Synthesis and Modular Reactivity of Pyrazole 5-Trifluoroborates: Intermediates for the Preparation of Fully Functionalized Pyrazoles

Article abstract of DOI:10.1021/acs.joc.6b02847

The regioselective condensation of hydrazines and ynone trifluoroborates provides access to a range of pyrazole 5-trifluoroborates. The stability of the borate unit allows chemoselective halogenation of the heteroaromatic ring, thereby delivering pyrazole scaffolds that allow orthogonal functionalization at C5 and C4. The modular reactivity of these intermediates is exemplified by cross-coupling reactions, enabling regiocontrolled synthesis of fully functionalized pyrazole derivatives.

Full text of DOI:10.1021/acs.joc.6b02847

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Article
Synthesis and Modular Reactivity of Pyrazole 5-Trifluoroborates:
Intermediates for the Preparation of Fully-Functionalized Pyrazoles
Prisca Fricero, Laurent Bialy, Andrew W. Brown, Werngard
Czechtizky, Maria Mendez, and Joseph P.A. Harrity
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02847 • Publication Date (Web): 13 Jan 2017
Downloaded from http://pubs.acs.org on January 13, 2017
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Synthesis and Modular Reactivity of Pyrazole 5-Trifluoroborates: Intermediates for the
Preparation of Fully-Functionalized Pyrazoles
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Prisca Fricero,[a] Laurent Bialy,[b] Andrew W. Brown,[a] Werngard Czechtizky,[b] María Méndez,[b]
Joseph P.A. Harrity*[a]
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[a] Department of Chemistry, University of Sheffield, Brook Hill,, S3 7HF, UK.
[b] Sanofi-Aventis Deutschland GmbH, R&D, Industriepark Höchst, G838, D-65926 Frankfurt Am
Main, Germany.
j.harrity@sheffield.ac.uk
Abstract: The regioselective condensation of hydrazines and ynone trifluoroborates provides access to
a range of pyrazole 5ꢀtrifluoroborates. The stability of the borate unit allows chemoselective
halogenation of the heteroaromatic ring, thereby delivering pyrazole scaffolds that allow orthogonal
functionalization at C5 and C4. The modular reactivity of these intermediates is exemplified by crossꢀ
coupling reactions, enabling regiocontrolled synthesis of fullyꢀfunctionalized pyrazole derivatives.
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Introduction
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Functionalized pyrazoles represent the core of numerous biologically active molecules and have been
heavily targeted by the pharmaceutical and agrochemicals industries.1 Broadly speaking, pyrazoles are
accessed through two strategies comprising condensation or cycloaddition reactions.2 With respect to
the latter approach, alkyne cycloaddition/retroꢀcycloaddition reactions of sydnones offer a direct means
to access highlyꢀsubstituted analogs.3 Moreoever, this chemistry is amenable to the synthesis of pyazole
boronic acid derivatives by the use of alkynylboronates.4 In contrast, the direct synthesis of pyrazole
boronic acid derivatives by condensation routes has received scant attention. Molander has pioneered
the use of stable aryltrifluoroborate salts for heterocycle synthesis via cycloaddition and condensation
reactions.5 Moreover, and with specific regard to pyrazoles, we recently introduced ynone
trifluoroborates as stable threeꢀcarbon atom containing acceptors, and showed how these participate in
condensation reactions with hydrazides.6 We envisaged that this chemistry could deliver a series of
pyrazoles that offered the opportunity to carry out lateꢀstage elaboration in a modular fashion. As shown
in Figure 1, if we were able to perform a chemoselective halogenation of a pyrazole 5ꢀtrifluoroborate
(i.e. electrophilic substitution at C4 rather than C5), then we would have access to a denselyꢀ
functionalized scaffold with a rich potential for further derivatization. This approach would further
avoid the challenge of performing chemistry at C3,7 or the regioselective alkylation of a free pyrazole ꢀ
NH. We report herein the realization of chemoselective chemistries that offer modular derivation
strategies for the synthesis of denselyꢀsubstituted pyrazole products.
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Figure 1. Strategy for late-stage diversification of pyrazoles.
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Results and Discussion
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Previous studies on the condensation of hydrazines with ynone trifluoroborates were conducted at, or
above, room temperature and offered quite variable regioselectivities (7:1 to >98:2).6 In preparing a
broader range of substrates for the chemoselective functionalization chemistry we decided to reꢀ
examine this step. In the event, we found that addition of methylhydrazine at 0 °C and slowly raising
the temperature to 20 °C gave consistently higher levels of regiocontrol in the condensation step
(Scheme 1). Only in case of Bocꢀpiperidinyl derivative did we observe the minor isomer, and a 90:10
ratio was recorded in this instance. All reactions were high yielding, however, it was essential to ensure
complete conversion of the ynone salt as this was difficult to separate from the desired pyrazole product.
In this regard, reactions were conveniently monitored by either LCꢀMS or 19F NMR spectroscopy.
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Scheme 1. Synthesis of N1,C3-substituted pyrazole trifluoroborates.
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Having successfully exemplified the introduction of a diverse array of substituents at C3, we
investigated the reaction of a series of hydrazines in order to vary the substituent at N1 (Table 1).
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Table 1. Hydrazine scope.
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Entry
R
Ratio A:B[a]
ꢀꢀ
Yield[b]
93%, 10
98%, 11
98%, 12
77%, 13
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2
3
4
H
CH2C(CH3)CH2
CH2CH2OH
CH2CH2CN
76:24
92:8
29:71
[a] Determined by 1H NMR spectroscopy; [b] Yield of the isolated mixture of isomers.
Hydrazine gave Nꢀunsubstituted pyrazole 10 in 93% yield (entry 1), however, methallylhydrazine
provided a surprisingly poor level of regiocontrol, generating both 11A/B in a ~3:1 ratio (entry 2). 2ꢀ
Hydroxyethylhydrazine proved to be an efficient substrate providing the pyrazole 12 in high yield and
regioselectivity (entry 3). Interestingly, and in contrast, condensation of the ynone trifluoroborate with
2ꢀcyanoethylhydrazine (entry 4) led to an inverted ratio of regioisomers, which was not influenced by
altering the reaction temperature. Arylhydrazides were not included in this study although our
preliminary work has highlighted the propensity for these to generate pyrazoles with type B
regiochemistry.6 The regiochemical assignments were based on a combination of ROESY spectroscopy
and NMR correlation, further details are provided in the supporting information.
With a selection of pyrazole trifluoroborate salts in hand, we turned our attention to the
functionalization of the remaining position on the pyrazole ring. Pyrazoles are typically reacted at C4
via the introduction of a halogen. We wanted to assess whether this chemistry was compatible with the
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trifluoroborate group as this is known to undergo halodeborylation.8 Using our model substrate 1, we
first investigated bromination at C4 using bromine and K2CO3 in acetonitrile (Table 2). Unfortunately,
the BF3K substituent was found to be too reactive resulting in formation of the dibrominated product 15.
Further careful optimization using NBS allowed us to identify a reproducible and selective bromination
reaction leading to a 12:1 ratio of 14 over 15.
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Table 2. Optimization of C4 bromination.
Entry Brominating agent Conditions
Ratio 14:15[a]
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4
Br2 (1.1 eq)[b]
NBS (1 eq)
K2CO3 (2 eq), MeCN 0:1
MeCN
4:1
NBS (1 eq)[c]
NBS (1 eq)[c,d]
MeCN[b]
MeCN[b]
5:1
12:1
[a] Determined by 1H NMR spectroscopy; [b] 2 Equiv of K2CO3 added; [c] Reaction conducted at 0 °C;
[d] Introduced as a 0.2 M solution in acetonitrile.
We next investigated the scope of the halogenation reaction (Scheme 2). By analogy to bromination
with NBS, chlorination and iodination of trifluoroborate 1 with NCS and NIS led to monohalogenated
derivatives 16 and 17 in 75% and 50% yield, respectively. Moreover, chlorination of pyrazoles bearing
various substituents at C3 under the same reaction conditions yielded the corresponding monoꢀ
chlorinated derivatives 18 – 22.
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Scheme 2. C4 halogenation of pyrazole 5-trifluoroborates.
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In parallel, we investigated the exchange of the BF3K residue by a Bdan group to develop an alternative
class of 4ꢀhalogenated 5ꢀboronates. Boronamides are known to be inert to transmetalation9 and so these
offered the prospect of developing a new series of modular intermediates. Pleasingly, employing a
similar approach to that described by Churches et al.10, treatment of the pyrazole trifluoroborate 1 with
TMSCl, 1,8ꢀdiaminonaphthalene and triethylamine yielded the desired 5ꢀBdan product 23 in 77% yield.
Disappointingly however, all attempts to monohalogenate 23 failed and only the dibromide 15 and
unreacted starting material 23 were isolated from this reaction (Scheme 3).
Scheme 3. Synthesis and halogenation of 5-Bdan derivatives.
With a series of functionalized pyrazoles in hand, we were in a position to investigate the modular
derivatization of these scaffolds. As such, we opted to first use SuzukiꢀMiyaura coupling as a means of
differentiating the borate and halide groups. More specifically, we envisaged that substrates 18, 20 and
22 would enable us to prepare a small family of polyarylated pyrazoles, whereby all possible isomers
could be accessed by sequential coupling reactions. Aryl substituted pyrazoles constitute an important
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class of targets and they have been shown to be successful drug candidates.11 Our results towards this
goal are summarized in Scheme 4.
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We opted to first carry out the crossꢀcoupling of the trifluoroborate group in each case, as we envisaged
that we could tune the catalyst and conditions to favor reaction with a substrate arylbromide, thereby
avoiding competitive reaction at the pyrazole chloride in each case. Pleasingly, a combination of
Pd(OAc)2, XPhos and NEt3 in EtOH successfully yielded the corresponding C5ꢀarylated products in
acceptable yield, leaving the C4ꢀCl substituent intact. Subsequent coupling of the arylchloride moiety
with substituted aryl boronic acids proceeded effectively using Buchwald’s PdXPhosG2 preꢀcatalyst
and sodium carbonate in a 1:1 mix of DME and water. Ultimately therefore, we were able to access
fullyꢀfunctionalized pyrazoles 24 – 29 with judicious control of the position of the aromatic group,
simply by manipulating the order of the coupling sequence.
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Scheme 4. Orthogonal cross-coupling at C4 and C5. Yields shown are over two steps. See
Supporting Information for the yields of individual steps.
[a]10 mol % catalyst used in the first step.
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In conclusion, we report that pyrazole 5ꢀtrifluoroborates offer a platform for the rapid and
regiocontrolled synthesis of denselyꢀsubstituted heterocycles. The trifluoroborates undergo slow
halodeborylation in the presence of Nꢀhalosuccinimides, allowing chemoselective halogenation to take
place at the pyrazole C4 position. Subsequent orthogonal derivatization of these fullyꢀfunctionalized
pyrazoles by crossꢀcoupling reactions is viable, allowing polysubstituted analogs to be readily accessed
with complete regiocontrol. Further studies on the reactivity of 5ꢀBF3K pyrazoles as well as on the
versatility of ynone trifluoroborates as starting materials for the synthesis of alternative heteroaromatics
are underway and will be reported in due course.
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Experimental Section
The following substrates were prepared according to a previously reported procedures 1ꢀ(pꢀ
Chlorophenyl)ꢀpropꢀ2ꢀynꢀ1ꢀol 3a,12 tertꢀbutyl 4ꢀ(1ꢀhydroxypropꢀ2ꢀynꢀ1ꢀyl)piperidineꢀ1ꢀcarboxylate
7a,13 1ꢀbenzyloxybutꢀ3ꢀynꢀ2ꢀol 9a,14 potassium trifluoro(3ꢀoxoꢀ3ꢀphenylpropꢀ1ꢀynꢀ1ꢀyl)borate 1c,6
potassium trifluoro(3ꢀ(4ꢀmethoxyphenyl)ꢀ3ꢀoxopropꢀ1ꢀynꢀ1ꢀyl)borate 2c,6 potassium trifluoro(3ꢀ(4ꢀ
trifluoromethyl)phenyl)ꢀ3ꢀoxopropꢀ1ꢀynꢀ1ꢀyl)borate 4c,6 potassium trifluoro(3ꢀoxobutꢀ1ꢀynꢀ1ꢀyl)borate
6c,6 potassium trifluoro(1ꢀmethylꢀ3ꢀphenylꢀ1Hꢀpyrazolꢀ5ꢀyl)borate 1,6 potassium trifluoro(3ꢀ(4ꢀ
methoxyphenyl)ꢀ1ꢀmethylꢀ1Hꢀpyrazolꢀ5ꢀyl)borate
2,6
potassium
trifluoro(1ꢀmethylꢀ3ꢀ(4ꢀ
(trifluoromethyl)phenyl)ꢀ1Hꢀpyrazolꢀ5ꢀyl)borate 46 a and potassium (1,3ꢀdimethylꢀ1Hꢀpyrazolꢀ5ꢀ
yl)trifluoroborate 6.6
General procedure A: Addition of Grignard reagent.6 To a solution of ethynylmagnesium bromide (0.5
M THF, 1.25 eq) in anhydrous THF (0.5 M) under nitrogen, aldehyde (1 eq) was added dropwise at ꢀ
78 °C. The mixture was allowed to warm to rt. Upon completion, the reaction was quenched with
saturated NH4Cl, extracted with ethyl acetate and the organic extracts dried over MgSO4. The solvent
was removed under vacuum and the residue purified by flash chromatography on silica gel to yield the
desired terminal alkynes.
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Synthesis of 1-(p-Chlorophenyl)-prop-2-yn-1-ol 3a.12 Following general procedure A, using pꢀchloroꢀ
benzaldehyde (1.41 g, 10.0 mmol) and ethynylmagnesium bromide (25.0 mL, 12.5 mmol) in THF (20
mL), the crude product was obtained after 2 h. Chromatographic purification using petrol/EtOAc 80/20
afforded the title compound as a yellow oil (1.58 g, 95% yield). 1H NMR (400 MHz, CDCl3), ppm: 7.46
– 7.41 (m, 2H), 7.36 – 7.30 (m, 2H), 5.39 (dd, J = 6.0, 2.0 Hz, 1H), 3.60 (d, J = 6.0 Hz, 1H), 2.68 (d, J =
2.0 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3), ppm: 138.5, 134.2, 128.8, 128.1, 83.2, 75.2, 63.5.
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Synthesis of 1-(1-methyl-1H-pyrazol-5-yl)prop-2-yn-1-ol, 5a. Following general procedure A, using 1ꢀ
methylꢀ1Hꢀpyrazoleꢀ5ꢀcarboxaldehyde (1.0 g, 9.1 mmol) and ethynylmagnesium bromide (23.0 mL,
11.4 mmol) in THF (17 mL), the crude product was obtained after 2 h. The crude material was triturated
in dichloromethane by stirring at rt for 30 min and filtering to yield the title compound as a light brown
solid (0.98 g, 79% yield). 1H NMR (400 MHz, DMSOꢀd6), ppm: 7.29 (d, J = 2.0 Hz, 1H), 6.24 (d, J =
13
2.0 Hz, 1H), 5.55 (d, J = 2.5 Hz, 1H), 3.82 (s, 3H), 3.56 (d, J = 2.5 Hz, 1H), 3.40 (s, 1H). C{1H}
NMR (101 MHz, DMSOꢀd6), ppm: 141.7, 137.0, 104.8, 83.1, 75.6, 54.6, 36.8. M. pt. = 107 °C. FTIR
(neat, cmꢀ1), νmax: 3392 (w), 3231 (m), 3120 (m), 3036 (m), 2115 (w), 1420 (s). HRMS calculated for
C7H8N2O (ESI+): 137.0709. Found: 137.0711.
Synthesis of tert-butyl 4-(1-hydroxyprop-2-yn-1-yl)piperidine-1-carboxylate, 7a.13 Following general
procedure A, using 4ꢀformylcyclohexanecarboxylic acid tertꢀbutyl ester (3.03 g, 14.1 mmol) and
ethynylmagnesium bromide (42.0 mL, 21.1 mmol) in THF (28 mL), the crude product was obtained
after 2 h. Chromatographic purification using petrol/EtOAc 70/30 afforded the title compound as a
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yellow oil (2.43 g, 72% yield). H NMR (400 MHz, CDCl3), ppm: 4.21 – 4.13 (m, 3H), 2.69 (tt, J =
13.0, 3.0 Hz, 2H), 2.49 (d, J = 2.0 Hz, 1H), 1.99 (br, 1H), 1.86 – 1.77 (m, 2H), 1.77 – 1.68 (m, 1H),
1.46 (s, 9H), 1.40ꢀ1.23 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3), ppm: 154.9, 83.2, 79.5, 74.3, 66.1,
43.6, 42.4, 28.5, 27.7, 27.2.
Synthesis of 1-tetrahydro-2Hꢀpyran-4-yl)prop-2-yn-1-ol, 8a. Following general procedure A, using 4ꢀ
formyltetrahydropyran (0.66 g, 5.8 mmol) and ethynylmagnesium bromide (15 mL, 7.2 mmol) in THF
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(11 mL), the crude product was obtained after 2 h. Chromatographic purification using petrol/EtOAc
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60/40 afforded the title compound as a yellow oil (0.40 g, 49% yield). H NMR (400 MHz, CDCl3),
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1.88 – 1.78 (m, 3H), 1.56 – 1.45 (m, 2H). C{1H} NMR (101 MHz, CDCl3), ppm: 83.2, 74.2, 67.6,
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66.3, 41.4, 28.6, 28.1. FTIR (neat, cmꢀ1), νmax: 3319 (s), 3258 (s), 2954 (m), 2946 (m), 2858 (s), 2109 (s),
1080 (s), 1037 (s), 1023 (s). HRMS calculated for C8H12O2 (ESI+): 140.0837. Found: 140.0836.
Synthesis of 1-benzyloxybut-3-yn-2-ol, 9a.14 Following general procedure A, using
benzyloxyacetaldehyde (5.0 g, 33 mmol) and ethynylmagnesium bromide (83.0 mL, 41.6 mmol) in
THF (61 mL), the crude product was obtained after 2 h. Chromatographic purification using
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petrol/EtOAc 60/40 afforded the title compound as a yellow oil (5.42 g, 92% yield). H NMR (400
MHz, CDCl3), ppm: 7.39 – 7.28 (m, 5H), 4.64 (d, J = 12.0 Hz, 1H), 4.60 (d, J = 12.0 Hz, 1H), 4.56 (ddd,
J = 7.0, 3.5, 2.0 Hz, 1H), 3.66 (dd, J = 10.0, 3.5 Hz, 1H), 3.59 (dd, J = 10.0, 7.0 Hz, 1H), 2.46 (d, J =
13
2.0 Hz, 1H), 2.39 (s, 1H). C{1H} NMR (101 MHz, CDCl3), ppm: 137.5, 128.6, 128.0, 127.9, 81.7,
73.8, 73.5, 73.4, 61.6.
General procedure B: Borylation of terminal alkynes.6 To a solution of terminal alkyne (1 eq) in
anhydrous THF under nitrogen, nꢀBuLi (~2.5 M in hexanes, 2.2 eq) was added dropwise at ꢀ78 °C.
After stirring the resulting mixture at ꢀ78 °C for 1 h, isoꢀpropoxyꢀpinacolborane (3 eq) was added
dropwise and the mixture was allowed to warm to ꢀ20 °C over 1 h. To this mixture was added slowly a
saturated solution of aqueous hydrogen potassium difluoride (12 eq) and the mixture allowed to warm
to rt over 1 h. The solvent was then removed under vacuum to yield a solid. The residue was stirred in
acetone for 30 min and filtered. The solvent was removed under vacuum and the residue redissolved in
minimum of acetone, Et2O was added and a solid precipitated to yield the desired compound.
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Note that for the following trifluoroborate compounds, C NMR spectra are missing a signal for the
carbon atom directly attached to the boron due to broadening arising from the quadrupolar relaxation
effect.
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Synthesis of potassium trifluoro(3-hydroxy-3-(4-chlorophenyl)prop-1-yn-1-yl)borate, 3b. Following
general procedure B using 3a (0.99 g, 6.0 mmol), nꢀBuLi (6.8 mL, 13 mmol), B(OiPr)Pin (3.5 mL, 18
mmol) in THF (25 mL) and KHF2 (5.43 g, 71.0 mmol) dissolved in water (20 mL) yielded the title
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compound as a colorless solid (1.13 g, 70% yield). H NMR (400 MHz, DMSOꢀd6), ppm: 7.46 (d, J =
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8.5 Hz, 2H), 7.38 (d, J = 8.5 Hz, 2H), 5.72 (d, J = 5.0 Hz, 1H), 5.18 (d, J = 5.0 Hz, 1H). 13C{1H} NMR
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(126 MHz, DMSOꢀd6), ppm: 142.7, 131.4, 128.3, 127.8, 89.9, 62.4. F NMR (377 MHz, DMSOꢀd6),
ppm: ꢀ131.6. 11B NMR (128 MHz, DMSOꢀd6), ppm: 5.0. M. pt. >290 °C. FTIR (neat, cmꢀ1), νmax: 3537
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(w), 2929 (w), 1001 (s), 933 (s). HRMS calculated for C9H6 BOF3 Cl (ESIꢀ): 233.0152. Found:
233.0163.
Synthesis of potassium 1-(1-methyl-1H-pyrazol-5-yl)-3-(trifluoroboranyl)prop-2-yn-1-ol, 5b.
Following general procedure B using 5a (0.80 g, 5.8 mmol), nꢀBuLi (5.5 mL, 13 mmol), B(OiPr)Pin
(3.6 mL, 18 mmol) in THF (23 mL) and KHF2 (5.57 g, 70.1 mmol) dissolved in water (18 mL) yielded
the title compound as a brown solid (0.52 g, 37% yield). 1H NMR (400 MHz, DMSOꢀd6), ppm: 7.25 (d,
J = 2.0 Hz, 1H), 6.16 (d, J = 2.0 Hz, 1H), 5.78 (s, 1H), 5.33 (s, 1H), 3.82 (s, 3H). 13C{1H} NMR (101
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MHz, DMSOꢀd6), ppm: 143.7, 137.1, 104.9, 74.0, 55.9, 37.3. F NMR (376 MHz, DMSOꢀd6), ppm: ꢀ
131.8. 11B NMR (128 MHz, DMSOꢀd6), ppm: 5.2. M. pt. = 111 °C. FTIR (neat, cmꢀ1), νmax: 3598 (m),
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3316 (w), 2219 (w), 1645 (w), 1630 (w). HRMS calculated for C7H7 BOF3N2Na (ESI+): 225.0538.
Found: 225.0535.
Synthesis of potassium tert-butyl 4-(1-hydroxy-3-(trifluoroboranyl)prop-2-yn-1-yl)piperidine-1-
carboxylate, 7b. Following general procedure B using 7a (2.78 g, 12.0 mmol), nꢀBuLi (12 mL, 26
mmol), B(OiPr)Pin (7.5 mL, 35 mmol) in THF (48 mL) and KHF2 (10.93 g, 139.0 mmol) dissolved in
water (40 mL) yielded the title compound as a colorless solid (2.91 g, 73% yield). 1H NMR (400 MHz,
DMSOꢀd6), ppm: 4.89 (d, J = 5.0 Hz, 1H), 4.02ꢀ3.90 (m, 2H), 3.88 ꢀ 3.82 (m, 1H), 2.62 (br, 2H), 1.69
(app. d, J = 12.0 Hz, 2H), 1.49 – 1.39 (m, 10H), 1.17ꢀ1.03 (m, 2H). 13C{1H} NMR (101 MHz, DMSOꢀ
d6), ppm: 153.9, 78.4, 64.9, 42.4, 28.1, 27.6, 27.4, 24.9. 19F NMR (376 MHz, DMSOꢀd6), ppm: ꢀ131.3.
11B NMR (128 MHz, DMSOꢀd6), ppm: 5.0. M. pt. >290 °C. FTIR (neat, cmꢀ1), νmax: 3402 (br, w),
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2975(w), 2931 (w), 2860 (w), 2214 (w), 1690 (m), 1667 (m), 1479 (m), 1425 (m). HRMS calculated for
C13H2011BO3F3N (ESIꢀ): 306.1494. Found: 306.1504.
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Synthesis of potassium 1-(tetrahydro-2H-pyran-4-yl)-3-(trifluoroboranyl)prop-2-yn-1-ol, 8b. Following
general procedure B using 8a (0.78 g, 6.0 mmol), nꢀBuLi (5.0 mL, 12 mmol), B(OiPr)Pin (3.5 mL, 17
mmol) in THF (22 mL) and KHF2 (5.29 g, 67.0 mmol) dissolved in water (18 mL) yielded the title
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compound as a colorless solid (0.52 g, 38% yield). H NMR (400 MHz, DMSOꢀd6), ppm: 4.86 (d, J =
5.5 Hz, 1H), 3.90 – 3.77 (m, 3H), 3.28 – 3.16 (m, 2H), 1.67 – 1.56 (m, 2H), 1.57 – 1.44 (m, 1H), 1.31 –
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1.20 (m, 2H). C{1H} NMR (101 MHz, DMSOꢀd6), ppm: 66.9, 65.3, 41.6, 28.7, 28.3. 19F NMR (376
MHz, DMSOꢀd6), ppm: ꢀ131.3. 11B NMR (128 MHz, DMSOꢀd6), ppm: 5.1. M. pt. > 290 °C. FTIR (neat,
cmꢀ1), νmax: 3496 (s), 2957 (m), 2917 (m), 2872 (m), 2854 (m), 1238 (s), 1082 (s), 1024 (s). HRMS
calculated for C8H1111BO2F3 (ESIꢀ): 207.0810. Found: 207.0817.
Synthesis of potassium 1-(benzyloxy)-4-(trifluoroboranyl)but-3-yn-2-ol, 9b. Following general
procedure B using 9a (5.38 g, 31.0 mmol), nꢀBuLi (30 mL, 67 mmol), B(OiPr)Pin (19 mL, 92 mmol) in
THF (125 mL) and KHF2 (28.61 g, 366.0 mmol) dissolved in water (102 mL) yielded the title
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compound as a colorless solid (8.12 g, 94% yield). H NMR (400 MHz, DMSOꢀd6), ppm: 7.36 – 7.24
(m, 5H), 5.07 (d, J = 6.0 Hz, 1H), 4.52 (s, 2H), 4.26 – 4.19 (m, 1H), 3.43 – 3.33 (m, 2H). 13C{1H}
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NMR (101 MHz, DMSOꢀd6), ppm: 139.0, 128.6, 128.0, 127.8, 89.9, 75.4, 72.5, 61.3, 25.5. F NMR
(376 MHz, DMSOꢀd6), ppm: ꢀ131.8. 11B NMR (128 MHz, DMSOꢀd6), ppm: 5.1. M. pt. = 86 °C. FTIR
(neat, cmꢀ1), νmax: 3512 (w), 3376 (w), 3034 (w), 2869 (w), 2217 (w), 1097 (s), 1064 (s). HRMS
calculated for C11H1111BO2F3 (ESIꢀ): 243.0810. Found: 243.0819.
General procedure C: Oxidation to ynone trifluoroborates.6 To a suspension of manganese (IV) oxide
(5 eq) in acetone (0.3 M), was added trifluoroborate (1 eq) portionwise at rt. The reaction was followed
by 19F NMR spectroscopy. Upon completion, the mixture was filtered through Celite. All volatiles were
removed from the filtrate under vacuum. Then the residue was redissolved in minimum of acetone and
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upon addition of Et2O a solid precipitated. The solid was filtered and washed with Et2O and dried to
yield the title compound.
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Synthesis of potassium trifluoro(3-oxo-3-(4-chlorophenyl)prop-1-yn-1-yl)borate, 3c. Following general
procedure C using 3b (1.9 g, 7.0 mmol) and manganese (IV) oxide (3.01 g, 34.9 mmol) in acetone (22
mL) yielded the title compound as a pale yellow solid (1.44 g, 76% yield). 1H NMR (500 MHz, DMSOꢀ
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d6), ppm: 8.05 (d, J = 9.0 Hz, 2H), 7.65 (d, J = 9.0 Hz, 2H). C{1H} NMR (126 MHz, DMSOꢀd6),
ppm: 176.9, 138.8, 135.5, 130.7, 129.0, 87.9. 19F NMR (377 MHz, Acetoneꢀd6), ppm: ꢀ136.3. 11B NMR
(128 MHz, DMSOꢀd6), ppm: ꢀ1.8. M. pt. >300 °C. FTIR (neat, cmꢀ1), νmax: 2946 (w), 1661 (s), 1222 (s),
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984 (s). HRMS calculated for C9H4 BOF3 Cl (ESIꢀ): 231.0152. Found: 231.0163.
Synthesis of potassium 1-(1-methyl-1H-pyrazol-5-yl)-3-(trifluoroboranyl)prop-2-yn-1-one, 5c.
Following general procedure C using 5b (0.41 g, 1.7 mmol) and manganese (IV) oxide (0.75 g, 8.5
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mmol) in acetone (5.5 mL) yielded the title compound as a light brown solid (0.12 g, 30% yield). H
NMR (400 MHz, DMSOꢀd6), ppm: 7.53 (d, J = 2.0 Hz, 1H), 6.95 (d, J = 2.0 Hz, 1H), 4.05 (s, 3H).
13C{1H} NMR (126 MHz, DMSOꢀd6), ppm: 167.7, 139.6, 137.7, 114.2, 89.0, 39.6. 19F NMR (376 MHz,
DMSOꢀd6), ppm: ꢀ133.3. 11B NMR (128 MHz, DMSOꢀd6), ppm: ꢀ1.9. M. pt. = 252 °C (deg). FTIR (neat,
cmꢀ1), νmax: 3142 (s), 2962 (s), 2191 (m), 3392 (w), 3231 (m), 3120 (m), 3036 (m), 2115 (w), 1420 (s).
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HRMS calculated for C7H5 BOF3N2 (ESIꢀ): 201.0453. Found: 201.0462.
Synthesis of potassium tert-butyl 4-(3-(trifluoroboranyl)propioloyl)piperidine-1-carboxylate, 7c.
Following general procedure C using 7b (0.17 g, 0.50 mmol) and manganese (IV) oxide (0.21 g, 2.5
mmol) in acetone (1.5 mL) yielded the title compound as a colorless solid (0.07 g, 42% yield). 1H NMR
(400 MHz, DMSOꢀd6), ppm: 3.89 – 3.84 (m, 2H), 2.89 – 2.71 (m, 2H), 2.49 (m 1H), 1.86 – 1.80 (m,
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2H), 1.41ꢀ1.28 (m, 11H). C{1H} NMR (126 MHz, DMSOꢀd6), ppm: 190.0, 153.8, 88.9, 78.6, 49.0,
40.1, 28.1, 27.2. 19F NMR (376 MHz, DMSOꢀd6), ppm: ꢀ133.2. 11B NMR (128 MHz, DMSOꢀd6), ppm:
ꢀ1.9. M. pt. = 169 °C. FTIR (neat, cmꢀ1), νmax: 2932 (w), 2187 (w), 1679 (m), 1658 (m). HRMS
calculated for C13H1811BO3F3N (ESIꢀ): 304.1337. Found: 304.1351.
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Synthesis of potassium 1-(tetrahydro-2H-pyran-4-yl)-3-(trifluoroboranyl)prop-2-yn-1-one, 8c.
Following general procedure C using 8b (0.56 g, 2.3 mmol) and manganese (IV) oxide (1.03 g, 11.4
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mmol) in acetone (7 mL) yielded the title compound as a colorless solid (0.19 g, 34% yield). H NMR
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(400 MHz, DMSOꢀd6), ppm: 3.84 – 3.79 (m, 2H), 3.35 (td, J = 11.5, 2.0 z, 2H), 2.58 – 2.50 (m 1H),
1.81 – 1.74 (m, 2H), 1.55 – 1.44 (m, 2H). 13C{1H} NMR (126 MHz, DMSOꢀd6), ppm: 190.0, 88.6, 66.1,
48.1, 27.9. 19F NMR (376 MHz, DMSOꢀd6), ppm: ꢀ133.2. 11B NMR (128 MHz, DMSOꢀd6), ppm: ꢀ1.9.
M. pt. = 158 °C. FTIR (neat, cmꢀ1), νmax: 2960 (w), 2851 (w) 2183 (w), 1649 (m), 1110, (s), 1008 (s).
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HRMS calculated for C8H9 BO2F3 (ESIꢀ): 205.0653. Found: 205.0659.
Synthesis of potassium 1-(benzyloxy)-4-(trifluoroboranyl)but-3-yn-2-one, 9c. Following general
procedure C using 9b (3.30 g, 11.7 mmol) and manganese (IV) oxide (5.12 g, 58.5 mmol) in acetone
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(35 mL) yielded the title compound as an orange solid (0.37 g, 11% yield). H NMR (400 MHz,
DMSOꢀd6), ppm: 7.37 – 7.26 (m, 5H), 4.52 (s, 2H), 4.23 (s, 2H). 13C{1H} NMR (126 MHz, DMSOꢀd6),
ppm: 185.4, 137.8, 128.2, 127.8, 127.6, 87.7, 75.8, 72.1. 19F NMR (376 MHz, DMSOꢀd6), ppm: ꢀ133.5.
11B NMR (128 MHz, DMSOꢀd6), ppm: ꢀ1.1. M. pt. = 116ꢀ117 °C. FTIR (neat, cmꢀ1), νmax: 3032 (w),
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2868 (w), 2182 (w), 1676 (s), 1455ꢀ1380 (s), 1087 (s). HRMS calculated for C11H9 BO2F3 (ESIꢀ):
241.0653. Found: 241.0658.
General procedure D: Synthesis of N-methylpyrazoles. To a solution of ynone (1 eq) in ethanol (0.14
M) at 0 °C, Nꢀmethylhydrazine (1.2 or 2.4 eq) was added dropwise under nitrogen. The flask was
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covered with foil and left to stir at rt. The reaction was followed by F NMR. Upon completion, the
mixture was evaporated to dryness. The residue was redissolved in the minimum of acetone and upon
addition of Et2O a solid precipitated. The solid was filtered and washed with Et2O and dried to yield the
title compound.
Synthesis of potassium trifluoro(1-methyl-3-(4-chlorophenyl)-1H-pyrazol-5-yl)borate, 3. Following
general procedure D using 3c (0.50 g, 1.9 mmol) and methylhydrazine (0.1 mL, 2 mmol) in ethanol (12
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mL) yielded the title compound as a colorless solid (0.47 g, 84% yield, > 98:2). H NMR (400 MHz,
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DMSOꢀd6), ppm: 7.71 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 8.5 Hz, 2H), 6.31 (s, 1H), 3.78 (s, 3H). 13C{1H}
NMR (101 MHz, DMSOꢀd6), ppm: 146.9, 134.3, 130.9, 128.8, 126.9, 106.1, 38.6. 19F NMR (377 MHz,
DMSOꢀd6), ppm: ꢀ137.1. 11B NMR (128 MHz, DMSOꢀd6), ppm: 1.6. M. pt. > 300 °C. FTIR (neat, cmꢀ1),
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νmax: 2950 (w), 1425 (m), 1191 (m), 1168 (s), 935 (s). HRMS calculated for C10H8 B35ClF3N2 (ESIꢀ):
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259.0429. Found: 259.0437.
Synthesis of potassium 1,2'-dimethyl-5-(trifluoroboranyl)-1H,2'H-3,3'-bipyrazole, 5. Following general
procedure D using 5c (100 mg, 0.373 mmol) and methylhydrazine (60 ꢁL, 0.9 mmol) in ethanol (3 mL)
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yielded the title compound as a colorless solid (93 mg, 83% yield, > 90:10). H NMR (400 MHz,
DMSOꢀd6), ppm: 7.33 (d, J = 2.0 Hz, 1H), 6.36 (d, J = 2.0 Hz, 1H), 6.18 (s, 1H), 4.01 (s, 3H), 3.80 (s,
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3H). C{1H} NMR (101 MHz, DMSOꢀd6), ppm: 139.4, 137.53, 137.47, 108.0, 104.0, 38.3, 38.1. F
NMR (376 MHz, DMSOꢀd6), ppm: ꢀ137.2. 11B NMR (128 MHz, DMSOꢀd6), ppm: 1.7. M. pt. >300 °C.
FTIR (neat, cmꢀ1), νmax: 3152 (s), 3127 (s), 1386 (s). HRMS calculated for C8H9 BF3N4 (ESIꢀ):
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229.0878. Found: 229.0888.
Synthesis of potassium tert-butyl 4-(1-methyl-5-(trifluoroboranyl)-1H-pyrazol-3-yl)piperidine-1-
carboxylate, 7. Following general procedure D using 7c (200 mg, 0.539 mmol) and methylhydrazine
(55 ꢁL, 1.1 mmol) in ethanol (4 mL) yielded the title compound as a light yellow solid (177 mg, 82%
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yield, > 90:10). H NMR (400 MHz, DMSOꢀd6), ppm: 5.67 (s, 1H), 3.95 – 3.90 (m, 2H), 3.64 (s, 3H),
2.84 – 2.75 (m, 2H), 2.60 (tt, J = 11.5, 4.0 Hz, 1H), 1.80 – 1.75 (m, 2H), 1.40 ꢀ 1.32 (m, 11H). 13C{1H}
NMR (101 MHz, DMSOꢀd6), ppm: 154.0, 152.4, 104.8, 78.4, 37.6, 34.8, 32.0, 28.1, 26.8. 19F NMR
(376 MHz, DMSOꢀd6), ppm: ꢀ136.9. 11B NMR (128 MHz, DMSO-d6), ppm: 1.6. M. pt. = 161 °C. FTIR
(neat, cmꢀ1), νmax: 2934 (w), 1674 (m), 1425 (m), 1366 (m). HRMS calculated for C14H2211BO2F3N3
(ESIꢀ): 332.1763. Found: 332.1779.
Synthesis of potassium 1-methyl-3-(tetrahydro-2H-pyran-4-yl)-5-(trifluoroboranyl)-1H-pyrazole, 8.
Following general procedure D using 8c (204 mg, 0.750 mmol) and methylhydrazine (110 ꢁL, 1.80
mmol) in ethanol (6 mL) yielded the title compound as a light yellow solid (181 mg, 80% yield, >
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90:10). 1H NMR (400 MHz, DMSOꢀd6), ppm: 5.69 (s, 1H), 3.88 – 3.83 (m, 2H), 3.65 (s, 3H), 3.37 (td, J
= 11.5, 2.0 Hz, 2H), 2.66 (tt, J = 11.5, 4.0 Hz, 1H), 1.75 – 1.69 (m, 2H), 1.55 (qd, J = 11.5, 4.0 Hz).
13C{1H} NMR (101 MHz, DMSOꢀd6), ppm: 152.7, 104.8, 67.2, 37.6, 34.0, 33.0. 19F NMR (376 MHz,
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DMSOꢀd6), ppm: ꢀ136.9. 11B NMR (128 MHz, DMSOꢀd6), ppm: 1.6. M. pt. > 290 °C. FTIR (neat, cmꢀ1),
νmax: 2937 (w), 2918 (w), 2850 (w), 1444 (w), 1428 (w), 1168 (m), 1126 (m). HRMS calculated for
C9H1311BOF3N2 (ESIꢀ): 233.1079. Found: 233.1086.
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Synthesis of potassium 3-((benzyloxy)methyl)-1-methyl-5-(trifluoroboranyl)-1H-pyrazole, 9. Following
general procedure D using 9c (167 mg, 0.596 mmol) and methylhydrazine (80 ꢁL, 1.7 mmol) in ethanol
(5 mL) yielded the title compound as an orange oil (110 mg, 70% yield, > 90:10). 1H NMR (400 MHz,
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DMSOꢀd6), ppm: 7.32 – 7.22 (m, 5H), 5.88 (s, 1H), 4.44 (s, 2H), 4.34 (s, 2H), 3.70 (s, 3H). C{1H}
NMR (101 MHz, DMSOꢀd6), ppm: 145.9, 138.8, 128.1, 127.4, 127.2, 107.9, 70.6, 65.6, 37.7. 19F NMR
(376 MHz, DMSOꢀd6), ppm: ꢀ137.0. 11B NMR (128 MHz, DMSOꢀd6), ppm: 1.7. FTIR (neat, cmꢀ1),
νmax: 3031 (w), 2933 (w), 2865 (w), 1453 (m), 1164 (m), 1148 (m). HRMS calculated for
C12H1311BOF3N2 (ESIꢀ): 269.1079. Found: 269.1086.
General procedure E: Synthesis of N-alkylpyrazoles. To a solution of ynone (1 eq) in ethanol (0.14 M)
at 0 °C, Nꢀalkylhydrazine (2.4 eq) was added dropwise under nitrogen. The mixture was left to stir at
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0 °C for 4ꢀ6 h and left to warm to rt overnight. The reaction was followed by F NMR spectroscopy.
Upon completion, the mixture was evaporated to dryness. The residue was redissolved in the minimum
of acetone and upon addition of Et2O a solid precipitated. The solid was filtered and washed with Et2O
and dried to yield the title compound.
Synthesis of potassium 1-(2-methylallyl)-3-phenyl-5-(trifluoroboranyl)-1H-pyrazole, 11A and
Potassium 1-(2-methylallyl)-5-phenyl-3-(trifluoroboranyl)-1H-pyrazole, 11B. Following general
procedure E using 1c (200 mg, 0.847 mmol) and (2ꢀmethylꢀ2ꢀpropenyl)hydrazine (182 mg, 2.03 mmol)
in ethanol (6 mL) yielded the title compound as a mixture of the 2 regioisomers A/B in a 76:24 ratio
(254 mg, 98% yield). 1H NMR (400 MHz, DMSOꢀd6), ppm: 7.69 (d, J = 7.0 Hz, 1.5H), 7.44 – 7.34 (m,
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1.25H), 7.32 (t, J = 7.0Hz, 1.5H), 7.18 (t, J = 7.0 Hz, 0.75H), 6.30 (s, 0.75H), 6.10 (s, 0.25H), 4.76 (s,
1.5H), 4.67 (s, 2H), 4.58 (s, 0.5H), 1.58 (s, 2.25H), 1.56 (s, 0.75H). 13C{1H} NMR (101 MHz, DMSOꢀ
d6), ppm: 148.8, 143.5, 143.2, 141.8, 135.5, 132.6, 129.0, 128.8, 128.3, 127.8, 126.7, 125.3, 111.6,
111.4, 110.0, 105.7, 56.5, 54.7, 20.4, 20.3. 19F NMR (376 MHz, DMSOꢀd6), ppm: ꢀ136.2. 11B NMR
(128 MHz, DMSOꢀd6), ppm: 1.7. FTIR (neat, cmꢀ1), νmax: 2973 (w), 1640 (w), 1604 (w), 1458 (m),
1190 (m), 1136 (s). HRMS calculated for C13H1311BF3N2 (ESIꢀ): 265.1129. Found: 265.1142.
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Synthesis of potassium 2-(3-phenyl-5-(trifluoroboranyl)-1H-pyrazol-1-yl)ethan-1-ol, 12A and
Potassium 2-(5-phenyl-3-(trifluoroboranyl)-1H-pyrazol-1-yl)ethan-1-ol, 12B. Following general
procedure E using 1c (200 mg, 0.847 mmol) and 2ꢀhydroxyethylhydrazine (186 mg, 2.03 mmol) in
ethanol (6 mL) yielded the title compound as a mixture of the 2 regioisomers A/B in a 92:8 ratio (244
mg, 98% yield). Upon trituration in acetone, isomer B remained insoluble and it was filtered off. Isomer
A was precipitated by addition of ether. Isomer 12A was isolated as an orange oil (151 mg, 61% yield).
1H NMR (400 MHz, DMSOꢀd6), ppm: 7.69 (d, J = 8.0 Hz, 2H), 7.32 (t, J = 8.0 Hz, 2H), 7.19 (t, J = 8.0
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Hz, 1H), 6.29 (s, 1H), 4.67 (t, J = 6.0 Hz, 1H), 4.17 (t, J = 7.0 Hz, 2H), 3.73 – 3.69 (m, 2H). C{1H}
NMR (101 MHz, DMSOꢀd6), ppm: 147.9, 134.9, 128.3, 126.2, 124.8, 105.4, 61.1, 52.6. 19F NMR (376
MHz, DMSOꢀd6), ppm: ꢀ136.7. 11B NMR (128 MHz, DMSOꢀd6), ppm: 2.2. FTIR (neat, cmꢀ1), νmax
:
3364 (br. w), 2947 (w), 1604 (w), 1430 (m), 1189 (s), 1139 (s). HRMS calculated for C11H1111BOF3N2
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(ESIꢀ): 255.0922. Found: 255.0928. Isomer 12B was isolated as a colorless solid (8 mg, 3% yield). H
NMR (400 MHz, DMSOꢀd6), ppm: 7.48 – 7.41 (m, 4H), 7.38 – 7.33 (m, 1H), 6.03 (s, 1H), 4.96 (t, J =
5.0 Hz, 1H), 4.02 (t, J = 6.0 Hz, 2H), 3.76 – 3.72 (m, 2H). 13C{1H} NMR (101 MHz, DMSOꢀd6), ppm:
141.5, 132.0, 128.5, 128.5, 127.3, 109.2, 60.6, 50.3. 19F NMR (376 MHz, DMSOꢀd6), ppm: ꢀ136.3. 11B
NMR (128 MHz, DMSOꢀd6), ppm: 2.2. M. pt. = 222ꢀ223 °C. FTIR (neat, cmꢀ1), νmax: 3193 (br. w),
2930 (w), 2920 (w), 1460 (m), 1429 (m), 1407 (m), 1140 (s). HRMS calculated for C11H1111BOF3N2
(ESIꢀ): 255.0922. Found: 255.0933.
Synthesis of potassium 3-(5-phenyl-3-(trifluoroboranyl)-1H-pyrazol-1-yl)propanenitrile, 13B.
Following general procedure E using 1c (203 mg, 0.860 mmol) and 2ꢀhydroxyethylhydrazine (126 mg,
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2.06 mmol) in ethanol (6 mL) yielded the title compound as a mixture of the 2 regioisomers A/B in a
29:71 ratio (218 mg, 84% yield). Trituration in acetone and filtration provided a pure sample of 13B as
a colorless solid. 1H NMR (400 MHz, DMSOꢀd6), ppm: 7.49ꢀ7.38 (m, 5H), 6.06 (s, 1H), 4.20 (t, J = 6.5
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Hz, 2H), 3.03 (t, J = 6.5 Hz, 2H). C{1H} NMR (101 MHz, DMSOꢀd6), ppm: 141.7, 131.5, 128.6,
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128.5, 127.7, 118.9, 109.8, 43.7, 18.4. F NMR (376 MHz, DMSOꢀd6), ppm: ꢀ136.4. B NMR (128
MHz, DMSOꢀd6), ppm: 2.3. M. pt. = 199 °C. FTIR (neat, cmꢀ1), νmax: 3059 (w), 2977 (w), 2247 (w),
1486 (m), 1134 (s). HRMS calculated for C12H1011BF3N3 (ESIꢀ): 264.0925. Found: 264.0951.
Naphthalen(1-methyl-3-phenyl-1H-pyrazol-5-yl)boronamide, 23. To a solution of pyrazole 1 (103 mg,
0.436 mmol) and 1,8ꢀdiaminonaphthalene (68 mg, 0.48 mmol) in toluene (10 mL) under nitrogen, NEt3
(0.1 mL, 0.8 mmol) was added. After 5 min, TMSꢀCl (0.20 mL, 1.2 mmol) was added dropwise then the
mixture was heated at reflux overnight. The solvent was removed under vacuum and the crude was
purified by flash chromatography on silica gel (petrol / CH2Cl2, gradient from 100/0 to 0/100) to yield
1
the title compound as a pink oil (100 mg, 77% yield). H NMR (400 MHz, DMSOꢀd6), ppm: 8.24 (s,
2H), 7.23 (d, J = 7.5 Hz, 2H), 4.42 (t, J = 7.5 Hz, 2H), 7.29 (t, J = 7.5 Hz, 1H), 7.13 ꢀ7.08 (m, 2H), 7.06
(s, 1H), 6.95 (dd, J = 8.0, 1.0 Hz, 2H), 6.57 (dd, J = 7.5, 1.0 Hz, 2H), 4.07 (s, 3H). 13C{1H} NMR (101
MHz, DMSOꢀd6), ppm: 149.1, 141.8, 135.9, 133.4, 128.7, 127.6, 127.2, 125.0, 119.8, 116.8, 110.1,
105.9, 39.6. B NMR (128 MHz, DMSOꢀd6), ppm: 27.3. FTIR (neat, cmꢀ1), νmax: 3403 (w), 3280 (br),
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3049 (w), 1596 (s), 1398 (s), 764 (s). HRMS calculated for C20H1811BN4 (ESI+): 325.1619. Found:
325.1639.
General procedure F: Halogenation of pyrazoles. A solution of halogenating agent (1 eq) in MeCN (0.2
M) was added to the pyrazole (1 eq) and the mixture stirred for 1 h at rt. The solvent was removed in
vacuo and a small amount of CH2Cl2 was added. EtOAc was added dropwise to the suspension with
stirring until all material was solubilized. The solution was transferred to a larger vessel before CH2Cl2
was added leading to the precipitation of a solid. The solid was isolated by filtration and washed with
CH2Cl2.
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Synthesis of potassium trifluoro(1-methyl-3-phenyl-4-bromo-1H-pyrazol-5-yl)borate, 14. Following
general procedure F using 1 (0.1 g, 0.4 mmol), Nꢀbromosuccinimide (0.07 g, 0.4 mmol) in acetonitrile
(3 mL) yielded the title compound as a colorless solid (0.11 g, 83% yield). 1H NMR (400 MHz, DMSOꢀ
d6), ppm: 7.76 (d, J = 7.0 Hz, 2H), 7.39 (t, J = 7.0 Hz, 2H), 7.30 (t, J = 7.0 Hz, 1H), 3.82 (s, 3H).
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13C{1H} NMR (101 MHz, DMSOꢀd6), ppm: 145.9, 134.0, 128.5, 127.8, 127.4, 94.2, 30.0. F NMR
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(377 MHz, DMSOꢀd6), ppm: ꢀ135.4. B NMR (128 MHz, DMSOꢀd6), ppm: 0.9. M. pt. 221ꢀ222 °C.
FTIR (neat, cmꢀ1), νmax: 2901 (w), 2845 (w), 1440 (m), 1426 (m), 1182 (s), 1144 (m), 986 (s), 936 (s).
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HRMS calculated for C10H8 B79BrF3N2 (ESIꢀ): 302.9921. Found: 302.9935.
Synthesis of potassium trifluoro(1-methyl-3-phenyl-4-chloro-1H-pyrazol-5-yl)borate, 16. Following
general procedure F using 1 (0.1 g, 0.4 mmol), Nꢀchlorosuccinimide (0.05 g, 0.4 mmol) in acetonitrile
(3 mL) yielded the title compound as a colorless solid (0.09 g, 75% yield). 1H NMR (400 MHz, DMSOꢀ
d6), ppm: 7.78 (d, J = 7.5 Hz, 2H), 7.39 (t, J = 7.5 Hz, 2H), 7.28 (t, J = 7.5 Hz, 1H), 3.79 (s, 3H).
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13C{1H} NMR (101 MHz, DMSOꢀd6), ppm: 144.1, 133.6, 128.6, 127.4, 127.3, 109.1, 40.6. F NMR
(377 MHz, DMSOꢀd6), ppm: ꢀ135.7. 11B NMR (128 MHz, DMSOꢀd6), ppm: 1.3. FTIR (neat, cmꢀ1),
νmax: 2950 (w), 2875 (w), 1430 (w), 1197 (m), 1144 (m), 1005 (s), 966 (s), 924 (s). HRMS calculated
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for C10H8 B35ClF3N2 (ESIꢀ): 258.0463. Found: 258.0471.
Synthesis of potassium trifluoro(1-methyl-3-phenyl-4-iodo-1H-pyrazol-5-yl)borate, 17. Following
general procedure F using 1 (0.1 g, 0.4 mmol), Nꢀiodosuccinimide (0.09 g, 0.4 mmol) in acetonitrile (3
mL) yielded the title compound as a colorless solid (0.06 g, 50% yield). 1H NMR (400 MHz, DMSOꢀd6),
ppm: 7.69 (d, J = 7.0 Hz, 2H), 7.39 (t, J = 7.0 Hz, 2H), 7.30 (t, J = 7.0 Hz, 1H), 3.85 (s, 3H). 13C{1H}
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NMR (101 MHz, DMSOꢀd6), ppm: 149.6, 134.9, 128.6, 128.3, 127.4, 60.9, 40.6. F NMR (377 MHz,
DMSOꢀd6), ppm: ꢀ134.9. 11B NMR (128 MHz, DMSOꢀd6), ppm: 1.2. FTIR (neat, cmꢀ1), νmax: 2957 (w),
1436 (m), 1424 (m), 1171, (m) 1140 (m), 1028 (m), 974 (s), 935 (s). HRMS calculated for
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C10H8 BF3IN2 (ESIꢀ): 349.9819. Found: 349.9822.
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Synthesis of potassium 5-(1-methyl-3-(4-methoxyphenyl)-4-chloropyrazole) trifluoroborate, 18.
Following general procedure F using 2c (500 mg, 1.70 mmol) and Nꢀchlorosuccinimide (227 mg, 1.70
1
mmol) in MeCN (8.5 mL), 18 was isolated as a colorless solid (450 mg, 81%). H NMR (400 MHz,
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DMSOꢀd6), ppm: 7.69 (d, J = 9.0 Hz, 2H), 6.95 (d, J = 9.0 Hz, 2H), 3.77 (s, 3H), 3.76 (s, 3H). 13C{1H}
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NMR (101 MHz, DMSOꢀd6), ppm: 158.3, 143.5, 128.1, 125.7, 113.6, 108.2, 55.1, 29.5. 19F NMR (377
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MHz, DMSOꢀd6), ppm: ꢀ135.8. B NMR (128 MHz, DMSOꢀd6), ppm: 1.40. FTIR (neat, cmꢀ1), νmax
:
2947 (w), 1614 (w), 1533 (m), 1438 (m), 1245 (m), 1177 (s), 1026 (s), 996 (s), 938 (s). HRMS (ESIꢀ)
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calculated for C11H1011B N2OF3 Cl: 289.0527. Found: 289.0513.
Synthesis of potassium 5-(1-methyl-3-(4-chlorophenyl)-4-chloropyrazole) trifluoroborate, 19.
Following general procedure F using 3c (250 mg, 0.837 mmol) and Nꢀchlorosuccinimide (112 mg,
0.837 mmol) in MeCN (4 mL), 19 was isolated as a colorless solid (212 mg, 76%). 1H NMR (400 MHz,
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DMSOꢀd6), ppm: 7.81 (d, J = 8.5 Hz, 2H), 7.44 (d, J = 8.5 Hz, 2H), 3.79 (s, 3H). C{1H} NMR (101
MHz, DMSOꢀd6), ppm: 142.4, 132.0, 131.5, 128.4, 128.2, 108.7, 29.5. 19F NMR (377 MHz, DMSOꢀd6),
ppm: ꢀ135.9. 11B NMR (128 MHz, DMSOꢀd6), ppm: 1.28. FTIR (neat, cmꢀ1), νmax: 2948 (w), 1611 (m),
1439 (m), 1321 (m), 1246 (m), 1109 (s), 1070 (s), 1007 (s), 836 (s). HRMS (ESI+) calculated for
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C10H8 B N2F3 Cl2K: 322.9747. Found: 322.9732.
Synthesis of potassium 5-(1-methyl-3-(4-trifluoromethylphenyl)-4-chloropyrazole) trifluoroborate, 20.
Following general procedure F using 4c (500 mg, 1.51 mmol) and Nꢀchlorosuccinimide (201 mg, 1.51
1
mmol) in MeCN (7.6 mL), 20 was isolated as a colorless solid (529 mg, 96%). H NMR (400 MHz,
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DMSOꢀd6), ppm: 8.03 (d, J = 8.0 Hz, 2H), 7.75 (d, J = 8.0 Hz, 2H), 3.82 (s, 3H). C{1H} NMR (101
MHz, DMSOꢀd6), ppm: 142.1, 137.1, 127.98, 127.09 (q, J = 32 Hz), 125.2 (d, J = 4 Hz), 124.5 (q, J =
272 Hz) 109.3, 29.5. 19F NMR (377 MHz, DMSOꢀd6), ppm: ꢀ60.9, ꢀ136.0. 11B NMR (128 MHz,
DMSOꢀd6), ppm: 1.15. FTIR (neat, cmꢀ1), νmax: 1620 (m), 1325 (s), 1200 (m), 1108 (s), 1067 (s), 965 (s),
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846 (s). HRMS (ESIꢀ) calculated for C11H7 B N2F6 Cl: 327.0295. Found: 327.0283.
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Synthesis of potassium tert-butyl 4-(4-chloro-1-methyl-5-(trifluoroboranyl)-1H-pyrazol-3-yl)piperidine-
1-carboxylate, 21. Following general procedure F using 7 (102 mg, 0.274 mmol), Nꢀchlorosuccinimide
(37 mg, 0.27 mmol) in acetonitrile (2.1 mL) and heated at 45 °C yielded the title compound as a
colorless solid (36 mg, 33% yield). 1H NMR (400 MHz, DMSOꢀd6), ppm: 3.99 – 3.94 (m, 2H), 3.66 (s,
3H), 2.89 – 2.75 (m, 2H), 2.71 (tt, J = 11.5, 4.0, 1H), 1.73 – 1.68 (m, 2H), 1.57 – 1.43 (m, 2H), 1.40 (s,
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9H). C{1H} NMR (101 MHz, DMSOꢀd6), ppm: 153.9, 148.2, 108.3, 78.4, 43.3, 32.9, 30.6, 28.1. F
NMR (376 MHz, DMSOꢀd6), ppm: ꢀ135.8. 11B NMR (128 MHz, DMSOꢀd6), ppm: 0.8. FTIR (neat, cmꢀ
1), νmax: 2977 (w), 2950 (w), 2860 (w), 1664 (s), 1429 (s),1162 (s), 971 (s), 956 (s). HRMS calculated
for C14H2111B35ClO2F3N3 (ESIꢀ): 366.1373. Found: 366.1389.
Synthesis of potassium 4-chloro-1-methyl-3-(tetrahydro-2H-pyran-4-yl)-5-(trifluoroboranyl)-1H-
pyrazole, 22. Following general procedure F using 8 (100 mg, 0.367 mmol), Nꢀchlorosuccinimide (50
mg, 0.37 mmol) in acetonitrile (3 mL) heated at 45 °C yielded the title compound as a colorless solid
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(60 mg, 53% yield). H NMR (400 MHz, DMSOꢀd6), ppm: 3.90 – 3.86 (m, 2H), 3.67 (s, 3H), 3.42 –
3.34 (m, 2H), 2.82 – 2.71 (m, 1H), 1.75 – 1.62 (m, 4H). 13C{1H} NMR (101 MHz, DMSOꢀd6), ppm:
148.9, 108.8, 67.7, 32.0, 28.6, 26.5.19F NMR (376 MHz, DMSOꢀd6), ppm: ꢀ135.8. 11B NMR (128 MHz,
DMSOꢀd6), ppm: 0.8. FTIR (neat, cmꢀ1), νmax: 2958 (w), 2919 (m), 2855 (w), 1238 (m), 1060 (s), 953
(s), 930 (s). HRMS calculated for C9H1211B35ClOF3N2 (ESIꢀ): 267.0689. Found: 267.0680.
General Procedure G: Suzuki-Miyaura of pyrazole trifluoroborates. A flask was charged with
trifluoroborate (1 eq), aryl bromide (2 eq), palladium acetate (0.03 – 0.1 eq), XPhos (0.06 – 0.2 eq),
triethylamine (2 eq) and thoroughly degassed EtOH (0.1 M) and the reaction heated at reflux for 14 h.
The mixture was allowed to cool to ambient temperature, poured into aqueous NaHCO3, extracted with
EtOAc, dried over MgSO4 and volatiles removed in vacuo. The crude residue was purified by flash
silica chromatography (gradient 100% petroleum ether – 40% ethyl acetate in petroleum ether)
affording the target pyrazoles.
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Synthesis of 1-Methyl-3-phenyl-4-chloro-5-(4-methoxyphenyl)pyrazole, 24a. Following general
procedure G using 16 (50 mg, 0.17 mmol) 4ꢀbromoanisole (62 mg, 0.34 mmol), palladium acetate (1
mg, 0.005 mmol), XPhos (5 mg, 0.01 mmol) and NEt3 (34 mg, 0.34 mmol) in EtOH (1.5 mL), 24a was
isolated as a colorless solid (32 mg, 64%). 1H NMR (400 MHz, CDCl3), ppm: 7.97ꢀ7.92 (m, 2H), 7.49ꢀ
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7.33 (m, 5H), 7.05 (d, J = 9.0 Hz, 2H), 3.88 (s, 3H), 3.84 (s, 3H). C{1H} NMR (101 MHz, CDCl3),
ppm: 160.4, 146.5, 141.2, 132.1, 131.2, 128.5, 128.1, 127.5, 120.5, 114.4, 106.5, 55.5, 38.3. FTIR (neat,
cmꢀ1), νmax: 2948 (w), 1609 (m), 1485 (m), 1443 (m), 1358 (w), 1293 (m), 1247 (s), 1181 (s), 1015 (s),
1007 (s), 851 (s). HRMS (ESI+) calculated for C17H15N2O35Cl: 299.0946. Found: 299.0950.
Synthesis of 1-Methyl-3-phenyl-4-chloro-5-(4-trifluoromethylphenyl)pyrazole, 25a. Following general
procedure G using 16 (50 mg, 0.17 mmol) 4ꢀbromotrifluoromethylbenzene (75 mg, 0.34 mmol),
palladium acetate (1 mg, 0.005 mmol), XPhos (5 mg, 0.01 mmol) and NEt3 (34 mg, 0.34 mmol) in
EtOH (1.5 mL), 25a was isolated as a colorless solid (36 mg, 64%). 1H NMR (400 MHz, CDCl3), ppm:
7.98ꢀ7.90 (m, 2H), 7.81 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 8.0 Hz, 2H), 7.46 (t, J = 7.5 Hz, 2H), 7.42ꢀ7.36
(m, 1H), 3.88 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3), ppm: 146.9, 139.8, 131.7, 131.4 (q, J = 33.0
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Hz), 130.3, 128.6, 128.4, 128.0, 127.5, 126.0 (q, J = 3.5 Hz), 124.0 (q, J = 272.5 Hz), 107.2, 38.5. F
NMR (377 MHz, CDCl3), ppm: ꢀ62.8. FTIR (neat, cmꢀ1), νmax: 1621 (w), 1445 (m), 1322 (s), 1155 (m),
1120 (s), 1108 (s), 1068 (s), 1009 (m), 845 (s). HRMS (ESI+) calculated for C17H13N2F3 Cl: 337.0719.
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Found: 337.0709.
Synthesis of 1-Methyl-3-(4-trifluoromethylphenyl)-4-chloro-5-(4-methoxyphenyl)-pyrazole, 26a.
Following general procedure G using 20 (50 mg, 0.14 mmol) 4ꢀbromoanisole (51 mg, 0.27 mmol),
palladium acetate (3 mg, 0.01 mmol), XPhos (13 mg, 0.027 mmol) and NEt3 (28 mg, 0.27 mmol) in
EtOH (1.4 mL), 26a was isolated as a colorless solid (32 mg, 64%). 1H NMR (400 MHz, CDCl3), ppm:
8.09 (d, J = 8.0 Hz, 2H), 7.70 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 9.0 Hz, 2H), 7.06 (d, J = 9.0 Hz, 2H),
3.89 (s, 3H), 3.85 (s, 3H). C{1H} NMR (101 MHz, CDCl3), ppm: 158.5, 147.0, 142.7, 137.4, 131.6,
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130.3, 129.1 (q, J = 32.0 Hz), 128.7, 128.2, 125.3 (q, J = 3.5 Hz), 124.5 (q, J = 272.0 Hz), 114.0, 55.2,
37.7. 19F NMR (377 MHz, CDCl3), ppm: ꢀ62.5. FTIR (neat, cmꢀ1), νmax: 2966 (w), 1611 (m), 1492 (m),
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C18H15N2OF3 Cl: 367.0825. Found: 367.0810.
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Synthesis of 1-Methyl-3-(4-trifluoromethylphenyl)-4-chloro-5-phenylpyrazole, 27a. Following general
procedure G using 20 (50 mg, 0.14 mmol) bromobenzene (43 mg, 0.27 mmol), palladium acetate (3 mg,
0.01 mmol), XPhos (13 mg, 0.027 mmol) and NEt3 (28 mg, 0.27 mmol) in EtOH (1.4 mL), 27a was
isolated as a colorless solid (29 mg, 64%). 1H NMR (400 MHz, CDCl3), ppm: 8.09 (d, J = 8.0 Hz, 2H),
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7.70 (d, J = 8.0 Hz, 2H), 7.58ꢀ7.45 (m, 5H), 3.87 (s, 3H); C{1H} NMR (101 MHz, CDCl3), ppm:
145.1, 141.7, 135.6, 130.0 (q, J = 32.0 Hz), 129.9, 129.6, 129.0, 128.0, 127.6, 125.5 (q, J = 3.5 Hz),
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124.4 (q, J = 272.0 Hz), 107.1, 38.5. F NMR (377 MHz, CDCl3), ppm: ꢀ62.5. FTIR: νmax 2929 (w),
1619 (w), 1323 (s), 1158 (m), 1112 (s), 1066 (s), 1013 (m), 850 (s). HRMS (ESI+) calculated for
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C17H13N2F3 Cl: 337.0719. Found: 337.0735.
Synthesis of 1-Methyl-3-(4-methoxyphenyl)-4-chloro-5-(4-trifluoromethylphenyl)-pyrazole, 28a.
Following general procedure G using 18 (50 mg, 0.15 mmol) 4ꢀbromotrifluoromethylbenzene (68 mg,
0.30 mmol), palladium acetate (3 mg, 0.02 mmol), XPhos (14 mg, 0.03 mmol) and NEt3 (31 mg, 0.30
1
mmol) in EtOH (1.5 mL), 28a was isolated as a colorless solid (32 mg, 57%). H NMR (400 MHz,
CDCl3), ppm: 7.87 (d, J = 9.0 Hz, 2H), 7.80 (d, J = 8.0 Hz, 2H), 7.61 (d, J = 8.0 Hz, 2H), 6.99 (d, J =
13
9.0 Hz, 2H), 3.86 (s, 3H,), 3.86 (s, 3H). C{1H} NMR (101 MHz, CDCl3), ppm: 159.8, 146.8, 139.7,
132.0, 131.4 (q, J = 33.0 Hz), 130.3, 128.8, 125.9 (q, J = 3.5 Hz), 124.3, 124.0 (q, J = 272.5 Hz), 114.1,
106.8, 55.4, 38.4. 19F NMR (377 MHz, CDCl3), ppm: ꢀ62.8. FTIR (neat, cmꢀ1), νmax: 2943 (w), 1611 (m),
1531 (m), 1439 (m), 1321 (s), 1246 (m), 1167 (s), 1123 (s), 1109 (s), 1071 (m), 1031 (m), 1012 (m),
35
836 (s). HRMS (ESI+) calculated for C18H14N2OF3 Cl: 367.0820. Found: 367.0822.Synthesis of 1-
Methyl-3-(4-methoxyphenyl)-4-chloro-5-phenylpyrazole, 29a. Following general procedure G using 18
(50 mg, 0.15 mmol), bromobenzene (48 mg, 0.30 mmol), palladium acetate (3 mg, 0.02 mmol), XPhos
(14 mg, 0.029 mmol) and NEt3 (31 mg, 0.30 mmol) in EtOH (1.5 mL), 29a was isolated as a colorless
1
solid (29 mg, 64%). H NMR (400 MHz, CDCl3), ppm: 7.88 (d, J = 9.0 Hz, 2H), 7.58ꢀ7.44 (m, 5H),
13
6.99 (d, J = 9.0 Hz, 2H), 3.86 (s, 3H), 3.84 (s, 3H). C{1H} NMR (101 MHz, CDCl3), ppm: 159.7,
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146.5, 141.2, 129.9, 129.4, 128.9, 128.8, 128.4, 124.7, 114.0, 106.3, 55.4, 38.3. FTIR (neat, cmꢀ1), νmax
:
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2947 (w), 1612 (m), 1579 (m), 1529 (m), 1482 (m), 1451 (m), 1438 (m), 1300 (m), 1246 (s), 1182 (s),
1171 (s), 1031 (s), 1010 (s). HRMS (ESI+) calculated for C17H15N2O35Cl: 299.0946. Found: 299.0948.
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General Procedure H: Suzuki-Miyaura of 4-chloropyrazoles. A flask was charged with chloropyrazole
(1 eq), aryl boronic acid (2 eq), XPhosPdG2 (0.1 eq), sodium carbonate (3 eq), degassed 1,2ꢀ
dimethoxyethane:water (1/1, 0.1 M) and the reaction heated at 80 °C for 14 h. The mixture was allowed
to cool to ambient temperature, poured into aqueous NaHCO3, extracted with EtOAc, dried over MgSO4
and volatiles removed in vacuo. The crude residue was purified by flash silica chromatography
(gradient 100% petroleum ether – 40% ethyl acetate in petroleum ether) affording the target pyrazoles.
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Synthesis
of
1-Methyl-3-phenyl-4-(4-methoxyphenyl)-5-(4-trifluoromethylphenyl)pyrazole,
24.
Following general procedure H using 24a (50 mg, 0.15 mmol) 4ꢀmethoxyphenylboronic acid (45 mg,
0.30 mmol), XPhosPdG2 (12 mg, 0.015 mmol), Na2CO3 (47 mg, 0.44 mmol) in 1,2ꢀDME:H2O (1:1, 1.5
mL), 24 was isolated as a colorless solid (55 mg, 91%). 1H NMR (400 MHz, CDCl3), ppm: 7.63 (d, J =
8.0 Hz, 2H), 7.50ꢀ7.45 (m, 2H), 7.37 (d, J = 8.0 Hz, 2H), 7.31ꢀ7.25 (m, 3H), 6.95 (d, J = 8.5 Hz, 2H),
13
6.75 (d, J = 8.5 Hz, 2H), 3.89 (s, 3H), 3.77 (s, 3H). C{1H} NMR (101 MHz, CDCl3), ppm: 159.9,
147.0, 142.6, 137.3, 131.5, 130.5, 129.2 (q, J = 32.0 Hz), 128.5, 128.2, 126.8, 125.1 (q, J = 3.5 Hz),
19
124.3 (q, J = 272.0 Hz), 122.0, 119.6, 114.2, 103.5, 55.4, 37.6. F NMR (377 MHz, CDCl3), ppm: ꢀ
62.7. FTIR (neat, cmꢀ1), νmax: 2941 (w), 1619 (m), 1525 (m), 1437 (m), 1326 (s), 1244 (s), 1162 (m),
1115 (s), 1069 (s), 1031 (m). HRMS (ESI+) calculated for C24H19N2OF3: 409.1522. Found: 409.1524.
Synthesis
of
1-Methyl-3-phenyl-4-(4-trifluoromethylphenyl)-5-(4-methoxyphenyl)pyrazole,
25.
Following general procedure H using 25a (50 mg, 0.17 mmol) 4ꢀtrifluoromethylphenylboronic acid (62
mg, 0.34 mmol), XPhosPdG2 (13 mg, 0.017 mmol), Na2CO3 (53 mg, 0.50 mmol) in 1,2ꢀDME / H2O
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(1:1, 1.7 mL), 25 was isolated as a colorless solid (56 mg, 82%). H NMR (400 MHz, CDCl3), ppm:
7.45ꢀ7.38 (m, 4H), 7.34ꢀ7.27 (m, 3H), 7.18ꢀ7.11 (m, 4H), 6.92 (d, J = 9.0 Hz, 2H), 3.86 (s, 3H), 3.84 (s,
13
3H). C{1H} NMR (101 MHz, CDCl3), ppm: 160.1, 148.8, 142.6, 137.6, 133.3, 131.5, 130.5, 128.5,
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128.4, 127.8, 125.2 (q, J = 4.0 Hz), 124.4 (q, J = 272.0 Hz), 121.9, 117.7, 114.4, 55.4, 37.4 (one sp2
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4
5
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carbon not observed). F NMR (377 MHz, CDCl3), ppm: ꢀ62.3; FTIR (neat, cmꢀ1), νmax: 2939 (w),
1611 (m), 1446 (m), 1330 (s), 1253 (s), 1156 (m), 1102 (s), 1064 (s), 906 (m). HRMS (ESI+) calculated
for C24H19N2OF3: 409.1522. Found: 409.1530.
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Synthesis
of
1-Methyl-3-(4-trifluoromethylphenyl)-4-phenyl-5-(4-methoxyphenyl)pyrazole,
26.
Following general procedure H using 26a (50 mg, 0.14 mmol) phenylboronic acid (33 mg, 0.27 mmol),
XPhosPdG2 (11 mg, 0.014 mmol), Na2CO3 (43 mg, 0.41 mmol) in 1,2ꢀDME:H2O (1:1, 1.4 mL), 26 was
isolated as a colorless solid (33 mg, 59%). 1H NMR (400 MHz, CDCl3), ppm: 7.58 (d, J = 8.0 Hz, 2H),
7.51 (d, J = 8.0 Hz, 2H), 7.23ꢀ7.19 (m, 3H), 7.16 (d, J = 8.5 Hz, 2H), 7.08ꢀ7.02 (m, 2H), 6.89 (d, J = 8.5
Hz, 2H), 3.87 (s, 3H), 3.82 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3), ppm: 159.9, 147.0, 142.6, 137.3,
133.3, 131.5, 130.5, 129.2 (q, J = 32.0 Hz), 128.5, 128.2, 125.7, 125.3 (q, J = 3.5 Hz), 124.5 (q, J =
272.0 Hz), 122.0, 119.6, 114.2, 55.4, 37.6. 19F NMR (377 MHz, CDCl3), ppm: ꢀ62.4. FTIR (neat, cmꢀ1),
νmax: 2961 (w), 1617 (m), 1322 (s), 1249 (m), 1165 (s), 1105 (s), 1065 (s), 841 (s). HRMS (ESI+)
calculated for C24H19N2OF3: 409.1522. Found: 409.1526.
Synthesis
of
1-Methyl-3-(4-trifluoromethylphenyl)-4-(4-methoxyphenyl)-5-phenylpyrazole,
27.
Following general procedure H using 27a (50 mg, 0.15 mmol) 4ꢀmethoxyphenylboronic acid (45 mg,
0.30 mmol), XPhosPdG2 (12 mg, 0.015 mmol), Na2CO3 (47 mg, 0.44 mmol) in 1,2ꢀDME:H2O (1:1, 1.5
1
mL), 27 was isolated as a colorless oil (49 mg, 81%). H NMR (400 MHz, CDCl3), ppm: 7.60 (d, J =
8.0 Hz, 2H), 7.52 (d, J = 8.0 Hz, 2H), 7.40ꢀ7.35 (m, 3H), 7.28ꢀ7.20 (m, 2H), 6.96 (d, J = 8.5 Hz, 2H),
6.75 (d, J = 8.5 Hz, 2H), 3.88 (s, 3H), 3.77 (s, 3H). C{1H} NMR (101 MHz, CDCl3), ppm: 160.5,
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145.0, 141.6, 135.7, 131.2, 130.2, 129.9 (q, J = 32.5 Hz), 127.5, 127.4, 125.7, 125.5 (q, J = 3.5 Hz),
124.4 (q, J = 272.0 Hz), 120.1, 114.5, 107.0, 55.5, 38.4 (one sp2 carbon not observed). F NMR (377
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MHz, CDCl3), ppm: ꢀ62.4. FTIR (neat, cmꢀ1), νmax: 2941 (w), 1616 (m), 1513 (m), 1325 (s), 1240 (m),
1161 (m), 1107 (s), 1066 (s), 1015 (m). HRMS (ESI+) calculated for C24H19N2OF3: 409.1522. Found:
409.1526.
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Synthesis
of
1-Methyl-3-(4-methoxyphenyl)-4-phenyl-5-(4-trifluoromethylphenyl)pyrazole,
28.
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Following general procedure H using 28a (50 mg, 0.14 mmol) phenylboronic acid (33 mg, 0.27 mmol),
XPhosPdG2 (11 mg, 0.014 mmol), Na2CO3 (43 mg, 0.41 mmol) in 1,2ꢀDME:H2O (1:1, 1.4 mL), 28 was
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isolated as a colorless oil (37 mg, 67%). H NMR (400 MHz, CDCl3), ppm: 7.62 (d, J = 8.0 Hz, 2H),
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7.44ꢀ7.34 (m, 4H), 7.22ꢀ7.16 (m, 3H), 7.07ꢀ7.01 (m, 2H), 6.81 (d, J = 9.0 Hz, 2H), 3.88 (s, 3H), 3.79 (s,
13
3H). C{1H} NMR (101 MHz, CDCl3), ppm: 159.2, 148.6, 140.8, 134.0, 133.2, 130.6, 130.6 (q, J =
33.0 Hz), 130.5, 129.4, 128.5, 126.8, 125.8, 125.6 (q, J = 3.5 Hz), 124.0 (q, J = 272.0 Hz), 119.5, 113.8,
55.3, 37.6. 19F NMR (377 MHz, CDCl3), ppm: ꢀ62.7. FTIR (neat, cmꢀ1), νmax: 2940 (w), 1612 (m), 1530
(m), 1434 (m), 1324 (s), 1248 (s), 1164 (s), 1115 (s), 1071 (s), 1020 (s), 840 (s). HRMS (ESI+)
calculated for C24H19N2OF3: 409.1522. Found: 409.1528.
Syntheis of 1-Methyl-3-(4-methoxyphenyl)-4-(4-trifluoromethylphenyl)-5-phenylpyrazole, 29. Following
general procedure H using 29a (53 mg, 0.18 mmol) 4ꢀtrifluoromethylphenylboronic acid (67 mg, 0.35
mmol), XPhosPdG2 (14 mg, 0.018 mmol), Na2CO3 (56 mg, 0.53 mmol) in 1,2ꢀDME:H2O (1:1, 1.8 mL),
29 was isolated as a colorless solid (46 mg, 64%). 1H NMR (400 MHz, CDCl3), ppm: 7.43ꢀ7.38 (m, 5H),
7.35 (d, J = 9.0 Hz, 2H), 7.24ꢀ7.20 (m, 2H), 7.12 (d, J = 8.0 Hz, 2H), 6.84 (d, J = 9.0 Hz, 2H), 3.85 (s,
13
3H), 3.81 (s, 3H). C{1H} NMR (101 MHz, CDCl3), ppm: 159.4, 148.7, 142.6, 137.6, 130.5, 130.3,
129.9, 129.6, 129.0, 128.9, 128.3 (q, J = 32.0 Hz), 125.7, 125.2 (q, J = 4.0 Hz), 124.4 (q, J = 272.0 Hz),
117.5, 114.0, 55.3, 37.4. 19F NMR (377 MHz, CDCl3), ppm: ꢀ62.4. FTIR (neat, cmꢀ1), νmax: 2932 (w),
1616 (m), 1526 (m), 1434 (m), 1331 (s), 1247 (s), 1158 (m), 1115 (s), 1065 (s), 839 (s). HRMS (ESI+)
calculated for C24H19N2OF3: 409.1522. Found: 409.1521.
Acknowledgements
We are grateful to Sanofi for financial support. This work was funded by the FP7 Marie Curie Actions
of the European Commission via the ITN COSSHNET network.
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Supporting Information Available: H, 13C, F and B NMR spectra for selected compounds and
structure elucidation analyses performed on selected compounds. This material is available free of
charge at http://pubs.acs.org
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