Expanding available pyrazole substitution patterns by sydnone cycloaddition reactions

Article abstract of DOI:10.1016/j.tet.2017.04.049

We report the use of alkynylsilanes for the regiocontrolled synthesis of pyrazoles from functionalised sydnones. The strategies outlined herein allow a range of pyrazoles to be accessed with substitution patterns that are otherwise not directly obtained with high selectivity by alkyne cycloadditions. Moreover, this study serendipitously highlighted a simple and convenient procedure for the synthesis of aryl monofluoromethyl ethers through the combination of TBAF and dichloromethane.

Full text of DOI:10.1016/j.tet.2017.04.049

Accepted Manuscript
Expanding available pyrazole substitution patterns by sydnone cycloaddition
reactions
A.W. Brown, J.P.A. Harrity
PII:
S0040-4020(17)30439-8
10.1016/j.tet.2017.04.049
TET 28650
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 9 March 2017
Revised Date: 3 April 2017
Accepted Date: 20 April 2017
Please cite this article as: Brown AW, Harrity JPA, Expanding available pyrazole substitution patterns by
sydnone cycloaddition reactions, Tetrahedron (2017), doi: 10.1016/j.tet.2017.04.049.
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ACCEPTED MANUSCRIPT
Expanding available pyrazole substitution patterns by sydnone cycloaddition reactions
A. W. Brown and J. P. A. Harrity*
Department of Chemistry, University of Sheffield, Sheffield, S3 7HF (U.K.). j.harrity@sheffield.ac.uk
Abstract
We report the use of alkynylsilanes for the regiocontrolled synthesis of pyrazoles from
functionalised sydnones. The strategies outlined herein allow a range of pyrazoles to be
accessed with substitution patterns that are otherwise not directly obtained with high
selectivity by alkyne cycloadditions. Moreover, this study serendipitously highlighted a
simple and convenient procedure for the synthesis of aryl monofluoromethyl ethers through
the combination of TBAF and dichloromethane.
Introduction
Pyrazoles are a privileged class of heteroaromatic compounds and they constitute the
core motif of a number of compounds of medicinal and agrochemical significance.1 Classical
approaches to pyrazoles have broadly encompassed condensation and cycloaddition
reactions.2 Work in our labs has sought to exploit both strategies for the direct formation of
borylated pyrazoles where the borate is introduced during annelation, rather than through ring
functionalisation.3 With respect to cycloadditions, sydnones have emerged as effective
precursors to pyrazoles, and they offer a regiocontrolled route to 1,3-disubstituted and 1,3,5-
trisubstituted diazoles when reacted with terminal alkynes.4 This product substitution pattern
is the result of the innate selectivity of alkyne cycloadditions with 4-H and 4-substituted
sydnone substrates. We have been interested in developing strategies that overturn this innate
selectivity, and report herein how alkynylsilanes can access alternative substitution patterns,
thereby expanding the scope of sydnone cycloaddition methodology for pyrazole synthesis
(Scheme 1).5

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Scheme 1. Sydnone cycloadditions of alkynes to form pyrazoles.
Results and Discussion
1,5-Disubstituted pyrazoles: We initially started our investigations into expanding the
scope of the preparation of 1,5-disubstituted pyrazoles. Our strategy was to employ
trimethylsilylacetylene as a non-gaseous acetylene equivalent in cycloaddition reactions of 4-
substituted sydnones, which were in turn prepared by direct arylation6 or by metalation
chemistry. In all cases attempted, the cycloaddition proceeded efficiently and with high
(albeit ultimately inconsequential) regioselectivity favouring the 3-substituted pyrazole
(Scheme 2). In contrast, TBAF-mediated removal of the trimethylsilyl group proved
somewhat less general. While pyrazoles 2, 4 and 8 were successfully prepared in good yield
(see below for discussion of compound 10), Weinreb amide-substituted pyrazole 5 only
afforded a complex mixture of products. Moreover, in the case of oxazoline-substituted
pyrazole 11, product 12 was afforded in only moderate yield.

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Scheme 2. Preparation of 1,5-disubstituted pyrazoles. aR2 in the starting sydnone was used as
the corresponding TBS-ether.
These studies highlighted some unexpected outcomes in the TBAF mediated
protodesilylation of 3-trimethylsilylpyrazoles. With regard to the low yield observed in the
synthesis of 12, we were able to isolate (23%, 1:1 E:Z) and characterise a major by-product of
this reaction which proved to be nitrile 13 (Scheme 3). The isolation and characterisation of
13 highlights the propensity of electron deficient pyrazoles to undergo elimination under
strongly basic conditions.7
Scheme 3. TBAF-mediated elimination.
With regard to the conversion of 9→10, we noted that significantly lower yields of
product were observed in the presence of CH2Cl2 (carried over from chromatography).
Specifically, when 9 was subjected to refluxing TBAF solution, a small amount of 10 was
isolated together with mono-fluoromethylated phenol 14. In addition, fluoromethylation
product 14 could be generated in higher yield when the reaction vessel was charged with
dichloromethane, TBAF and heated at reflux (Scheme 4).
TMS
N
N
N
TBAF (1 M, THF)
N
N
HO
FH2CO
MeO
+
N
TBSO
MeO
(trace CH2Cl2)
Reflux
TMP
TMP
TMP
MeO
9
10; 14%
14; 22%
TBAF (1 M, THF)
CH2Cl2
N
N
N
N
HO
FH2CO
Reflux
TMP
TMP
MeO
MeO
10
14; 49%
Scheme 4. TBAF-mediated protodesilylation and monofluoromethylation studies.
TMP:3,4,5-(MeO)3C6H2.
Current interest in developing methods for the simple incorporation of fluorous
hydrocarbons suggested that this method could represent a powerful tool in the synthesis of
organofluorine compounds. Monofluoromethyl ethers are much less prevalent in the literature

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than their difluoro- and trifluoro- counterparts. However, Hu et al. recently reported the
monofluoromethylation of phenols and other nucleophiles using fluoroalkyl sulfoximines.8 In
order to explore the generality of our method for the synthesis of monofluoromethyl ethers,
we attempted to repeat the reaction shown in Scheme 4 on 4-bromophenol and 3-hydroxy-4-
methoxybenzaldehyde, our results are depicted in Scheme 5. Subjecting 4-bromophenol to
1
TBAF/CH2Cl2 led to fluoromethylation product 15, as judged by H NMR analysis of the
crude reaction mixture. However, the product was found to be contaminated with the
corresponding acetal 16. Unfortunately, 15 and 16 could not be separated by
chromatography. Furthermore, 15 was found to undergo conversion to acetal 16 on various
chromatographic supports, or on standing. In this context, the instability of
monofluoromethyl ethers has been noted by Hu and Sheng.8,9 Interestingly however, 17 could
be isolated cleanly after chromatography on Florisil®, albeit in modest yield (Scheme 5).
These experiments suggested that the fluoromethyl ether formation outlined here may be
useful, but only in cases where the final products undergo slow hydrolysis. Finally, with
regard to the mechanism of fluoromethyl ether formation, Zhang et al. have shown that
chlorofluoromethane is capable of alkylating phenols.10 We therefore propose that CH2Cl2
and TBAF combine to form FCH2Cl as an alkylating agent. The potential for
fluoromethylation via an interrupted Reimer-Tiemann reaction11 was discounted as CD2Cl2
provided the d-17 with >95% D-incorporation.
Scheme 5. TBAF-mediated monofluoromethylation of phenols.
1,4,5-Trisubstituted pyrazoles: We next turned our attention to the synthesis of more
heavily decorated pyrazoles. We envisaged that an alkynylboronate bearing a trimethylsilyl
group could provide general access to 1,4,5-substituted products, assuming appropriate
regiochemical insertion of the alkyne. Specifically, the TMS-group could act as a surrogate

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for a C3-H while the boronate would offer a means for diversifying at C4. Our results
towards this objective are summarised in Scheme 6. The cycloaddition reactions generally
proceeded in moderate to good yield and afforded single regioisomers in the cases of 18, 21,
and 27, in a similar manner to our previous report on alkynylboronate cycloadditions.3b,c
Interestingly, slightly lower regioselectivities were observed for products 24 and 30, possibly
due to the electron-rich nature of the sydnone 4-substituents in these cases. Suzuki-Miyaura
coupling of the cycloadducts proceeded smoothly for all examples, affording fully-substituted
pyrazole cores. TBAF-mediated TMS cleavage successfully furnished products 23, 29 and
32, although a particularly low yield was isolated in the case of 26. Unfortunately, 19 was not
a viable substrate for this final step and desilylation resulted in a complex mixture of
products.
Scheme 6. Preparation of 1,4,5-disubstituted pyrazoles.
Regiocontrolled 3,4-substituted pyrazole synthesis: Generally speaking, the
employment of internal alkynes in sydnone cycloadditions results in a mixture of pyrazole
regioisomers.12 While this issue is somewhat alleviated by the employment of
alkynylboronates, sydnones with a C4-substituent are typically required.3c As terminal
alkynes generally undergo highly regioselective cycloadditions with sydnones, we envisaged

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that a bromination and cross-coupling sequence would represent a more controlled and
predictable strategy for the synthesis of 1,3,4- and 1,3,4,5-substituted pyrazoles. In order to
investigate this approach, we subjected a small series of N-arylsydnones to cycloaddition, and
these afforded 33, 35 and 37 in good to high yield and high regioselectivity (Scheme 7). The
cycloadducts were then brominated and immediately subjected to Suzuki-Miyaura cross-
coupling with boronic acid derivatives. Gratifyingly, the 1,3,4-trisubsubstituted pyrazoles 34,
36 and 38 were isolated in moderate to good yield. Furthermore, 4-substituted sydnones
underwent cycloaddition with terminal alkynes with excellent regioselectivity. In the case of
the oxazine-substituted sydnone, a significant amount of decomposition was observed
resulting in a very low isolated yield of pyrazole 39. Subsequent bromination and cross-
coupling afforded fully-substituted pyrazoles 40, 42 and 46, albeit with generally low yields
because of steric hindrance. Unfortunately, Weinreb amide 43 was not stable to the
bromination/Suzuki-Miyaura strategy. Overall this strategy provides rapid access to fully-
substituted pyrazole cores bearing useful functionality, with near complete control of
regiochemistry. A diverse range of structures can be installed with predictable
regiochemistry.
Scheme 7. Preparation of 1,3,4-trisubstituted- and 1,3,4,5-tetrasubstituted pyrazoles.

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Conclusions
We have developed a flexible strategy for the synthesis of a diverse range of
pyrazoles with high and predictable regiocontrol. A range of functional groups are tolerant of
the cycloaddition conditions and a number of functionalised pyrazoles have been prepared.
These studies have highlighted the potential of TBAF-CH2Cl2 mixtures to transfer
fluoromethyl groups, although the generality of this process appears to be narrow at present
due to instability in the resulting products.
Experimental Section
1H NMR spectra were recorded on a Bruker AVIII HD 400 (400 MHz), Bruker AVI
400 (400 MHz), or DPX-400 (400 MHz) supported by an Aspect 3000 data system. Chemical
shifts are reported in parts per million (ppm) from tetramethylsilane with the residual protic
solvent resonance as the internal standard (CHCl3: δ 7.26, DMSO: δ 2.50). Data are reported
as follows: chemical shift, integration, multiplicity (s = singlet, d = doublet, t = triplet, q =
13
quartet, m = multiplet, br = broad), coupling constants (Hz), assignments. C NMR spectra
were recorded on a Bruker AVIII HD 400 (100.6 MHz), Bruker AVI 400 (100.6 MHz), or
DPX-400 (100.6 MHz) with complete proton decoupling. Chemical shifts are reported in
ppm from tetramethylsilane with the solvent as the internal reference (CDCl3: δ 77.16,
DMSO: δ 39.52). High-resolution mass spectra (HRMS), recorded for accurate mass
analysis, were performed on electrospray mode (TOF ES+). Infrared (IR) spectra were
recorded on a Perkin Elmer Paragon 100 FTIR spectrophotometer, νmax in cm-1. Samples
were recorded as thin films using sodium chloride plates, as a dichloromethane solution or as
solids using a solid probe. Bands were characterised as broad (br), strong (s), medium (m),
and weak (w). All solvents and reagents were purified using standard laboratory techniques
according to methods published in “Purification of Laboratory Chemicals” by Armarego and
Perrin (Pergamon Press, 2009). Flash chromatography was performed on silica gel (BDH
Silica Gel 60 43-60). Thin layer chromatography (TLC) was performed on aluminium backed
plates pre-coated with silica (0.2 mm, Merck DC-alufolien Kieselgel 60 F254) which were
developed using standard visualising agents: ultraviolet (UV) light or potassium
permanganate.
N-Methyl-, N-benzyl-, N-phenyl-, N-(4-methoxyphenyl)-, N-(4-fluorophenyl)-, and N-(3,4,5-
trimethoxyphenyl)sydnone were prepared by standard methods (cyclodehydration of N-

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nitrosoamino acid with trifluoroacetic anhydride).6 4-(4-Tolyl)-N-methylsydnone1 and 4-(4-
tolyl)-N-phenylsydnone6 were prepared according to procedures described previously.
General Procedure A: Preparation of 3,4-diarylsydnones:
A mixture of sydnone (1 eq.), aryl halide (1.5 eq.), palladium acetate (5 mol %), XPhos (10
mol%) and potassium carbonate (2 eq.) in DMF (0.5 M) under an atmosphere of nitrogen was
heated at 80 °C (for 3-alkylsydnones) or 120 °C (for 3-arylsydnones) for 14 h before the
reaction was allowed to cool to r.t. and water was added. The resulting mixture was extracted
with ethyl acetate:40-60 petroleum ether (9:1) and the combined organic layers dried over
MgSO4 and concentrated in vacuo. Flash silica chromatography (eluting solvent 20%-100%
ethyl acetate in 40-60 petroleum ether) afforded the target 3,4-diarylsydnones. The
compounds could be further purified by recrystallisation from ethanol or
dichloromethane/petrol.
General Procedure B: Cycloadditions of Sydnones with Terminal Alkynes:
A Schlenk tube was charged with sydnone (1 eq.), alkyne (2-4 eq.) and xylenes (1 M). The
ο
tube was then sealed and heated at 160 C for 24 h. The mixture was allowed to cool to r.t.
and loaded onto a short plug of silica and washed with 40-60 petroleum ether before elution
with ethyl acetate. Volatiles were removed in vacuo and the crude residue purified by flash
silica chromatography (gradient starting with 100% 40-60 petroleum ether and ending with
40% ethyl acetate in 40-60 petroleum ether) affording the target 1,3,5-trisubstituted pyrazoles
as major products.
General Procedure C: Trimethylsilyl Group Cleavage:
A flask equipped with a reflux condenser was charged with pyrazole (1 eq.), and TBAF (10
eq. 1 M solution in THF) and heated at reflux under an inert atmosphere of nitrogen for 24 h.
The mixture was allowed to cool to r.t., poured into water and extracted with ethyl acetate.
The combined organic layers were dried over MgSO4 and concentrated in vacuo. Flash silica
chromatography (gradient starting with 100% 40-60 petroleum ether and ending with 60%
ethyl acetate in 40-60 petroleum ether) afforded the target desilated pyrazoles.
General Procedure D: Thermal Cycloaddition of Sydnones with Alkynylboronates:
A Schlenk tube was charged with sydnone (1 eq.), alkyne (2 eq.) and xylenes (1 M). The tube
ο
was then sealed and heated at 180 C for 48 h. The mixture was allowed to cool to r.t. and

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loaded onto a short plug of silica and washed with 40-60 petroleum ether before elution with
ethyl acetate. Volatiles were removed in vacuo and the crude residue purified by flash silica
chromatography (gradient starting with 100% 40-60 petroleum ether and ending with 40%
ethyl acetate in 40-60 petroleum ether) affording the target pyrazole boronic esters. The
products were isolated as single regioisomers unless otherwise stated and contaminated with
small amounts of protodeboronated by-product. 13C NMR spectra of organoboron compounds
are missing a signal for the carbon atom directly attached to the boron due to broadening
arising from the quadrupolar relaxation effect.
General Procedure E: Suzuki-Miyaura Coupling of Pyrazole Boronic Acid Derivatives:
A flask equipped with a reflux condenser was charged with pyrazole boronic ester (1 eq.),
XPhosPdG2 (0.1 eq.), sodium carbonate (2 eq.) and degassed 1,2-dimethoxyethane:water
(1:1, 0.1 M) and heated at 80 οC under an inert atmosphere of nitrogen for 14 h. The mixture
was allowed to cool to r.t., poured into water and extracted with ethyl acetate. The combined
organic layers were dried over MgSO4 and concentrated in vacuo. Flash silica
chromatography (gradient starting with 100% 40-60 petroleum ether and ending with 40%
ethyl acetate in 40-60 petroleum ether) afforded the target cross-coupled pyrazoles as an
inseparable mixture of the target material and the product arising from protodeboronation.
Only characterisation for the target material is reported.
General Procedure F: Bromination and Subsequent Suzuki-Miyaura Coupling of Pyrazoles:
To a flask containing pyrazole (1 eq.) was added a solution of N-bromosuccinimide (1 eq.) in
acetonitrile (0.2 M). The resulting mixture was stirred for 1 h at r.t., before being poured into
water. The mixture was extracted with ethyl acetate and the combined organic layers washed
with aqueous sodium hydroxide (1 M). The organic layer was dried over MgSO4, filtered and
volatiles removed in vacuo. The crude material was concentrated into a flask. The flask was
then charged with aryl/vinyl boronate (1.5 eq.), XPhosPdG2 (10 mol%), sodium carbonate
(2eq. for boronic esters or 3 eq. for boronic acids) and thoroughly degassed 1,2-
dimethoxyethane:water (1:1, 0.1 M). The mixture was heated at 80 οC for 14 h, cooled to r.t.,
poured into water and extracted with ethyl acetate. The combined organic layers were dried
over MgSO4, filtered and volatiles removed in vacuo. Flash silica chromatography (gradient
starting with 100% 40-60 petroleum ether and ending with 100% ethyl acetate in 40-60
petroleum ether) afforded the target pyrazoles.

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4-(3,4,5-Trimethoxyphenyl)-3-(4-methoxyphenyl)sydnone:
Following general procedure A using N-(4-methoxyphenyl)sydnone (100 mg, 0.521 mmol)
and 5-bromo-1,2,3-trimethoxybenzene (193 mg, 0.781 mmol), the title compound was
isolated as a yellow solid (132 mg, 71%). The title compound was recrystallised from EtOH
and isolated as yellow plates.
M.p.: 155-157 °C (dec.); 1H NMR (400 MHz, CDCl3): δ 3.65 (6H, s), 3.82 (3H, s), 3.89 (3H,
13
s), 6.55 (2H, s), 7.06 (2H, d, J = 9.0 Hz), 7.44 (2H, d, J = 9.0 Hz); C NMR (101 MHz,
CDCl3): δ 56.0, 56.1, 61.1, 104.2, 107.9, 115.3, 120.0, 126.6, 127.5, 138.5, 153.4, 162.3,
167.1. FTIR: νmax 3116 (w), 3091 (w), 2944 (w), 2841 (w), 1729 (s), 1578 (s), 1125 (s), 991
(m) cm-1; HRMS (ESI-TOF) m/z [M+H]+ calculated for C18H19N2O6: 359.1238. Found:
359.1239.
1-(4-Methoxyphenyl)-3-(trimethylsilyl)-5-(3,4,5-trimethoxyphenyl)-pyrazole, 1a and 1-(4-
methoxyphenyl)-4-(trimethylsilyl)-5-(3,4,5-trimethoxyphenyl)-pyrazole 1b:
Following
general
procedure
B
using
4-(3,4,5-trimethoxyphenyl)-3-(4-
methoxyphenyl)sydnone (200 mg, 0.558 mmol) and trimethylsilylacetylene (219 mg, 2.23
mmol) in xylenes (0.56 mL), an inseparable mixture of pyrazole 1a and 1b was isolated as a
brown oil (230 mg, 100%, 95:5).
1H NMR (400 MHz, CDCl3) δ 0.36 (9H, s), 3.67 (6H, s), 3.80 (3H, s), 3.84 (3H, s), 6.41 (2H,
13
s), 6.57 (1H, s), 6.87 (2H, d, J = 9.0 Hz), 7.26 (2H, d, J = 9.0 Hz); C NMR (101 MHz,
CDCl3) δ -0.8, 55.7, 56.1, 61.1, 106.1, 113.3, 114.2, 126.3, 127.1, 133.8, 137.8, 143.1, 153.1,
153.6, 159.0; FTIR: νmax 2955 (w), 2835 (w), 1584 (m), 1514 (s), 1244 (s), 1125 (s) cm-1;
HRMS (ESI-TOF) m/z [M+H]+ calculated for C22H29N2O4Si: 413.1892. Found: 413.1905.
1-(4-Methoxyphenyl)-5-(3,4,5-trimethoxyphenyl)-pyrazole, 2:
Following general procedure C using a mixture of pyrazoles 1a and 1b (222 mg, 0.539 mmol,
95:5) and TBAF in THF (1.0 M, 5.4 mL, 5.4 mmol), pyrazole 2 was isolated as an orange
solid (137 mg, 75%). The title compound was recrystallised from CH2Cl2/40-60 petroleum
ether and isolated as an orange powder.
ο
M.p.: 92-94 C; 1H NMR (400 MHz, CDCl3) δ 3.66 (6H, s), 3.80 (3H, s), 3.84 (3H, s), 6.41
(2H, s), 6.47 (1H, d, J = 2.0 Hz), 6.87 (2H, d, J = 9.0 Hz), 7.23 (2H, d, J = 9.0 Hz), 7.67 (1H,
13
d, J = 2.0 Hz); C NMR (101 MHz, CDCl3) δ 55.6, 56.1, 61.0, 106.1, 106.9, 114.1, 126.0,

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126.9, 133.5, 138.0, 140.0, 142.9, 153.1, 159.0; FTIR: νmax 2931 (w), 2835 (w), 1586 (m),
1514 (s), 1415 (m), 1241 (s), 1121 (s), 1002 (m), 835 (s) cm-1; HRMS (ESI-TOF) m/z
[M+H]+ calculated for C19H21N2O4: 341.1496. Found: 341.1504.
4-(3-Amino-4-methoxyphenyl)-3-(3,4,5-trimethoxyphenyl)sydnone:
Following general procedure A using N-(3,4,5-trimethoxyphenyl)sydnone (100 mg, 0.396
mmol) and 5-bromo-2-methoxyaniline (120 mg, 0.595 mmol), the title compound was
isolated as an orange solid (135 mg, 91%). The title compound was recrystallised from
CH2Cl2/40-60 petroleum ether and isolated as an orange powder.
1
M.p.: 173-174 °C; H NMR (400 MHz, CDCl3) δ 3.77 (6H, s), 3.80 (3H, s), 3.83 (2H, s),
3.90 (3H, s), 6.52 (1H, dd, J = 8.5, 2.0 Hz), 6.64 (1H, d, J = 8.5 Hz), 6.68 (2H, s), 6.85 (1H,
d, J = 2.0 Hz); 13C NMR (101 MHz, CDCl3) δ 55.6, 56.6, 61.2, 102.5, 108.4, 110.2, 113.4,
117.1, 118.1, 130.1, 136.6, 140.5, 147.7, 154.0, 167.2; FTIR: νmax 3471 (w), 3367 (w), 2941
(w), 2838 (w), 1732 (s), 1606 (m), 1224 (s), 1127 (s) cm-1; HRMS (ESI-TOF) m/z [M+H]+
calculated for C18H20N3O6 : 374.1347. Found: 374.1353.
1-(3,4,5-Trimethoxyphenyl)-3-(trimethylsilyl)-5-(3-amino-4-methoxyphenyl)-pyrazole,
3a
and 1-(3,4,5-trimethoxyphenyl)-4-(trimethylsilyl)-5-(3-amino-4-methoxyphenyl)-pyrazole,
3b:
Following
general
procedure
B
using
4-(3-amino-4-methoxyphenyl)-3-(3,4,5-
trimethoxyphenyl)sydnone (150 mg, 0.402 mmol) and trimethylsilylacetylene (158 mg, 1.61
mmol), an inseparable mixture of pyrazole 3a and 3b was isolated as a brown oil (156 mg,
91%, 95:5).
1H NMR (400 MHz, CDCl3) δ 0.35 (9H, s), 3.69 (6H, s), 3.76-3.81 (8H, m), 6.50 (1H, s),
13
6.53-6.58 (3H, m), 6.62 (1H, d, J = 2.0 Hz), 6.67 (1H, d, J = 8.5 Hz); C NMR (101 MHz,
CDCl3) δ -0.9, 55.6, 56.1, 61.0, 103.2, 110.1, 113.5, 115.1, 119.1, 123.7, 136.1, 136.3, 137.1,
143.4, 147.2, 153.1, 153.6; FTIR: νmax 3465 (br), 3372 (br), 2955 (w), 2836 (w), 1598 (m),
1505 (s), 1455 (m), 1418 (m), 1228 (s), 1125 (s), 980 (m), 835 (s) cm-1; HRMS (ESI-TOF)
m/z [M+H]+ calculated for C22H30N3O4Si: 428.2000. Found: 428.2023.
1-(3,4,5-Trimethoxyphenyl)-5-(3-amino-4-methoxyphenyl)-pyrazole, 4:
Following general procedure C using a mixture of pyrazoles 3a and 3b (156 mg, 0.365
mmol) and TBAF in THF (1.0 M, 3.7 mL, 3.7 mmol), pyrazole 4 was isolated as a tan solid

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(99 mg, 76%). The title compound was recrystallised from CH2Cl2/40-60 petroleum ether and
isolated as tan prisms.
ο
1
M.p.: 100-101 C; H NMR (400 MHz, CDCl3) δ 3.70 (6H, s), 3.79 (2H, br), 3.84 (3H, s),
3.84 (3H, s), 6.40 (1H, d, J = 2.0 Hz), 6.56 (2H, s), 6.58 (1H, dd, J = 8.5, 2.0 Hz), 6.64 (1H,
13
d, J = 2.0 Hz), 6.70 (1H, d, J = 8.5 Hz), 7.66 (1H, d, J = 2.0 Hz); C NMR (101 MHz,
CDCl3) δ 55.7, 56.2, 61.1, 102.8, 107.4, 110.2, 115.2, 119.3, 123.5, 136.2, 136.2, 137.1,
140.1, 143.4, 147.4, 153.1; FTIR: νmax 3444 (w), 3346 (w), 3303 (w), 3198 (w), 2934 (w),
2837 (w), 1598 (m), 1500 (s), 1463 (s), 1419 (s), 1229 (s), 1120 (s), 1029 (m), 991 (m) cm-1;
HRMS (ESI-TOF) m/z [M+H]+ calculated for C19H22N3O4: 356.1605. Found: 356.1615.
3-Phenylsydnone-4-carboxylic acid:13
To a solution of N-phenylsydnone (3.55 g, 21.9 mmol) in THF (75 mL) at -78 οC was added
a solution of n-butyl lithium (~2.17 M in hexanes, 11.1 mL, 24.1 mmol). The reaction
mixture was stirred for 1 hour at -78 οC. The resulting solution was transferred by cannula to
a flask containing excess solid CO2 and stirred for 1 hour at -78 οC. The reaction was allowed
to warm to room temperature (caution extra venting required) and stirred for a further 2 h.
The reaction was poured into water and the aqueous layer washed with ethyl acetate. The
aqueous layer was then acidified to pH 1 and extracted with ethyl acetate. The combined
organic layers were dried over MgSO4, filtered, and volatiles removed in vacuo to afford the
title compound as an orange solid (4.11 g, 91%). The title compound was recrystallised from
EtOH and isolated as colourless plates.
M.p.: 190-191 °C (lit.13 193 οC); 1H NMR (400 MHz, DMSO-d6) δ 7.56-7.83 (5H, m), 13.37
13
(1H, s); C NMR (101 MHz, CDCl3) δ 100.7, 125.7, 129.2, 132.0, 135.3, 157.9, 164.5;
FTIR: νmax 2944 (br), 2558 (br), 2159 (br), 2031 (w), 1807 (s), 1674 (s), 1489 (s), 1308 (m),
1212 (s), 1063 (m), 1027 (m) cm-1; HRMS (ESI-TOF) m/z [M+H]+ calculated for C9H7N2O4:
207.0400. Found: 207.0413.
N-Methoxy-N-methyl-3-phenylsydnone-4-carboxamide:
To a solution of 3-phenylsydnone-4-carboxylic acid (500 mg, 2.43 mmol) in CH2Cl2 (10 mL)
ο
at 0 C was added oxalyl chloride (924 mg, 7.28 mmol) and DMF (3 drops) and the mixture
ο
stirred for 10 minutes at 0 C. The reaction was allowed to warm to room temperature and
stirred for a further 3 h. Volatiles were then removed in vacuo and the resulting yellow solid
dissolved in CH2Cl2 (10 mL). Triethylamine (541 mg, 5.35 mmol) and N,O-

Page 13
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dimethylhydroxylamine hydrogen chloride (284 mg, 2.92 mmol) were added at 0 οC and the
reaction stirred for 14 h at RT. The reaction was poured into water, extracted with CH2Cl2,
the combined organic layers were dried over MgSO4 and volatiles removed in vacuo. The
resulting crude material was purified by flash silica chromatography (gradient 100% 40-60
petroleum ether to 60% ethyl acetate) affording the title compound as a yellow oil (394 mg,
65%).
1H NMR (400 MHz, CDCl3) δ 3.28 (3H, s), 3.86 (3H, s), 7.50-7.61 (4H, m), 7.61-7.69 (1H,
13
m); C NMR (101 MHz, CDCl3) δ 33.3, 62.2, 102.8, 124.0, 129.7, 132.3, 134.7, 157.3,
164.4; FTIR: νmax 1765 (s), 1651 (m), 1480 (m), 1443 (w), 1269 (w), 1173 (w), 1051 (w),
990 (w) cm-1; HRMS (ESI-TOF) m/z [M+H]+ calculated for C11H11N3O4: 250.0822. Found:
250.0821.
1-(Phenyl)-3-(trimethylsilyl)-5-[(N-Methoxy-N-methyl)amide]-pyrazole, 5a and 1-(phenyl)-
4-(trimethylsilyl)-5-[(N-Methoxy-N-methyl)amide]-pyrazole, 5b:
Following general procedure B using 4-[(N-methoxy-N-methyl)amide]-N-phenylsydnone
(213 mg, 0.855 mmol) and trimethylsilylacetylene (336 mg, 3.42 mmol), an inseparable
mixture of pyrazole 5a and 5b was isolated as an orange oil (231 mg, 89%, >95:5).
1H NMR (400 MHz, CDCl3) δ 0.34 (9H, s), 3.18 (3H, s), 3.53 (3H, s), 6.79 (1H, s), 7.31-
13
7.39 (1H, m), 7.40-7.46 (2H, m), 7.47-7.53 (2H, m); C NMR (101 MHz, CDCl3) δ -1.0,
33.6, 61.5, 115.1, 123.8, 127.9, 129.2, 135.3, 140.5, 154.0, 162.4; FTIR: νmax 2954 (w), 1650
(m), 1599 (m), 1499 (m), 1310 (m), 1113 (m), 977 (w), 836 (s) cm-1; HRMS (ESI-TOF) m/z
[M+H]+ calculated for C15H21N3O2Si: 304.1476. Found: 304.1481.
4-(3-trifluoromethylphenyl)-3-benzylsydnone:
Following general procedure A using N-benzylsydnone (500 mg, 2.84 mmol) and 3-
bromotrifluoromethyl benzene (958 mg, 4.26 mmol), the title compound was isolated as a
colourless solid (342 mg, 38%). The title compound was recrystallised from CH2Cl2/40-60
petroleum ether and isolated as colourless flakes.
M.p.: 81-82 °C; 1H NMR (400 MHz, CDCl3) δ 5.54 (2H, s), 7.15-725 (2H, m), 7.34-7.45
13
(3H, m), 7.50-7.60 (2H, m), 7.60-7.72 (2H, m); C NMR (101 MHz, CDCl3) δ 56.1, 106.4,
123.6 (q, J = 272.5 Hz), 125.1 (q, J = 3.5 Hz), 125.4, 126.1 (q, J = 3.5 Hz), 127.6, 129.6,
129.86, 129.91, 130.9, 131.65 (q, J = 33.0 Hz), 131.68, 167.3; 19F NMR (377 MHz, CDCl3) δ
-62.9; FTIR: νmax 2954 (w), 1732 (s), 1524 (m), 1432 (m), 1360 (m), 1321 (m), 1159 (s),

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1112 (s), 1005 (s), 907 (s), 815 (m) cm-1; HRMS (ESI-TOF) m/z [M+H]+ calculated for
C16H12F3N2O2: 321.0845. Found: 321.0848.
1-(Benzyl)-3-(trimethylsilyl)-5-(3-trifluoromethylphenyl)-pyrazole, 7a and 1-(benzyl)-4-
(trimethylsilyl)-5-(3-trifluoromethylphenyl)-pyrazole, 7b:
Following general procedure B using 4-(3-trifluoromethylphenyl)-3-benzylsydnone (99 mg,
0.31 mmol) and trimethylsilylacetylene (104 mg, 1.06 mmol), an inseparable mixture of
pyrazole 7a and 7b was isolated as an orange oil (89 mg, 77%, 95:5).
1H NMR (400 MHz, CDCl3) δ 0.36 (9H, s), 5.40 (2H, s), 6.50 (1H, s), 7.01 (2H, d, J = 6.5
13
Hz), 7.20-7.30 (3H, m), 7.40-7.51 (3H, m), 7.60 (1H, d, J = 7.5 Hz); C NMR (101 MHz,
CDCl3) δ -0.9, 53.7, 113.7, 122.6 (s, q not distinguishable), 125.1 (q, J = 3.5 Hz), 125.8 (q, J
= 3.5 Hz), 126.8, 127.7, 128.8, 129.2, 131.0 (q, J = 32.5 Hz), 131.9, 132.1, 137.6, 142.5,
19
153.0; F NMR (377 MHz, CDCl3) δ -62.3; FTIR: νmax 2958 (w), 1455 (m), 1311 (s), 1248
(m), 1167 (s), 1125 (s), 1073 (s), 983 (m), 837 (s) cm-1; HRMS (ESI-TOF) m/z [M+H]+
calculated for C20H21F3N2Si: 375.1499. Found: 375.1508.
1-(Benzyl)- 5-(3-trifluoromethylphenyl)-pyrazole, 8:
Following general procedure C using a mixture of pyrazoles 7a and 7b (81 mg, 0.22 mmol)
and TBAF in THF (1.0 M, 2.2 mL, 2.2 mmol), pyrazole 8 was isolated as a yellow oil (45
mg, 69%).
1H NMR (400 MHz, CDCl3) δ 5.34 (2H, s), 6.40 (1H, d, J = 2.0 Hz), 7.01-7.10 (2H, m),
13
7.23-7.34 (3H, m), 7.46-7.57 (3H, m), 7.61-7.68 (2H, m); C NMR (101 MHz, CDCl3) δ
53.7, 107.2, 123.9 (q, J = 272.5 Hz), 125.5 (q, J = 3.5 Hz), 126.0 (q, J = 3.5 Hz), 126.9,
127.9, 128.9, 129.3, 131.3 (q, J = 32.5 Hz), 131.6, 132.3, 137.3, 139.4, 142.6; 19F NMR (377
MHz, CDCl3) δ -62.8; FTIR: νmax 2668 (w), 1340 (m), 1321 (s), 1166 (s), 1118 (s), 1072 (s),
928 (m), 906 (m) cm-1; HRMS (ESI-TOF) m/z [M+H]+ calculated for C17H13F3N2: 303.1104.
Found: 303.1107.
4-(3-Hydroxy-4-methoxyphenyl)-3-(3,4,5-trimethoxyphenyl)sydnone:
Following general procedure A using N-(3,4,5-trimethoxyphenyl)sydnone (500 mg, 1.98
mmol) and 5-bromo-2-methoxyphenol (604 mg, 2.97 mmol). Flash silica chromatography
(eluting solvent 10%-30% ethyl acetate in dichloromethane) afforded the title compound as a

Page 15
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yellow solid (599 mg, 81%). The title compound was recrystallised from EtOH and isolated
as yellow prisms.
1
M.p.: 237-239 °C (dec.); H NMR (400 MHz, DMSO-d6): δ 3.73 (9H, s), 3.76 (3H, s), 6.71
(1H, dd, J = 8.5, 2.0 Hz), 6.88 (1H, d, J = 2.0 Hz), 6.91 (1H, d, J = 8.5 Hz), 7.13 (2H, s), 9.28
(1H, s); 13C NMR (101 MHz, DMSO-d6): δ 55.5, 56.5, 60.4, 103.9, 108.1, 112.0, 114.1,
117.0, 118.5, 129.9, 139.8, 146.3, 148.1, 153.5, 166.2; FTIR: νmax 3415 (br), 3062 (w), 2947
(w), 1718 (s), 1605 (m), 1243 (s), 1125 (s), 1014 (s), 949 (m) cm-1; HRMS (ESI-TOF) m/z
[M+H]+ calculated for C18H19N2O7: 375.1187. Found: 375.1192.
4-(3-[(Tert-butyldimethylsilyl)oxy]-4-methoxyphenyl)-3-(3,4,5-trimethoxyphenyl)sydnone:
To a solution of 4-(3-hydroxy-4-methoxyphenyl)-3-(3,4,5-trimethoxyphenyl)sydnone (200
mg, 0.535 mmol) and TBSCl (161 mg, 1.07 mmol) in DMF (2 mL), under an atmosphere of
nitrogen, was added DIPEA (138 mg, 1.07 mmol) and the reaction stirred at room
temperature for 14 h. Aqueous NH4Cl was added and the mixture extracted with ethyl
acetate. The organic phase was dried over MgSO4 and the volatiles were removed in vacuo.
Flash silica chromatography (gradient 100% 40-60 petroleum ether to 40% ethyl acetate)
afforded the title compound as an orange solid (211 mg, 81%). The title compound was
recrystallised from CH2Cl2/40-60 petroleum ether and isolated as an orange powder.
ο
M.p.: 97-98 C; 1H NMR (400 MHz, CDCl3) δ 0.03 (6H, s), 0.90 (9H, s), 3.79 (6H, s), 3.80
(3H, s), 3.91 (3H, s), 6.67 (1H, d, J = 2.5 Hz), 6.68 (2H, s), 6.82 (1H, d, J = 8.5 Hz), 7.18
13
(1H, dd, J = 8.5, 2.5 Hz); C NMR (101 MHz, CDCl3) δ -4.7, 18.4, 25.7, 55.6, 56.6, 61.2,
102.6, 108.1, 112.2, 117.1, 119.7, 121.6, 130.1, 140.7, 145.1, 151.8, 154.2, 167.1; FTIR: νmax
2933 (w), 1729 (m), 1606 (m), 1460 (m), 1225 (s), 1125 (s), 1015 (m), 999 (m), 946 (m), 837
(s) cm-1; HRMS (ESI-TOF) m/z [M+H]+ calculated for C24H33N2O7Si: 489.2052. Found:
489.2081.
1-(3,4,5-Trimethoxyphenyl)-3-(trimethylsilyl)-5-(3-[(tert-butyldimethylsilyl)oxy]-4-
methoxyphenyl)-pyrazole, 9a and 1-(3,4,5-trimethoxyphenyl)-4-(trimethylsilyl)-5-(3-[(tert-
butyldimethylsilyl)oxy]-4-methoxyphenyl) -pyrazole, 9b:
Following general procedure B using 4-(3-[(tert-butyldimethylsilyl)oxy]-4-methoxyphenyl)-
3-(3,4,5-trimethoxyphenyl)sydnone (150 mg, 0.307 mmol) and trimethylsilylacetylene (121
mg, 1.23 mmol), an inseparable mixture of pyrazoles 9a and 9b was isolated as a clear oil
(136 mg, 82%, 95:5).

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1H NMR (400 MHz, CDCl3) δ 0.01 (6H, s), 0.35 (9H, s), 0.90 (9H, s), 3.70 (6H, s), 3.79 (3H,
s), 3.81 (3H, s), 6.52 (1H, s), 6.54 (2H, s), 6.68 (1H, d, J = 2.0 Hz), 6.79 (1H, d, J = 8.5 Hz),
13
6.87 (1H, dd, J = 8.5, 2.0 Hz); C NMR (101 MHz, CDCl3) δ -4.8, -0.9, 18.4, 25.7, 55.6,
56.1, 61.0, 103.3, 111.8, 113.4, 121.4, 122.4, 123.6, 136.2, 137.2, 143.0, 144.8, 151.1, 153.2,
153.7; FTIR: νmax 2954 (w), 2930 (w), 2857 (w), 1598 (m), 1496 (m), 1463 (m), 1415 (m),
1229 (s), 1127 (s), 1007 (m), 979 (m) 980 (m), 937 (m) cm-1; HRMS (ESI-TOF) m/z [M+H]+
calculated for C28H43N2O5Si2: 543.2705. Found: 543.2728.
1-(3,4,5-Trimethoxyphenyl)-5-(3-hydroxy-4-methoxyphenyl)-pyrazole, 10 and 1-(3,4,5-
trimethoxyphenyl)-5-(3-fluoromethoxy-4-methoxyphenyl)-pyrazole, 14:
Following general procedure C using a mixture of pyrazoles 9a and 9b (131 mg, 0.241 mmol,
95:5) and TBAF in THF (1.0 M, 2.4 mL, 2.4 mmol), pyrazole 10 was isolated as a colourless
solid (12 mg, 14%) and pyrazole 14 was isolated as a clear oil (21 mg, 22%). Compound 10
was recrystallised from CH2Cl2/40-60 petroleum ether and isolated as a colourless powder.
10: M.p.: 102-103 °C; 1H NMR (400 MHz, CDCl3) δ 3.68 (6H, s), 3.83 (3H, s), 3.86 (3H, s),
5.99 (1H, br), 6.42 (1H, d, J = 2.0 Hz), 6.53 (2H, s), 6.69 (1H, dd, J = 8.5, 2.0 Hz), 6.76 (1H,
13
d, J = 8.5, Hz), 6.87 (1H, d, J = 2.0, Hz), 7.65 (1H, d, J = 2.0 Hz); C NMR (101 MHz,
CDCl3) δ 56.0, 56.2, 61.1, 102.9, 107.9, 110.6, 115.2, 121.0, 123.8, 135.9, 137.2, 140.1,
142.9, 145.6, 146.8, 153.1; FTIR: νmax 3133 (br), 2933 (w), 2840 (w), 1601 (m), 1499 (s),
1458 (m), 1420 (m), 1272 (m), 1232 (s), 1118 (s), 1010 (m), 1002 (m), 933 (m) cm-1; HRMS
(ESI-TOF) m/z [M+H]+ calculated for C19H21N2O5: 357.1445. Found: 357.1446.
1
14: H NMR (400 MHz, CDCl3) δ 3.70 (6H, d, J = 1.5 Hz), 3.84 (3H, d, J = 1.5 Hz), 3.88
(3H, d, J = 1.5 Hz), 5.58 (2H, dd, J = 54.5, 1.5 Hz), 6.48 (1H, t, J = 1.5 Hz), 6.53 (2H, d, J =
1.5 Hz), 6.88 (1H, dd, J = 8.5, 1.5 Hz), 6.98-7.05 (2H, m), 7.69 (1H, t, J = 1.5 Hz); 13C NMR
(101 MHz, CDCl3) δ 56.2, 56.3, 61.1, 101.4 (d, J = 220.5 Hz), 103.2, 107.3, 112.1, 118.3,
123.4, 125.0, 135.8, 137.5, 140.2, 142.3, 145.4, 149.9, 153.3; 19F NMR (377 MHz, CDCl3) δ
-149.1 (t, J = 54 Hz); FTIR: νmax 2933 (w), 2838 (w), 1598 (m), 1505 (s), 1455 (m), 1417 (m),
1229 (s), 1119 (s), 1002 (m), 972 (m) cm-1; HRMS (ESI-TOF) m/z [M+H]+ calculated for
C20H22N2O5F: 389.1507. Found: 389.1499.
1-(3,4,5-Trimethoxyphenyl)-5-(3-hydroxy-4-methoxyphenyl)-pyrazole, 10:

Page 17
ACCEPTED MANUSCRIPT
Following general procedure C a mixture of pyrazoles 9a and 9b (100 mg, 0.184 mmol) and
TBAF in THF (1.0 M, 1.8 mL, 1.8 mmol), pyrazole 10 was isolated as a colourless solid (46
mg, 70%).
See above for characterisation data.
N-(2-Hydroxy-1,1-dimethylethyl)-3-phenylsydnone-4-carboxamide:
To a solution of 3-phenylsydnone-4-carboxylic acid (825 mg, 4.00 mmol) in CH2Cl2 (40 mL)
ο
at 0 C was added oxalyl chloride (1.52 g, 12.0 mmol) and DMF (3 drops) and the mixture
ο
stirred for 10 minutes at 0 C. The reaction was allowed to warm to room temperature and
stirred for a further 3 h. Volatiles were then removed in vacuo and the resulting yellow solid
dissolved in CH2Cl2 (40 mL). Triethylamine (486 mg, 4.80 mmol) and 2-amino-2-
ο
methylpropanol (428 mg, 4.80 mmol) were added at 0 C and the reaction stirred for 14 h at
RT. The reaction was poured into water, extracted with CH2Cl2, the combined organic layers
were dried over MgSO4 and volatiles removed in vacuo. The resulting crude material was
purified by flash silica chromatography (eluting solvent 100% ethyl acetate) affording the
title compound as a yellow solid (975 mg, 88%). The title compound was recrystallised from
CH2Cl2/40-60 petroleum ether and isolated as yellow prisms.
M.p.: 184 °C; 1H NMR (400 MHz, CDCl3) δ 1.33 (6H, s), 3.59 (2H, s), 4.03 (1H, br), 7.42 –
13
7.86 (5H, m); C NMR (101 MHz, CDCl3) δ 24.7, 56.8, 70.2, 102.2, 125.3, 129.4, 132.5,
134.6, 155.9, 167.3; FTIR: νmax 3318 (br), 1751 (s), 1675 (s), 1494 (w), 1303 (w), 1059 (w)
cm-1; HRMS (ESI-TOF) m/z [M+H]+ calculated for C13H16N3O4: 278.1135. Found: 278.1148.
4-(4,4-Dimethyl-2-oxazoline)-3-phenylsydnone:
Triethylamine (5.28 g, 52.2 mmol) and carbon tetrachloride (12.3 g, 80.0 mmol) were added
respectively to a suspension of N-(2-hydroxy-1,1-dimethylethyl)-3-phenylsydnone-4-
carboxamide (964 mg, 3.48 mmol) and triphenylphosphine (3.65 g, 13.9 mmol) in
acetonitrile (17 mL) at r.t.. The reaction was allowed to stir for 2 h before being diluted with
ethyl acetate and washed with aqueous sodium hydrogen carbonate. The aqueous layer was
extracted with ethyl acetate, the organics combined, dried over magnesium sulfate and the
solvent removed in vacuo. The resulting residue was purified by flash silica chromatography
(gradient 0 – 60% ethyl acetate in 40/60 petroleum ether) affording the title compound as a
yellow solid (475 mg, 53%). The title compound was recrystallised from CH2Cl2/40-60
petroleum ether and isolated as yellow plates.

Page 18
ACCEPTED MANUSCRIPT
M.p.: 131-133 °C; 1H NMR (400 MHz, CDCl3) δ 1.22 (6H, s), 3.87 (2H, s), 7.43 – 7.71 (5H,
13
m); C NMR (101 MHz, CDCl3) δ 28.1, 68.2, 79.0, 98.8, 125.1, 129.5, 132.5, 135.0, 151.0,
165.5; FTIR: νmax 1785 (s), 1754 (m), 1658 (m), 1485 (m) cm-1; HRMS (ESI-TOF) m/z
[M+H]+ calculated for C13H14N3O3: 260.1030. Found: 260.1039.
1-(Phenyl)-3-(trimethylsilyl)-5-(4,4-dimethyl-2-oxazoline)-pyrazole, 11a and 1-(phenyl)-4-
(trimethylsilyl)-5-(4,4-dimethyl-2-oxazoline)-pyrazole, 11b:
Following general procedure B using 4-(4,4-dimethyl-2-oxazoline)-3-phenylsydnone (98 mg,
0.38 mmol) and trimethylsilylacetylene (149 mg, 1.51 mmol), an inseparable mixture of
pyrazole 11a and 11b was isolated as an orange oil (103 mg, 87%, 95:5).
1H NMR (400 MHz, CDCl3) δ 0.31 (9H, s), 1.32 (6H, s), 3.94 (2H, s), 7.08 (1H, s), 7.34-7.51
13
(5H, m); C NMR (101 MHz, CDCl3) δ -1.0, 28.1, 67.8, 79.3, 118.0, 125.3, 128.1, 128.6,
131.6, 140.6, 154.2, 155.3; FTIR: νmax 2961 (w), 2896 (w), 1667.0 (m), 1599 (m), 1500 (m),
1312 (m), 1248 (m), 1192 (m), 1068 (s), 1006 (m), 979 (m), 837 (s) cm-1; HRMS (ESI-TOF)
m/z [M+H]+ calculated for C17H23N3OSi: 314.1683. Found: 314.1696.
1-(Phenyl)-5-(4,4-dimethyl-2-oxazoline)-pyrazole, 12 and 3-(phenylamino)-3-(4,4-dimethyl-
2-oxazoline)-2-propenenitrile (E+Z), 13:
Following general procedure C using a mixture of pyrazoles 11a and 11b (102 mg, 0.325
mmol) and TBAF in THF (1.0 M, 3.3 mL, 3.3 mmol), pyrazole 12 was isolated as an orange
oil (37 mg, 47%) and nitrile 13 was isolated as an orange oil (18 mg, 23%, E:Z ~1:1).
`12: 1H NMR (400 MHz, CDCl3) δ 1.30 (6H, s), 3.93 (2H, s), 6.89 (1H, d, J = 2.0 Hz), 7.35-
13
7.48 (5H, m), 7.68 (1H, d, J = 2.0 Hz); C NMR (101 MHz, CDCl3) δ 28.0, 68.0, 79.2,
111.1, 125.1, 128.2, 128.6, 129.9, 131.5, 140.2, 154.7; FTIR: νmax 2965 (w), 1662 (m), 1588
(s), 1499 (s), 1394 (m), 1355 (m), 1289 (m), 1084 (m), 999 (s), 955 (s) cm-1; HRMS (ESI-
TOF) m/z [M+H]+ calculated for C14H16N3O: 242.1288. Found: 242.1290.
1
13 (1:1 mixture of E/Z isomers): H NMR (400 MHz, CDCl3) δ 1.36 (3H, s), 1.38 (3H, s),
4.14 (1H, s), 4.29 (1H, s), 4.92 (0.5H, d, J = 1.5 Hz), 4.95 (0.5H, d, J = 1.5 Hz), 7.14 (0.5H,
br), 7.15-7.25 (3.5H, m), 7.39 (1H, t, J = 7.5 Hz); 13C NMR (101 MHz, CDCl3) δ 28.3, 67.4,
68.3, 68.6, 69.0, 80.7, 81.2, 116.8, 118.7, 123.7, 125.0, 126.0, 126.5, 129.0, 129.9, 137.5,
137.9, 142.8, 144.3, 158.9, 159.2; FTIR: νmax 2974 (w), 2200 (w), 1681 (m), 1587 (s), 1495
(m), 1448 (m), 1366 (m), 1300 (m), 962 (m) cm-1; HRMS (ESI-TOF) m/z [M+H]+ calculated
for C14H16N3O: 242.1288. Found: 242.1288.

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1-(3,4,5-trimethoxyphenyl)-5-(3-fluoromethoxy-4-methoxyphenyl)-pyrazole, 14:
A flask was charged with pyrazole 10 (51 mg, 0.14 mmol), CH2Cl2 (0.5 mL) and TBAF in
THF (1.0 M, 1.5 mL, 1.5 mmol) and the reaction heated at reflux for 14 h. The reaction was
allowed to cool to r.t. and poured into aq. NaHCO3, extracted with ethyl acetate and volatiles
removed in vacuo. The resulting crude material was purified by flash silica chromatography
(gradient 100% petroleum ether – 60% ethyl acetate in petroleum ether) affording 14 as a
colourless oil (27 mg, 49%) and recovered pyrazole 10 (13 mg, 25%).
See above for characterisation data.
1-Bromo-4-fluoromethoxybenzene, 15 and 1,1’-[methylenebis(oxy)]bis[4-bromobenzene]
16:14
A flask was charged with 4-bromophenol (100 mg, 0.585 mmol), CH2Cl2 (0.5 mL) and TBAF
in THF (1.0 M, 6 mL, 6 mmol) and the reaction heated at reflux for 14 h. The reaction was
allowed to cool to r.t. and poured into aq. NaHCO3, extracted with ethyl acetate and volatiles
removed in vacuo. The resulting crude material was purified by flash silica chromatography
(gradient 100% petroleum ether – 10% ethyl acetate in petroleum ether) affording a mixture
1
of 15 and 16 as a colourless oil (20 mg, 17%, 85:15). The mixture was characterised by H
and 19F NMR only.
1H NMR (400 MHz, CDCl3) δ 5.68 (2H, d, J = 54.5 Hz), 6.91-7.04 (2H, m), 7.38-7.48 (2H,
m); 19F NMR (128 MHz, CDCl3) δ -149.1 (t, J = 54.5 Hz).
3-Fluoromethoxy-4-methoxybenzaldehyde, 17:
A flask was charged with 3-hydroxy-4-methoxybenzaldehyde (50 mg, 0.33 mmol), CH2Cl2
(0.5 mL) and TBAF in THF (1.0 M, 3.3 mL, 3.3 mmol) and the reaction heated at reflux for
14 h. The reaction was allowed to cool to r.t. and poured into aq. NaHCO3, extracted with
ethyl acetate and volatiles removed in vacuo. The resulting crude material was purified by
flash silica chromatography (gradient 100% petroleum ether – 40% ethyl acetate in petroleum
ether) affording 17 as a colourless solid (25 mg, 41%). The title compound was recrystallised
from CH2Cl2/40-60 petroleum ether and isolated as a colourless powder.
1
M.p.: 59-61 °C; H NMR (400 MHz, CDCl3) δ 3.97 (3H, s), 5.77 (2H, d, J = 54.0 Hz), 7.05
(1H, d, J = 8.5 Hz), 7.63 (1H, d, J = 8.5, 2.0 Hz), 7.66-7.67 (1H, m), 9.86 (1H, s); 13C NMR
(101 MHz, CDCl3) δ 56.4, 101.0 (d, J = 221.0 Hz), 111.8, 116.4, 128.5, 130.2, 146.3 (d, J =

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19
2.5 Hz), 155.1, 190.5; F NMR (128 MHz, CDCl3) δ -149.8 (t, J = 54.0 Hz); FTIR: νmax
1686 (s), 1601 (m), 1587 (m), 1508 (s), 1439 (s), 1404 (m), 1262 (s), 1228 (s), 1173 (m),
1135 (s), 1079 (m), 1016 (s), 943 (s) cm-1; HRMS (ESI-TOF) m/z [M]+ calculated for
C9H9FO3: 184.0530. Found: 184.0526.
3-Hydroxy-4-methoxybenzaldehyde - control reaction:
A flask was charged with 3-hydroxy-4-methoxybenzaldehyde (50 mg, 0.33 mmol), CH2Cl2
(0.5 mL) THF (3.3 mL) and the reaction heated at reflux for 14 h. The reaction was allowed
to cool to r.t. and volatiles removed in vacuo, resulting in the recovery of starting material.
3-Dideuterofluoromethoxy 4-methoxybenzaldehyde, d-17:
A flask was charged with 3-hydroxy-4-methoxybenzaldehyde (50 mg, 0.33 mmol), CD2Cl2
(0.5 mL) and TBAF in THF (1 M, 3.3 mL, 3.3 mmol) and the reaction heated at reflux for 14
h. The reaction was allowed to cool to r.t. and poured into aq. NaHCO3, extracted with ethyl
acetate and volatiles removed in vacuo. The resulting crude material was purified by flash
silica chromatography (gradient 100% petroleum ether – 40% ethyl acetate in petroleum
ether) affording d-17 as a colourless solid (19 mg, 31%). The title compound was
recrystallised from CH2Cl2/40-60 petroleum ether and isolated as a colourless powder.
1
M.p.: 57-59 °C; H NMR (400 MHz, CDCl3) δ 3.97 (3H, s), 7.05 (1H, d, J = 8.5 Hz), 7.64
13
(2H, m), 9.86 (1H, s); C NMR (101 MHz, CDCl3) δ 56.4, 98.5-102.1 (m), 111.8, 116.3,
19
128.5, 130.2, 146.3, 155.1, 190.5; F NMR (128 MHz, CDCl3) δ -151.1- -151.2 (m); FTIR:
νmax 1690 (s), 1603 (m), 1587 (m), 1508 (s), 1435 (s), 1266 (s), 1164 (m), 1129 (s), 1016 (s),
916 (s) cm-1; HRMS (ESI-TOF) m/z [M+H]+ calculated for C9H7D2FO3: 187.0734. Found:
187.0734.
1-(Phenyl)-3-(trimethylsilyl)-4-(pinacolatoborolane)-5-(4-tolyl)-pyrazole, 18:15
Following general procedure D using 4-(4-tolyl)-3-phenylsydnone (200 mg, 0.793 mmol) and
4,4,5,5-tetramethyl-2-[2-(trimethylsilyl)ethynyl]-1,3,2-dioxaborolane (356 mg, 1.59 mmol),
pyrazole 18 was isolated as a tan solid (187 mg, 74%).
1H NMR (400 MHz, CDCl3) δ 0.41 (9H, s), 1.24 (12H, s), 2.34 (3H, s), 7.05 (2H, d, J = 8.0
13
Hz), 7.11 (2H, d, J = 8.0 Hz), 7.19-7.28 (5H, m); C NMR (101 MHz, CDCl3) δ -0.4, 21.5,
25.0, 83.2, 114.1, 125.5, 127.0, 128.4, 128.7, 130.6, 137.8, 140.3, 150.0, 159.6.
1-(Phenyl)-3-(trimethylsilyl)-4-(4-methoxyphenyl)-5-(4-tolyl)-pyrazole, 19:

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Following general procedure E using pyrazole 18 (200 mg, 0.462 mmol) and 4-bromoanisole
(130 mg, 0.694 mmol), pyrazole 19 was isolated as a yellow solid (172 mg, 90%).
1H NMR (400 MHz, CDCl3) δ 0.22 (9H, s), 2.27 (3H, s), 3.81 (3H, s), 6.82 (2H, d, J = 9.0
Hz), 6.89 (2H, d, J = 8.0 Hz), 6.97 (2H, d, J = 8.0 Hz), 7.10 (2H, d, J = 9.0 Hz), 7.21-7.34
13
(5H, m); C NMR (101 MHz, CDCl3) δ -0.3, 21.4, 55.2, 110.7, 113.4, 114.3, 119.5, 120.4,
125.2, 127.0, 128.8, 129.0, 130.2, 131.8, 137.5, 140.6, 152.6, 158.5; FTIR: νmax 3050 (w),
2955 (w), 1598 (m), 1520 (m), 1492 (m), 1449 (s), 1325 (m), 1243 (s), 1037 (m), 990 (m) cm-
1; HRMS (ESI-TOF) m/z [M+H]+ calculated for C26H29N2OSi: 413.2044. Found: 413.2042.
4-(2-Pyridyl)-3-phenylsydnone:16
Following general procedure A using N-phenylsydnone (1.50 g, 9.25 mmol) and 2-
bromopyridine (2.19 g, 13.9 mmol), the title compound was isolated as colourless crystals
(2.19 g, 99%). The title compound was recrystallised from EtOH and isolated as colourless
prisms.
ο
1
M.p.: 111-112 °C (lit.16 142-143 C); H NMR (400 MHz, CDCl3) δ 7.11 (1H, ddd, J = 7.5,
5.0, 1.0 Hz), 7.46-7.58 (4H, m), 7.60-7.66 (1H, m), 7.74 (1H, td, J = 8.0, 2.0 Hz), 8.09 (1H,
13
dt, J = 8.0, 1.0 Hz), 8.23 (1H, ddd, J = 5.0, 2.0, 1.0 Hz); C NMR (101 MHz, CDCl3) δ
107.1, 121.8, 122.7, 125.1, 129.3, 131.6, 136.0, 136.8, 144.9, 149.1, 167.1.
1-(Phenyl)-3-(trimethylsilyl)-4-(pinacolatoborolane)-5-(2-pyridyl)-pyrazole, 21:
Following general procedure D using 4-(2-pyridyl)-3-phenylsydnone (200 mg, 0.836 mmol)
and 4,4,5,5-tetramethyl-2-[2-(trimethylsilyl)ethynyl]-1,3,2-dioxaborolane (375 mg, 1.67
mmol), pyrazole 21 was isolated as a yellow solid (184 mg, 52%).
1H NMR (400 MHz, CDCl3) δ 0.41 (9H, s), 1.22 (12H, s), 7.16-7.28 (7H, m), 7.57 (1H, td, J
= 7.5, 2.0 Hz), 8.56 (1H, ddd, J = 5.0, 2.0, 1.0 Hz); 13C NMR (101 MHz, CDCl3) δ -0.5, 25.1,
83.3, 115.4, 122.7, 125.2, 125.6, 127.2, 128.8, 135.5, 140.3, 149.1, 151.1, 159.5; FTIR: νmax
2971 (w), 1593 (m), 1496 (m), 1410 (m), 1312 (m), 1140 (m), 1043 (m) cm-1; HRMS (ESI-
TOF) m/z [M+H]+ calculated for C23H3110BN3O2Si: 419.2309. Found: 419.2311.
1-(Phenyl)-3-(trimethylsilyl)-4-(4-methoxyphenyl)-5-(2-pyridyl)-pyrazole, 22:
Following general procedure E using pyrazole 21 (158 mg, 0.377 mmol) and 4-bromoanisole
(106 mg, 0.565 mmol), pyrazole 22 was isolated as a yellow solid (90 mg, 60%).

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1H NMR (400 MHz, CDCl3) δ 0.20 (9H, s), 3.80 (3H, s), 6.81 (2H, d, J = 9.0 Hz) 7.05 (1H,
dt, J = 8.0, 1.0 Hz), 7.07-7.15 (3H, m), 7.20-7.25 (1H, m), 7.26-7.30 (4H, m), 7.50 (1H, td, J
= 7.5, 2.0 Hz), 8.45 (1H, ddd, J = 5.0, 2.0, 1.0 Hz); 13C NMR (101 MHz, CDCl3) δ -0.3, 55.2,
113.4, 122.4, 124.8, 125.7, 126.6, 127.0, 128.7, 130.7, 131.7, 136.0, 139.3, 140.6, 149.7,
150.4, 152.6, 158.7; FTIR: νmax 3047 (w), 2965 (w), 2836 (w), 1584 (m), 1500 (m), 1246 (s),
1175 (m), 1034 (m) cm-1; HRMS (ESI-TOF) m/z [M+H]+ calculated for C24H26N3OSi:
400.1840. Found: 400.1848
1-(Phenyl)-4-(4-methoxyphenyl)-5-(2-pyridyl)-pyrazole, 23:
Following general procedure C using pyrazole 22 (83 mg, 0.21 mmol) and TBAF in THF (1.0
M, 2.1 mL, 2.1 mmol), pyrazole 23 was isolated as a yellow crystalline solid (30 mg, 44%).
The title compound was recrystallised from CH2Cl2/40-60 petroleum ether and isolated as
yellow prisms.
M.p.: 138-139 °C; 1H NMR (400 MHz, CDCl3) δ 3.81 (3H, s), 6.60 (2H, d, J = 7.5 Hz), 6.75
(1H, s), 6.90 (2H, d, J = 9.0 Hz), 7.06-7.11 (2H, m), 7.33 (1H, ddd, J = 6.0, 5.0, 2.5 Hz), 7.45
(2H, d, J = 9.0 Hz), 7.67-7.76 (2H, m), 8.72 (1H, dt, J = 5.0, 1.5 Hz ); 13C NMR (101 MHz,
CDCl3) δ 55.5, 91.4, 114.8, 120.7, 121.2, 123.2, 124.8, 125.3, 125.6, 129.0, 130.1, 136.9,
140.4, 150.0, 151.3, 152.5, 159.5; FTIR: νmax 2925 (w), 1580 (m), 1509 (s), 1377 (m), 1282
(m), 1109 (s), 944 (s) cm-1; HRMS (ESI-TOF) m/z [M+H]+ calculated for C21H17N3O:
328.1444. Found: 328.1449.
4-(2-Thiophenyl)-3-phenylsydnone:
Following general procedure A using N-phenylsydnone (500 mg, 3.08 mmol) and 2-
chlorothiophene (549 mg, 4.63 mmol), the title compound was isolated as a yellow solid (636
mg, 85%). The title compound was recrystallised from EtOH and isolated as yellow prisms.
1
M.p.: 168-170 °C; H NMR (400 MHz, CDCl3) δ 6.98 (1H, dd, J = 5.0, 4.0 Hz), 7.24 (1H,
dd, J = 5.0, 1.0 Hz), 7.29 (1H, dd, J = 4.0, 1.0 Hz), 7.55-7.60 (2H, m), 7.64-7.70 (2H, m),
13
7.73-7.80 (1H, m); C NMR (101 MHz, CDCl3) δ 106.5, 125.6, 126.0, 126.3, 126.6, 127.6,
130.4, 132.8, 133.9, 165.9; FTIR: νmax 3108 (w), 3077 (w), 1725 (s), 1703 (m), 1250 (s),
1046 (m) cm-1; HRMS (ESI-TOF) m/z [M+H]+ calculated for C12H9N2O2S: 245.0385. Found:
245.0376.
1-(Phenyl)-3-(trimethylsilyl)-4-(pinacolatoborolane)-5-(2-thiophenyl)-pyrazole, 24a and 1-
(Phenyl)-3-(pinacolatoborolane)-4-(trimethylsilyl)-5-(2-thiophenyl)-pyrazole, 24b:

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Following general procedure D using 4-(2-thiophenyl)-3-phenylsydnone (200 mg, 0.819
mmol) and 4,4,5,5-tetramethyl-2-[2-(trimethylsilyl)ethynyl]-1,3,2-dioxaborolane (367 mg,
1.64 mmol), pyrazole 24a isolated as a yellow solid (221 mg, 64%) and pyrazole 24b was
isolated as a brown oil (21 mg, 6%).
24a: 1H NMR (400 MHz, CDCl3) δ 0.42 (9H, s), 1.27 (12H, s), 6.95 (1H, dd, J = 5.0, 3.5 Hz),
7.00 (1H, dd, J = 3.5, 1.0 Hz), 7.25-7.33 (6H, m); 13C NMR (101 MHz, CDCl3) δ -0.4, 25.0,
83.4, 125.7, 126.5, 127.3, 127.6, 128.8, 129.9, 131.5, 140.1, 143.0, 159.8; FTIR: νmax 2979
(w), 1596 (w), 1496 (s), 1440 (m), 1317 (m), 1241 (s), 1137 (s), 1020 (s) cm-1; HRMS (ESI-
TOF) m/z [M+H]+ calculated for C22H3010BN2O2SSi: 424.1921. Found: 424.1923.
1
24b: H NMR (400 MHz, CDCl3) δ 0.12 (9H, s), 1.38 (12H, s), 6.91 (1H, dd, J = 3.5, 1.0
13
Hz), 6.95 (1H, dd, J = 5.0, 3.5 Hz), 7.22-7.33 (6H, m); C NMR (101 MHz, CDCl3) δ -0.5,
25.1, 84.2, 125.1, 126.0, 126.7, 127.7, 127.9, 128.5, 130.8, 132.5, 139.9, 141.1; FTIR: νmax
2976 (w), 1598 (w), 1456 (m), 1245 (s), 1221 (m), 1137 (s), 1030 (m) cm-1; HRMS (ESI-
TOF) m/z [M+H]+ calculated for C28H3010BN2O2SSi: 424.1921. Found: 424.1918.
1-(Phenyl)-3-(trimethylsilyl)-4-(4-tolyl)-5-(2-thiophenyl)-pyrazole, 25:
Following general procedure E using pyrazole 24a (202 mg, 0.476 mmol) and 4-
bromotoluene (122 mg, 0.714 mmol), pyrazole 25 was isolated as a yellow solid (131 mg,
71%).
1H NMR (400 MHz, CDCl3) δ 0.19 (9H, s), 2.37 (3H, s), 6.65 (1H, dd, J = 3.5, 1.0 Hz), 6.84
(1H, dd, J = 5.0, 3.5 Hz), 7.10-7.17 (4H, m), 7.20 (1H, dd, J = 5.0, 1.0 Hz), 7.29-7.43 (5H,
13
m); C NMR (101 MHz, CDCl3) δ -0.4, 21.4, 110.7, 119.3, 120.3, 125.6, 126.8, 127.1,
127.6, 128.7, 128.8, 128.9, 130.6, 134.0, 136.7, 140.2, 152.5; FTIR: νmax 3067 (w), 2955 (w),
1595 (w), 1498 (s), 1310 (m), 991 (m) cm-1; HRMS (ESI-TOF) m/z [M+H]+ calculated for
C23H25N2SSi: 389.1502. Found: 389.1500.
1-(Phenyl)4-(4-tolyl)-5-(2-thiophenyl)-pyrazole, 26:
Following general procedure C using pyrazole 25 (129 mg, 0.332 mmol) and TBAF in THF
(1.0 M, 3.3 mL, 3.3 mmol), pyrazole 26 was isolated as an orange crystalline solid (20 mg,
19%). The title compound was recrystallised from EtOH and isolated as orange prisms.
M.p.: 150-151 °C; 1H NMR (400 MHz, CDCl3) δ 2.35 (3H, s), 6.40 (1H, s), 6.70 (2H, d, J =
7.5 Hz), 6.95-7.00 (1H, m), 7.09 (1H, dd, J = 5.0, 3.5 Hz), 7.12-7.23 (4H, m), 7.39 (2H, d, J

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= 7.5 Hz), 7.44 (1H, dd, J = 5.0, 1.0 Hz), 7.70 (1H, dd, J = 3.5, 1.0 Hz); 13C NMR (101 MHz,
CDCl3) δ 21.4, 91.7, 102.5, 121.5, 123.3, 127.7, 128.4, 129.2, 129.9, 130.2, 130.5, 132.0,
136.0, 138.3, 141.2, 146.4; FTIR: νmax 2950 (w), 1575 (s), 1509 (s), 1493 (s), 1421 (s), 1234
(m), 1109 (m), 947 (m) cm-1; HRMS (ESI-TOF) m/z [M+H]+ calculated for C20H17N2S:
317.1107. Found: 317.1106.
1-(Methyl)-3-(trimethylsilyl)-4-(pinacolatoborolane)-5-(4-tolyl)-pyrazole, 27:
Following general procedure D using 4-(4-tolyl)-N-methylsydnone (150 mg, 0.789 mmol)
and 4,4,5,5-tetramethyl-2-[2-(trimethylsilyl)ethynyl]-1,3,2-dioxaborolane (354 mg, 1.58
mmol), pyrazole 27 was isolated as a yellow solid (162 mg, 55%).
1H NMR (400 MHz, CDCl3) δ 0.38 (9H, s), 1.19 (12H, s), 2.41 (3H, s), 3.78 (3H, s), 7.20
(2H, d, J = 8.0 Hz), 7.25 (2H, d, J = 8.0 Hz); 13C NMR (101 MHz, CDCl3) δ -0.4, 21.5, 24.9,
37.1, 82.9, 112.6 (br), 128.5, 130.2, 138.1, 151.1, 158.7; FTIR: νmax 2976 (w), 2897 (w),
1497 (s), 1301 (s), 1239 (s), 1141 (s), 1039 (s) cm-1; HRMS (ESI-TOF) m/z [M+H]+
calculated for C20H3210BN2O2Si: 370.2357. Found: 370.2358.
1-(Methyl)-3-(trimethylsilyl)-4-(4-tolyl)-5-(3-trifluoromethylphenyl)-pyrazole, 28:
Following general procedure E using pyrazole 27 (162 mg, 0.437 mmol) and 3-
trifluoromethylbromobenzene (147 mg, 0.656 mmol), pyrazole 28 was isolated as a yellow
solid (93 mg, 55%)
1H NMR (400 MHz, CDCl3) δ 0.19 (9H, s), 2.35 (3H, s), 3.86 (3H, s), 7.07 (2H, d, J = 8.0
Hz), 7.15 (2H, d, J = 8.0 Hz), 7.24 (1H, d, J = 8.0 Hz), 7.31 (1H, t, J = 7.5 Hz), 7.46 (1H, d, J
13
= 8.0 Hz), 7.50 (1H, s); C NMR (101 MHz, CDCl3) δ -0.2, 21.4, 37.5, 110.7, 119.9 (d, J =
99.5 Hz), 123.2 (dd, J = 7.5, 3.5 Hz), 124.3 (q, J = 272.5 Hz), 126.9, 127.2-127.5 (m), 129.7
(d, J = 52.5 Hz), 130.24 (q, J = 32.0 Hz), 133.6, 136.2, 138.5, 141.6, 150.5; 19F NMR (377
MHz, CDCl3) δ -62.7; FTIR: νmax 2956 (w), 1733 (m), 1580 (m), 1510 (m), 1325 (m), 1309
(m), 1157 (s), 1117 (s), 1014 (m) cm-1; HRMS (ESI-TOF) m/z [M+H]+ calculated for
C21H24F3N2Si: 389.1655. Found: 389.1652.
1-(Methyl)-4-(3,trifluoromethylphenyl)-5-(4-tolyl)-pyrazole, 29:
Following general procedure E using pyrazole 28 (93 mg, 0.24 mmol) and TBAF in THF (1.0
M, 2.4 mL, 2.4 mmol), pyrazole 29 was isolated as a colourless solid (51 mg, 67%). The title

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compound was recrystallised from CH2Cl2/40-60 petroleum ether and isolated as a colourless
powder.
1
M.p.: 72 °C; H NMR (400 MHz, CDCl3) δ 2.42 (3H, s), 3.78 (3H, s), 7.18 (2H, d, J = 8.0
13
Hz), 7.24-7.30 (4H, m), 7.35-7.40 (1H, m), 7.45 (1H, s), 7.76 (1H, s); C NMR (101 MHz,
CDCl3) δ 21.5, 37.4, 119.7, 122.7 (d, J = 3.5 Hz), 124.0 (d, J = 3.5 Hz), 124.2 (q, J = 272.0
Hz), 127.0, 128.9, 129.9, 130.0, 130.4, 130.9 (q, J = 32.0 Hz), 134.2, 137.5, 139.3, 140.6; 19F
NMR (377 MHz, CDCl3) δ -62.9; FTIR: νmax 2923 (w), 1520 (m), 1364 (m), 1314 (s), 1156
(s), 1119 (s), 991 (m), 905 (m) cm-1; HRMS (ESI-TOF) m/z [M+H]+ calculated for
C18H16F3N2: 317.1260. Found: 317.1258.
4-(4-Methoxyphenyl)-3-(4-ethoxyphenyl)sydnone:
Following general procedure A using N-(4-ethoxyphenyl)sydnone (500 mg, 2.42 mmol) and
4-bromoanisole (680 mg, 3.64 mmol), the title compound was isolated as a tan solid (566 mg,
75%). The title compound was recrystallised from EtOH and isolated as tan prisms.
M.p.: 169 °C; 1H NMR (400 MHz, CDCl3) δ 1.46 (3H, t, J = 7.0 Hz), 3.78 (3H, s), 4.10 (2H,
q, J = 7.0 Hz), 6.82 (2H, d, J = 9.0 Hz), 7.00 (2H, d, J = 9.0 Hz), 7.24 (2H, d, J = 9.0 Hz),
7.37 (2H, d, J = 9.0 Hz); 13C NMR (101 MHz, CDCl3) δ 14.7, 55.4, 64.3, 108.0, 114.4, 115.6,
117.1, 126.3, 127.3, 129.0, 159.8, 161.5, 167.4; FTIR: νmax 2980 (w), 2936 (w), 1737 (s),
1608 (m), 1533 (m), 1516 (m), 1251 (s), 1185 (m), 1013 (m), 998 (m), 971 (m) cm-1; HRMS
(ESI-TOF) m/z [M+H]+ calculated for C17H17N2O4: 313.1183. Found: 313.1177.
1-(4-Ethoxyphenyl)-3-(trimethylsilyl)-4-(pinacolatoborolane)-5-(4-methoxyphenyl)-pyrazole,
30a and 1-(4-ethoxyphenyl)-3-(pinacolatoborolane)-4-(trimethylsilyl)-5-(4-methoxyphenyl)-
pyrazole, 30b:
Following general procedure D using 4-(4-methoxyphenyl)-N-(4-ethoxyphenyl)sydnone (177
mg, 0.567 mmol) and 4,4,5,5-tetramethyl-2-[2-(trimethylsilyl)ethynyl]-1,3,2-dioxaborolane
(254 mg, 1.13 mmol), pyrazole 30a was isolated as a brown solid (179 mg, 64%) and
pyrazole 30b was isolated as a brown oil (28 mg, 10%, ~85% purity).
30a:1H NMR (400 MHz, CDCl3) δ 0.41 (9H, s), 1.24 (12H, s), 1.39 (3H, t, J = 7.0 Hz), 3.80
(3H, s), 3.99 (2H, q, J = 7.0 Hz), 6.74-6.81 (4H, m), 7.09-7.17 (4H, m); 13C NMR (101 MHz,
CDCl3) δ -0.3, 14.9, 25.0, 55.3, 63.7, 83.1, 113.0, 114.4, 123.8, 126.8, 132.0, 133.5, 149.8,
157.9, 159.3, 159.4; FTIR: νmax 2977 (w), 2898 (w), 1615 (w), 1543 (w), 1515 (s), 1410 (m),

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1238 (s), 1139 (s), 1042 (s), 1033 (s) cm-1; HRMS (ESI-TOF) m/z [M+H]+ calculated for
C27H3810BN2O4Si: 492.2725. Found: 492.2722.
30b:1H NMR (400 MHz, CDCl3) δ 0.06 (9H, s), 1.33-1.40 (15H, m), 3.78 (3H, s), 3.95 (2H,
q, J = 7.0 Hz), 6.69 (2H, d, J = 9.0 Hz), 6.78 (2H, d, J = 8.5 Hz), 7.03 (2H, d, J = 8.5 Hz),
7.09 (2H, d, J = 9.0 Hz).
1-(4-Ethoxyphenyl)-3-(trimethylsilyl)-4-(2-methoxyphenyl)-5-(4-methoxyphenyl)-pyrazole,
31:
Following general procedure E using pyrazole 30a (150 mg, 0.305 mmol) and 2-
bromoanisole (85 mg, 0.47 mmol), pyrazole 31 was isolated as a yellow oil (132 mg, 92%).
1H NMR (400 MHz, CDCl3) δ 0.18 (9H, s), 1.43 (3H, t, J = 7.0 Hz), 3.62 (3H, s), 3.74 (3H,
s), 4.03 (2H, q, J = 7.0 Hz), 6.68 (2H, d, J = 9.0 Hz), 6.81-6.86 (3H, m), 6.89 (1H, dd, J =
7.5, 1.0 Hz), 6.94 (2H, d, J = 9.0 Hz), 6.89 (1H, dd, J = 7.5, 1.5 Hz), 7.24-7.29 (3H, m); 13C
NMR (101 MHz, CDCl3) δ -0.6, 14.9, 55.1, 55.3, 63.7, 110.6, 113.5, 114.5, 120.1, 123.4,
124.1, 125.1, 126.6, 128.6, 130.0, 131.0, 133.0, 133.8, 140.4, 152.3, 157.8, 158.8; FTIR: νmax
2950 (w), 1518 (m), 1477 (m), 1314 (s), 1243 (m), 1156 (s), 1118 (s), 991 (m) cm-1; HRMS
(ESI-TOF) m/z [M+H]+ calculated for C28H33N2O3Si: 473.2255. Found: 473.2260.
1-(4-Ethoxyphenyl)-3-4-(2-methoxyphenyl)-5-(4-methoxyphenyl)-pyrazole, 32:
Following general procedure E using pyrazole 31 (106 mg, 0.224 mmol) and TBAF in THF
(1.0 M, 2.2 mL, 2.2 mmol), pyrazole 32 was isolated as a colourless solid (61 mg, 68%).
Note: product was contaminated with significant amounts of protodeboronated product from
the previous steps.
1H NMR (400 MHz, CDCl3) δ 1.40 (3H, t, J = 6.0 Hz), 3.76 (3H, s), 3.89 (3H, s), 4.01 (2H,
q, J = 6.0 Hz), 6.74 (2H, d, J = 9.0 Hz), 6.79-6.84 (2H, m), 6.95-7.00 (4H, m), 7.13-7.20 (2H,
13
m), 7.88 (1H, s), 7.90 (2H, d, J = 9.0 Hz); C NMR (101 MHz, CDCl3) δ 14.9, 15.1, 55.3,
55.4, 55.7, 55.9, 63.8, 63.8, 64.2, 206.8, 111.1, 112.5, 113.8, 114.0, 114.2 114.5, 114.7,
115.8, 116.5, 117.8, 120.6, 121.6, 122.2, 123.3, 124.2, 126.1, 126.8, 128.1, 130.1, 130.8,
131.4, 131.9, 133.5, 136.4, 139.9, 140.0, 140.1, 142.9, 156.9, 157.9, 159.2, 159.5, 160.5,
164.2; FTIR: νmax 2980 (w), 2935 (w), 2837 (w), 1597 (s), 1512 (s), 1244 (m), 1168 (m),
1025 (m) cm-1; HRMS (ESI-TOF) m/z [M+H]+ calculated for C25H25N2O3: 401.1860. Found:
401.1856.

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1-(Phenyl)-3-(n-hexyl)-pyrazole, 33a and 1-(phenyl)-4-(n-hexyl)pyrazole, 33b:
Following general procedure B using N-phenylsydnone (200 mg, 1.23 mmol) and 1-octyne
(544 mg, 4.93 mmol), an inseparable mixture of pyrazole 33a and 33b was isolated as a
yellow oil (182 mg, 65%, 9:1).
1H NMR (400 MHz, CDCl3) δ 0.83-0.94 (3H, m), 1.26-1.46 (6H, m), 1.64-1.76 (2H, m),
2.66-2.78 (2H, m), 6.26 (1H, d, d, J = 2.5 Hz), 7.20-7.29 (1H, m), 7.37-7.48 (2H, m), 7.62-
13
7.69 (2H, m), 7.82 (1H, d, J = 2.5 Hz); C NMR (101 MHz, CDCl3) 14.2, 22.8, 28.6, 29.3,
29.8, 31.8, 106.6, 119.1, 126.0, 127.4, 129.5, 140.4, 155.6; FTIR: νmax 2925 (m), 2854 (m),
1600 (s), 1530 (s), 1503 (s), 1457 (m), 1389 (s), 1324 (m), 1224 (m), 1042 (s), 946 (m) cm-1;
HRMS (ESI-TOF) m/z [M+H]+ calculated for C15H21N2: 229.1699. Found: 229.1700.
1-(Phenyl)-3-(n-hexyl)-4-vinylpyrazole, 34:
Following general procedure F using pyrazoles 33a and 33b (182 mg, 0.797 mmol), NBS
(142 mg, 0.797 mmol), vinyllboronic acid pinacol ester (184 mg, 1.20 mmol), XPhosPdG2
(63 mg, 0.08 mmol) and Na2CO3 (169 mg, 1.59 mmol) for 17 h, pyrazole 34 was isolated as
an orange oil (146 mg, 72%).
1H NMR (400 MHz, CDCl3) δ 0.84-0.95 (3H, m), 1.25-1.48 (6H, m), 1.65-1.76 (2H, m),
2.68-2.79 (2H, m), 5.36 (1H, dd, J = 11.0, 1.5 Hz), 5.47 (1H, dd, J = 17.5, 1.5 Hz), 6.57 (1H,
dd, J = 17.5, 11.0 Hz), 7.20-7.28 (1H, m), 7.39-7.58 (2H, m), 7.65 (2H, dd, J = 7.5, 1.0 Hz),
13
7.93 (1H, s); C NMR (101 MHz, CDCl3) δ 14.2, 22.8, 27.3, 29.4, 29.5, 31.8, 112.9, 119.0,
124.3, 126.2, 126.8, 129.5, 140.1, 141.1, 153.3; FTIR: νmax 2924 (m), 2854 (m), 1599 (m),
1554 (m), 1503 (s), 1463 (m), 1383 (m), 1219 (m), 1053 (s), 953 (m) cm-1; HRMS (ESI-TOF)
m/z [M+H]+ calculated for C17H23N2: 255.1856. Found: 255.1862.
1-(4-Fluorophenyl)-3-(phenyl)pyrazole, 35a and 1-(4-fluorophenyl)-4-(phenyl)-pyrazole,
35b:17
Following general procedure B using N-(4-fluorophenyl)sydnone (200 mg, 1.10 mmol) and
phenylacetylene (453 mg, 4.44 mmol), an inseparable mixture of pyrazole 35a and 35b was
isolated as a yellow solid (264 mg, 100%, 9:1).
1H NMR (400 MHz, CDCl3) δ 6.78 (1H, d, J = 2.5 Hz), 7.13-7.21 (2H, m), 7.31-7.38 (1H,
13
m), 7.44 (2H, t, J = 7.5 Hz), 7.71-7.77 (2H, m), 7.88-7.94 (3H, m); C NMR (101 MHz,

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CDCl3) δ 105.3, 116.4 (d, J = 23.0 Hz), 121.0 (d, J = 8.5 Hz), 126.0, 128.3, 128.8, 130.2,
133.1, 136.7, 153.2, 161.2 (d, J = 246.5 Hz); 19F NMR (376 MHz, CDCl3) δ -116.1.
1-(4-Fluorophenyl)-3-(phenyl)-4-(4-methoxyphenyl)pyrazole, 36:
Following general procedure F using pyrazoles 35a and 35b (264 mg, 1.10 mmol), NBS (197
mg, 1.10 mmol), 4-methoxyphenylboronic acid (253 mg, 1.67 mmol), XPhosPdG2 (87 mg,
0.11 mmol) and Na2CO3 (353 mg, 3.33 mmol) for 17 h, pyrazole 36 was isolated as an
amorphous orange solid (135 mg, 35%).
1H NMR (400 MHz, CDCl3) δ 3.84 (3H, s), 6.90 (2H, d, J = 9.0 Hz), 7.17 (2H, dd, J = 9.0,
8.5 Hz), 7.25-7.30 (2H, m), 7.33-7.42 (3H, m), 7.62-7.64 (m, 2H), 7.75 (2H, ddd, J = 10.5,
13
5.0, 3.0 Hz), 7.90 (1H, s); C NMR (101 MHz, CDCl3) δ 55.3, 110.7, 114.1, 116.3 (d, J =
23.0 Hz), 120.7 (d, J = 8.5 Hz), 122.8, 125.1, 126.5, 128.0, 128.5, 130.0, 133.2, 136.5 (d, J =
2.5 Hz), 150.5, 158.9, 161.2 (d, J = 245.5 Hz); 19F NMR (376 MHz, CDCl3) δ -116.2 - -116.0
(m); FTIR: νmax 2835 (w), 1556 (m), 1499 (s), 1448 (m), 1290 (m), 1245 (s), 1175 (s), 1027
(s), 958 (m) cm-1; HRMS (ESI-TOF) m/z [M+H]+ calculated for C22H18FN2O: 345.1398.
Found: 345.1398.
1-(4-Methoxyphenyl)-3-(cyclopropyl)pyrazole,
37a
and
1-(4-Methoxyphenyl)-4-
(cyclopropyl)pyrazole, 37b:
Following general procedure B using N-(4-methoxyphenyl)sydnone (200 mg, 1.04 mmol)
and cyclopropylacetylene (275 mg, 4.16 mmol), an inseparable mixture of pyrazole 37a and
37b was isolated as a yellow oil (203 mg, 91%, 9:1).
1H NMR (400 MHz, CDCl3) δ 0.73-0.83 (2H, m), 0.93-1.02 (2H, m), 2.04 (1H, tt, J = 8.5, 5.0
Hz), 3.83 (3H, s), 6.07 (1H, d, J = 2.5 Hz), 6.94 (2H, d, J = 9.0 Hz), 7.54 (2H, d, J = 9.0 Hz),
13
7.68 (1H, d, J = 2.5 Hz); C NMR (101 MHz, CDCl3) δ 8.2, 9.4, 55.7, 103.6, 114.6, 120.6,
120.7, 127.5, 156.7, 158.0; FTIR: νmax 3007 (w), 1530 (m), 1512 (s), 1382 (m), 1299 (m),
1242 (s), 1180 (m), 1108 (m), 1026 (s), 949 (s) cm-1; HRMS (ESI-TOF) m/z [M+H]+
calculated for C13H15N2O: 215.1179. Found: 215.1176.
1-(4-Methoxyphenyl)-3-(cyclopropyl)-4-(4-trifluoromethylphenyl)pyrazole, 38:
Following general procedure F using pyrazoles 37a and 37b (191 mg, 0.891 mmol), NBS
(159 mg, 0.891 mmol), 4-trifluomethylphenylboronic acid (254 mg, 1.34 mmol), XPhosPdG2

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(70 mg, 0.089 mmol) and Na2CO3 (189 mg, 1.78 mmol) for 17 h, pyrazole 38 was isolated as
an amorphous orange solid (234 mg, 73%).
1H NMR (400 MHz, CDCl3) δ 0.96-1.04 (2H, m), 1.06-1.15 (2H, m), 2.00 (1H, tt, J = 8.5, 5.0
Hz), 3.84 (3H, s), 6.96 (2H, d, J = 9.0 Hz), 7.58 (2H, d, J = 9.0 Hz), 7.67 (2H d, J = 8.5 Hz),
13
7.73 (2H d, J = 8.5 Hz), 7.91 (1H, s); C NMR (101 MHz, CDCl3) δ 8.1, 8.6, 55.7, 110.7,
114.7, 120.7, 121.3 (q, J = 260.5 Hz), 125.7 (q, J = 3.5 Hz), 125.8, 127.9, 128.5 (q, J = 32.5
Hz), 133.8, 137.1, 152.5, 158.3; 19F NMR (376 MHz, CDCl3) δ -62.3; FTIR: νmax 3011 (w),
2834 (w), 1620 (w), 1522 (s), 1321 (s), 1252 (m), 1163 (m), 1104 (s), 1065 (s), 1021 (s), 956
(m), 849 (s) cm-1; HRMS (ESI-TOF) m/z [M+H]+ calculated for C20H18F3N2O: 359.1366.
Found: 359.1376.
N-3-Hydroxypropyl-3-phenylsydnone-4-carboxamide:
To a solution of 3-phenylsydnone-4-carboxylic acid (2.00 g, 9.70 mmol) in CH2Cl2 (50 mL)
ο
at 0 C was added oxalyl chloride (3.69 g, 29.1 mmol) and DMF (3 drops) and the mixture
ο
stirred for 10 minutes at 0 C. The reaction was allowed to warm to room temperature and
stirred for a further 3 h. Volatiles were then removed in vacuo and the resulting yellow solid
dissolved in CH2Cl2 (50 mL). Triethylamine (982 mg, 9.70 mmol) and 3-aminopropanol (874
mg, 11.6 mmol) were added at 0 οC and the reaction stirred for 14 h at RT. The reaction was
poured into water, extracted with CH2Cl2, the combined organic layers were dried over
MgSO4 and volatiles removed in vacuo. The resulting crude material was purified by flash
silica chromatography (eluting solvent 100% ethyl acetate) affording the title compound as a
colourless solid (2.00 g, 78%). The title compound was recrystallised from CH2Cl2/40-60
petroleum ether and isolated as a colourless powder.
M.p.: 84-86 °C; 1H NMR (400 MHz, CDCl3) δ 1.74 (2H, td, J = 12.0, 6.0 Hz), 2.64 (1H, t, J
= 6.0 Hz), 3.49 (2H, dd, J = 12.0, 6.0 Hz), 3.62 (2H, q, J = 6.0 Hz), 7.53-7.62 (4H, m), 7.68
(1H, ddt, J = 8.0, 6.5, 1.5 Hz), 7.75 (1H, s); 13C NMR (101 MHz, CDCl3) δ 32.3, 35.8, 59.5,
101.9, 125.3, 129.4, 132.5, 134.6, 156.4, 167.3; FTIR: νmax 3449 (br), 3335 (m), 2930 (w),
1759 (s), 1653 (s), 1534 (s), 1493 (w), 1291 (m), 1215 (m), 956 (m) cm-1; HRMS (ESI-TOF)
m/z [M+H]+ calculated for C12H14N3O4: 264.0979. Found: 264.0974.
4-[2-(5,6-Dihydro-4H-1,3-oxazine)]-3-phenylsydnone:
ο
To a solution of triphenylphosphine oxide (1.90 g, 6.84 mmol) in CH2Cl2 (35 mL) at 0 C
was added triflic anhydride (804 mg, 2.85 mmol) and the reaction stirred for 30 minutes at 0