Synthesis of 4-fluoromethylsydnones and their participation in alkyne cycloaddition reactions

Article

pubs.acs.org/joc

Synthesis of 4‑Fluoromethylsydnones and their Participation in

Alkyne Cycloaddition Reactions

Robert S. Foster,^†Harry Adams,^†Harald Jakobi,^‡and Joseph P. A. Harrity*^,†

^†Department of Chemistry, University of Sheﬃeld, Sheﬃeld S3 7HF, U.K.

^‡Research-Weed Control Chemistry, Bayer CropScience, AG 65926 Frankfurt am Main, Germany

S

* Supporting Information

ABSTRACT: We report the synthesis and some structural studies of 4-triﬂuoromethyl, 4-

diﬂuoromethyl-, and 4-monoﬂuoromethylsydnones. All but the latter compounds are stable and

represent eﬀective precursors to a range of pyrazoles after cycloaddition reactions with alkynes. The

cycloadditions are generally highly regioselective and provide 5-ﬂuoromethylpyrazole products,

although we have observed that Bn-substituted sydnones can provide an unexpected alkyne insertion

mode that generates the 3-ﬂuoromethyl isomer.

method exploits the ready availability of triﬂuoroacetic acid

INTRODUCTION

■

derived precursors.⁷Such reactions also very often provide

mixtures of the 3- and 5-triﬂuoromethyl products, although

good regiocontrol for the 3-CF₃pyrazoles can be achieved by

use of ﬂuorinated solvents.⁸Moreover, the eﬃcient synthesis of

5-CF₃-substituted pyrazoles is further hampered by the fact that

the intermediate 5-triﬂuoromethyl-5-hydroxypyrazolines under-

go rather slow dehydration.⁹As an alternative to the

cyclocondenstaion route, the cycloaddition of alkynes with

sydnones represents a convenient approach for the regiose-

lective synthesis of these azoles.^10,11In a related study, Meazza

reported the synthesis of 3- and 4-triﬂuoromethylpyrazoles

through cycloadditions with triﬂuoromethylacetylenes.¹²More-

over, diazomethane functions as an eﬀective precursor to

stannylated 4-ﬂuoro- and 4-triﬂuoromethylated pyrazoles.¹³

However, employing cycloaddition techniques to provide the

analogous 5-triﬂuoromethylpyrazoles is rather under-developed

(Scheme 1). Recent studies in our laboratory have endeavored

to develop the scope of sydnone functionalization and alkyne

cycloaddition chemistry, with the goal of establishing this area

as enabling chemistry for pyrazole synthesis.¹⁴We envisaged

that this chemistry could provide a convenient and general

solution to the regiocontrolled synthesis of various 5-

ﬂuoromethyl-substituted pyrazoles via the corresponding 4-

ﬂuoromethylsydnones.¹⁵Our studies toward this end are

delineated herein.

The prevalence of ﬂuorinated aromatic and heterocyclic

compounds in agrochemicals and small molecule therapeutics

has led to a signiﬁcant interest in developing new and more

convenient synthetic procedures for the preparation of these

molecules. As a speciﬁc subclass, pyrazoles bearing ﬂuorocar-

bon substituents are becoming increasingly prevalent as

synthetic targets and building blocks within the ﬁne chemicals

sector.¹Several bioactive ﬂuorinated pyrazoles have emerged in

recent years and have shown activity in pharmaceutical²and

agrochemical screens.³Of the more established commercial

ﬂuorinated pyrazoles, particularly noteworthy examples include

nonsteroidal anti-inﬂammatory drugs of the coxib class such as

celecoxib and deracoxib,⁴as well as the herbicide ﬂuazolate⁵

(Figure 1).

Figure 1. Bioactive ﬂuorinated pyrazoles.

RESULTS AND DISCUSSION

■

The [3 + 2] cycloaddition of nitrilimines and alkynes and the

cyclocondensation of a hydrazine with 1,3-diketones or α,β-

unsaturated carbonyl compounds represent the most common

strategies of pyrazole ring synthesis. However, these approaches

can suﬀer from the formation of regioisomeric mixtures with

respect to substituents incorporated at the pyrazole 3- and 5-

positions.⁶In the context of triﬂuoromethylpyrazoles, these

compounds are typically synthesized by the cyclocondensation

approach using 1,1,1-triﬂuoromethyl-1,3-diketones, as this

Sydnones are typically prepared in two steps by nitrosation of

N-substituted amino acids followed by cyclodehydration of the

resulting nitrosamines. Therefore, we began our investigations

by developing a scalable route to the requisite 4-triﬂuorome-

thylsydnones via their respective triﬂuoromethylalanines.

Received: February 21, 2013

Published: April 2, 2013

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Recourse to alternative reducing agents such as trichlorosilane

only gave trace amounts of the desired amino ester.

Scheme 1. Synthetic Approaches to

Triﬂuoromethylpyrazoles

Overall therefore, with a view to implementing a general

approach to triﬂuoromethylsydnones, the route outlined in

Scheme 2 raised some serious limitations. In addition to the

potential for functional group incompatibility highlighted in

Scheme 3, the synthetic sequence is lengthy, linear, and

a

Scheme 3. Uncontrolled Reduction of N-PNP Imine 6

a

PNP: 4-nitrophenyl.

incorporates the N-substituent at the start of the process. We

envisaged that a more convenient strategy would be to develop

a late-stage triﬂuoromethylation of sydnones, as this would

provide a more direct means to incorporate a range of N-

substituents. In this regard, we reported that the Suzuki cross-

coupling of 4-bromosydnones provided a convenient method of

incorporating aryl-substituents.^14bWe envisaged that an

analogous strategy could prove to be an eﬀective method for

generating 4-triﬂuoromethyl sydnones.

Scheme 2 shows the route employed to access compounds

5a,b. The aza-Wittig reaction of iminophosphoranes 1a,b and

a

Scheme 2. Synthesis of 4-Triﬂuoromethylsydnones

Copper-promoted triﬂuoromethylations using Ruppert’s

reagent are one of the most widely used techniques for the

direct incorporation of a CF₃group,¹⁹although the use of

organoboron-based coupling partners is also well established.²⁰

In the event, however, successful triﬂuoromethylation of 7 was

achieved by the Cu-promoted addition of methyl ﬂuorosulfo-

nyldiﬂuoroacetate²¹in DMF at 80 °C. The scope of the

triﬂuoromethylation was examined, and the results are

summarized in Scheme 4. The reaction of 4-iodo-N-phenyl-

Scheme 4. Triﬂuoromethylation of 4-Iodosydnones

a

PMP: 4-methoxyphenyl.

methyl triﬂuoromethylpyruvate furnished imines 2a,b,¹⁶which

were reduced to the corresponding amino esters 3a,b using zinc

metal.¹⁷Ester hydrolysis proved to be challenging; saponiﬁca-

tion provided a complex mixture whereas hydrolysis under acid

catalysis proved to be capricious. Ultimately, however, we

found that heating the amino esters at reﬂux with lithium iodide

in ethyl acetate for 4 h¹⁸consistently delivered the amino acids

4a,b in high yield. Finally, the desired 4-triﬂuoromethylsyd-

nones were generated by the well-established nitrosation−

cyclodehydration sequence, thereby allowing gram quantities of

5a and 5b to be produced in good overall yield.

sydnone 7 (R = Ph) provided triﬂuoromethylsydnone 5a in

79% yield. The presence of an electron-donating PMP group

was also highly eﬃcient, giving 5b in similar yield. However, the

electron-withdrawing PNP group required a much longer

reaction time but provided the previously inaccessible

compound 5c in acceptable yield. Nonaromatic groups were

also tolerated, delivering the methyl and benzyl protected

sydnones 5d and 5e. Overall, therefore, the direct triﬂuor-

Our eﬀorts to further extend this chemistry to produce other

triﬂuoromethylsydnones highlighted some limitations with this

approach. Speciﬁcally, our attempts to reduce the PNP-imine 6

with zinc metal resulted in mixtures of the reduction products.

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omethylation described in Scheme 4 complements and

improves upon the stepwise procedure described earlier

(Scheme 2) and in our preliminary report of this work¹⁵and

oﬀers a practical approach to a selection of ﬂuorous sydnone

analogues.

Having developed eﬀective routes to CF₃-substituted

sydnones, we next turned our attention to their cycloaddition

reaction with alkynes to form pyrazoles. We were particularly

interested in establishing the eﬀect of the triﬂuoromethyl group

on cycloaddition regioselectivity, and our results are summar-

ized in Table 1. Alkyne cycloaddition reactions with N-Ph

regioselectivity in some cases. Moreover, disubstituted alkynes

also participated in the reaction, but with generally lower levels

of regiocontrol (entries 9−11). These general trends were

continued with N-arylsydnones 5b and 5c, although cyclo-

additions of PNP-sydnone 5c needed only 8 h, in accord with

the documented increased reactivity of these mesoionic

compounds (entries 12−16).^14cFinally, the cycloaddition of

N-Me-sydnone 5d also provided the corresponding pyrazoles in

excellent yield and regiocontrol (entries 17−20). However, in

extending this method to the cycloaddition with 5-chloropent-

1-yne, we were surprised to recover the bicyclic 3-

triﬂuoromethyl pyrazole 29. In this case, we believe that

pyrazole 28 is formed initially but then undergoes a cyclization

to provide 29 upon demethylation (Scheme 5).

a

Table 1. Synthesis of 5-Triﬂuoromethylpyrazoles

Scheme 5. Unexpected Formation of 3-Triﬂuoromethyl

Pyrazole 29

The study highlighted in Table 1 suggested that the

chemistry would have limited use in the direct synthesis of

tetrasubstituted pyrazoles, as the observed regioselectivities

were found to be rather low (entries 9 and 10). Related work in

our laboratories has highlighted the potential of alkynylboro-

nates in the synthesis of these compounds,¹⁴as they typically

aﬀord high selectivites for the 4-borylated isomer. We therefore

decided to investigate the cycloaddition of these substrates, and

our results are summarized in Table 2. In the event, the

reactions required heating at 140 °C over a period of 24−72 h;

however, the corresponding products 30−34 were generated in

good yield and with useful levels of regiocontrol. Notably, the

terminal alkyne exhibited the opposite regiochemical insertion

mode and follow the trend whereby the sterically more

Table 2. Synthesis of 5-Triﬂuoromethylpyrazole Boronic

Esters

a

Reaction complete within 8 h. PMP: 4-methoxyphenyl. PNP: 4-

b

nitrophenyl. Product isolated as an inseparable mixture of isomers.

sydnone 5a were generally complete within 24 h when

conducted at 180 °C in a sealed vessel. We were pleased to

ﬁnd that the cycloaddition of 5a with a range of terminal

alkynes proceeded in good to excellent yields and with almost

complete regiocontrol in each case (entries 1−8). Indeed, the

selectivity of formation of 11 is notable; cycloadditions of 4-

Me- and 4-Prⁱ-substituted sydnones with 2-ethynylpyridine

proceed with lower levels of regiocontrol (<6:1)^14fsuggesting

that the CF₃group can also enhance cycloaddition

entry

R¹

R²

time (h)

yield (%)

a/b

a

1

2

3

4

5

Ph; 5a

Me; 5d

Ph; 5a

PNP; 5c

Ph; 5a

H

72

48

24

72

30: 69

31: 44

32: 64

33: 55

34: 55

7:93

4:96

H

Me₃Si

Bu

90:10

>98:2

95:5

a

Product isolated as an inseparable mixture of regioisomers. o-DCB:

1,2-dichlorobenzene.

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demanding group is placed adjacent to the nitrogen atom, in

line with our previous observations.^14c

Representative functionalization reactions conﬁrmed the

potential of the pyrazole boronic esters for the divergent

synthesis of 5-CF₃pyrazoles (Scheme 6). Both 3- and 4-

examine the cycloaddition of 4-triﬂuoromethyl-N-benzylsyd-

none 5e, with a view to studying Bn hydrogenolysis of the

product pyrazoles. To our surprise, however, the reaction of 5e

with both phenylacetylene and 1-hexyne yielded a mixture of

the expected 5-CF₃-substituted pyrazoles 39a and 40a, together

with the corresponding 3-CF₃isomers 39b and 40b²⁵(Table

3). We were able to improve the selectivity to favor regioisomer

Scheme 6. Functionalization of 5-Triﬂuoromethylpyrazole

Boronic Esters

Table 3. Synthesis of 3- and 5-Triﬂuoromethyl-N-

benzylpyrazoles

b

entry

R

temp (°C)

time (h)

yield (%)

a/b

1

2

Ph (2)

Bu (2)

Ph (2)

Ph (10)

180

140

180

24

48

24

39a,b: 61

40a,b: 48

39a,b: 34

39a,b: 66

39a,b: 64

64:36

72:28

96:4

a

3

4

5

88:12

a

b

48% conversion. The values in parentheses refer to the equivalents

of alkyne used.

a by lowering the reaction temperature (entries 3 and 4) or

using a large excess of alkyne (entry 5), but in each case a small

amount of the 3-triﬂuoromethyl isomer remained.

The observation that sydnones can incorporate alkynes into

the 4,5-position of a pyrazole under thermal conditions is

unprecedented to the best of our knowledge. In order to

explain this curious result, we decided to ﬁrst explore the

potential for Bn-migration in the pyrazole products. As outlined

in Scheme 8, subjecting samples of 39a,b containing diﬀerent

borylated compounds underwent Suzuki coupling in good

yields. Of particular note is the regioselective synthesis of 16a,

which was produced as a 1:1 mixture by reaction of 5a with 1-

phenyl-1-hexyne (see Table 1, entry 9). Similarly, both 3- and

4-borylated 30b and 32a underwent oxidation with hydrogen

peroxide at ambient temperature to provide 35 and 36 in good

yields. The product pyrazoles oﬀer the opportunity to access

the bioactive pyrazole phenyl ether series.²²

Scheme 8. Probing Product Isomerization

A limitation of the sydnone cycloaddition route to pyrazoles

is the requirement for a substituent to be present at nitrogen.

However, we envisaged that PMP-substituted sydnone 5b

oﬀered the opportunity to generate pyrazoles bearing a free N-

H after oxidative cleavage using ceric ammonium nitrate

(CAN).²³To ensure full conversion a large excess of CAN was

required²⁴which not only gave the expected pyrazole 37 in

47% yield but also 13% of the nitrated product 38, which

appears to be deactivated toward oxidation (Scheme 7).

The low yield observed in the CAN deprotection of 19

prompted us to explore other systems that could oﬀer more

eﬃcient deprotection strategies. In this respect, we decided to

ratios of regioisomers to heating under the reaction conditions

resulted in recovery of the pyrazoles with no detectable changes

in regioisomer ratios. We speculated that sydnone 5e could

function as an electrophilic source of Bn-cation, thereby

promoting product isomerization by a benzylation−debenzyla-

tion mechanism along similar lines to the process highlighted in

Scheme 5. Again, however, heating mixtures of 39a,b in the

presence of sydnone 5e resulted in no detectable changes in

pyrazole isomer ratios.

Scheme 7. CAN Deprotection of N-PMP-Protected 5-

Triﬂuoromethylpyrazole 19

The control experiments outlined in Scheme 8 suggested that

the 3-CF₃isomer did not originate via pyrazole isomerization,

and we began to consider pathways under which the 3-

triﬂuoromethyl isomer could originate from the sydnone. In

this regard, 41 has been proposed to undergo a disrotary

electrocyclic ring closure under photolytic conditions to give a

bicyclic intermediate 43 which evolves CO₂to produce a

nonisolable nitrile imine 44.²⁶Alkyne cycloaddition of 44 with

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dimethyl acetylenedicarboxylate (DMAD) gave pyrazole 42b in

67% yield. In contrast, the thermally promoted reaction of

sydnone 41 with DMAD provides isomeric pyrazole 42a

(Scheme 9).

pyrazole-forming reaction. Indeed, Tanaka has demonstrated

that a closely related intermediate triﬂuoroacetonitrile imine 49

undergoes cycloaddition with phenylacetylene to give 3-CF₃-

pyrazole 50 (Scheme 12).²⁷Studies aimed at providing

Scheme 12. Proposed Mechanism of Formation of 3-CF₃

Pyrazoles

Scheme 9. Photolytic and Thermal Reactions of Sydnones

with DMAD

In order to test whether the formation of 39b was occurring

via a visible light promoted nitrile imine formation, the

cycloaddition with phenyl acetylene was conducted simulta-

neously in the presence and absence of light (Scheme 10).

However, both reactions yielded approximately the same ratio

of isomers under these conditions.

experimental evidence for intermediates 46 and 47 and to

explore other such migration reactions in 3,4-disubstituted

pyrazoles are ongoing and will be reported in due course.

From a synthetic standpoint, our initial goal was to undertake

cycloadditions of 5e so that we could carry out a subsequent

debenzylation to furnish N-unsubstituted pyrazoles. In this

regard, it is unimportant that we observe compound mixtures in

this particular case as both isomers converge to a single

pyrazole upon hydrogenolysis. For example, compounds 39a,b

provided pyrazole 37 in 75% yield (Scheme 13).²⁸

Scheme 10. Visible Light Dependence on the Cycloaddition

of Sydnone 5e

Scheme 13. Catalytic Hydrogenolysis of Bn-Protected 3- and

5-Triﬂuoromethylpyrazoles

In order to establish the eﬀect of reaction temperature on

product distribution, we exploited the enhanced reactivity of

DMAD in sydnone cycloadditions so that 5e could be reacted

with DMAD at 120 and 180 °C. At the lower temperature, the

reaction produced 5-CF₃pyrazole 45a in 54% yield and

essentially as a single regioisomer. In contrast, conducting the

reaction at 180 °C produced a mixture of 45a and 45b in a ratio

of 63:37 (Scheme 11).

Having established a robust method for the introduction of

the triﬂuoromethyl group into pyrazoles, we wondered if the

concept could be extended to include monoﬂuoromethyl and

diﬂuoromethyl substituents. While monoﬂuoromethyl pyra-

zoles are rather rare, diﬂuoromethyl-substituted analogues can

be prepared via hydrazine condensation reactions with the

respective diﬂuoromethyl-1,3-diketones. As with the triﬂuor-

omethyl analogues, the 3-ﬂuoromethyl isomer predominates.²⁹

Therefore, as an extension to the synthesis and cycloadditions

of triﬂuoromethyl sydnones, we envisioned that the known 4-

formyl- and 4-hydroxymethylsydnones³⁰could be transformed

into the corresponding ﬂuoromethylsydnones using deoxoﬂuor.

These sydnones could then be utilized as novel precursors to

diverse 5-ﬂuoromethyl- and 5-diﬂuoromethylpyrazoles.

Scheme 11. Comparison of Thermal Cycloaddition

Reactions of Sydnone 5e

Taken together, these results suggest that the benzylsydnone

5e undergoes transformation to a new intermediate at elevated

temperatures and that this undergoes cycloaddition to provide a

3-CF₃pyrazole product. We propose that a Bn migration takes

place to form an intermediate 1,2,3-oxadiazolidin-5-one 46 that

undergoes decarboxylation to generate nitrile imine 47 and that

this dipolar intermediate is the reactive species in the 3-CF₃

Although the direct synthesis of 4-formyl-N-phenylsydnone

is reported,³⁰we had diﬃculties reproducing the published

methods. However, we were able to generate the 4-ethyl ester

52 via lithiation of N-phenylsydnone 51, followed by addition

to ethyl chloroformate. Sydnone 52 was then reduced to the

alcohol 53 in excellent yield by stirring with lithium

borohydride overnight, and this alcohol could subsequently

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be oxidized to the 4-formyl sydnone 54 using MnO₂(Scheme

14).

thylpyrazoles in high yield with good regioselectivities. Notably,

the sterically less demanding diﬂuoromethyl group provides

lower selectivities in the case of 2-ethynylpyridine and ethyl

propiolate, in comparison to the triﬂuoromethyl analogue

(compare entries 2 and 5 in Table 4 with entries 4 and 20 in

Table 1).

Scheme 14. Synthesis of Sydnones 53 and 54

We next turned our attention to the alkyne cycloaddition

reactions of 4-ﬂuoromethyl-N-phenylsydnone 55. To our

disappointment, the reaction of phenylacetylene resulted in

decomposition. The situation could not be improved by

reducing the temperature to 120 °C. We next opted to exploit

the reactivity of DMAD and were pleased to ﬁnd that

cycloaddition could be achieved by conducting the reaction at

100 °C. However, as illustrated in Scheme 16, we discovered

that the resulting pyrazole was actually the 5-hydroxymethyl

analogue 63.

Deoxoﬂuorination of the hydroxymethyl sydnone 53 was

highly eﬃcient, providing 4-ﬂuoromethyl-N-phenylsydnone 55

in 80% yield after stirring at ambient temperature for 2 h. The

same reaction with 4-formyl-N-phenylsydnone 54 required

signiﬁcantly more forceful conditions (5 equiv of

[(CH₃OCH₂CH₂)₂NSF₃] deoxoﬂuor, 48 h), but 4-diﬂuor-

omethyl-N-phenylsydnone 56 was isolated in 81% yield

(Scheme 15).

Scheme 16. Fluoromethyl Sydnone 55 Cycloaddition

We decided to explore the susceptibility of sydnone 55 to

hydrolysis by exposing this compound to deuteromethanol,

allowing the reaction progress to be conveniently monitored by

¹H NMR spectroscopy. At room temperature, full conversion

to sydnone 64 occurred over several days but this time was

reduced to 44 h if the reaction mixture was heated at reﬂux

(Scheme 17).

Scheme 15. Synthesis of Fluorinated Sydnones by

Deoxoﬂuorination

Scheme 17. Solvolysis Studies of 55 in CD₃OD

The cycloaddition of diﬂuoromethylsydnone 56 with a

selection of alkynes was undertaken, and the results are

summarized in Table 4. The reaction was found to be generally

very eﬃcient and provided the corresponding 5-diﬂuorome-

As we were unable to productively use ﬂuoromethylsydnone

55 in our cycloaddition reactions, we synthesized 1,3-diphenyl-

5-hydroxymethylpyrazole 65 from 4-hydroxymethyl-N-phenyl-

sydnone 53 in 72% yield. The subsequent reaction with

deoxoﬂuor appeared to proceed to full conversion within 2 h.³¹

Unfortunately, however, upon workup either by quenching with

NaHCO_3(aq)or submitting directly to ﬂash chromatography on

silica gel, a signiﬁcant proportion of the desired ﬂuorinated

pyrazole 66 was found to have hydrolyzed to pyrazole 65,

showing the susceptibility of this compound to hydrolysis

(Scheme 18).

Table 4. Synthesis of 5-Diﬂuoromethylpyrazoles

Finally, the 4-ﬂuoromethylated sydnones 5a and 56 were

crystalline, and we therefore decided to analyze these

compounds by X-ray diﬀraction; the structures of both

compounds are shown in Figure 2. The crystal structure of

diﬂuoromethyl sydnone 56 shows an alignment of the C−H

and C−O bonds. The conformation may simply reﬂect reduced

A(1,3) strain, or favorable C−O and C−F bond dipole

alignments (or a combination of both). Curiously however, the

triﬂuoromethyl-substituted sydnone 5a highlights a similar

alignment in the solid phase resulting in a close contact

between the oxygen and ﬂuorine atoms.³²

a

Product isolated as an inseparable mixture of regioisomers. o-DCB:

1,2-dichlorobenzene.

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Synthesis of Triphenylphosphine (p-Methoxyphenyl)imide

1b. To a stirring solution of 1-azido-4-methoxybenzene (18.40 g,

123.37 mmol) in ether (200 mL) was slowly added a solution of

triphenylphosphine (32.36 g, 123.37 mmol) in ether (200 mL). The

mixture was stirred for 2 h, and then the volatiles were removed in

vacuo. The crude material was puriﬁed by recrystallization from

ethanol to yield triphenylphosphine (p-methoxyphenyl)imide 1b as a

yellow solid (41.51 g, 88%): mp 116−118 °C (lit.³⁴mp 117−118 °C);

¹H NMR (400 MHz, CDCl₃) δ 7.82−7.78 (m, 6H), 7.54−7.50 (m,

Scheme 18. Attempted Synthesis of 5-Fluoromethylpyrazole

66

3H), 7.47−7.42 (m, 6H), 6.83−6.81 (m, 2H), 6.68−6.66 (m, 2H),

3.70 (s, 3H); ¹³C NMR (100.6 MHz, CDCl₃) δ 152.0, 144.5 (d, J = 2.5

Hz), 132.7 (d, J = 9.5 Hz), 131.6 (d, J = 2.5 Hz), 131.5 (d, J = 99.0

Hz), 128.6 (d, J = 12.0 Hz), 123.9 (d, J = 16.5 Hz), 114.3, 55.6; ³¹P

NMR (101.1 MHz, CDCl₃) δ 2.49; HRMS m/z [MH]⁺calcd for

C₂₅H₂₃NOP 384.1517, found 384.1512.

Synthesis of (Z)-Methyl 3,3,3-Triﬂuoro-2-(phenylimino)-

propanoate 2a.¹⁶To a stirring solution of methyl triﬂuoropyruvate

(11.70 g, 75.00 mmol) in toluene (200 mL) was added solid

tetraphenylphosphine imide 1a (26.50 g, 75.00 mmol) in one portion.

The mixture was stirred for 2 h before the volatiles were removed in

vacuo. The crude material was suspended in petroleum ether, ﬁltered,

and washed with more petroleum ether before the volatiles were

removed in vacuo. This procedure was repeated until the precipitation

of triphenylphosphine oxide had ceased to yield (Z)-methyl 3,3,3-

triﬂuoro-2-(phenylimino)propanoate 2a as a yellow oil (15.95 g, 92%).

Note: Compound 2a could alternatively be puriﬁed by ﬂash

chromatography on silica gel (eluting with 10% EtOAc in petroleum

ether): ¹H NMR (400 MHz, CDCl₃) δ 7.43−7.39 (m, 2H), 7.31−7.27

(m, 1H), 7.00−6.97 (m, 2H), 3.73 (s, 3H); ¹³C NMR (100.6 MHz,

CDCl₃) δ 159.9, 148.5 (q, J = 37.0 Hz), 146.4, 129.2, 127.3, 119.2,

118.2 (q, J = 278.5), 52.9; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −69.8;

FTIR 2930 (w), 2856 (w), 1749 (s), 1326 (m), 1263 (s), 1190 (m),

Figure 2. X-ray crystal structures of sydnones 5a and 56.

+

1155 (s), 1037 (s) cm⁻¹; HRMS m/z [MH] calcd for C₁₀H₉F₃NO₂

232.0585, found 232.0591.

Synthesis of (Z)-Methyl 3,3,3-Triﬂuoro-2-(para-methoxy-

phenylimino)propanoate 2b.³⁵To a stirring solution of methyl

triﬂuoropyruvate (2.84 g, 16.02 mmol) in toluene (25 mL) was added

solid triphenylphosphine (p-methoxyphenyl)imide 1b (6.14 g, 18.17

mmol) in one portion. The mixture was stirred for 2 h before the

volatiles were removed in vacuo. The crude material was suspended in

petroleum ether, ﬁltered, and washed with more petroleum ether

before the volatiles were removed in vacuo. This procedure was

repeated until the precipitation of triphenylphosphine oxide had

ceased to yield (Z)-methyl 3,3,3-triﬂuoro-2-(p-methoxyphenylimino)-

propanoate 2b as an orange oil (3.77 g, 96%).

Note: Compound 1b could alternatively be puriﬁed by ﬂash

chromatography on silica gel (eluting with 10% EtOAc in petroleum

ether): ¹H NMR (400 MHz, CDCl₃) δ 7.03 (d, J = 9.0 Hz, 2H), 6.92

(d, J = 9.0 Hz, 2H), 3.83 (s, 3H), 3.79 (s, 3H); ¹³C NMR (100.6 MHz,

CDCl₃) δ 160.9, 159.6, 146.1 (q, J = 37.0 Hz), 138.9, 122.4, 118.4 (q, J

= 278.0 Hz), 114.5, 55.4, 52.9; ¹⁹F NMR (376.5 MHz, CDCl₃) δ

−69.6; FTIR 3462 (br), 2967 (w), 2845 (w), 1748 (s), 1508 (s), 1256

(s), 1162 (s), 1035 (s), 844 (m) cm⁻¹; HRMS m/ z [MH]⁺calcd for

C₁₁H₁₁F₃NO₃262.0691, found 262.0680.

CONCLUSION

■

In conclusion, we have demonstrated that 4-triﬂuoromethyl-

sydnones can be prepared by ring synthesis and ring

functionalization approaches. These compounds function as

valuable precursors to 5-triﬂuoromethylpyrazoles via highly

regioselective cycloaddition reactions, although the N-Bn

sydnone 5e delivers an unexpected alkyne insertion reaction

to provide both 5- and 3-CF₃pyrazoles. The CF₃-pyrazole

boronic esters can be further fucntionalized through established

and widely utilized organoboron chemistry, demonstrated by

the synthesis of key intermediates for biologically active

compounds. This chemistry has been extended toward the

synthesis of 4-ﬂuoromethyl- and 4-diﬂuoromethylsydnones.

While there are inherent stability issues regarding the 4-

ﬂuoromethyl compounds, 4-diﬂuoromethyl-N-phenylsydnone

56 proved to be a valuable precursor for the preparation of a

range of 5-diﬂuoromethylpyrazoles.

EXPERIMENTAL SECTION

Synthesis of Methyl 3,3,3-Triﬂuoro-2-(phenylamino)-

propanoate 3a.³⁶To a stirring suspension of zinc dust (8.26 g,

126.31 mmol) in AcOH (75 mL) was added (Z)-methyl 3,3,3-

triﬂuoro-2-(phenylimino)propanoate 2a (14.60 g, 63.16 mmol). The

mixture was stirred at ambient temperature for 2 h, ﬁltered, and

neutralized with NaHCO₃. The solution was extracted with EtOAc (3

× 50 mL), washed with water (25 mL), and dried over MgSO₄before

the volatiles were removed to yield methyl 3,3,3-triﬂuoro-2-

■

Synthesis of Triphenylphosphine Phenylimide 1a. To a

stirring solution of azidobenzene (15.86 g, 133.12 mmol) in ether (200

mL) was slowly added a solution of triphenylphosphine (34.92 g,

133.12 mmol) in ether (200 mL). The mixture was stirred for 2 h, and

then the volatiles were removed in vacuo. The crude material was

puriﬁed by recrystallization from ethanol to yield tetraphenylphos-

phine imide 1a as a yellow solid (37.25 g, 79%): mp 134 − 135 °C

1

(lit.³³mp 135−136 °C); H NMR (400 MHz, CDCl₃) δ 7.82−7.76

1

(phenylamino)propanoate 3a as a colorless oil (11.49 g, 78%): H

NMR (400 MHz, CDCl₃) δ 7.29−7.25 (m, 2H), 6.92−6.98 (m, 1H),

6.77−6.75 (m, 2H), 4.70−4.59 (m, 2H), 3.89 (s, 3H); ¹³C NMR

(100.6 MHz, CDCl₃) δ 166.8, 145.1, 129.5, 123.3 (q, J = 283.5), 120.1,

114.2, 59.6 (q, J = 31.5 Hz), 53.6; ¹⁹F NMR (376.5 MHz, CDCl₃) δ

−72.7 (d, J = 6.0 Hz); FTIR 3391 (br), 3038 (w), 2965 (w), 2853 (w),

1756 (s), 1606 (s), 1514 (s), 1441 (m), 1304 (s), 1218 (s), 1183 (s)

(m, 6H), 7.57−7.53 (m, 3H), 7.50−7.45 (m, 6H), 7.07−7.01 (m, 2H),

6.85−6.81 (m, 2H), 6.71−6.65 (m, 1H); ¹³C NMR (100.6 MHz,

CDCl₃) δ 151.1 (d, J = 2.5 Hz), 132.6 (d, J = 9.5 Hz), 131.7 (d, J = 2.5

Hz), 131.4 (d, J = 99.0 Hz), 128.7 (d, J = 12.0 Hz), 128.6, 123.5 (d, J =

17.5 Hz), 117.3; ³¹P NMR (101.1 MHz, CDCl₃) δ 2.89; HRMS m/z

[MH]⁺calcd for C₂₄H₂₁NP 354.1412, found 354.1411.

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cm⁻¹; HRMS m/z [MH]⁺calcd for C₁₀H₁₁F₃NO₂234.0742, found

234.0744.

Note: Compound 5a could alternatively be puriﬁed by ﬂash

chromatography on silica gel (eluting with 20% EtOAc in petroleum

1

ether): mp 112−114 °C; H NMR (400 MHz, CDCl₃) δ 7.78 (t, J =

Synthesis of Methyl 3,3,3-Triﬂuoro-2-(p-methoxyphenyl-

amino)propanoate 3b. To a stirring suspension of zinc dust (1.82

g, 27.81 mmol) in AcOH (15 mL) was added (Z)-methyl 3,3,3-

triﬂuoro-2-(p-methoxyphenylimino)propanoate 2b (3.63 g, 13.91

mmol). The mixture was stirred at ambient temperature for 2 h,

ﬁltered, and neutralized with NaHCO₃. The solution was extracted

with EtOAc (3 × 25 mL), washed with water (25 mL), and dried over

MgSO₄before the volatiles were removed in vacuo to yield methyl

3,3,3-triﬂuoro-2-(p-methoxyphenylamino)propanoate 3b as a yellow

oil (2.45 g, 67%): ¹H NMR (400 MHz, CDCl₃) δ 6.83 (d, J = 9.0 Hz,

2H), 6.73 (d, J = 9.0 Hz, 2H), 4.57−4.50 (quint, J = 7.0 Hz, 1H), 4.39

(d, J = 7.5 Hz, 1H), 3.85 (s, 3H), 3.77 (s, 3H); ¹³C NMR (100.6 MHz,

CDCl₃) δ 167.1, 154.0, 139.0, 123.4 (q, J = 283.0), 116.2, 115.0, 61.0

(q, J = 31.0 Hz), 55.6, 53.5; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −72.7

(d, J = 6.5 Hz); FTIR 3374 (br), 2955 (w), 3836 (w), 1758 (s), 1519

(s), 1245 (s), 1126 (s), 1032 (m), 823 (m) cm⁻¹; HRMS m/z [MH]⁺

calcd for C₁₁H₁₃F₃NO₃264.0848, found 264.0853.

7.5 Hz, 1H), 7.69 (t, J = 7.5 Hz, 2H), 7.62 (d, J = 7.5 Hz, 2H); ¹³C

NMR (100.6 MHz, CDCl₃) δ 163.2, 133.5, 133.3, 130.2, 124.6, 119.3

(q, J = 268.0 Hz), 98.1 (q, J = 41.0 Hz); ¹⁹F NMR (376.5 MHz,

CDCl₃) δ −56.3; FTIR 1791 (s), 1479 (m), 1330 (m), 1215 (m),

1120 (s), 1024 (m) cm⁻¹; HRMS m/z [MH]⁺calcd for C₉H₆F₃N₂O ₂

231.0381, found 231.0389.

Synthesis of 4-Triﬂuoromethyl-N-(p-methoxyphenyl)-

sydnone 5b. To a stirring solution of 3,3,3-triﬂuoro-2-(p-

methoxyphenylamino)propanoic acid 4b (4.75 g, 19.08 mmol) in

dimethyoxyethane (20 mL) was added isoamyl nitrite (2.81 mL, 20.99

mmol). The reaction was stirred for 3 h and then concentrated in

vacuo to yield an oil that was triturated with petroleum ether, ﬁltered,

and dried in vacuo to be used without further puriﬁcation.

(CAUTION: this nitrosamine intermediate is a suspected carcinogen.)

To a stirring suspension of the solid in DCM (20 mL) was added

triﬂuoroacetic anhydride (5.30 mL, 38.16 mmol) at 0 °C. The reaction

was warmed to ambient temperature and stirred for 1 h, then

approximately 10 mL of water was added and the mixture was

neutralized with NaHCO₃. The organic layer was extracted with DCM

(3 × 25 mL) and dried over MgSO₄before the volatiles were removed

in vacuo. The crude material was puriﬁed by recrystallization from

ethanol to yield 4-triﬂuoromethyl-N-(p-methoxyphenyl)sydnone 5b as

a tan solid (2.78 g, 56%).

Note: Compound 5b could alternatively be puriﬁed by ﬂash

chromatography on silica gel (eluting with 20% EtOAc in petroleum

ether): mp 65−66 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.54 (d, J = 9.0

Hz, 2H), 7.12 (d, J = 9.0 Hz, 2H), 3.94 (s, 3H); ¹³C NMR (100.6

MHz, CDCl₃) δ 163.2, 163.1, 125.9, 119.5 (q, J = 264.0 Hz), 115.5,

115.2, 98.0 (q, J = 43.0 Hz), 55.9; ¹⁹F NMR (376.5 MHz, CDCl₃) δ

−56.4; FTIR 2948 (w), 1790 (s), 1512 (m), 1476 (m), 1205 (m),

1124 (s), 1018 (s), 979 (m), 837 (m) cm⁻¹; HRMS m/ z [MH]⁺calcd

for C₁₀H₈F₃N₂O₃261.0487, found 261.0481.

General Procedure 1: Triﬂuoromethylation of Iodosydnones

(See Scheme 4). To a stirring suspension of the iodosydnone (1

equiv) and CuI (1 equiv) in DMF (0.2 M) was added methyl

ﬂuorosulfonyldiﬂuoroacetate (5 equiv) under a nitrogen atmosphere,

and the mixture was heated at 80 °C for the designated time. The

reaction was ﬁltered, brine was added to the ﬁltrate, and the solution

was extracted with EtOAc. The organic fractions were subsequently

washed with brine and dried over MgSO₄before the volatiles were

removed in vacuo. The crude material was puriﬁed by ﬂash

chromatography on silica gel (eluting with 20% EtOAc in petroleum

ether, unless otherwise stated) to yield the title sydnones.

4-Triﬂuoromethyl-N-phenylsydnone 5a. Following general

procedure 1 using 4-iodo-N-phenylsydnone 7a (1.44 g, 5.00 mmol),

CuI (920 mg, 5.00 mmol), and methyl ﬂuorosulfonyldiﬂuoroacetate

(4.80 g, 25.00 mmol) in DMF (25 mL), stirring for 20 h, 4-

triﬂuoromethyl-N-phenylsydnone 5a was isolated as a tan solid (906

mg, 79%).

Synthesis of 3,3,3-Triﬂuoro-2-(phenylamino)propanoic Acid

4a. To a stirring solution of methyl 3,3,3-triﬂuoro-2-(phenylamino)-

propanoate 3a (3.33 g, 14.28 mmol) in EtOAc (60 mL), shielded from

light, was added lithium iodide (9.56 g, 71.40 mmol). The reaction was

heated at reﬂux for 4 h and then cooled before water (25 mL) was

added and the mixture was acidiﬁed with 1 M HCl_(aq)to ∼pH 3. The

solution was extracted with EtOAc (3 × 25 mL), washed with water

(25 mL), and dried over MgSO₄before the volatiles were removed in

vacuo to yield 3,3,3-triﬂuoro-2-(phenylamino)propanoic acid 4a as a

1

brown solid (2.72 g, 85%): mp 101−103 °C; H NMR (400 MHz,

CDCl₃) δ 7.29−7.25 (m, 2H), 6.92−6.90 (m, 1H), 6.77−6.75 (m,

2H), 4.70 (q, J = 7.0 Hz, 1H); ¹³C NMR (100.6 MHz, CDCl₃) δ

170.6, 144.7, 129.6, 123.1 (q, J = 283.5 Hz), 120.5, 114.3, 59.6 (q, J =

32.0 Hz); ¹⁹F NMR (376.5 MHz, CDCl₃) δ −72.4 (d, J = 7.0 Hz);

FTIR 2994 (w), 1624 (m), 1520 (m), 1260 (s), 1181 (s), 1145 (s),

1031 (m), 778 (m), 658 (m) cm⁻¹HRMS m/z [MH]⁺calcd for

C₉H₉F₃NO₂220.0585, found 220.0587.

Synthesis of 3,3,3-Triﬂuoro-2-(p-methoxyphenylamino)-

propanoic Acid 4b. To a stirring solution of methyl 3,3,3-

triﬂuoro-2-(p-methoxyphenylamino)propanoate 3b (8.02 g, 30.47

mmol) in EtOAc (100 mL), shielded from light, was added lithium

iodide (16.31 g, 121.88 mmol). The reaction was heated at reﬂux for 4

h and then cooled before water (25 mL) was added and the mixture

was acidiﬁed with 1 M HCl_(aq)to ∼pH 3. The solution was extracted

with EtOAc (3 × 25 mL), washed with water (25 mL), and dried over

MgSO₄before the volatiles were removed in vacuo to yield 3,3,3-

triﬂuoro-2-(p-methoxyphenylamino)propanoic acid 4b as a brown

solid (5.76 g, 76%): mp 120−123 °C; ¹H NMR (400 MHz, CDCl₃) δ

6.84 (d, J = 9.0 Hz, 2H), 6.74 (d, J = 9.0 Hz, 2H), 6.52 (br, 1H), 4.56

(q, J = 7.0 Hz, 1H), 3.78 (s, 3H); ¹³C NMR (100.6 MHz, CDCl₃) δ

170.2, 154.2, 138.6, 122.5 (q, J = 283.5 Hz), 116.4, 115.1, 61.0 (q, J =

31.5 Hz), 55.7; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −72.5 (d, J = 7.0

Hz); HRMS m/z [MH]⁺calcd for C₁₀H₁₀F₃NO₃249.1865, found

249.1869.

Synthesis of 4-Triﬂuoromethyl-N-phenylsydnone 5a. To a

stirring solution of 3,3,3-triﬂuoro-2-(phenylamino)propanoic acid 4a

(3.20 g, 14.60 mmol) in dimethyoxyethane (15 mL) was added

isoamyl nitrite (2.16 mL, 16.06 mmol). The reaction was stirred for 5

h and then concentrated in vacuo to yield an oil that was triturated

with petroleum ether, ﬁltered, and dried in vacuo to be used without

further puriﬁcation. (CAUTION: this nitrosamine intermediate is a

suspected carcinogen). To a stirring suspension of the solid in DCM

(15 mL) was added triﬂuoroacetic anhydride (4.06 mL, 29.20 mmol)

at 0 °C. The reaction was warmed to ambient temperature and stirred

for 1 h, and then approximately 10 mL of water was added and the

mixture was neutralized with NaHCO₃. The organic layer was

extracted with DCM (3 × 25 mL) and dried over MgSO₄before

the volatiles were removed in vacuo. The crude material was puriﬁed

by recrystallization from ethanol to yield 4-triﬂuoromethyl-N-phenyl-

sydnone 5a as a tan solid (2.31 g, 69%).

4-Triﬂuoromethyl-N-(p-methoxyphenyl)sydnone 5b. Follow-

ing general procedure 1 using 4-iodo-N-(para-methoxyphenyl)-

sydnone 7b (1.59 g, 5.0 mmol), CuI (952 mg, 5.0 mmol), and

methyl ﬂuorosulfonyldiﬂuoroacetate (4.80 g, 25.00 mmol) in DMF

(25 mL), stirring for 20 h, 4-triﬂuoromethyl-N-(p-methoxyphenyl)-

sydnone 5b was isolated as a tan solid (1.04 g, 80%).

4-Triﬂuoromethyl-N-(p-nitrophenyl)sydnone 5c. Following

general procedure 1 using 4-iodo-N-(p-nitrophenyl)sydnone 7c

(1.33 g, 4.00 mmol), CuI (762 mg, 4.00 mmol), and methyl

ﬂuorosulfonyldiﬂuoroacetate (3.84 g, 20 mmol) in DMF (20 mL),

stirring for 40 h, 4-triﬂuoromethyl-N-(p-nitrophenyl)sydnone 5c was

1

isolated as a yellow solid (605 mg, 55%): mp 110−111 °C; H NMR

(400 MHz, CDCl₃) δ 8.58 (d, J = 9.0 Hz, 1H), 7.92 (d, J = 9.0 Hz,

2H); ¹³C NMR (100.6 MHz, CDCl₃) δ 162.5, 150.5, 137.7, 126.4,

125.7, 120.5 (q, J = 268.0 Hz), 98.4 (q, J = 43.0 Hz); ¹⁹F NMR (376.5

MHz, CDCl₃) δ −56.0; FTIR 3125 (w), 1780 (s), 1531 (s), 1349 (s),

1210 (s), 1119 (s), 1028 (s), 851 (s), 764 (m) cm⁻¹; HRMS m/ z

[EI]⁺calcd for C₉H₄F N₃O₄275.0154, found 275.0165.

3

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4-Triﬂuoromethyl-N-methylsydnone 5d. Following general

procedure 1 using 4-iodo-N-methylsydnone 7d (1.13 g, 5.00 mmol),

CuI (952 mg, 5.00 mmol), and methyl ﬂuorosulfonyldiﬂuoroacetate

(4.80 g, 25.00 mmol) in DMF (25 mL), stirring for 20 h, 4-

triﬂuoromethyl-N-methylsydnone 5d was isolated as a colorless oil

idine (103 mg, 1.0 mmol), heating for 24 h, 2-(1-phenyl-5-

triﬂuoromethyl-1H-pyrazol-3-yl)pyridine 11a was isolated as a yellow

oil (121 mg, 84%): ¹H NMR (400 MHz, CDCl₃) δ 8.68 (ddd, J = 1.0,

5.0, 7.5 Hz, 1H), 8.07 (td, J = 1.0, 8.0 Hz, 1H), 7.76 (td, J = 2.0, 7.5

Hz, 1H), 7.59−7.51 (m, 6H), 7.28 (ddd, J = 1.0, 5.0, 7.5 Hz, 1H); ¹³C

NMR (100.6 MHz, CDCl₃) δ 152.0, 150.8, 149.6, 139.2, 136.7, 134.2

(q, J = 39.5 Hz), 129.4, 129.1, 125.8, 123.3, 120.2, 119.7 (q, J = 269.0

Hz), 107.7 (br); ¹⁹F NMR (376.5 MHz, CDCl₃) δ −57.7; FTIR 3076

(w), 1599 (w), 1499 (m), 1415 (m), 1282 (m), 1232 (s), 1136 (s),

994 (m), 732 (s), 694 (s) cm⁻¹; HRMS m/ z [MH]⁺calcd for

C₁₅H₁₁F₃N₃290.0905, found 290.0909.

1

(605 mg, 72%): H NMR (400 MHz, CDCl₃) δ 4.23 (s, 3H); ¹³C

NMR (100.6 MHz, CDCl₃) δ 163.2, 119.7 (q, J = 267.5 Hz), 96.9 (q, J

= 44.0 Hz), 40.2; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −58.3; FTIR 3051

(w), 1774 (s), 1516 (m), 1353 (m), 1196 (s), 1126 (s), 1004 (s), 743

+

(m), 600 (m) cm⁻¹; HRMS m/z [EI] calcd for C₄H₄F₃N₂O₂

169.0225, found 169.0228.

4-Triﬂuoromethyl-N-benzylsydnone 5e. Following general

procedure 1 using 4-iodo-N-benzylsydnone 7e (1.51 g, 5.00 mmol),

CuI (952 mg, 5.00 mmol), and methyl ﬂuorosulfonyldiﬂuoroacetate

(4.80 g, 25.00 mmol) in DMF (25 mL), stirring for 20 h, 4-

triﬂuoromethyl-N-benzylsydnone 5e was isolated as a yellow solid

(580 mg, 48%): mp 50−51 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.46−

7.44 (m, 3H), 7.39−7.38 (m, 2H), 5.61 (s, 2H, CH₂); ¹³C NMR

(100.6 MHz, CDCl₃) δ 163.4, 130.3, 129.4, 129.3, 128.5, 119.6 (q, J =

267.5 Hz), 96.2 (q, J = 43.5 Hz), 58.1; ¹⁹F NMR (376.5 MHz, CDCl₃)

δ −57.2; FTIR 2919 (w), 1768 (s), 1513 (m), 1383 (m), 1173 (m),

1114 (s), 1021 (s), 729 (m), 695 (s) cm⁻¹; HRMS m/z [EI]⁺calcd for

C₁₀H₇F₃N₂O₂244.0460, found 244.0459.

Synthesis of 1-Phenyl-3-(cyclohex-1-enyl)-5-triﬂuorometh-

yl-1H-pyrazole 12a. Following general procedure 2 using 4-

triﬂuoromethyl-N-phenylsydnone 5a (115 mg, 0.5 mmol) and 2-

ethynylcyclohexene (106 mg, 1.0 mmol), heating for 24 h, 1-phenyl-3-

(cyclohex-1-enyl)-5-triﬂuoromethyl-1H-pyrazole 12a was isolated as a

1

yellow solid (130 mg, 89%): mp 55−57 °C; H NMR (400 MHz,

CDCl₃) δ 7.53−7.46 (m, 5H), 6.86 (s, 1H), 6.45−6.43 (m, 1H),

2.53−2.50 (m, 2H), 2.27−2.22 (m, 2H), 1.83−1.77 (m, 2H), 1.74−

1.68 (m, 2H); ¹³C NMR (100.6 MHz, CDCl₃) δ 153.6, 139.4, 133.1

(q, J = 42.5 Hz), 129.6, 129.0 (2), 126.5, 127.0, 119.9 (q, J = 269.0

Hz), 105.0 (br), 25.8, 25.5, 22.5, 22.2; ¹⁹F NMR (376.5 MHz, CDCl₃)

δ −57.6; FTIR 3063 (w), 2939 (m), 2860 (w), 1600 (m), 1505 (s),

1450 (m), 1288 (m), 1231 (s), 1139 (s), 989 (m), 817 (w), 771 (m),

697 (m) cm⁻¹; HRMS m/ z [MH]⁺calcd for C₁₆H₁₆F₃N₂293.1266,

found 293.1267.

General Procedure 2: Cycloaddition Reactions of 4-

Triﬂuoromethylsydnones and Alkynes (See Table 1). A solution

of a 4-triﬂuoromethylsydnone (1 equiv) and an alkyne (2 equiv) in o-

DCB (0.5 M) in a sealed microwave vessel was heated at 180 °C for

the designated length of time. After cooling, the crude materials were

puriﬁed by ﬂash chromatography on silica gel (eluting with 5% EtOAc

in petroleum ether, unless otherwise stated) to yield the title pyrazoles.

Synthesis of 1,3-Diphenyl-5-triﬂuoromethyl-1H-pyrazole 8a.

Following general procedure 2 using 4-triﬂuoromethyl-N-phenyl-

sydnone 5a (115 mg, 0.5 mmol) and ethynylbenzene (102 mg, 1.0

mmol), heating for 24 h, 1,3-diphenyl-5-triﬂuoromethyl-1H-pyrazole

8a was isolated as a colorless solid (125 mg, 87%): mp 50−53 °C (lit.⁹

Synthesis of 1-Phenyl-3-cyclopropyl-5-triﬂuoromethyl-1H-

pyrazole 13a. Following general procedure 2 using 4-triﬂuoromethyl-

N-phenylsydnone 5a (115 mg, 0.5 mmol) and ethynylcyclopropane

(66 mg, 1.0 mmol), heating for 24 h, 1-phenyl-3-cyclopropyl −5-

triﬂuoromethyl-1H-pyrazole 13a was isolated as a yellow oil (111 mg,

1

88%): H NMR (400 MHz, CDCl₃) δ 7.50−7.46 (m, 5H), 6.50 (s,

1H), 2.03 (tt, J = 5.0, 8.5 Hz, 1H), 1.03−0.99 (m, 2H), 0.87−0.82 (m,

2H); ¹³C NMR (100.6 MHz, CDCl₃) δ 155.5, 139.3, 132.9 (q, J = 39.0

Hz), 129.0, 128.9, 125.6, 119.8 (q, J = 269.0 Hz), 105.6 (br), 8.9, 8.2;

¹⁹F NMR (376.5 MHz, CDCl₃) δ −57.6; FTIR 3060 (w), 2936 (m),

1

mp 50−52 °C); H NMR (400 MHz, CDCl₃) δ 7.92−7.90 (m, 2H),

7.62−7.39 (m, 8H), 7.16 (s, 1H); ¹³C NMR (100.6 MHz, CDCl₃) δ

151.7, 139.2, 134.0 (q, J = 39.0 Hz), 131.8, 129.3, 129.2, 128.8, 128.7,

125.9, 125.8, 119.8 (q, J = 269.0 Hz), 106.1 (br); ¹⁹F NMR (376.5

MHz, CDCl₃) δ −57.6; FTIR 3073 (w), 1600 (w), 1505 (m), 1447

(m), 1288 (m), 1237 (s), 1167 (s), 989 (m), 770 (s), 693 (s) cm⁻¹;

HRMS m/ z [MH]⁺calcd for C₁₆H₁₂F₃N₂289.0953, found 289.0943.

Synthesis of 1-Phenyl-3-n-butyl-5-triﬂuoromethyl-1H-pyra-

zole 9a.¹⁰Following general procedure 2 using 4-triﬂuoromethyl-N-

phenylsydnone 5a (115 mg, 0.5 mmol) and 1-hexyne (82 mg, 1.0

mmol), heating for 24 h, 1-phenyl-3-n-butyl-5-triﬂuoromethyl-1H-

pyrazole 9a was isolated as a yellow oil (105 mg, 78%): ¹H NMR (400

MHz, CDCl₃) δ 7.49−7.44 (m, 5H), 6.64 (s, 1H), 2.73 (t, J = 7.5 Hz,

2H), 1.76−1.68 (m, 2H), 1.50−1.41 (m, 2H), 0.98 (m, 3H); ¹³C

NMR (100.6 MHz, CDCl₃) δ 153.8, 139.3, 132.9 (q, J = 39.0 Hz),

129.0, 128.9, 125.6, 119.7 (q, J = 269.0 Hz), 107.7 (br), 31.5, 27.7,

22.4, 13.8; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −57.5; FTIR 3060 (w),

2968 (m), 2939 (m), 2862 (w), 1600 (m), 1505 (s), 1470 (m), 1390

(w), 1295 (m), 1186 (s), 1129 (s), 989 (m), 763 (m), 693 (m) cm⁻¹;

HRMS m/z [MH]⁺calcd for C₁₄H₁₆F₃N₂269.1269, found 269.1266.

Synthesis of 1-Phenyl-3-trimethylsilyl-5-triﬂuoromethyl-1H-

pyrazole 10a. Following general procedure 2 using 4-triﬂuoromethyl-

N-phenylsydnone 5a (115 mg, 0.5 mmol) and ethynyltrimethylsilane

(98 mg, 1.0 mmol), heating for 24 h, 1-phenyl-3-trimethylsilyl-5-

triﬂuoromethyl-1H-pyrazole 10a was isolated as a colorless oil (106

2856 (w), 1603 (w), 1508 (m), 1288 (m), 1234 (m), 1177 (m), 1136

(s), 989 (m), 771 (m), 690 (m) cm⁻¹; HRMS m/z [MH]⁺calcd for

C₁₃H₁₂F₃N₂253.0953, found 253.0957.

Synthesis of 3-(Benzyloxymethyl)-1-phenyl-5-triﬂuorometh-

yl-1H-pyrazole 14a. Following general procedure 2 using 4-

triﬂuoromethyl-N-phenylsydnone 5a (115 mg, 0.5 mmol) and benzyl

2-propynyl ether (146 mg, 1.0 mmol), heating for 24 h, 3-

(benzyloxymethyl)-1-phenyl-5-triﬂuoromethyl-1H-pyrazole 14a was

isolated as a yellow oil (139 mg, 84%): ¹H NMR (400 MHz,

CDCl₃) δ 7.54−7.39 (m, 10H), 6.93 (s, 1H), 4.69 (s, 2H), 4.69 (s,

2H); ¹³C NMR (100.6 MHz, CDCl₃) δ 150.3, 139.1, 137.9, 133.6 (q, J

= 39.0 Hz), 129.3, 129.1, 128.5, 128.0, 127.8, 125.7, 119.8 (q, J = 269.0

Hz), 108.4 (br), 72.8, 65.5; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −57.6;

FTIR 3069 (w), 3034 (w), 2870 (m), 1732 (w), 1507 (s), 1299 (s),

1188 (s), 1084 (s), 992 (m), 736 (m), 701 (s) cm⁻¹; HRMS m/z

+

[MH] calcd for C₁₈H₁₆F₃N₂O₂333.1215, found 333.1228.

Synthesis of 1-Phenyl-3-(3-chloro)propyl-5-triﬂuoromethyl-

1H-pyrazole 15a. Following general procedure 2 using 4-

triﬂuoromethyl-N-phenylsydnone 5a (115 mg, 0.5 mmol) and 5-

chloro-1-pentyne (103 mg, 1.0 mmol), heating for 24 h, 1-phenyl-3-(3-

chloro)propyl-5-triﬂuoromethyl-1H-pyrazole 15a was isolated as a

1

yellow oil (101 mg, 70%): H NMR (400 MHz, CDCl₃) δ 7.49 (m,

5H), 6.67 (s, 1H), 3.65 (t, J = 6.5 Hz, 2H), 2.91 (t, J = 7.0 Hz, 2H),

2.25−2.18 (m, 2H); ¹³C NMR (100.6 MHz, CDCl₃) δ 151.8, 139.2,

133.1 (q, J = 39.5 Hz), 129.1, 129.0, 125.6, 119.8 (q, J = 269.0 Hz),

107.9 (br), 44.2, 31.9, 25.2; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −57.5;

FTIR 3063 (w), 2958 (w), 2869 (w), 1600 (m), 1508 (s), 1470 (m),

1295 (m), 1183 (s), 1136 (s), 989 (m), 817 (w), 767 (m), 690 (m)

cm⁻¹; HRMS m/z [MH]⁺calcd for C₁₃H₁₃ClF₃N₂289.0719, found

289.0708.

Synthesis of 1,4-Diphenyl-4-n-butyl-5-triﬂuoromethyl-1H-

pyrazole 16a and 1,3-Diphenyl-3-n-butyl-5-triﬂuoromethyl-

1H-pyrazole 16b. Following general procedure 2 using 4-

triﬂuoromethyl-N-phenylsydnone 5a (115 mg, 0.5 mmol) and 1-

1

mg, 75%): H NMR (400 MHz, CDCl₃) δ 7.52−7.48 (m, 5H), 6.92

(s, 1H), 0.38 (s, 9H); ¹³C NMR (100.6 MHz, CDCl₃) δ 153.9, 139.4,

132.9 (q, J = 39.0 Hz), 129.1, 129.0, 125.8, 120.4 (q, J = 269.0 Hz),

114.8 (br), −1.2; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −57.1; FTIR 3088

(w), 2960 (m), 1604 (m), 1504 (m), 1283 (m), 1171 (s), 975 (m),

850 (s), 761 (m), 689 (m) cm⁻¹; HRMS m/ z [MH]⁺calcd for

C₁₃H₁₆F₃N₂Si 285.1035, found 285.1047.

Synthesis of 2-(1-Phenyl-5-triﬂuoromethyl-1H-pyrazol-3-yl)-

pyridine 11a.¹¹Following general procedure 2 using 4-triﬂuor-

omethyl-N-phenylsydnone 5a (115 mg, 0.5 mmol) and 2-ethynylpyr-

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phenyl-1-hexyne (158 mg, 1.0 mmol), heating for 24 h, 1,4-diphenyl-4-

n-butyl-5-triﬂuoromethyl-1H-pyrazole 16a and 1,3-diphenyl-3-n-butyl-

5-triﬂuoromethyl-1H-pyrazole 16b were isolated as an inseparable

Synthesis of 1-(p-Methoxyphenyl)-3-n-butyl-5-triﬂuoro-

methyl-1H-pyrazole 20a. Following general procedure 2 using 4-

triﬂuoromethyl-N-(p-methoxyphenyl)sydnone 5b (130 mg, 0.5 mmol)

and 1-hexyne (82 mg, 1.0 mmol), heating for 24 h, 1-(p-

methoxyphenyl)-3-n-butyl-5-triﬂuoromethyl-1H-pyrazole 20a was iso-

1

mixture (48:52, 16a/16b) as a yellow solid (103 mg, 62%): H NMR

(400 MHz, CDCl₃) δ 7.68−7.66 (m, 1H), 7.58−7.42 (m, 8H), 7.39−

7.37 (m, 1H), 2.78 (t, J = 7.5 Hz, 0.96H), 2.64 (t, J = 7.5 Hz, 1.04H),

1.67−1.57 (m, 2H), 1.46−1.29 (m, 2H), 0.95 (t, J = 7.5 Hz, 1.44H),

0.87 (t, J = 7.5 Hz, 1.56H); ¹³C NMR (100.6 MHz, CDCl₃) δ 152.5,

151.8, 140.0, 139.9, 132.6, 131.2, 130.0, 129.1, 129.0, 128.9 (2), 128.6,

128.5, 128.2, 127.8, 126.2, 126.0, 123.9, 122.7, 120.8 (q, J = 269.0 Hz),

120.4 (q, J = 269.0 Hz), 33.6, 31.3, 26.0, 23.2, 22.7, 22.5, 13.8, 13.7;

¹⁹F NMR (376.5 MHz, CDCl₃) δ −54.3 (0.52F), −55.5 (0.48F);

FTIR 3061 (w), 2961 (w), 2877 (w), 1594 (w), 1503 (m), 1319 (m),

1174 (s), 1117 (s), 979 (m), 773 (m), 692 (s), 524 (m) cm⁻¹; HRMS

1

lated as a yellow oil (106 mg, 71%): H NMR (400 MHz, CDCl₃) δ

7.39 (d, J = 9.0 Hz, 2H), 6.97 (d, J = 9.0 Hz, 2H), 6.59 (s, 1H), 3.86

(s, 3H), 2.71 (t, J = 7.5 Hz, 2H), 1.74−1.66 (m, 2H), 1.48−1.39 (m,

2H), 0.97 (t, J = 7.5 Hz, 3H); ¹³C NMR (100.6 MHz, CDCl₃) δ 160.0,

153.4, 133.0 (q, J = 38.5 Hz), 132.3, 127.1, 180.6 (q, J = 269.0 Hz),

114.1, 107.1, 55.5, 31.6, 27.7, 22.4, 13.8; ¹⁹F NMR (376.5 MHz,

CDCl₃) δ −57.8; FTIR 2956 (m), 2931 (m), 2860 (w), 1523 (s),

1466 (m), 1250 (s), 1186 (s), 1125 (s), 990 (m), 837 (m) cm⁻¹;

HRMS m/ z [MH]⁺calcd for C₁₅H₁₈F₃N₂O 299.1371, found

299.1375.

+

m/z [MH] calcd for C₂₀H₂₀F₃N₂: 345.1579, found 345.1566 and

Synthesis of 1-(p-Methoxyphenyl)-3-cyclopropyl-5-triﬂuor-

omethyl-1H-pyrazole 21a. Following general procedure 2 using 4-

triﬂuoromethyl-N-(p-methoxyphenyl)sydnone 5b (130 mg, 0.5 mmol)

and ethynylcyclopropane (102 mg, 1.0 mmol), heating for 24 h, 1-

(para-methoxyphenyl)-3-cyclopropyl-5-triﬂuoromethyl-1H-pyrazole

21a was isolated as a yellow oil (106 mg, 75%): ¹H NMR (400 MHz,

CDCl₃) δ 7.38 (d, J = 9.0 Hz, 2H), 6.97 (d, J = 9.0 Hz, 2H), 6.45 (s,

1H), 3.87 (s, 3H), 2.01 (tt, J = 5.0, 8.5 Hz, 1H), 1.02−0.97 (m, 2H),

0.84−0.80 (m, 2H); ¹³C NMR (100.6 MHz, CDCl₃) δ 160.0, 155.1,

133.1 (q, J = 38.5 Hz), 132.2, 127.2, 119.8 (q, J = 269.0 Hz), 114.1,

105.0, 55.5, 8.91, 8.16; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −57.9; FTIR

3090 (w), 3010 (w), 2840 (w), 1519 (s), 1485 (m), 1253 (s), 1177

(s), 1132 (s), 1033 (m), 986 (m), 836 (m) cm⁻¹; HRMS m/z [MH]⁺

calcd for C₁₄H₁₄F₃N₂O 283.1058, found 283.1057.

345.1570.

Synthesis of Methyl 3-Methyl-1-phenyl-5-triﬂuoromethyl-

1H-pyrazole-4-carboxylate 17a and Methyl 4-Methyl-1-phe-

nyl-5-triﬂuoromethyl-1H-pyrazole-3-carboxylate 17b. Follow-

ing general procedure 2 using 4-triﬂuoromethyl-N-phenylsydnone 5a

(115 mg, 0.5 mmol) and methyl-2-butynoate (196 mg, 2.0 mmol),

heating for 24 h, eluting with (10% EtOAc in petroleum ether), 3-

methyl-1-phenyl-5-triﬂuoromethyl-1H-pyrazole-4-carboxylate 17a was

isolated as a yellow solid (217 mg, 76%) and methyl 4-methyl-1-

phenyl-5-triﬂuoromethyl-1H-pyrazole-3-carboxylate 17b was isolated

as a yellow solid (39 mg, 14%).

17a: mp 78−79 °C (lit.¹²mp 81−83 °C); H NMR (400 MHz,

1

CDCl₃) δ 7.50−7.47 (m, 3H), 7.42−7.39 (m, 2H), 3.91 (s, 3H), 2.50

(s, 3H); ¹³C NMR (100.6 MHz, CDCl₃) δ 162.6, 151.6, 139.4, 133.1

(q, J = 39.5 Hz), 129.7, 129.1, 125.8, 119.1 (q, J = 271.5 Hz), 114.1,

52.1, 13.5; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −55.8; FTIR 3048 (w),

2950 (w), 1720 (s), 1553 (m), 1317 (m), 1250 (s), 1170 (s), 1140 (s),

1098 (s), 999 (m), 959 (w), 785 (s) cm⁻¹; HRMS m/ z [MH]⁺calcd

for C₁₃H₁₂F₃N₂O₂285.0851, found 285.0849.

Synthesis of 1-(p-Nitrophenyl)-3-phenyl-5-triﬂuoromethyl-

1H-pyrazole 22a. Following general procedure 2 using 4-

triﬂuoromethyl-N-(p-nitrophenyl)sydnone 5c (138 mg, 0.5 mmol)

and ethynylbenzene (102 mg, 1.0 mmol), heating for 8 h, 1-(p-

nitrophenyl)-3-phenyl-5-triﬂuoromethyl-1H-pyrazole 22a was isolated

as a yellow solid (141 mg, 85%): mp 97−99 °C (lit.⁸mp 102 °C); ¹H

NMR (400 MHz, CDCl₃) δ 8.42 (d, J = 9.0 Hz, 2H), 7.90−7.88 (m,

2H), 7.84 (d, J = 9.0 Hz, 2H), 7.51−7.42 (m, 3H), 7.23 (s, 1H); ¹³C

NMR (100.6 MHz, CDCl₃) δ 152.9, 147.5, 144.0, 134.0 (q, J = 39.5

Hz), 131.0, 129.3, 129.0, 126.0, 125.6, 124.7, 119.6 (q, J = 269.5 Hz),

108.0 (br); ¹⁹F NMR (376.5 MHz, CDCl₃) δ −57.1; FTIR 3100 (w),

1596 (m), 1517 (m), 1346 (s), 1229 (s), 1124 (s), 987 (m), 853 (s),

17b: mp 65−67 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.50−7.47 (m,

3H), 7.44−7.42 (m, 2H), 3.95 (s, 3H), 2.53 (q, J = 2.0 Hz, 3H); ¹³C

NMR (100.6 MHz, CDCl₃) δ 162.4, 141.9, 139.2, 131.1 (q, J = 37.5

Hz), 129.9, 129.1, 126.3, 124.2, 120.1, (q, J = 270.5 Hz), 52.1, 8.9; ¹⁹F

NMR (376.5 MHz, CDCl₃) δ −55.9; FTIR 3059 (w), 2959 (w), 1719

(s), 1501 (m), 1230 (s), 1187 (s), 1118 (s), 1043 (s), 980 (m), 776

(m) cm⁻¹; HRMS m/z [MH]⁺calcd for C₁₃H₁₂F₃N₂O₂285.0851,

found 285.0846.

Synthesis of 1,3,4-Triphenyl-5-triﬂuoromethyl-1H-pyrazole

18. Following general procedure 2 using 4-triﬂuoromethyl-N-phenyl-

sydnone 5a (115 mg, 0.5 mmol) and 1,2-diphenylethyne (178 mg, 1.0

mmol), heating for 24 h, 1,3,4-triphenyl-5-triﬂuoromethyl-1H-pyrazole

18 was isolated as an oﬀ-white solid (97 mg, 53%): mp 139−140 °C.

¹H NMR (400 MHz, CDCl₃) δ 7.65−7.63 (m, 2H), 7.58−7.53 (m,

+

774 (s), 690 (s) cm⁻¹; HRMS m/z [MH] calcd for C₁₆H₁₁F₃N₃O₂

334.0803, found 334.0802.

Synthesis of 1-(p-Nitrophenyl)-3-(3-chloro)propyl-5-triﬂuor-

omethyl-1H-pyrazole 23a. Following general procedure 2 using 4-

triﬂuoromethyl-N-(p-nitrophenyl)sydnone 5c (138 mg, 0.5 mmol)

and 5-chloro-1-pentyne (103 mg, 1.0 mmol), heating for 8 h, 1-(p-

nitrophenyl)-3-(3-chloro)propyl-5-triﬂuoromethyl-1H-pyrazole 23a

1

was isolated as a yellow solid (114 mg, 68%): mp 50−51 °C; H

3H), 7.46−7.42 (m, 5H), 7.38−7.35 (m, 2H), 7.28−7.26 (m, 3H); ¹³C

NMR (100.6 MHz, CDCl₃) δ 150.4, 139.8, 131.7, 131.1, 130.4 (q, J =

36.5 Hz), 129.3, 129.1, 128.4, 128.3, 128.2, 128.0, 126.1, 122.3, 120.1

(q, J = 271.0 Hz), unable to unequivocally assign 2 × CH signals; ¹⁹F

NMR (376.5 MHz, CDCl₃) δ −54.3; FTIR 1504 (m), 1443 (m), 1224

(m), 1171 (s), 1121 (s), 976 (m), 777 (m), 689 (s), 547 (m) cm⁻¹;

HRMS m/z [MH]⁺calcd for C₂₂H₁₆F ₃N₂365.1266, found 365.1257.

Synthesis of 1-(p-Methoxyphenyl)-3-phenyl-5-triﬂuoro-

methyl-1H-pyrazole 19a. Following general procedure 2 using 4-

triﬂuoromethyl-N-(p-methoxyphenyl)sydnone 5b (130 mg, 0.5 mmol)

and ethynylbenzene (102 mg, 1.0 mmol), heating for 24 h, 1-(p-

methoxyphenyl)-3-phenyl-5-triﬂuoromethyl-1H-pyrazole 19a was iso-

lated as a yellow solid (135 mg, 85%): mp 89−90 °C; ¹H NMR (400

MHz, CDCl₃) δ 7.91−7.87 (d, J = 9.0 Hz, 2H), 7.51−7.39 (m, 5H),

7.11 (s, 1H), 7.06−7.01 (d, J = 9.0 Hz, 2H), 3.89 (s, 3H); ¹³C NMR

(100.6 MHz, CDCl₃) δ 160.2, 151.4, 134.0 (q, J = 39.0 Hz), 132.2,

131.9, 128.8, 128.6, 127.3, 125.9, 119.9 (q, J = 269.0 Hz), 114.3, 105.6,

55.6; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −57.9; FTIR 3066 (w), 1512

(m), 1236 (m), 1166 (s), 1124 (s), 1028 (m), 986 (m), 838 (m)

NMR (400 MHz, CDCl₃) δ 8.38 (d, J = 9.0 Hz, 2H), 7.74 (d, J = 9.0

Hz, 2H), 6.77 (s, 1H), 3.66 (t, J = 6.5 Hz, 2H), 2.93 (t, J = 7.5 Hz,

2H), 2.26−2.19 (m, 2H); ¹³C NMR (100.6 MHz, CDCl₃) δ 153.4,

147.4, 143.9, 133.3 (q, J = 39.5 Hz), 125.4, 124.7, 119.6 (q, J = 269.0

Hz), 110.0 (br), 44.1, 31.6, 26.2; ¹⁹F NMR (376.5 MHz, CDCl₃) δ

−57.1; FTIR 3140 (W), 2963 (w), 2850 (w), 1601 (m), 1527 (s),

1350 (s), 1220 (m), 1125 (s), 991 (m), 857 (s), 692 (m) cm⁻¹;

HRMS m/ z [MH]⁺calcd for C₁₃H₁₂ClF₃N₃O₂334.0582, found

334.0570.

Synthesis of 1-Methyl-3-phenyl-5-triﬂuoromethyl-1H-pyra-

zole 24a.⁸Following general procedure 2 using 4-triﬂuoromethyl-N-

methylsydnone 5d (84 mg, 0.5 mmol) and ethynylbenzene (102 mg,

1.0 mmol), 1-methyl-3-phenyl-5-triﬂuoromethyl-1H-pyrazole 24a was

isolated as a yellow oil (107 mg, 95%): ¹H NMR (400 MHz, CDCl₃) δ

7.83−7.81 (m, 2H), 7.47−7.43 (m, 2H), 7.40−7.35 (m, 1H), 6.93 (s,

1H), 4.05 (s, 3H); ¹³C NMR (100.6 MHz, CDCl₃) δ 150.4, 133.1 (q, J

= 39.0 Hz), 132.2, 128.8, 128.3, 125.6, 120.1 (q, J = 268.5 Hz), 104.5,

38.1; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −60.5; HRMS m/z [MH]⁺

calcd for C₁₁H₁₀F₃N₂227.0796, found 227.0807.

+

cm⁻¹; HRMS m/z [MH] calcd for C₁₇H₁₄F₃N₂O 319.1058, found

Synthesis of 1-Methyl-3-(cyclohex-1-enyl)-5-triﬂuorometh-

yl-1H-pyrazole 25a. Following general procedure 2 using 4-

319.1053.

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triﬂuoromethyl-N-methylsydnone 5d (84 mg, 0.5 mmol) and 2-

ethynylcyclohexene (106 mg, 1.0 mmol), heating for 24 h, 1-methyl-3-

(cyclohex-1-enyl)-5-triﬂuoromethyl-1H-pyrazole 25a was isolated as a

yellow oil (94 mg, 82%): ¹H NMR (400 MHz, CDCl₃) δ 6.63 (s, 1H),

6.33−6.30 (m, 1H), 3.96 (s, 3H), 2.45−2.41 (m, 2H), 2.23−2.18 (m,

2H), 1.80−1.73 (m, 2H), 1.71−1.66 (m, 2H); ¹³C NMR (100.6 MHz,

CDCl₃) δ 152.4, 132.4 (q, J = 39.0 Hz), 129.5, 125.5, 120.2 (q, J =

268.5 Hz), 103.3 (br), 37.8, 25.8, 25.4, 22.5, 22.2; ¹⁹F NMR (376.5

MHz, CDCl₃) δ −60.5; FTIR 3138 (w), 2925 (m), 2864 (w), 1458

(m), 1270 (s), 1188 (m), 1127 (s), 1049 (s), 813 (m), 718 (m) cm⁻¹;

HRMS m/z [MH]⁺calcd for C₁₁H₁₄F₃N₂231.1109, found 231.1100.

Synthesis of 3-(Benzyloxymethyl)-1-methyl-5-triﬂuoro-

methyl-1H-pyrazole 26a. Following general procedure 2 using 4-

triﬂuoromethyl-N-methylsydnone 5d (84 mg, 0.5 mmol) and benzyl 2-

propynyl ether (146 mg, 1.0 mmol), heating for 24 h, 3-

(benzyloxymethyl)-1-methyl-5-triﬂuoromethyl-1H-pyrazole 26a was

isolated as a yellow oil (120 mg, 89%): ¹H NMR (400 MHz,

CDCl₃) δ 7.39−7.33 (m, 4H), 7.34−7.31 (m, 1H), 6.68 (s, 1H), 4.61

(s, 2H), 4.56 (s, 2H), 3.99 (s, 3H); ¹³C NMR (100.6 MHz, CDCl₃) δ

148.7, 137.8, 132.8 (q, J = 39.0 Hz), 128.5, 128.0, 127.8, 120.0 (q, J =

269.0 Hz), 107.0 (br), 72.6, 65.3, 38.0; ¹⁹F NMR (376.5 MHz,

CDCl₃) δ −60.5; FTIR 3029 (w), 2950 (w), 2863 (w), 1458 (m),

1270 (s), 1178 (s), 1117 (s), 1038 (s), 824 (m), 736 (m), 697 (s)

cm⁻¹; HRMS m/z [MH]⁺calcd for C₁₃H ₁₄F₃N₂O 271.1058, found

271.1053.

1128 (s), 1046 (s), 760 (m), 691 (s) cm⁻¹; HRMS m/z [MH] ⁺calcd

for C₁₇H₁₄F₃N₂303.1109, found 303.1108.

39b: mp 53−54 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.48−7.43 (m,

3H), 7.35−7.30 (m, 5H), 7.10−7.08 (m, 2H), 6.64 (s, 1H), 5.41 (s,

2H); ¹³C NMR (100.6 MHz, CDCl₃) δ 145.6, 142.1 (q, J = 38.0 Hz),

136.4, 129.4, 129.3, 129.1, 128.9, 128.8, 127.9, 126.9, 121.5 (q, J =

268.5 Hz), 104.8 (br), 53.9; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −61.9;

FTIR 3075 (w), 3031 (w), 1475 (m), 1211 (m), 1128 (s), 1106 (m),

989 (s), 758 (m), 692 (s) cm⁻¹; HRMS m/z [MH]⁺calcd for

C₁₇H₁₄F₃N₂303.1109, found 303.1096.

Synthesis of 1-Benzyl-3-n-butyl-5-triﬂuoromethyl-1H-pyra-

zole 40a and 1-Benzyl-3- triﬂuoromethyl-5-n-butyl-1H-pyr-

azole 40b. Following general procedure 2 using 4-triﬂuoromethyl-N-

benzylsydnone 5e (122 mg, 0.5 mmol) and 1-hexyne (82 mg, 1.0

mmol), heating for 24 h, 1-benzyl-3-n-butyl-5-triﬂuoromethyl-1H-

pyrazole 40a was isolated as a yellow oil (49 mg, 35%) and 1-benzyl-3-

triﬂuoromethyl-5-n-butyl-1H-pyrazole 40b was isolated as a yellow oil

(19 mg, 13%).

40a: ¹H NMR (400 MHz, CDCl₃) δ 7.37−7.28 (m, 3H), 7.20−7.18

(m, 2H), 6.48 (s, 1H), 5.40 (s, 2H), 2.67 (t, J = 7.5 Hz, 2H), 1.70−

1.62 (m, 2H), 1.46−1.47 (m, 2H), 0.97 (t, J = 7.5 Hz, 3H); ¹³C NMR

(100.6 MHz, CDCl₃) δ 153.0, 136.3, 132.2 (q, J = 39.0 Hz), 128.6,

127.9, 127.1, 120.2 (q, J = 269.0 Hz), 106.4 (br), 54.4, 31.7, 27.7, 22.4,

13.9; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −59.1; FTIR 3033 (w), 2956

(w), 2931 (w), 2861 (w), 1565 (w), 1453 (m), 1264 (s), 1159 (s),

1127 (s), 1036 (s), 808 (m), 693 (m) cm⁻¹; HRMS m/z [MH]⁺calcd

for C₁₅H₁₈F₃N₂283.1422, found 283.1415.

Synthesis of Ethyl 1-Methyl-5-triﬂuoromethyl-1H-pyrazole-

3-carboxylate 27a and Ethyl 1-Methyl-5-triﬂuoromethyl-1H-

pyrazole-4-carboxylate 27b.⁸Following general procedure 2 using

4-triﬂuoromethyl-N-methylsydnone 5d (84 mg, 0.5 mmol) and

ethylpropiolate (98 mg, 1.0 mmol), eluting with 15% EtOAc in

petroleum ether, ethyl 1-methyl-5-triﬂuoromethyl-1H-pyrazole-3-

carboxylate 27a and ethyl 1-methyl-5-triﬂuoromethyl-1H-pyrazole-4-

carboxylate 27b were isolated as an inseparable mixture (93:7, 27a/

27b) as a yellow oil (104 mg, 94%).

40b: ¹H NMR (400 MHz, CDCl₃) δ 7.37−7.31 (m, 3H), 7.12−7.10

(m, 2H), 6.36 (s, 1H), 5.36 (s, 2H), 2.52 (t, J = 7.5 Hz, 2H), 1.59−

1.51 (m, 2H), 1.39−1.31 (m, 2H), 0.89 (t, J = 7.5 Hz, 3H); ¹³C NMR

(100.6 MHz, CDCl₃) δ 145.1, 141.5 (q, J = 37.5 Hz), 136.0, 128.9,

128.0, 126.8, 121.6 (q, J = 269.0 Hz), 103.2, 53.8, 30.2, 25.2, 22.2,

13.7; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −61.9; FTIR 3032 (w), 2964

(w), 2930 (w), 2847 (w), 1609 (m), 1494 (m), 1214 (s), 1120 (s),

984 (m), 806 (m), 725 (m) cm⁻¹; HRMS m/z [MH]⁺calcd for

C₁₅H₁₈F₃N₂283.1422, found 283.1415.

Synthesis of Dimethyl 1-Benzyl-5-triﬂuoromethyl-1H-pyra-

zole-3,4-dicarboxylate 45a and Dimethyl 1-Benzyl-3-triﬂuor-

omethyl-1H-pyrazole-4,5-dicarboxylate 45b. Following general

procedure 2 using 4-triﬂuoromethyl-N-benzylsydnone 5e (122 mg, 0.5

mmol) and DMAD (142 mg, 1.0 mmol), heating at 120 °C for 24 h,

dimethyl 1-benzyl-5-triﬂuoromethyl-1H-pyrazole-3,4-dicarboxylate

45a and dimethyl 1-benzyl-3-triﬂuoromethyl-1H-pyrazole-4,5-dicar-

boxylate 45b were isolated as an inseparable mixture (96:4, 45a/45b)

as a yellow oil (93 mg, 54%).

Spectroscopic data only reported for 27a: ¹H NMR (400

MHz, CDCl₃) δ 7.12 (s, 1H), 4.40 (q, J = 7.0 Hz, 2H), 4.06 (s, 3H),

1.38 (t, J = 7.0 Hz, 3H); ¹³C NMR (100.6 MHz, CDCl₃) δ 161.1,

142.6, 133.3 (q, J = 40.0 Hz), 119.4 (q, J = 269.0 Hz), 110.3, 61.4,

38.9, 14.3; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −61.0; FTIR 3147 (w),

2986 (w), 1723 (m), 1447 (m), 1270 (s), 1214 (s), 1119 (s), 1046 (s),

994 (s), 825 (m), 783 (s), 709 (m) cm⁻¹; HRMS m/z [MH]⁺calcd

for C₈H₁₀F₃N₂O₂223.0694, found 223.0686.

Synthesis of 2-Triﬂuoromethyl-5,6-dihydro-4H-pyrrolo[1,2-

b]pyrazole 29. Following general procedure 2 using 4-triﬂuor-

omethyl-N-methylsydnone 5d (84 mg, 0.5 mmol) and 5-chloro-1-

pentyne (103 mg, 1.0 mmol), heating for 24 h, eluting with 30%

EtOAc in petroleum ether, 2-triﬂuoromethyl-5,6-dihydro-4H-pyrrolo-

[1,2-b]pyrazole 29 was isolated as a yellow oil (56 mg, 64%): ¹H NMR

(400 MHz, CDCl₃) δ 6.25 (s, 1H), 4.20 (t, J = 7.0 Hz, 2H), 2.94 (t, J =

7.0 Hz, 2H), 2.70−2.62 (m, 2H); ¹³C NMR (100.6 MHz, CDCl₃) δ

147.0, 146.2 (q, J = 37.5 Hz), 121.2 (q, J = 268.5 Hz), 97.6 (br), 48.1,

26.1, 23.0; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −62.1; FTIR 3143 (w),

2972 (w), 2880 (w), 1484 (m), 1239 (m), 1161 (s), 1117 (s), 1086

(s), 977 (s), 802 (m), 702 (m) cm⁻¹; HRMS m/ z [MH]⁺calcd for

Spectroscopic data only reported for 45a: ¹H NMR (400

MHz, CDCl₃) δ 7.37−7.34 (m, 3H), 7.26−7.24 (m, 2H), 5.54 (s, 2H),

3.96 (s, 3H), 3.94 (s, 3H); ¹³C NMR (100.6 MHz, CDCl₃) δ 162.6,

160.5, 140.6, 134.0, 131.0 (q, J = 40.5 Hz), 128.9, 128.7, 127.5, 119.1,

118.8 (q, J = 271.0 Hz), 56.4, 53.2, 52.8; ¹⁹F NMR (376.5 MHz,

CDCl₃) δ −58.4; FTIR 3043 (w), 2956 (w), 1729 (s), 1496 (m), 1315

(m), 1250 (s), 1176 (s), 1142 (s), 1047 (s), 965 (m), 831 (m), 731

(m) cm⁻¹; HRMS m/ z [MH]⁺calcd for C₁₅H₁₄F₃N₂O₄343.0906,

found 343.0922.

Synthesis of Dimethyl 1-Benzyl-5-triﬂuoromethyl-1H-pyra-

zole-3,4-dicarboxylate 45a and Dimethyl 1-Benzyl-3-triﬂuor-

omethyl-1H-pyrazole-4,5-dicarboxylate 45b. Following general

procedure 2 using 4-triﬂuoromethyl-N-benzylsydnone 5e (122 mg, 0.5

mmol) and DMAD (142 mg, 1.0 mmol), dimethyl 1-benzyl-5-

triﬂuoromethyl-1H-pyrazole-3,4-dicarboxylate 45a and dimethyl 1-

benzyl-3-triﬂuoromethyl-1H-pyrazole-4,5-dicarboxylate 45b were iso-

lated as an inseparable mixture (63:37, 45a/45b) as a yellow oil (87

mg, 51%): ¹H NMR (400 MHz, CDCl₃) δ 7.38−7.33 (m, 3H), 7.29−

7.24 (m, 2H), 5.67 (s, 0.75H), 5.54 (s, 1.25H), 3.97 (s, 1.88H), 3.95

(s, 1.88H), 3.90 (s, 1.22H), 3.88 (s, 1.22H); ¹³C NMR (100.6 MHz,

CDCl₃) δ 162.6, 161.6, 160.5, 158.9, 140.6, 139.7 (q, J = 39.0 Hz),

134.7, 134.4, 134.0, 131.0 (q, J = 40.0 Hz), 128.9 (2), 128.7, 128.6,

128.0, 127.5, 120.1 (q, J = 270.0 Hz), 119.1, 118.8 (q, J = 271.0 Hz),

56.4, 56.1, 53.2, 53.1, 52.8 (2), unable to unequivocally assign 1 × C

signal; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −58.4 (0.63F), −61.7

C₇H₈F N₂177.0640, found 177.0645.

3

Synthesis of 1-Benzyl-3-phenyl-5-triﬂuoromethyl-1H-pyra-

zole 39a and 1-Benzyl-3- triﬂuoromethyl-5-phenyl-1H-pyra-

zole 39b. Following general procedure 2 using 4-triﬂuoromethyl-N-

benzylsydnone 5e (122 mg, 0.5 mmol) and ethynylbenzene (102 mg,

1.0 mmol), heating for 24 h, eluting with 5% ether in petroleum ether,

1-benzyl-3-phenyl-5-triﬂuoromethyl-1H-pyrazole 39a was isolated as

yellow oil (59 mg, 39%) and 1-benzyl-3-triﬂuoromethyl-5-phenyl-1H-

pyrazole 39b was isolated as a colorless solid (33 mg, 22%).

39a: ¹H NMR (400 MHz, CDCl₃) δ 7.85−7.83 (m, 2H), 7.47−7.43

(m, 2H), 7.40−7.32 (m, 4H), 7.30−7.28 (m, 2H), 6.97 (s, 1H), 5.50

(s, 2H); ¹³C NMR (100.6 MHz, CDCl₃) δ 150.1, 135.9, 133.1 (q, J =

39.0 Hz), 132.1, 128.8, 128.7, 128.4, 128.1, 127.3, 125.7, 120.0 (q, J =

269.0 Hz), 104.9 (br), 54.9; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −59.2;

FTIR 3067 (w), 3028 (w), 2930 (w). 1445 (m), 1269 (s), 1153 (s),

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(0.37F); FTIR 3029 (w), 2968 (w), 1734 (s), 1496 (m), 1244 (s),

1187 (s), 1134 (s), 1060 (s), 964 (m), 876 (m), 719 (m) cm⁻¹;

HRMS m/z [MH]⁺calcd for C₁₅H₁₄F₃N₂O₄343.0906, found

343.0922.

General Procedure 3: Cycloaddition Reactions of 4-

Triﬂuoromethylsydnones and Alkynylboronates (See Table

2). A solution of a 4-triﬂuoromethylsydnone (0.5 mmol) and an

alkynylboronate (2.0 mmol) in o-DCB (1 M) in a sealed microwave

vessel was heated at 140 °C for the designated length of time. After

cooling, the crude materials were puriﬁed by ﬂash chromatography on

silica gel (eluting with 5% EtOAc in petroleum ether, unless otherwise

stated) to yield the title pyrazoles.

Synthesis of 1-(p-Nitrophenyl)-3-trimethylsilyl-4-(4,4,5,5-

tetramethyl-1,3,2-dioxaborolan-2-yl)-5-triﬂuoromethyl-1H-

pyrazole 33a. Following general procedure 3 using 4-triﬂuoromethyl-

N-(p-nitrophenyl)sydnone (136 mg, 0.5 mmol) and trimethyl-

((4,4,5,5-tetramethyl-1,3,2-dixaborolan-2-yl)ethynyl)silane (448 mg,

2.0 mmol), heating for 24 h, 1-(p-nitrophenyl)-3-trimethylsilyl-4-

(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-triﬂuoromethyl-1H-

pyrazole 33a was isolated as a yellow solid (125 mg, 55%).

Note: Compound 33a was isolated as an inseparable mixture (9:1)

1

with the protodeboronated pyrazole: H NMR (400 MHz, CDCl₃) δ

8.37 (d, J = 9.0 Hz, 2H), 7.69 (d, J = 9.0 Hz, 2H), 1.40 (s, 12H), 0.40

(s, 9H); ¹³C NMR (100.6 MHz, CDCl₃) δ 160.6, 147.5, 144.5, 137.3

(q, J = 38.0 Hz), 126.4, 124.4, 123.1 (q, J = 271.0 Hz), 84.5, 25.0,

−0.8; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −54.0; FTIR 2984 (w), 1525

(m), 1357 (m), 1256 (s), 1135 (s), 1037 (s), 982 (m), 838 (s), 755

(m) cm⁻¹; HRMS m/z [MH]⁺calcd for C₁₉H₂₆¹¹BF₃N₃O₄Si

456.1738, found 456.1756.

Synthesis of 1-Phenyl-3-n-butyl-4-(4,4,5,5-tetramethyl-

1,3,2-dioxaborolan-2-yl)-5-triﬂuoromethyl-1H-pyrazole 34a.

Following general procedure 3 using 4-triﬂuoromethyl-N-phenyl-

sydnone 5a (115 mg, 0.5 mmol) and 2-(hex-1-yn-1-yl)-4,4,5,5-

tetramethyl-1,3,2-dioxaborolane (416 mg, 2.0 mmol), heating for 72

h, 1-phenyl-3-n-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-

5-triﬂuoromethyl-1H-pyrazole 34a was isolated as a yellow oil (108

mg, 55%): ¹H NMR (400 MHz, CDCl₃) δ 7.48−7.42 (m, 5H), 2.84−

2.80 (m, 2H), 1.73−1.64 (m, 2H), 1.48−1.39 (m, 2H), 1.38 (s, 12H),

0.96 (t, J = 7.5 Hz, 3H); ¹³C NMR (100.6 MHz, CDCl₃) δ 159.2,

139.5, 136.8 (q, J = 38.0 Hz), 129.0, 128.9, 126.0, 120.1 (q, J = 270.5

Hz), 84.0, 32.7, 28.1, 24.7, 22.7, 13.9; ¹⁹F NMR (376.5 MHz, CDCl₃)

δ −55.1; FTIR 2959 (m), 2923 (m), 2872 (w), 1510 (m), 1331 (m),

1239 (s), 1176 (s), 4468 (s), 1076 (s), 984 (m), 855 (m), 771 (m)

cm⁻¹; HRMS m/z [MH]⁺calcd for C₂₀H₂₇¹¹BF₃N₂O₂395.2118, found

395.2120.

Synthesis of 1-Phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxa-

borolan-2-yl)-5-triﬂuoromethyl-1H-pyrazole 30a and 1-Phe-

nyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-triﬂuoro-

methyl-1H-pyrazole 30b. Following general procedure 3 using 4-

triﬂuoromethyl-N-phenylsydnone 5a (115 mg, 0.5 mmol) and 2-

ethynyl-4,4,5,5-tetramethyl-1,3,2-dioaborolane (304 mg, 2.0 mmol),

heating for 72 h, eluting with 40% EtOAc in petroleum ether, 1-

phenyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-triﬂuoro-

methyl-1H-pyrazole 30a and 1-phenyl-3-(4,4,5,5-tetramethyl-1,3,2-

dioxaborolan-2-yl)-5-triﬂuoromethyl-1H-pyrazole 30b were isolated

as an inseparable mixture (7:93, 30a/30b) as a brown solid (117 mg,

1

69%): mp 111−113 °C Spectroscopic data only reported for 30b: H

NMR (400 MHz, CDCl₃) δ 7.50−7.47 (m, 5H), 7.21 (s, 1H), 1.39 (s,

12H); ¹³C NMR (100.6 MHz, CDCl₃) δ 139.1, 133.2 (q, J = 39.0 Hz),

129.4, 128.8, 126.1, 120.0 (q, J = 269.0 Hz), 116.0, 84.5, 24.8; ¹⁹F

NMR (376.5 MHz, CDCl₃) δ −57.5; FTIR 2988 (w), 1561 (w), 1485

(m), 1366 (m), 1290 (m), 1171 (s), 1125 (s), 995 (m), 853 (m), 777

(m), 697 (m) cm⁻¹; HRMS m/z [MH]⁺calcd for C₁₆H ¹¹BF₃N₂O₂

19

339.1492, found 339.1477.

Synthesis of 1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxa-

borolan-2-yl)-5-triﬂuoromethyl-1H-pyrazole 31b. Following

general procedure 3 using 4-triﬂuoromethyl-N-methylsydnone 5d

(84 mg, 0.5 mmol) and 2-ethynyl-4,4,5,5-tetramethyl-1,3,2-dioabor-

olane (304 mg, 2.0 mmol), heating for 72 h, eluting with 40% EtOAc

in petroleum ether, 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-

lan-2-yl)-5-triﬂuoromethyl-1H-pyrazole 31b was isolated as a brown

oil (122 mg, 44%): ¹H NMR (400 MHz, CDCl₃) δ 7.00 (s, 1H), 4.04

(s, 3H), 1.34 (s, 12H); ¹³C NMR (100.6 MHz, CDCl₃) δ 132.3 (q, J =

39.0 Hz), 120.3 (q, J = 268.5 Hz), 115.0, 84.4, 38.2, 24.8; ¹⁹F NMR

(376.5 MHz, CDCl₃) δ −60.5; FTIR 2977 (m), 1554 (m), 1236 (s),

1161 (s), 1121 (s), 1050 (s), 993 (m), 856 (m), 719 (m), 635 (w)

cm⁻¹; HRMS m/ z [MH]⁺calcd for C₁₁H₁₇¹¹BF₃N₂O₂277.1335,

found 277.1328.

Synthesis of 3-triﬂuoromethyl-5-phenyl-1H-pyrazole 37 and

1-(4-Methoxy-3-nitrophenyl)-3-phenyl-5-triﬂuoromethyl-1H-

pyrazole 38. To an ice-cooled stirring suspension of 1-(p-

methoxyphenyl)-3-phenyl-5-triﬂuoromethyl-1H-pyrazole 19a (80 mg,

0.25 mmol) in a mixture of acetonitrile and water (4:1, 6.25 mL) was

added a cooled solution of CAN (1.37 g, 2.50 mmol) in water (5 mL).

The reaction was warmed to ambient temperature, stirred for 22 h,

and then concentrated in vacuo. Water (10 mL) was added to the

residue which was then extracted with DCM (3 × 10 mL). The

organic fractions were washed with saturated NaHCO_3(aq)then dried

over MgSO₄before the volatiles were removed in vacuo. The crude

material was puriﬁed by ﬂash chromatography on silica gel (eluting

with 15% EtOAc in petroleum ether) to isolate 3-triﬂuoromethyl-5-

phenyl-1H-pyrazole as a yellow solid 37 (24 mg, 47%) and 1-(4-

methoxy-3-nitrophenyl)-3-phenyl-5-triﬂuoromethyl-1H-pyrazole was

isolated as a yellow solid 38 (12 mg, 13%).

Synthesis of 1-Phenyl-3-trimethylsilyl-4-(4,4,5,5-tetrameth-

yl-1,3,2-dioxaborolan-2-yl)-5-triﬂuoromethyl-1H-pyrazole 32a

and 1-phenyl-4-trimethylsilyl-3-(4,4,5,5-tetramethyl-1,3,2-di-

oxaborolan-2-yl)-5-triﬂuoromethyl-1H-pyrazole 32b. Following

general procedure 3 using 4-triﬂuoromethyl-N-phenylsydnone 5a (115

mg, 0.5 mmol) and trimethyl((4,4,5,5-tetramethyl-1,3,2-dixaborolan-2-

yl)ethynyl)silane (448 mg, 2.0 mmol), heating for 48 h, 1-phenyl-3-

trimethylsilyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-triﬂuor-

omethyl-1H-pyrazole 32a was isolated as a yellow solid (120 mg, 58%)

and 1-phenyl-4-trimethylsilyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-

lan-2-yl)-5-triﬂuoromethyl-1H-pyrazole 32b was isolated as a yellow

solid (13 mg, 6%).

37: mp 121−123 °C (lit.³⁷mp 122−123 °C); ¹H NMR (400 MHz,

CDCl₃) δ 10.54 (br, 1H), 7.60−7.58 (m, 2H), 7.49−7.43 (m, 3H),

6.74 (s, 1H); ¹³C NMR (100.6 MHz, CDCl₃) δ 145.1, 143.7 (q, J =

38.5 Hz), 129.5, 129.3, 127.9, 125.6, 121.1 (q, J = 267.0 Hz), 101.1;

¹⁹F NMR (376.5 MHz, CDCl₃) δ −62.2; HRMS m/z [MH]⁺calcd for

C₁₀H₈F₃N₂213.0640, found 213.0630.

38: ¹H NMR (400 MHz, CDCl₃) δ 8.15 (d, J = 2.5 Hz, 1H), 7.87−

7.85 (m, 2H), 7.78 (dd, J = 2.5, 9.0 Hz, 1H), 7.49−7.42 (m, 3H), 7.24

(d, J = 9.0 Hz, 1H), 7.15 (s, 1H), 4.08 (s, 3H); ¹³C NMR (100.6 MHz,

CDCl₃) δ 153.4, 152.3, 139.2, 134.1 (q, J = 39.5 Hz), 131.4, 131.3,

131.1, 129.0, 128.9, 125.9, 123.5, 119.6 (q, J = 269.5 Hz), 113.9, 106.6,

57.0; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −57.6; HRMS m/z [MH]⁺

calcd for C₁₇H₁₃F₃N₃O₃364.0909, found 364.0908.

1

32a: mp 115−117 °C; H NMR (400 MHz, CDCl₃) δ 7.49−7.46

(m, 5H), 1.40 (s, 12H), 0.40 (s, 9H); ¹³C NMR (100.6 MHz, CDCl₃)

δ 159.9, 140.3, 137.8 (q, J = 37.5 Hz), 129.7, 129.5, 126.7, 121.3 (q, J =

270.5 Hz), 84.6, 25.7, 0.0; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −54.5;

FTIR 2976 (w), 1504 (w), 1338 (m), 1252 (m), 1139 (s) 1048 (m),

848 (s), 765 (m), 693 (m) cm⁻¹; HRMS m/z [MH]⁺calcd for

C₁₉H₂₇¹¹BF₃N₂O₂Si 411.1887, found 411.1890.

Synthesis of 3-Triﬂuoromethyl-5-phenyl-1H-pyrazole 37.³⁷

A solution of 1-benzyl-3-phenyl-5-triﬂuoromethyl-1H-pyrazole 39a

and 1-benzyl-3-triﬂuoromethyl-5-phenyl-1H-pyrazole 39b (71:29,

39a/39b; 76 mg, 0.25 mmol) in methanol (5 mL) and AcOH (5

drops) was ﬂowed through a H-Cube continuous ﬂow hydrogenator

(1 mL min⁻¹) with a 20% Pd(OH)₂/C catalyst cartridge at 80 °C

using controlled H₂mode (70 bar) as a continuous loop. Once the

reaction was complete by TLC analysis, the system was washed with

1

32b: mp 113−115 °C; H NMR (400 MHz, CDCl₃) δ 7.46−7.43

(m, 5H), 1.39 (s, 12H), 0.40 (s, 9H); ¹³C NMR (100.6 MHz, CDCl₃)

δ 139.3, 136.0 (q, J = 37.5 Hz), 128.4, 128.0, 125.6, 124.1, 120.1 (q, J =

270.5 Hz), 83.7, 24.3, 0.0; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −52.5;

FTIR 2980 (w), 1499 (w), 1241 (s), 1168 (s), 1139 (s), 988 (w), 847

(m), 772 (w) cm⁻¹; HRMS m/z [MH]⁺calcd for C₁₉H₂₇¹¹BF₃N₂O₂Si

411.1887, found 411.1901.

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methanol (10 mL). The reaction was subsequently neutralized with

NaHCO₃then ﬁltered and the volatiles were removed in vacuo. The

crude material was puriﬁed by ﬂash chromatography on silica gel

(eluting with 20% EtOAc in petroleum ether) to yield 3-

triﬂuoromethyl-5-phenyl-1H-pyrazole 37 as a colorless solid (40 mg,

75%).

Synthesis of 1,3-Diphenyl-5-triﬂuoromethyl-1H-pyrazole

8a.⁸A solution of 1-phenyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-

lan-2-yl)-5-triﬂuoromethyl-1H-pyrazole 5b (80 mg, 0.24 mmol),

bromobenzene (74 mg, 0.47 mmol), CsF (108 mg, 0.71 mmol), and

PdCl₂(dppf) (8 mg, 0.01 mmol) in a mixture of DME and water (1:1,

1 mL) in a sealed microwave vessel was heated at 140 °C for 30 min in

a CEM Microwave Explorer Reactor. After cooling, the volatiles were

removed in vacuo before the crude material was puriﬁed by ﬂash

chromatography on silica gel (eluting with 5% EtOAc in petroleum) to

yield 1,3-diphenyl-5-triﬂuoromethyl-1H-pyrazole 8a as a colorless solid

(40 mg, 59%).

129.0, 128.8, 125.6, 121.3 (q, J = 268.0 Hz), 116.1 (q, J = 37.0 Hz),

−1.4; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −55.9; FTIR 3268 (br), 2959

(w), 1898 (w), 1560 (m), 1249 (m), 1110 (s). 976 (m), 833 (s), 768

(m), 690 (m) cm⁻¹; HRMS m/ z [MH]⁺calcd for C₁₃H₁₆F₃N₂OSi

301.0984, found 301.0972.

Synthesis of 4-(Ethoxycarbonyl)-N-phenylsydnone 52. To a

stirring solution of the N-phenylsydnone 51 (4.86 g, 30 mmol) in

THF (150 mL) was added n-BuLi in hexanes (36 mmol) dropwise

under a nitrogen atmosphere at −78 °C. After 30 min, the solution

was transferred via cannula to a stirring solution of ethyl chloroformate

(14.28 mL, 150 mmol) in THF (50 mL) at −78 °C and slowly

warmed to ambient temperature overnight. The reaction was

subsequently quenched with 1 M HCl_(aq)and water (100 mL) and

extracted with DCM (3 × 25 mL), and the organic fractions were

dried over MgSO₄before the volatiles were removed in vacuo. The

crude material was puriﬁed by ﬂash chromatography on silica gel

(eluting with 40% EtOAc in petroleum ether) to yield 4-

(ethoxycarbonyl)-N-phenylsydnone 52 as a yellow solid (4.43 g,

63%): mp 105−106 °C (lit.³⁹mp 100−102 °C); ¹H NMR (400 MHz,

CDCl₃) δ 7.75−7.70 (m, 1H), 7.66−7.62 (m, 2H), 7.57−7.54 (m,

2H), 4.28 (q, J = 7.0 Hz, 2H), 1.28 (t, J = 7.0 Hz, 3H); ¹³C NMR

(100.6 MHz, CDCl₃) δ 164.5, 157.1, 134.8, 132.5, 129.5, 125.0, 99.7,

61.7, 14.1; FTIR 3064 (w), 2994 (w). 1799 (s), 1712 (s), 1447 (m),

1186 (s), 1064 (s), 760 (s), 669 (s) cm⁻¹; HRMS m/z [MH]⁺calcd

for C₁₁H₁₁N₂O₄235.0719, found 235.0709.

Synthesis of 4-Hydroxymethyl-N-phenylsydnone 53. To an

ice-cooled stirring suspension of LiBH₄(909 mg, 41.74 mmol) in THF

(40 mL) was added 4-(ethoxycarbonyl)-N-phenylsydnone 52 (3.26 g,

13.91 mmol) in THF (40 mL) dropwise under a nitrogen atmosphere,

and the mixture was warmed to ambient temperature overnight. The

reaction was subsequently quenched with saturated NaHCO_3(aq)and

then extracted with EtOAc (3 × 25 mL), and the organic fractions

were dried over MgSO₄before the volatiles were removed in vacuo.

The crude material was puriﬁed by trituration using pentanes and

ethanol (5:1) to yield 4-hydroxymethyl-N-phenylsydnone 53 as a

yellow solid (2.27 g, 83%).

Synthesis of 1-Phenyl-5-triﬂuoromethyl-1H-pyrazol-3(2H)-

one 35.³⁸To a stirring suspension of 1-phenyl-3-(4,4,5,5-tetramethyl-

1,3,2-dioxaborolan-2-yl)-5-triﬂuoromethyl-1H-pyrazole 5b (68 mg,

0.20 mmol) and Na₂CO₃(21 mg, 0.2 mmol) in ethanol (8 mL)

was added H₂O₂(30% w/w) (2 mL) dropwise. After 30 min, the

reaction mixture was concentrated in vacuo. The residue was dissolved

in water (20 mL) and then extracted with EtOAc (3 × 10 mL), and

the organic fractions were dried over MgSO₄before the volatiles were

removed in vacuo. The crude material was puriﬁed by ﬂash

chromatography on silica gel (eluting with 30% EtOAc in petroleum

ether) to yield 1-phenyl-5-triﬂuoromethyl-1H-pyrazol-3(2H)-one 35

1

as a colorless solid (27 mg, 59%): mp 159−160 °C; H NMR (400

MHz, CDCl₃) δ 11.26 (br, 1H), 7.55−7.46 (m, 5H), 6.18 (s, 1H); ¹³

C

NMR (100.6 MHz, CDCl₃) δ 161.7, 138.0, 133.7 (q, J = 39.5 Hz),

129.4, 129.3, 125.7, 119.1 (q, J = 270.0 Hz), 95.1; ¹⁹F NMR (376.5

MHz, CDCl₃) δ −58.3; FTIR 3065 (w), 1592 (m), 1481 (m), 1197

(s), 1120 (s), 1086 (s), 976 (m), 768 (s), 674 (s) cm⁻¹; HRMS m/z

[MH]⁺calcd for C₁₀H₈F₃N₂O 229.0589, found 229.0597.

Synthesis of 3-Butyl-1,4-diphenyl-5-triﬂuoromethyl-1H-pyr-

azole 16a. To a stirring suspension of 3-butyl-1-phenyl-4-(4,4,5,5-

tetramethyl-1,3,2-dioxaborolan-2-yl)-5-triﬂuoromethyl-1H-pyrazole

34a (79 mg, 0.20 mmol), PdCl₂(PPh₃)₂(16 mg, 0.01 mmol), and

K₃PO₄(1.27 g, 0.60 mmol) in 1,4-dioxane (1 mL) was added

bromobenzene (42 μL, 0.4 mmol) under a nitrogen atmosphere, and

the mixture was heated at 85 °C for 24 h. The reaction was quenched

with 1 M HCl_(aq)and extracted with DCM (3 × 10 mL), and the

organic fractions were dried over MgSO₄before the volatiles were

removed in vacuo. The crude material was puriﬁed by ﬂash

chromatography on silica gel (eluting with 5% EtOAc in petroleum

ether) to yield 1,4-diphenyl-4-n-butyl-5-triﬂuoromethyl-1H-pyrazole

Note: Compound 53 could alternatively be puriﬁed by ﬂash

chromatography on silica gel (eluting with 80% EtOAc in petroleum

ether): mp 98−100 °C (lit.^30amp 95−97 °C); H NMR (400 MHz,

1

CDCl₃) δ 7.86−7.84 (m, 2H), 7.74−7.64 (m, 3H), 4.50 (s, 2H), 4.01

(br, 1H); ¹³C NMR (100.6 MHz, CDCl₃) δ 166.1, 131.0, 129.6, 127.3,

121.5, 105.3, 48.3; FTIR 3351 (br), 3060 (w), 1705 (s), 1479 (m),

1245 (m), 1011 (s), 895 (m), 770 (s), 695 (s) cm⁻¹; HRMS m/z

[MH]⁺calcd for C₉H₉N₂O₃193.0613, found 193.0608.

Synthesis of 4-Formyl-N-phenylsydnone 54. To a stirring

suspension of MnO₂(4.78 g, 55.00 mmol) in DCM (100 mL) was

added 4-hydroxymethyl-N-phenylsydnone 53 (2.11 g, 11.00 mmol)

under a nitrogen atmosphere. After being stirred overnight, the

reaction mixture was ﬁltered through Celite before the volatiles were

removed in vacuo to yield 4-formyl-N-phenylsydnone 54 as a yellow

1

16a as a yellow oil (52 mg, 76%): H NMR (400 MHz, CDCl₃) δ

7.57−7.42 (m, 8H), 7.39−7.37 (m, 2H), 2.66−2.62 (m, 2H), 1.64−

1.56 (m, 2H), 1.37−1.28 (m, 2H), 0.86 (t, J = 7.0 Hz, 3H); ¹³C NMR

(100.6 MHz, CDCl₃) δ 152.5, 139.8, 131.2, 130.0, 129.0 (2), 128.2,

127.8, 126.0, 125.6, 123.9, 120.2 (q, J = 270.5 Hz), 31.3, 26.0, 22.5,

13.8; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −55.3; FTIR 3075 (w), 2930

(w), 2861 (w), 1501 (m), 1166 (s), 1119 (s), 990 (m), 755 (m), 694

(s) cm⁻¹; HRMS m/ z [MH]⁺calcd for C₂₀H₂₀F₃N₂345.1579, found

345.1589.

solid (1.81 g, 86%): mp 115−117 °C (lit.^30bmp 116−118 °C); H

1

NMR (400 MHz, CDCl₃) δ 9.59 (s, 1H), 7.79−7.74 (m, 1H), 7.70−

7.63 (m, 4H); ¹³C NMR (100.6 MHz, CDCl₃) δ 174.7, 166.4, 133.6,

133.2, 129.9, 124.6, 105.1; FTIR 3057 (w), 1778 (s), 1644 (s), 1470

(s), 1374 (s), 1304 (m), 878 (m), 761 (s), 687 (s) cm⁻¹; HRMS m/z

[MH]⁺calcd for C₉H₇N₂O₃191.0457, found 191.0449.

Synthesis of 1-Phenyl-5-triﬂuoromethyl-3-trimethylsilyl-1H-

pyrazol-4-ol 36. To a stirring suspension of 1-phenyl-3-trimethylsil-

yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-triﬂuoromethyl-

1H-pyrazole 32a (82 mg, 0.20 mmol) and Na₂CO₃(21 mg, 0.2 mmol)

in ethanol (8 mL) was added H₂O₂(30% w/w) (2 mL) dropwise.

After 2 h, the reaction mixture was concentrated in vacuo. The residue

was dissolved in water (20 mL) and then extracted with EtOAc (3 ×

10 mL), and the organic fractions were dried over MgSO₄before the

volatiles were removed in vacuo. The crude material was puriﬁed by

ﬂash chromatography on silica gel (eluting with 5% EtOAc in

petroleum ether) to yield 1-phenyl-5-triﬂuoromethyl-3-trimethylsilyl-

1H-pyrazol-4-ol 36 as a yellow solid (48 mg, 80%): mp 114−116 °C;

¹H NMR (400 MHz, CDCl₃) δ 7.48−7.45 (m, 5H), 5.00 (br, 1H),

Synthesis of 4-Monoﬂuoromethyl-N-phenylsydnone 55. To

an ice-cooled stirring solution of 4-hydroxymethyl-N-phenylsydnone

53 (961 mg, 5.00 mmol) in THF (25 mL) was added deoxoﬂuor (50%

solution in THF) (2.58 mL, 6.0 mmol) dropwise under a nitrogen

atmosphere. After 1 h, the reaction mixture was warmed to ambient

temperature and stirred for a further 1 h. The reaction was

subsequently quenched with saturated NaHCO_3(aq)(50 mL) and

extracted with DCM (3 × 10 mL), and the organic fractions were

dried over MgSO₄before the volatiles were removed in vacuo. The

crude material was puriﬁed by ﬂash chromatography on silica gel

(eluting with 30% EtOAc in petroleum ether) to yield 4-

monoﬂuoromethyl-N-phenylsydnone 55 as a yellow solid (780 mg,

1

80%): mp 89−90 °C; H NMR (400 MHz, CDCl₃) δ 7.80−7.68 (m,

0.40 (s, 9H); ¹³C NMR (100.6 MHz, CDCl₃) δ 148.4, 142.9, 139.8,

5H), 5.19 (d, J = 50.0 Hz, 2H); ¹³C NMR (100.6 MHz, CDCl₃) δ

4061

dx.doi.org/10.1021/jo400381a | J. Org. Chem. 2013, 78, 4049−4064

The Journal of Organic Chemistry

Article

167.6, 133.5, 133.0, 130.4, 124.3, 103.1 (d, J = 22.5 Hz), 70.2 (d, J =

170.0 Hz); ¹⁹F NMR (376.5 MHz, CDCl₃) δ −196.7 (t, J = 50.0 Hz);

FTIR 3069 (w), 1748 (s), 1476 (m), 1269 (m), 1073 (m), 952 (s),

887 (m), 765 (s), 687 (s) cm⁻1; HRMS m/z [MH]⁺calcd for

C₉H₈FN₂O₂195.0570, found 195.0561.

156.1, 139.0, 136.7 (t, J = 30.0 Hz), 129.4, 128.5, 124.8, 108.5 (t, J =

235.0 Hz), 103.8, 9.1, 8.2; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −109.8

(d, J = 53.5 Hz); FTIR 3087 (w), 2991 (w), 1502 (s), 1367 (m), 1154

(m), 1076 (s), 1023 (s), 1005 (s), 800 (m), 754 (s), 690 (s) cm⁻¹;

HRMS m/z [MH]⁺calcd for C₁₃H₁₃F₂N₂235.1047, found 235.1041.

Synthesis of 1-Phenyl-3-(3-chloro)propyl-5-diﬂuoromethyl-

1H-pyrazole 60a. Following general procedure 4 using 5-chloro-1-

pentyne (103 mg, 1.0 mmol), 1-phenyl-3-(3-chloro)propyl-5-diﬂuor-

omethyl-1H-pyrazole 60a was isolated as a yellow oil (79 mg, 58%):

¹H NMR (400 MHz, CDCl₃) δ 7.20−7.49 (m, 4H), 7.48−7.44 (m,

1H), 6.62 (t, J = 53.5 Hz, 1H), 6.61 (s, 1H), 3.65 (t, J = 6.5 Hz, 2H),

2.91 (t, J = 7.5 Hz, 2H), 2.25−2.18 (m, 2H); ¹³C NMR (100.6 MHz,

CDCl₃) δ 152.4, 138.9, 136.8 (t, J = 30.0 Hz), 129.5, 128.7, 124.8,

108.5 (t, J = 235.5 Hz), 106.3, 44.3, 32.1, 25.3; ¹⁹F NMR (376.5 MHz,

CDCl₃) δ −109.8 (d, J = 53.5 Hz); FTIR 3076 (w), 2956 (w), 1504

(s), 1358 (m), 1158 (m), 1080 (s), 1023 (s), 1001 (s), 816 (m), 767

(s), 687 (s) cm⁻¹; HRMS m/z [MH]⁺calcd for C₁₃H₁₄ClF₂N₂

271.0814, found 271.0809.

Synthesis of 4-Diﬂuoromethyl-N-phenylsydnone 56. To an

ice-cooled stirring solution of 4-formyl-N-phenylsydnone 54 (1.80 g,

9.47 mmol) in THF (20 mL), in a sealed nalgene bottle, was added

deoxoﬂuor (50% solution in THF) (20.32 mL, 94.66 mmol) dropwise

under a nitrogen atmosphere. After 1 h, the reaction mixture was

warmed to ambient temperature and stirred for a further 47 h. The

reaction was subsequently quenched with saturated NaHCO_3(aq)(150

mL) and extracted with DCM (3 × 25 mL), and the organic fractions

were dried over MgSO₄before the volatiles were removed in vacuo.

The crude material was puriﬁed by ﬂash chromatography on silica gel

(eluting with 25% EtOAc in petroleum ether) to yield 4-

diﬂuoromethyl-N-phenylsydnone 56 as a yellow solid (1.62 g, 81%):

mp 91−92 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.78−7.73 (m, 1H), δ

7.71−7.65 (m, 4H), 6.61 (t, J = 52.0 Hz, 1H); ¹³C NMR (100.6 MHz,

CDCl₃) δ 165.9, 133.9, 133.1, 130.1, 124.4, 107.3 (t, J = 235.5 Hz),

100.7 (t, J = 27.5 Hz); ¹⁹F NMR (376.5 MHz, CDCl₃) δ −110.7 (d, J

= 52.0 Hz); FTIR 3071 (w), 2922 (w), 1772 (s), 1478 (m), 1273 (m),

1090 (m), 1014 (s), 979 (s), 907 (m), 792 (s), 985 (s) cm⁻¹; HRMS

m/z [MH]⁺calcd for C₉H₇F₂N₂O₂213.0476, found 213.0469.

General Procedure 4: Cycloaddition Reactions of 4-

Diﬂuoromethyl-N-phenylsydnone and Alkynes (See Table 4).

A solution of a 4-diﬂuoromethyl-N-phenylsydnone 56 (106 mg, 0.5

mmol) and an alkyne (2 equiv) in o-DCB (1 mL) in a sealed

microwave vessel was heated at 180 °C for 24 h. After cooling, the

crude materials were puriﬁed by ﬂash chromatography on silica gel

(eluting with 10% EtOAc in petroleum ether unless otherwise stated)

to yield the title pyrazoles.

Synthesis of Ethyl 1-Phenyl-5-diﬂuoromethyl-1H-pyrazole-

3-carboxylate 61a and Ethyl 1-Phenyl-5-diﬂuoromethyl-1H-

pyrazole-4-carboxylate 61b.⁴⁰Following general procedure 4

using ethyl propiolate (98 mg, 1.0 mmol), ethyl 1-phenyl-5-

diﬂuoromethyl-1H-pyrazole-3-carboxylate 61a was isolated as a yellow

solid (97 mg, 73%) and ethyl 1-phenyl-5-diﬂuoromethyl-1H-pyrazole-

4-carboxylate 61b was isolated as a yellow oil (29 mg, 22%).

1

61a: mp 104−105 °C; H NMR (400 MHz, CDCl₃) δ 7.54 (br,

5H), 7.28 (s, 1H), 6.63 (t, J = 53.5 Hz, 1H), 4.47 (q, J = 7.0 Hz, 2H),

1.43 (t, J = 7.0 Hz, 3H); ¹³C NMR (100.6 MHz, CDCl₃) δ 161.2,

144.5, 138.3, 137.9 (t, J = 30.5 Hz), 129.8, 129.5, 125.5, 109.8, 107.9

(t, J = 236.5 Hz), 61.5, 14.4; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −110.7

(d, J = 53.5 Hz); FTIR 3080 (w), 2991 (w), 2942 (w), 1721 (s), 1448

(m), 1390 (s), 1229 (s), 1078 (s), 1039 (s), 999 (s), 755 (m), cm⁻¹;

HRMS m/z [MH]⁺calcd for C₁₃H₁₃F₂N₂O₂267.0945, found

267.0941.

Synthesis of 1,3-Diphenyl-5-diﬂuoromethyl-1H-pyrazole

57a. Following general procedure 4 using ethynylbenzene (102 mg,

1.0 mmol), 1,3-diphenyl-5-diﬂuoromethyl-1H-pyrazole 57a was

isolated as a brown oil (126 mg, 93%): ¹H NMR (400 MHz,

CDCl₃) δ 7.94−7.92 (m, 2H), 7.63−7.60 (m, 2H), 7.58−7.54 (m,

2H), 7.52−7.46 (m, 3H), 7.42−7.38 (m, 1H), 7.10 (s, 1H), 6.70 (t, J =

53.5 Hz, 1H); ¹³C NMR (100.6 MHz, CDCl₃) δ 152.2, 139.0, 137.6

(t, J = 30.0 Hz), 132.3, 129.5, 128.9, 128.8, 128.5, 125.9, 125.0, 108.5

(t, J = 235.0, Hz), 104.6; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −110.0 (d,

J = −53.5 Hz); FTIR 3082 (w), 1600 (m), 1489 (s), 1437 (m), 1369

(m), 1159 (m), 1074 (s), 1048 (s), 950 (m), 774 (s), 693 (s) cm⁻¹;

HRMS m/z [MH]⁺calcd for C₁₆H₁₃F₂N₂271.1047, found 271.1050.

Synthesis of 2-(1-Phenyl-5-diﬂuoromethyl-1H-pyrazol-3-yl)-

pyridine 58a and 2-(1-Phenyl-5-diﬂuoromethyl-1H-pyrazol-4-

yl)pyridine 58b. Following general procedure 4 using 2-ethynylpyr-

idine (103 mg, 1.0 mmol), eluting with 20% EtOAc in petroleum

ether, 2-(1-phenyl-5-diﬂuoromethyl-1H-pyrazol-3-yl)pyridine 58a and

2-(1-phenyl-5-diﬂuoromethyl-1H-pyrazol-4-yl)pyridine 58b isolated as

an inseparable mixture (83:17, 58a/58b) as an orange oil (122 mg,

1

61b: H NMR (400 MHz, CDCl₃) δ 8.11 (s, 1H), 7.57−7.55 (m,

2H), 7.53−7.51 (m, 3H), 7.49 (t, J = 53.0 Hz, 1H), 4.40 (q, J = 7.0 Hz,

2H), 1.42 (t, J = 7.0 Hz, 3H); ¹³C NMR (100.6 MHz, CDCl₃) δ 162.3,

141.9, 139.5, 137.2 (t, J = 24.5 Hz), 129.5, 129.0, 125.7, 116.0, 107.1

(t, J = 237.5 Hz), 61.1, 14.3; ¹⁹F NMR (376.5 MHz, CDCl₃) δ −112.8

(d, J = 53.0 Hz); FTIR 3074 (w), 2992 (w), 2942 (w), 1705 (s), 1490

(m), 1376 (m), 1233 (s), 1190 (m), 1119 (m), 1029 (s), 975 (m), 779

(s), 689 (s) cm⁻¹; HRMS m/z [MH]⁺calcd for C₁₃H₁₃F₂N₂O₂

267.0945, found 267.0935.

Synthesis of Dimethyl 5-Hydroxymethyl-1-phenyl-1H-pyr-

azole-3,4-dicarboxylate 63. A solution of 4-monoﬂuoromethyl-N-

phenylsydnone 55 (97 mg, 0.5 mmol) and DMAD (0.12 mL, 1.0

mmol) in o-DCB (1 mL) in a sealed microwave vessel was heated at

100 °C for 24 h. After cooling, the crude material was puriﬁed by ﬂash

chromatography on silica gel (eluting with 40% EtOAc in petroleum

ether) to yield dimethyl 5-hydroxymethyl-1-phenyl-1H-pyrazole-3,4-

dicarboxylate 63 as an orange solid (83 mg, 57%): mp 136−138 °C;

¹H NMR (400 MHz, CDCl₃) δ 7.60−7.57 (m, 2H), 7.51−7.48 (m,

1

90%): H NMR (400 MHz, CDCl₃) δ 8.70−8.67 (m, 0.83H), 8.66−

8.65 (m, 0.17H), 8.09−8.07 (m, 1H), 7.79−7.75 (m, 1H), 7.72 (t, J =

53.0 Hz, 0.17H), 7.65−7.48 (m, 5.17H), 7.44 (br, 0.83H), 7.30−7.27

(m, 0.83H), 7.25−7.22 (m, 0.17H), 6.69 (t, J = 53.5 Hz, 0.83H); ¹³C

NMR (100.6 MHz, CDCl₃) δ 152.4, 151.1, 150.9, 149.7, 149.6, 149.5,

140.1, 138.9, 137.8 (t, J = 30.0 Hz), 136.9, 136.7, 133.0 (t, J = 24.5

Hz), 129.5, 129.3, 129.2, 129.0 (x2), 125.7, 125.1, 123.1, 122.0, 121.6,

120.3, 108.7 (t, J = 236.0 Hz), 108.4 (t, J = 236.0 Hz), 106.3; ¹⁹F NMR

(376.5 MHz, CDCl₃) δ −110.2 (d, J = 53.5 Hz, 1.67F), −111.4 (d, J =

53.0 Hz, 0.33F); FTIR 3050 (w), 1593 (m), 1500 (s), 1415 (m), 1376

(m), 1164 (m), 1075 (s), 1024 (s), 786 (s), 765 (m), 688 (s) cm⁻¹;

HRMS m/z [MH]⁺calcd for C₁₅H₁₂F₂N₃272.0999, found 272.0989.

Synthesis of 1-Phenyl-3-cyclopropyl-5-diﬂuoromethyl-1H-

pyrazole 59a. Following general procedure 4 using ethynylcyclopro-

pane (66 mg, 1.0 mmol), 1-phenyl-3-cyclopropyl-5-diﬂuoromethyl-

3H), 4.76 (s, 2H), 3.97 (s, 3H), 3.85 (s, 3H); ¹³C NMR (100.6 MHz,

CDCl₃) δ 162.8, 162.4, 144.0, 141.8, 137.8, 129.5 (2), 125.2, 115.1,

60.5, 52.7, 52.2; FTIR 3399 (br), 2942 (w), 1713 (s), 1473 (m), 1313

(m), 1218 (s), 1104 (s), 988 (m), 762 (s), 693 (s) cm⁻¹; HRMS m/z

[MH]⁺calcd for C₁₄H₁₅N₂O₅291.0981, found 291.0974.

Synthesis of (1,3-Diphenyl-1H-pyrazol-5-yl)methanol 65. A

solution of 4-hydroxymethyl-N-phenylsydnone 53 (96 mg, 0.5 mmol)

and ethynylbenzene (102 mg, 1.0 mmol) in o-DCB (1 mL) in a sealed

microwave vessel was heated at 180 °C for 24 h. After cooling, the

crude material was puriﬁed by ﬂash chromatography on silica gel

(eluting with 40% EtOAc in petroleum ether) to yield (1,3-diphenyl-

1H-pyrazol-5-yl)methanol 65 as a yellow solid (180 mg, 72%): mp

111−112 °C (lit.⁴¹117−119 °C); H NMR (400 MHz, CDCl₃) δ

1

7.90−7.88 (m, 2H), 7.68−7.66 (m, 2H), 7.52−7.34 (m, 6H), 6.77 (s,

1H), 4.69 (s, 2H), 2.19 (br, 1H); ¹³C NMR (100.6 MHz, CDCl₃) δ

151.7, 143.5, 139.5, 132.9, 129.2, 128.7, 128.1, 127.9, 125.8, 124.5,

104.9, 55.7; FTIR 3299 (br), 3068 (w), 2879 (w), 1590 (m), 1502 (s),

1H-pyrazole 59a was isolated as a yellow oil (89 mg, 76%): H NMR

(400 MHz, CDCl₃) δ 7.50−7.49 (m, 4H), 7.45−7.42 (m, 1H), 6.59 (t,

J = 53.5 Hz, 1H), 6.43 (s, 1H), 2.04 (tt, J = 5.0, 8.5 Hz, 1H), 1.03−

0.98 (m, 2H), 0.86−0.82 (m, 2H); ¹³C NMR (100.6 MHz, CDCl₃) δ

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1369 (m), 1008 (m), 808 (m), 766 (s), 696 (s) cm⁻¹; HRMS m/z

[MH]⁺calcd for C₁₆H₁₅N₂O 251.1184, found 251.1175.

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Chem. Rev. 2011, 111, 6984−7034.

Synthesis of 5-Monoﬂuoromethyl-1,3-diphenyl-1H-pyrazole

66 and (1,3-Diphenyl-1H-pyrazol-5-yl)methanol 65.⁴¹To an ice-

cooled stirring solution of (1,3-diphenyl-1H-pyrazol-5-yl)methanol 65

(100 mg, 0.40 mmol) in THF (1 mL) was added deoxoﬂuor(50%

solution in THF) (0.10 mL, 0.48 mmol) dropwise under a nitrogen

atmosphere. After 1 h, the reaction mixture was warmed to ambient

temperature and stirred for a further 1 h. The reaction was

subsequently quenched with saturated NaHCO_3(aq)(5 mL) and

extracted with DCM (3 × 10 mL), and the organic fractions were

dried over MgSO₄before the volatiles were removed in vacuo. The

crude material was puriﬁed by ﬂash chromatography on silica gel

(eluting with 10% EtOAc in petroleum ether) to yield 5-

monoﬂuoromethyl-1,3-diphenyl-1H-pyrazole 66 as a yellow solid (32

mg, 32%) and (eluting with 30% EtOAc in petroleum ether) (1,3-

diphenyl-1H-pyrazol-5-yl)methanol 65 as a yellow solid (41 mg, 41%).

́

́ ́

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1

66: mp 87−89 °C; H NMR (400 MHz, CDCl₃) δ 7.93−7.91 (m,

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2H), 7.69−7.67 (m, 2H), 7.57−7.53 (m, 2H), 7.48−7.44 (m, 3H),

7.40−7.35 (m, 1H), 6.95 (d, J = 3.5 Hz, 1H), 5.38 (d, J = 49.0 Hz,

2H); ¹³C NMR (100.6 MHz, CDCl₃) δ 151.9, 139.2, 138.3 (d, J = 19.5

Hz), 132.7, 129.3, 128.7, 128.3, 128.2, 125.8, 124.6, 107.6 (br), 73.8

(d, J = 166.0 Hz); ¹⁹F NMR (376.5 MHz, CDCl₃) δ −196.9 (td, J =

3.5, 49.0 Hz); FTIR 3059 (w), 2975 (w), 1594 (m), 1500 (m), 1434

(m), 1368 (m), 1156 (m), 944 (s), 759 (s), 690 (s) cm⁻¹; HRMS m/z

[MH]⁺calcd for C₁₆H₁₄N₂F 253.1141, found 253.1149.

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1508.

ASSOCIATED CONTENT

■

S

* Supporting Information

¹H and ¹³C NMR spectra for selected compounds. This

material is available free of charge via the Internet at http://

pubs.acs.org.

AUTHOR INFORMATION

Corresponding Author

*E-mail: j.harrity@she ﬃ eld.ac.uk.

Notes

■

The authors declare no competing ﬁnancial interest.

(15) For a preliminary account of this work: Foster, R. S.; Jakobi, H.;

ACKNOWLEDGMENTS

We are grateful to the EPSRC and Bayer CropScience for

ﬁnancial support.

Harrity, J. P. A. Org. Lett. 2012, 14, 4858−4861.

■

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Synthesis of 4-fluoromethylsydnones and their participation in alkyne cycloaddition reactions

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