g, 37.0 mmoles, 2.0 equiv) kicker charge after 26 h at 105-110 oC and an additional 18 h age, isolated 1.46 g of 9k as a
pale yellow oil in 42% yield after ISCO purification (80 g column, flow rate 60 mL/min, gradient 100% hexanes for 1 CV, then to 30%
EtOAc over 3 CV, 30% EtOAc for 2 CV then to 100% EtOAc over 6 CV); Rf = 0.50 (2:1 hex:EtOAc); 1H NMR (500 MHz, CDCl3)
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δ 5.97 (s, 1 H), 4.01 (q, J= 7.5 Hz, 2 H), 2.23 (s, 3 H), 1.36 (t, J= 7.5 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 139.8, 124.2, 107.6, 44.1,
15.2, 10.7; HRMS-ESI (m/z) calcd for C6H10BrN2 [M + H]+ 189.0022, found 189.0020.
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1-Benzyl-3-bromo-5-methyl-1H-pyrazole (9l). Starting from crude 8l/DCM solution (25.00 g solution, 10.77 wt% 8l in DCM, 10.64
mmoles, 1.0 equiv), toluene (19 mL, 1.79 L/mole 8l) and manganese dioxide (9.25 g, 106 mmoles, 10.0 equiv), with a manganese
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dioxide (1.85 g, 21.3 mmoles, 2.0 equiv) kicker after 28 h at 105-110 C, and an additional 15 h age, isolated 1.32 g of 8l as a pale
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yellow oil in 49% yield after ISCO purification (120 g column, flow rate 85 mL/min, gradient 100% hexanes for 2 CV, then to 10%
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EtOAc over 3 CV, 10% EtOAc for 4 CV then to 20% EtOAc over 3 CV); Rf = 0.28 (5:1 hex:EtOAc); H NMR (500 MHz, CDCl3)
δ 7.35-7.27 (m, 3 H), 7.13 (d, J= 5.0 Hz, 2 H), 6.09 (s, 1 H), 5.25 (s, 2 H), 2.18 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 140.8, 136.1,
128.6, 127.6, 126.6, 124.7, 108.3, 53.2, 11.0; HRMS-ESI (m/z) calcd for C11H12BrN2 [M + H]+ 251.0178, found 251.0176.
General Procedure to Prepare 3-Chloropyrazoles. 3-Chloro-5-methyl-1-phenyl-1H-pyrazole (11a). To a -12 oC mixture of 6e (1.00
g, 5.68 mmoles, 1.00 equiv), dry tetraethylammonium chloride (282 mg, 1.70 mmoles, 0.30 equiv), 1,2-dichloroethane (6.00 mL, 6
L/kg) and triethylamine (712 µL, 5.11 mmoles, 0.90 equiv) was charged phosphorus oxychloride (686 µL, 7.38 mmoles, 1.30 equiv).
The mixture was then aged at 60 °C for 3 h. The clear solution was then cooled to room temperature and quenched by addition into a
1.0 M, pH = 7 sodium phosphate buffer (10 mL, 10 L/kg). The layers were separated and the organic layer was washed with saturated
aqueous brine (10 mL, 10 L/kg), dried over sodium sulfate, filtered and concentrated in vacuo to afford the intermediate
chlorodihydropyrazole as a dark oil (1.2 g). Charged acetonitrile (10 mL, 10 L/kg) and manganese dioxide (7.40 g, 85.12 mmoles, 15.00
equiv) and aged black slurry at 60 °C for 8 h. The reaction mixture was then cooled to room temperature and filtered through a plug of
Celite using acetonitrile to wash the cake (30 mL, 30 L/kg). The solution was then concentrated in vacuo to afford a dark red residue.
The residue was purified by flash column chromatography over silica gel (0 to 20% ethyl acetate in hexanes gradient) to afford 11a as
an orange oil (900 mg, 82% overall yield, 2 steps); 1H NMR (400 MHz, CDCl3) δ 7.50-7.38 (m, 5 H), 6.14 (d, J = 0.5 Hz, 1 H), 2.32 (d,
J = 0.8 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 140.9, 140.2, 139.0, 129.0, 128.0, 124.8, 106.0, 12.4; HRMS-ESI (m/z) calcd for
C10H10ClN2 [M + H]+ 193.0527, found 193.0525.
3-Chloro-1-methyl-5-phenyl-1H-pyrazole (11b). Starting from 6i (1.00 g, 5.68 mmoles, 1.00 equiv), dry tetraethylammonium chloride
(282 mg, 1.70 mmoles, 0.30 equiv), dichloromethane (6.00 mL, 6 L/kg), triethylamine (712 µL, 5.11 mmoles, 0.90 equiv) and
phosphorus oxychloride (686 µL, 7.38 mmoles, 1.30 equiv, added at -35 oC), with a 24 h age at 35 oC, followed by acetonitrile (10 mL,
10 L/kg) and manganese dioxide (7.40 g, 85.12 mmoles, 15.00 equiv) with a 17 h age at 60 oC, isolated 844 mg of 11b as a yellow waxy
solid in 77% yield (2-steps) after ISCO purification (0 to 20% ethyl acetate in hexanes gradient); 1H NMR (400 MHz, CDCl3) δ 7.50-
7.38 (m, 5 H), 6.23 (s, 1 H), 3.83 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 145.6, 138.4, 129.5, 129.0, 128.8, 128.7, 104.8, 37.6; HRMS-
ESI (m/z) calcd for C10H10ClN2 [M + H]+ 193.0527, found 193.0526.
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3-Chloro-5-n-hexyl-1-methyl-1H-pyrazole (11c). Starting from 6o (1.00 g, 5.43 mmoles, 1.00 equiv), dry tetraethylammonium chloride
(275 mg, 1.63 mmoles, 0.30 equiv), dichloromethane (6.00 mL, 6 L/kg), triethylamine (688 µL, 4.88 mmoles, 0.90 equiv) and
phosphorus oxychloride (664 µL, 7.05 mmoles, 1.30 equiv, added at -20 oC) with a 17 h age at 35 oC, followed by acetonitrile (10 mL,
10 L/kg) and manganese dioxide (4.72 g, 54.30 mmoles, 10.00 equiv) with a 4.5 h age at 60 oC, isolated 677 mg of 11c as orange oil in
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MHz, CDCl3) δ 5.93 (s, 1 H), 3.72 (s, 3 H), 2.54 (app t, J = 7.7 Hz, 2 H), 1.65-1.56 (m, 2 H), 1.41-1.28 (m, 6 H), 0.90 (app t, J = 6.8
Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 145.4, 137.7, 103.2, 36.2, 31.4, 28.8, 28.1, 25.6, 22.5, 14.0; HRMS-ESI (m/z) calcd for
C10H18ClN2 [M + H]+ 201.1153, found 201.1151.
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3-Chloro-1-n-hexyl-5-trifluoromethyl-1H-pyrazole (11d). To a 0 oC mixture of 6p (1.00 g, 4.20 mmoles, 1.00 equiv), dry
tetraethylammonium chloride (213 mg, 1.26 mmoles, 0.30 equiv), 1,2-dichloroethane (6.00 mL, 6 L/kg) and triethylamine (532 µL,
3.78 mmoles, 0.90 equiv) was charged phosphorus oxychloride (509 µL, 5.46 mmoles, 1.30 equiv). The mixture was then aged at 60
°C for 3 h. The reaction mixture was then cooled to room temperature, quenched by addition into a 1.0 M, pH = 7 sodium phosphate
buffer (20 mL, 20 L/kg) and the aqueous layer was extracted with dichloromethane (2 x 5 mL, 2 x 5 L/kg). The combined organic layers
were dried over sodium sulfate, filtered, washed with dichloromethane (2 x 3 mL, 2 x 3 L/kg), cooled to 0 °C and charged with N-
chlorosuccinimide (744 mg, 546 mmoles, 1.30 equiv). After 30 min, the mixture was warmed to room temperature, and after an
additional 30 min, was poured into a saturated aqueous sodium thiosulfate. The aqueous layer was extracted with dichloromethane (2
x 10 mL, 2 x 10 L/kg), and the combined organic layers were dried over sodium sulfate, filtered, concentrated and purified by ISCO
chromatography (0 to 5% ethyl acetate in hexanes gradient, UV detector set to 227 nm) to afford 598 mg 11d as a light brown oil in
56% overall yield (2 steps); 1H NMR (400 MHz, CDCl3) δ 6.51 (s, 1 H), 4.14 (app t, J = 7.4 Hz, 2 H), 1.88 (q, J = 7.3 Hz, 2 H), 1.39-
1.28 (m, 6 H), 0.89 (app t, J = 6.7 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 138.5, 133.2 (q, J = 40.0 Hz), 119.2 (q, J = 269.3 Hz), 106.2
(q, J = 2.9 Hz), 51.8, 31.2, 30.0, 26.0, 22.4, 13.9; HRMS-ESI (m/z) calcd for C10H15ClF3N2 [M + H]+ 255.0870, found 255.0866.
AUTHOR INFORMATION
Corresponding Author *E-mail: richard.fox@bms.com
ORCID Richard J Fox: 0000-0003-1117-7963
Notes The authors declare no competing financial interest.
ACKNOWLEDGMENT
The Chemical & Synthetic Development Senior Management is gratefully acknowledged for support during the execution of this work
and preparation of this manuscript. We thank Mr. Jonathan Marshall for the collection of all high-resolution mass spectral data and Dr.
Carlos A. Guerrero for helpful editorial comments.
ASSOCIATED CONTENT
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Supporting Information
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The Supporting Information is available free of charge on the ACS Publications website at DOI: XXX.
Copies of 1H and 13C NMR spectra for all products
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REFERENCES
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(1) (a) Lamberth, C. Heterocycles 2007, 71, 1467. (b) Jeschke, P. The Unique Role of Halogen Substituents in the Design of Modern
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Germany, 2007; pp 1189-1237. (c) Rouse, M.; Seefeld, M. A. WO 2010093885, 2010. (d) Le-Brun, A.; Thompson, F.; Tiraboschi, G.;
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(3) (a) For a review, see Janin, Y. L. Chem. Rev. 2012, 112, 3924 and references cited therein. (b) Bourrain, S.; Ridgill, M.; Collins, I.
Synlett 2004, 795.
(4) (a) Lahm, G. P.; Selby, T. P.; Stevenson, T. M. WO 2003015519, 2003. (b) Lahm, G. P.; Stevenson, T. M.; Selby, T. P.; Freudenberger,
D. C.; Flexner, L.; Bellin, C. A.; Dubas, C. M.; Smith, B. K.; Hughes, K. A.; Hollingshaus, G.; Clark, C. E.; Benner, E. A. Bioorg. Med.
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J.; Zhou, S.; Xiong, L.; Wang, H.; Zhao, Y. J. Heterocyclic Chem. 2016, 53, 1036. (e) Wu, J.; Song, B.-A.; Hu, D.-Y.; Yue, M.; Yang,
S. Pest Manag. Sci., 2012, 68, 801. (f) Wang, W.; Wang, L.-P.; Ning, B.-K.; Mao, M.-Z.; Xue, C.; Wang, H.-Y. Phosphorous, Sulfur and
Silicon 2016, 191, 1362. (g) Hua, X.; Mao, W.; Fan, Z.; Ji, X.; Li, F.; Zong, G.; Song, H.; Li, J.; Zhou, L.; Zhou, L.; Liang, X.; Wang,
G.; Chen, X. Aust. J. Chem. 2014, 67, 1491. (h) Berger, R. A.; Flexner, J. L. WO 2003024222, 2003. (i) Yang, Q.; Lorsbach, B.; Roth,
G.; Niyaz, N. M.; Nissen, J.; Ross, R. Jr.; Whiteker, G.; Deamicis, C.; Gray, K.; Zhang, Y. WO 2015058028, 2015. (j) Nishioka, M.;
Nakashita, H.; Suzuki, H.; Akiyama, S.; Yoshida, S.; Yamaguchi, I. J. Pestic. Sci. 2003, 28, 416. (k) Chupp, J. P. J. Heterocyclic Chem.
1994, 31, 1377. (l) Foti, F.; Grassi, G.; Risitano, F. Tetrahedron Lett. 1999, 40, 2605.
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(9) For the preparation of both 6e and 6j, it was optimal to use isopropyl versus methyl esters to minimize direct amidation.
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(10) (a) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah, R. D. J. Org. Chem. 1996, 61, 3849. (b) Taylor, E.;
Sobieray, D. M. Tetrahedron 1991, 47, 9599.
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(11) Compound 6e was also prepared via method B, but despite improved regioselectivity, isolated yield was lower.
(12) No reaction observed in DCM. Observed some product using CH3CN at 80 oC, but significant decomposition was also observed.
(13) When starting from 6*HBr salts, Et3N was added during bromination. Slightly different equivalents of Et3N, reaction temperatures
and aqueous workup protocols were found to be optimal for certain substrates. See Supporting Information for experimental details.
(14) Anelli, P. L.; Biffi, C.; Montanari, F.; Quici, S. J. Org. Chem. 1987, 52, 2559.
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(15) No over-bromination at C(4) was observed
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