Regioselective Thermal [3+2]-Dipolar Cycloadditions of α-Diazoacetates with α-Sulfenyl/Sulfinyl/Sulfonyl-β-Chloroacrylamide Derivatives to Form Densely Functionalised Pyrazoles

A Journal of

Accepted Article

Title: Regioselective Thermal [3+2]-Dipolar Cycloadditions

of α-Diazoacetates with α-Sulfenyl/Sulfinyl/Sulfonyl-β-

Chloroacrylamide Derivatives to form Densely Functionalised

Pyrazoles.

Authors: Aaran J. Flynn, Alan Ford, Udaya B. Rao Khandavilli, Simon

E. Lawrence, and Anita Rose Maguire

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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900494

Link to VoR: http://dx.doi.org/10.1002/ejoc.201900494

Supported by

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Regioselective Thermal [3+2]-Dipolar Cycloadditions of α-

Diazoacetates with α-Sulfenyl/Sulfinyl/Sulfonyl-β-

Chloroacrylamide Derivatives to form Densely Functionalised

Pyrazoles.

Aaran J. Flynn,^[a]Alan Ford,^[b]U. B. Rao Khandavilli,^[a]Simon E. Lawrence,^[a]and Anita R. Maguire*^[c]

Abstract: Highly regioselective synthetic methodology leading to

densely functionalised C(3), C(4) and C(5) substituted pyrazoles

10a-q, 14a-i and 16a-g via thermal [3+2]-dipolar cycloaddition,

have garnered significant interest in recent times predominantly

due to their usefulness as targets in drug discovery.^[2]Notably,

several commercialised synthetic pyrazoles have come to

of α-diazoacetates and α-thio-β-chloroacrylamides, at the sulfide, prominence in recent decades highlighting the diverse biological

sulfoxide and sulfone levels of oxidation, is described. This

method allows access to C(4)-sulfenyl or sulfonyl pyrazoles,

through migration of the sulfur substituent at the sulfide and

sulfone oxidation levels, while elimination of the sulfinyl group

leading to 3,5-disubstituted pyrazoles, is observed. While the

sulfide migration is readily rationalised, the carbon to carbon 1,2-

sulfonyl migration is unprecedented and mechanistically

intriguing. The synthetically versatile generation of densely

functionalised pyrazoles containing substituents amenable to

further modification offers advantages over alternative synthetic

routes. Isolation of the N-alkylated pyrazoles 11a and 12a as by-

products from the cycloaddition through further reaction of the

pyrazoles 10 with excess α-diazoacetate, proved useful in

rationalising the tautomeric behaviour evident in the NMR

spectra of the pyrazoles, with the position of tautomeric

equilibrium influenced by solvent and substituents.

effects associated with this critical scaffold. Celecoxib (1), a

COX-2 inhibitor is widely used as non-steroidal anti-

a

inflammatory drug,^[3]rimonabant (2) was used in the treatment of

obesity by acting as an inverse agonist of the cannabinoid

receptor CB1 prior to its withdrawal from market,^[4]fipronil (3) is

a broad spectrum insecticide that acts on GABA-gated and

glutamate-gated chloride channels in the insect nervous

system,^[5]sildenafil (4) is used for the treatment of erectile

dysfunction and pulmonary hypertension,^[6]and tartrazine (5) is

a synthetic lemon azo dye primarily used as a food colouring

(Figure 1).^[7]Of significant interest is the presence of highly

functionalised diversified substituents bonded to the pyrzazole

nucleus, many of which are electron withdrawing groups, that

are critical to the compound’s activity.

Introduction

Heterocycles are an indispensable and ubiquitous class of

compounds; notably they make up more than half of all known

organic compounds and have a broad range of biological,

chemical and physical properties spanning an expansive

spectrum of reactivity and stability.^[1]Among heterocycles, the

pyrazole moiety and its derivatives are an important class of

nitrogen containing five-membered heterocyclic compounds that

[a]

A. J. Flynn, Dr. U. B. Rao Khandavilli, Dr. S. E. Lawrence. School of

Chemistry, Analytical and Biological Chemistry Research Facility,

Synthesis and Solid State Pharmaceutical Centre, University

College Cork, Cork, Ireland

[b]

[c]

Dr. A. Ford. School of Chemistry, Analytical and Biological

Chemistry Research Facility, University College Cork, Cork, Ireland

Prof. A. R. Maguire. School of Chemistry and School of Pharmacy,

Analytical and Biological Chemistry Research Facility, Synthesis

and Solid State Pharmaceutical Centre, University College Cork,

Cork, Ireland

Figure 1. Commercialised substances containing the pyrazole moiety.

Email: a.maguire.ucc.ie

http://publish.ucc.ie/researchprofiles/V001/amaguire

Markedly, the condensation of 1,3-dicarbonyl compounds with

hydrazine derivatives remains the prevailing synthetic route

towards formation of the pyrazole scaffold despite its

associated limitations, namely the multistep sequences (in

Supporting information and ORCID(s) for the author(s) for this article are

available on the WWW under http://doi.org/10.1002/ejoc.201900494R1.

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many instances) required to generate the desired starting

materials, limited functional group tolerance, harsh reaction

conditions and poor regioselectivities (Scheme 1, A).^{[2e, 8]}The

safety aspects of using hydrazines and its derivatives must also

be considered.^[9]

A major advantage of the [3+2]-dipolar cycloaddition is that the

dipolarophile can be tuned to incorporate a comprehensive

range of functionality that would otherwise be a difficult task

using other methods. We have previously reported

comprehensively on the synthesis and reactivity of α-thio-β-

chloroacrylamides,^[15]a family of sulfur-containing compounds

that undergo a large range of reactions such as oxidation,^[16]

addition-substitution,^[17]Diels-Alder cycloaddition^[18]and [3+2]

dipolar cycloaddition.^[19]Significantly, while the [3+2] dipolar

cycloaddition of ethyl diazoacetate with a diverse range of

functionalised dipolarophiles is well explored, dipolarophiles

bearing halides capable of acting as a leaving group and as a

potential source of functional group migrations remains

substantially less studied. In this work, we present the use of α-

thio-β-chloroacrylamides as a unique dipolarophile scaffold at

each of the sulfide, sulfoxide and sulfone level of oxidation with

the electron deficient α-diazoacetates to generate a series of

novel highly functionalised pyrazoles at the C(3), C(4) and C(5)

positions (Scheme 1, C).

The [3+2]-dipolar cycloaddition offers a unique atom-economical

solution to many of the aforementioned problems with excellent

regioselectivities and tolerance of functional group diversity

characteristic of the reaction.^[10]The [3+2]-dipolar cycloaddition

of alkenes with diazoalkanes is well-documented generally

forming the 1-pyrazoline that readily isomerises to the more

thermodynamically stable 2-pyrazoline, however

a further

oxidative step is usually required to form the pyrazole (Scheme

1, B).^[11]

This problem can be circumvented by employing diazo

compounds with an in-built synthetic handle that is retained

through the cycloaddition, that can much more readily undergo

further synthetic transformations. While the use of inexpensive

commercially available ethyl diazoacetate as a 1,3-dipole is well-

known, and the ester moiety is an excellent synthetic handle, its

use is not without challenges. High temperatures,^[12]Lewis acid

catalysis,^[13]prolonged reaction times^[14]and structurally simple

dipolarophiles are typical in its use in [3+2]-dipolar

cycloadditions, several of which actively contribute to its known

degradation pathways and side reactions.

Results and Discussion

Fifteen α-thio-β-chloroacrylamides 8a-o were chosen for

investigation in this study, some of which were described in our

earlier work and others which are novel (8d, 8e, 8l, 8m). Each of

the known substrates were synthesised following our optimised

procedures as summarised in Scheme 2, affording multi-gram

quantities of these compounds, the majority of which were

amenable to storage at room temperature for several months

without any appreciable degradation. An exception to this

included the N-alkyl amide 8f and alkyl sulfides 8h-o used in this

study which required storage in the freezer to avoid degradation.

Scheme 1. Synthetic routes toward functionalised 3,4,5-substituted pyrazoles.

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Scheme 2. Synthetic route towards dipolarophile precursors (See Supporting

Information for more details).

were formed using optimised batch conditions described

previously.^[21]The novel α-thio-β-chloroacrylamides 8d, 8e, 8l,

8m are fully characterised in this work. Notably, the signal for

the β-H is very distinctive, and as a result, all novel α-thio-β-

chloroacrylamides generated in this work were assigned as the

Z-stereoisomer, in line with our earlier work. The α-thio-β-

chloroacrylamides underwent oxidation to their sulfoxide

derivatives by treatment with Oxone® overnight, without

evidence for over oxidation to the sulfone. The sulfoxides in

most instances were much more labile than the sulfide

derivatives and required storage in the freezer to avoid

degradation. In order to investigate the effect of replacing the

amide functionality with an ester moiety, with greater synthetic

potential, the α-thio-β-chloroacrylate 8p was also generated.^[15]

The synthesis of the novel precursors is summarised in Table 1.

The α-chloroamides were generated in almost quantitative yields

from commercially available 2-chloropropionyl chloride and the

requisite aromatic or aliphatic amine source and were sufficiently

pure to not require further purification. While previously

described α-thioamides were generated using either thiophenol,

benzyl mercaptan or 1-butanethiol in the presence of freshly

prepared sodium ethoxide, each of the novel α-thioamides 7d,

7e, 7l, 7m were generated using aqueous sodium hydroxide as

base, obviating the requirement for chromatographic purification.

While the generation of α-thio-β-chloroacrylamides in continuous

flow is amenable to scale up,^[20]all substrates used in this study

Table 1. Synthesis of novel dipolarophile precursors 8 and 9

Entry

R

α-Chloroamide

Yield^[a]

(%)

6

R¹

α-Thioamide

Yield^[a,b]

(%)

8

α-Thio-β-

chloroacrylamide

8

Yield^[c]

(%)

8

α-Sulfinyl-β-

chloroacrylamide

9

Yield^[c,d]

(%)

9

6

7

1

2

3

4

(CH₃)₃CCH₂

4-MeOC₆H₄

6d

98

Ph

Bn

Ph

Bn

7d

7l

98^[b]

86^[a]

89^[b]

94^[b]

8d

77

65

34

40

9d

-

96^[d]

-

8l

6e

97

7e

7m

8e^[e]

8m^[e]

9e

9h

79^[c]

92^[c]

[a] Isolated % yield post basic work up; column chromatography not required. [b] Isolated % yield post filtration; column chromatography not required. [c]

Isolated % yield after chromatography on silica gel. [d] Isolated % yield post aqueous work up; column chromatography not required. [e] Low yields of α-thio-β-

chloroacrylamide 8e and 8m due to the solubility issues encountered during chromatography.

[3+2]-Dipolar Cycloadditions of α-thio-β-chloroacrylamides

with ethyl diazoacetate

instances. As a result, despite evidence for residual α-thio-β-

chloroacrylamide 8 remaining after 24 hours, further ethyl

diazoacetate was not added to avoid increased formation of the

N–H insertion byproducts 11 and 12.

The dipolarophilic reactivity of the α-thio-β-chloroacrylamides

towards ethyl diazoacetate (EDA) as the 1,3-dipole was first

explored as shown in Table 2. An excess (8 equivalents) of ethyl

diazoacetate was added in one portion to a stirring solution of

the α-thio-β-chloroacrylamide in toluene (0.2 M) at room

temperature. The reaction solution was heated gradually to

100˚C and the temperature was maintained at this temperature

for 24 h. After 24 h the reaction mixture was cooled to room

temperature and an aliquot was concentrated under reduced

The pyrazoles 10a-q were isolated in moderate to good yields

across the α-thio-β-chloroacrylamides 8a-o substrate range,

predominantly as solids that proved stable on storage.

Interestingly, variation of the steric and electronic properties on

either the sulfur or amide substituent did not have a noticeable

impact on the outcome of the cycloaddition, highlighting the

generality of the method. In some instances (entries 2,4 and 11,

Table 2) the formation of the N–H insertion products 11 and 12,

through further reaction of the rearranged pyrazoles with ethyl

diazoacetate was significant; extensive optimization of the

reaction conditions was not attempted. In addition to variation of

the amide and sulfide substituents across 10a-o, the [3+2]-

1

pressure and analysed by H NMR spectroscopy. The H NMR

spectra indicated incomplete consumption of α-thio-β-

chloroacrylamide in all instances except for pyrazole 10c,

however characteristic methylene NCH₂signals for the two

regioisomeric N–H insertion 11 and 12 was observed in most

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dipolar cycloaddition between benzyl diazoacetate and α-thio-β-

chloroacrylamide 8a afforded the pyrazole 10q in 63% yield,

while the α-thio-β-chloroacrylate ester 8p also underwent

cycloaddition with ethyl diazoactetate to give the C(3) and C(5)

substituted dicarboxylate 10p in 49% yield.

Table 2. [3+2]-dipolar cycloaddition using α-thio-β-chloroacrylamides 8a-p.

Entry

R

α-thio-β-

chloro-

acrylamide 8

R¹

X

R²

Conversion^[a,b,c,d]

8 : 10: 11+12

Pyrazole 10

Yield^[e,f,g,h]

10 (%)

Pyrazole

Recovery^[i]

10 (%)

[b]

-

1

2

3

4

Et

8a

8b

8c

8d

Ph

NH

Tol

10a

10b

10c

10d

64^[e]

39^[e]

55^[e]

27^[f]

Bn

2 : 66 : 32

0 : 82 : 18

6 : 44 : 50

60

67

62

4-FC₆H₄

(CH₃)₃CCH₂

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5

Et

Bn

8e

8f

Ph

NH

NH₂

NH

O

4-MeOC₆H₄

12 : 66 : 22

7 : 78 : 15

8 : 86 : 5

10e

10f

40^[e]

67^[f]

71^[g,h]

52^[f]

28^[f]

60^[e]

19^[f]

59^[f]

55^[e]

44^[f]

35^[e]

49^[f]

63^[e,h]

60

85

83

74

38

76

49

87

90

57

42

6

Ph

n-Bu

7

8g

8h

8i

Bn

-

10g

10h

10i

8

Bn

n-Bu

17 : 70 : 13

5 : 74 : 21

12 : 79 : 9

3 : 38 : 58

24 : 68 : 8

39 : 61 : 0

9 : 77 : 14

2 : 84 : 14

9

Bn

Ph

10

11

12

13

14

15

16

17

8j

Bn

10j

8k

8l

Bn

4-FC₆H₄

(CH₃)₃CCH₂

4-MeOC₆H₄

Bn

10k

10l

Bn

8m

8n

8o

8p

8a

Bn

10m

10n

10o

10p

10q

n-Bu

Ph

Tol

Me

15 : 77 : 8

64

[d]

-

Ph

NH

Tol

[a] Estimated % conversion of α-thio-β-chloroacrylamide 8 to pyrazole 10 and combined N–H insertion products 11+12 were calculated from the ¹H NMR spectra

of the crude product in CDCl₃taken after 24 h. Estimated by integration of the β-H signal of 8, the pyrazole 10 NH signal, and the 2H, methylene NCH₂CO signals

of the NH insertion products 11 and 12. [b] ¹H NMR analysis of the crude reaction mixture for the generation of pyrazole 10a was not recorded. [c] NH insertion

products 11 and 12 not isolated except for 11a and 11b; assignment of the NH insertion products 11 and 12 in the crude ¹H NMR was made tentatively by analogy

using the methylene NCH₂CO signals. [d] Estimated % conversion for [3+2]-dipolar cycloaddition of α-thio-β-chloroacrylamide 8a with benzyl diazoacetate not

recorded as NH insertion products 11p and 12p (not isolated) could not readily be identified from the ¹H NMR of the crude reaction mixture. [e] Isolated % yield

after column chromatography on silica gel using hexane: ethyl acetate as eluent followed by trituration using diethyl ether. [f] Isolated % yield after column

chromatography (twice) on silica gel, first using hexane: ethyl acetate as eluent then dichloromethane: ethyl acetate. [g] Isolated % yield by filtration of the reaction

mixture. [h] As the NMR spectra of pyrazoles 10g and 10q were recorded in DMSO-d₆both the 3-, and 5-carboxylate tautomers were observed (see

Supplementary Information for more details). [i] Calculated % recovery of pyrazole 10 based on ratio of pyrazole 10 in the ¹H NMR spectrum of the crude product

mixture.

In line with the [3+2]-dipolar cycloadditions of α-diazoalkanes

with α-thio-β-chloroacrylamides,^[19]the reactions of 8a-o and α-

thio-β-chloroacrylate 8p were found to proceed with complete

regiocontrol, the carbon atom of ethyl diazoacetate adding to the

electrophilic β-carbon of the α-thio-β-chloroacrylamide, followed

by rearrangement to form pyrazoles 10a-q. From literature

precedent, [3+2]-dipolar cycloadditions of α-diazoacetates to

alkenes bearing electron withdrawing groups in direct

conjugation with the dipolarophilic component are generally

dipole-HOMO controlled, hence the predominant interaction

involves the two atoms with the largest orbital coefficients in the

dipole and dipolarophile respectively, which accounts for the

regiocontrol observed (Scheme 3).^{[11a, 22]}

The lower yields of pyrazoles 10d, 10i, 10k, 10l and 10n are

attributable in part to their co-elution during column

chromatography with the pyrazoline byproduct 13 derived from

the thermal decomposition of ethyl diazoacetate (Scheme 4).^[23]

Scheme 4. Thermal decomposition of ethyl diazoacetate and subsequent

formation of pyrazoline 13.

The N–H insertion byproducts 11a and 12a were isolated to

facilitate structural assignment, however, the other derivatives

11b-q and 12b-q were not isolated and characterised (Scheme

1

5). In all instances the pyrazole 11 is observed in the H NMR

spectrum of the crude product in greater amounts than 12

indicating that N–H insertion preferentially occurs to give the 5-

carboxylate 11.

Scheme 3. Regiochemistry of the [3+2]-dipolar cycloaddition of ethyl

diazoacetate with α-thio-β-chloroacrylamide.

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Figure 3. X-ray structure of pyrazole 11a (anisotropic displacement

parameters drawn at the 50% probability level).

Two potential mechanisms can be envisaged for the formation of

the rearranged pyrazoles 10a-q. Firstly, thermally induced

regiospecific [3+2]-dipolar cycloaddition of ethyl diazoacetate

with the α-thio-β-chloroacrylamides leads to the initial pyrazoline

cycloadduct (i). In the first instance an E₁elimination can be

considered, with loss of chloride to form a sulfur stabilised

carbocation [Scheme 6, Mechanism A, (ii)]. Subsequent

generation of an episulfonium ion intermediate (iii), followed by

deprotonation of the acidic α-carbon leads to ring opening of the

episulfonium ion and completes the sulfur migration to form (iv).

Finally, tautomerisation leads to aromatisation and the

rearranged pyrazoles.

Scheme 5. Formation of the 5-carboxylate 11a and 3-carboxylate 12a by N–H

insertion.

¹H-¹³C Heteronuclear multiple bond correlation spectroscopy

(HMBC) was used to determine the regiochemistry of the two N–

H insertion products 11a and 12a. The NMR experiment

revealed that the methylene protons at 5.58 ppm and the amide

NH at 10.01 ppm in pyrazole 12a both correlated to the same

C(5) ring carbon at 138.8 ppm. In pyrazole 11a the methylene

protons at 5.38 ppm correlated to the C(5) ring carbon at 137.2

ppm, however there was no correlation between the amide NH

at 9.07 ppm and C(5). Therefore, the pyrazole 12a was assigned

as the 3-carboxylate and pyrazole 11a as the 5-carboxylate

(Figure 2). As illustrated in Figure 2, the ¹³C NMR chemical shifts

of the C(3), C(4) and C(5) carbons of the pyrazole ring are

predominantly influenced by the regiochemistry of the pyrazole,

with limited impact of alteration of the substituent. Finally, X-ray

crystallography of pyrazole 11a following recrystallisation from

dichloromethane unambiguously confirmed the assignment of

pyrazole 11a as the 5-carboxylate (Figure 3).

Scheme 6. (Mechanism A). E₁elimination.

Figure 2. ¹H-¹³C HMBC 3 bond correlations indicating the assignments of NH-

insertion products 11a and 12a including relevant ¹H and ¹³C NMR chemical

shifts (in ppm).

Alternatively, the following E_1CB-like mechanism is postulated to

be more likely (Scheme 7, Mechanism B). Deprotonation of the

acidic α-carbon, adjacent to the ester moiety, in the initial

pyrazoline cycloadduct (i) generates an enolate (ii) that is

stabilised through extended conjugation. Subsequent elimination

of chloride generates the anti-aromatic pyrazole (iii). The sulfur

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could result in side reactions, or to the enhanced reactivity of the

migration can be envisaged to occur through an intramolecular

conjugate addition to generate the episulfonium ion intermediate

(iv), that subsequently ring opens to complete the sulfur

migration to form (v). Tautomerisation affords the aromatic

pyrazole 10a. It is believed that the driving force for the sulfur

migration in both mechanistic pathways is the restoration of the

α-sulfinyl-β-chloroacrylamides

relative

to

the

α-thio-β-

chloroacrylamides.

In all instances complete regiocontrol was observed, with the α-

carbon of the α-diazoacetate adding to the β-carbon of the

dipolarophile, with concomitant desulfinylation and aromatisation

to the 3,5-disubstituted pyrazoles observed. The regiochemistry

of the pyrazoles 14a-i was assigned by comparison of the

characteristic C(4) ring carbon of the ¹³C NMR spectra to

literature values for related compounds.^[19]For these reactions,

the outcome was comparable to our group’s earlier work using

trimethylsilyldiazomethane, both in terms of yield and

desulfinylation, albeit the α-diazoacetates requiring more forcing

conditions.

pyrazole

aromaticity.

In

our

earlier

work

with

trimethylsilyldiazomethane, formation of the carbocation (v)

analogous to (ii) (Scheme 6) was readily envisaged due to the

β-silicon effect, however in the ester derivative the formation of

the carbocation (ii) is less likely and as a result, the mechanistic

details may be altered by the different substituents on the 1,3-

dipole.^[19]Studies into the nature of the mechanistic pathway are

currently underway.

Table 3. [3+2]-Dipolar cycloadditions using α-sulfinyl-β-chloroacrylamides 9a-f

Scheme 7. (Mechanism B). E_1CB-like elimination.

[3+2]-Dipolar Cycloadditions of α-sulfinyl-β-

chloroacrylamides

Initial attempts to achieve [3+2]-dipolar cycloaddition of ethyl

diazoacetate (8 equivalents) and α-sulfinyl-β-chloroacrylamide

9a at room temperature or at reflux in dichloromethane did not

result in cycloaddition. Reverting to toluene at 100˚C resulted in

1

full consumption of the sulfoxide dipolarophile after 48 h. The H

Entry

R¹

α-Sulfinyl-

β-chloro-

acrylamide

9

R²

Pyrazole

14

Yield^[a,b,c,d]

(%) 14

NMR spectra of the crude product mixtures were complex,

hindering accurate determination of product ratios. Under these

conditions a series of α-benzenesulfinyl-β-chloroacrylamides

were reacted with ethyl diazoacetate and benzyl diazoacetate to

afford the novel pyrazoles 14a-i in yields of 13-47% (Table 3).

However, in most instances the 3,5-substituted pyrazoles

generated proved to be insoluble in toluene allowing isolation by

filtration from the reaction mixture on cooling (Table 3). Analysis

of the mother liquors demonstrated some loss of product

through the filtration process. In cases in which no precipitate

formed the pyrazoles were purified by column chromatography

(14d, 14f). The low yields of the desulfinylated pyrazoles may be

attributable to the generation of benzenesulfinyl chloride which

1

2

3

4

5

Et

9a

9b

9c

9d

9e

Tol

14a

14b

14c

14d

14e

47

Bn

31

4-FC₆H₄

(CH₃)₃CCH₂

4-MeOC₆H₄

27

19^[b]

17

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Alder cycloaddition between cyclopentadiene and sulfone 15a

(Scheme 9).^[18]Notably, an extensive oxidant screen including

H₂O₂, peracetic acid, KMnO₄, Oxone®, and MMPP determined

that mCPBA was the only oxidant that could actuate oxidation.

6

7

8

9

Et

9f

n-Bu

Tol

14f

14g

14h

14i

13^[b,d]

18

Bn

9a

9b

9c

Bn

27

4-FC₆H₄

49

[a] Isolated % yield collected by filtration of the reaction mixture unless

otherwise stated. [b] Isolated % yield after column chromatography. [c] As the

NMR spectra were recorded in DMSO-d₆(unless otherwise stated) the 3-, and

5-carboxylate tautomers were observed (see Supplementary Information for

more details).

[3+2]-Dipolar cycloaddition to form the initial pyrazoline

cycloadduct (i) is envisaged, followed by spontaneous syn-

elimination of benzenesulfinyl chloride from the pyrazoline

intermediate, leading to the desulfinylated cycloadduct (ii).

Subsequent tautomerisation affords the aromatic pyrazole 14

(Scheme 8).

Scheme

9.

Diels–Alder

cycloaddition

with

crude

α-sulfonyl-β-

chloroacrylamides 15a and cyclopentadiene.

With this is mind, the sulfoxide 9a was treated with m-CPBA (2

equiv.) in dichloromethane at room temperature for 43 h.

1

Reaction monitoring by H NMR spectroscopy over several time

increments indicated that the oxidation did not go to completion,

and that over time the impurity profile deteriorated. For this

reason, addition of ethyl diazoacetate was made once the level

of impurities was observed to significantly increase relative to

the increase of sulfone 15a. After the addition the reaction

mixture was stirred overnight at room temperature. The loading

of ethyl diazoacetate was decreased to 4 equivalents relative to

the 8 equivalents used at the sulfide and sulfoxide levels of

cycloaddition due to the anticipated increased reactivity of the

dipolarophile. The ¹H NMR spectrum of the crude reaction

mixture was very complex, however no evidence for residual

sulfone 15a was apparent. Repeated column chromatography

afforded the pure rearranged 4-sulfonylpyrazole 16a in 16%

yield over two steps.

Scheme 8. Mechanistic route toward desulfinylated 3,5-substituted pyrazoles

through 1,2-elimination of benzenesulfinyl chloride.

[3+2]-Dipolar Cycloadditions of α-sulfonyl-β-

chloroacrylamides

As the oxidation to form the sulfone is a limiting factor in the

overall transformation, optimisation was undertaken including

variation of time and/or increasing the reaction temperature to

reflux in dichloromethane. While it is clear that the sulfone is

sensitive to prolonged heating at reflux in dichloromethane, with

close monitoring of the reaction mixture by ¹H NMR

spectroscopy, optimal conversions can be achieved within 10-14

hours, leading to comparable results to when the oxidation was

conducted for 48 hours at room temperature.

Vinyl sulfones are among the most reactive and versatile

dipolarophiles,^[24]owing to the strongly electron withdrawing

character of the sulfone moiety. Namboothiri et al. have reported

extensively on the base-mediated [3+2]-dipolar cycloaddition of

phosphorylated and sulfonylated dipoles with various

dipolarophiles,

including vinyl

sulfones, to generate

functionalised C(3)-substituted sulfonylpyrazoles.^[25]However, in

light of our methodology forming the C(4)-substituted

sulfenylpyrazoles (Table 2) we were keen to explore whether α-

sulfonyl-β-chloroacrylamides would undergo cycloaddition with

α-diazoacetates, and if so, would sulfur migration be observed at

this level of oxidation.

Due to the unusual nature of the observed sulfone migration,

extension of this methodology to a range of α-sulfonyl-β-

chloroacrylamides with varying electronic and steric properties at

both the sulfone and amide was undertaken leading to a series

of 4-sulfonylpyrazoles 16a-g, albeit in low yields of 14-18%,

confirming that the sulfone migration was consistent across a

series of compounds (Table 4).

Previous work in our group demonstrated that the α-sulfonyl-β-

chloroacrylamides are extremely labile compounds, for example

as potent Michael acceptors, that can be generated and used

directly without isolation, for example in the successful Diels–

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Table 4. [3+2]-Dipolar cycloadditions with α-sulfonyl-β-chloroacrylamides 15.

Entry

R

R¹

α-sulfinyl-β-chloroacrylamide

Method^[a]

% α-sulfonyl-β-chloroacrylamide^[b]

Pyrazole

Yield^[c]

9

15

16

16 (%)

1

2

3

4

5

6

7

Ph

Bn

Tol

9a

9b

9c

9e

9f

A

B

78

71

63

16a

16b

16c

16d

16e

16f

16

18

14

16

9

Bn

4-FC₆H₄

4-MeOC₆H₄

n-Bu

30

[d]

4-FC₆H₄

4-MeOC₆H₄

9g

9h

16g

13

[a] Method A: 2 equiv. mCPBA in dichloromethane (15 ml) was added dropwise to a stirring solution of α-sulfinyl-β-chloroacrylamide 9 in dichloromethane (5ml)

at room temperature under nitrogen. The reaction mixture was stirred at room temperature for up to 48 h. Method B: 2 equiv. mCPBA in dichloromethane (15

ml) was added dropwise to a stirring solution of α-sulfinyl-β-chloroacrylamide 9 in dichloromethane (5ml) at room temperature under nitrogen. The reaction

mixture was heated to gentle efflux and stirred at this temperature for 10-14 h. Both methods were monitored by ¹H NMR spectroscopy at regular time

intervals. [b] Estimated % of α-sulfonyl-β-chloroacrylamide 15 present in the reaction mixture prior to the addition of ethyl diazoacetate. Determined from the ¹

H

NMR spectra of the crude reaction mixture. [c] Isolated % yield calculated over two steps after purification by repeated column chromatography. [d] %

conversion could not be accurately determined due to complexity of the ¹H NMR spectrum of the crude reaction mixture.

The regiochemistry of the [3+2]-dipolar cycloaddition and

subsequent rearrangement of pyrazole 16a was determined by

single X-ray crystallography following recrystallisation from

dichloromethane (Figure 4). Furthermore, the X-ray crystal

structure confirms that migration of the sulfone moiety has

occurred, with the sulfone at the C(4) position analogous to that

of the sulfide migration. The regiochemistry of the 4-

sulfenylpyrazole 10a was further confirmed by independently

oxidising 10a to the 4-sulfonylpyrazole 16a using mCPBA in

refluxing dichloromethane (see Table S2, supplementary

information).

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To the best of our knowledge, at the time of writing, carbon to

carbon 1,2-sulfonyl migration is unprecedented, thus the

rearrangement leading to 16 involving a 1,2-sulfonyl shift is

highly unusual. The mechanism for the formation of the

rearranged 4-sulfonylpyrazoles 16a-g is not well understood, but

several mechanistic routes can be considered based on the

confirmed regiochemistry of the products. In all instances,

regioselective [3+2]-dipolar cycloaddition of the crude α-sulfonyl-

β-chloroacrylamide leads to the initial pyrazoline cycloadduct (i),

which readily undergoes elimination of HCl to give the

intermediate cycloadduct (ii) (Scheme 10). While the sulfur

migration at the sulfide level can be readily understood due to

the nucleophilic character of the sulfide, extending this to

rationalise the unprecedented 1,2-sulfonyl shift is not feasible

Figure 4. X-ray structure of pyrazole 16a (anisotropic displacement

parameters drawn at the 50% probability level).

1

Comparison of the H, ¹³C and IR spectroscopic data confirmed

that the regiochemistry of the 4-sulfenylpyrazole 10a and 4-

sulfonylpyrazole 16a cycloadducts were identical.

Scheme 10. Proposed mechanistic routes for sulfone migration [(a) CONHTol substituent not shown in intermediate (ii)].

In light of the following two reports a [1,5]-sigmatropic shift can

be considered to rationalise the sulfonyl migration. Fuchs et al.

reported the thermally induced rearrangement of a γ-sulfonyl

enone to the rearranged sulfone in almost quantitative yields

(Scheme 11, A).^[26]The authors rationalised the transformation

through the formation of the enol intermediate which undergoes

a [1,5]-sigmatropic rearrangement. Notably, however this

reaction was carried out in toluene at 145˚C in a sealed tube.

Recently, Valdés et al. reported the synthesis of chiral pyrazoles

through

the

[3+2]-dipolar

cycloaddition

of

α-chiral

tosylhydrazones with alkynes (Scheme 11, B).^[27]Interestingly,

they observed that the initial cycloadduct underwent [1,5]-

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Unambiguous assignment of the ¹³C NMR signals for the C(3),

C(4) and C(5) carbons is particularly challenging, especially in

the absence of an adjoining proton (Figure 5). In order to

conclusively characterise our novel pyrazoles an in-depth ¹³C

NMR study was performed.

sigmatropic rearrangement with migration of the alkyl group.

Significantly in their study, they observed that the [1,5]-

sigmatropic rearrangement, which has two regioisomeric

outcomes, preferentially, but not exclusively, migrates to

nitrogen rather than the C(4) carbon. Forcing reaction conditions

(110˚C in 1,4-dioxane) were also required in this instance.

Considering these reports, we note that the pyrazoles 16 could

be generated through a [1,5]-sigmatropic shift of the sulfonyl

moiety (Scheme 10, Mechanistic Pathway A). However, the

[3+2]-dipolar cycloadditions in this work were carried out at room

temperature, while [1,5]-sigmatropic shifts generally require

much higher temperatures as can be seen above. While the

N(1)-substituted sulfone was not isolated or observed, since the

recoveries were very low it is impossible to exclude its formation.

Figure 5. Tautomeric forms of pyrazole 10a in solution.

An alternative mechanistic pathway can be envisaged with two

sequential [2,3]-sigmatropic rearrangements of the sulfonyl

moiety as illustrated in Scheme 10 (Mechanistic Pathway B)

followed by re-aromatisation via tautomerisation at the end of

the sequence to afford the C(3) carboxylate pyrazole 17a. The

second [2,3]-sigmatropic rearrangement is somewhat akin to an

allylic sulfinate-sulfone rearrangement.^[28]Alternatively, from the

intermediate (iv), homolytic cleavage of the weak N-O bond

The elucidation of the C(3), C(4) and C(5) pyrazole ring carbon

chemical shifts by ¹³C NMR at 75.5 MHz for pyrazoles 10 in

CDCl₃proved to be challenging, with the C(3) and C(5) carbons

not observed at this field strength, believed to be due to dynamic

tautomerism in conjunction with the absence of either direct or

indirect coupling to hydrogen. In most instances, however, a

weak signal was observed for the C(4) carbon as the chemical

shift of this carbon remains largely unaffected by tautomerism. In

contrast, at 150.9 MHz broad signals were observed for C(3),

C(4) and C(5). Interestingly when the spectra of the pyrazoles

10a-f and 10h-p were recorded at 150.9 MHz in the

noninteracting solvent CDCl₃only a single set of carbon signals

are seen indicating one of the following possibilities:

could be envisaged generating

a radical pair which on

recombination forms the more stable C–S bond (Scheme 10,

Mechanistic Pathway C).

A) one exclusive tautomer in solution, or

B) tautomers rapidly interconverting on the NMR

timescale, or

C) two tautomers in dynamic equilibrium with the

equilibrium highly favouring one tautomer with the

concentration of the minor tautomer so negligble that it

is not detectable by ¹³C NMR.

Due to the broadening of the signals for the C(3), C(4) and C(5),

it is unlikely that one tautomer exists exclusively in solution,

although the signal broadening could be due in part to the

quadrupolar moment of ¹⁴N rather than tautomerism only.

Furthermore, the ¹³C NMR spectra of the pyrazoles 11a and 12a

could readily be obtained at 75.5 MHz with each of the C(3),

C(4) and C(5) ring carbons observed as sharp signals,

consistent with the pyrazoles 11a and 12a being unable to

undergo prototropic tautomerism due to the alkylation of the

respective N(1) positions (Figure 2). This strongly suggests that

the signal broadening observed in pyrazole 10a is not due to the

¹⁴N quadrupolar moment. Direct comparison of the sp²region of

the ¹³C NMR spectra of the pyrazole 10a and the two N–H

insertion products 11a and 12a demonstrated that the chemical

shifts in pyrazole 10a and 12a were remarkably similar, and

substantially different to those of pyrazole 11a (Figure 6). This

observation allowed assignment of the major tautomer of 10a in

CDCl₃to be identified as the 3-carboxylate, however, it is not the

exclusive tautomer as both N-alkylated pyrazoles 11a and 12a

are formed through the N–H insertion reaction. This allows us to

conclude that for pyrazoles of the type 10 in the non-interacting

solvent CDCl₃that the tautomers exist in dynamic equilibrium

Scheme 11. Literature examples of 1) [1,5]-sigmatropic shift of sulfone moiety;

2) [1,5]-sigmatropic shift of alkyl group in pyrazole system.

Spectroscopic

Determination

of

the

Tautomeric

Composition of 3,4,5-substituted pyrazoles

Definitive spectroscopic analysis of unsubstituted NH pyrazole

scaffolds is complicated by the dynamic tautomeric nature of

these compounds. For this reason, significant attention has been

paid in the literature to the spectroscopic analysis of these

compounds particularly using ¹H-¹³C HMBC and NOE

experiments, often in conjunction with each other.^[29]

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by comparing the ¹³C NMR spectra for pyrazoles 10a, 11a and

12a in DMSO-d₆with those in CDCl₃. Notably in DMSO-d₆, two

distinct sets of broad signals were observed for pyrazole 10a at

150.9 MHz (see Figure S17, supplementary information),

characteristic of both the 3-carboxylate and 5-carboxylate

tautomer, with the 5-carboxylate predominating as the major

tautomer in solution as evidenced by comparison of carbon

signals with that of pyrazole 11a. For tautomer assignment one

of the characteristic features is that the C(4) chemical shift for

the 5-carboxylate tautomer is always more deshielded than that

for the 3-carboxylate. Accordingly, in the experimental section,

the pyrazoles 10g and 10q are characterised as a mixture of the

3-, and 5-carboxylate tautomers while pyrazoles 10a-f and 10h-

p were characterised as the major 3-carboxylate tautomer as

their spectra were recorded in CDCl₃(Figure 7). The impact of

solvent on the dynamic equilibrium between the 3- and 5-

carboxylate tautomers for pyrazole 10a is summarised in

Scheme 12.

albeit with the 5-carboxylate form present in undetectable

concentrations. An alternative possible explanation for the signal

broadening could be due to the presence of amide rotamers;

comparison of the ¹³C NMR spectra of pyrazole 10a with the two

NH insertion products 11a and 12a, however, highlights that the

signal broadening is due to tautomers, with no dynamic effects

observed in the ¹³C NMR spectra of 11a and 12a.

Figure 6. ¹³C NMR (150.9 MHz) spectra of pyrazole 10a and N–H insertion

products 11a and 12a illustrating that the major and minor tautomer of

pyrazole 10a in CDCl₃is the 3-carboxylate.

While it appears that the dynamic equilibrium in CDCl₃favours

the 3-carboxylate tautomeric form it is interesting that it is, in

fact, the minor tautomer that undergoes N–H insertion more

readily to give the pyrazole 11a as the major regioisomer. To

test whether this was due to the minor tautomer being more

reactive or whether the dynamic equilibrium tended towards the

5-carboxylate in the reaction solution, ¹³C NMR spectra for the

pyrazole 10a and the NH insertion products 11a and 12a were

recorded in toluene-d₈, the solvent used for the cycloaddition, at

150.9 Hz MHz (see Figure S16, supplementary information). As

was observed in CDCl₃, substantial overlap of the signals was

observed with those for N–H insertion product 12a, indicating

that the major tautomer present in toluene-d₈, and presumably

the reaction medium, is the 3-carboxylate. Therefore, despite the

observation that the equilibrium between the 3-carboxylate and

5-carboxylate tautomers in non-interacting solvents strongly

favours the 3-carboxylate tautomer, isolation of the 5-

carboxylate as the major NH insertion product 11a suggests that

the minor tautomer is significantly more reactive.

Scheme 12. Summary of solvent effects on the dynamic equilibrium between

the 3, and 5-carboxylate tautomers for pyrazole 10a.

Pyrazoles 14a-i were significantly less soluble than their 3,4,5,-

substituted counterparts, and DMSO-d₆was required to

solubilise these compounds for NMR spectroscopy. The NMR

spectra of 14f could be recorded in CDCl₃. Pyrazole 14f

exhibited one set of broad signals in the ¹³C NMR spectrum at

150.9 MHz in CDCl₃, while splitting of both the NH pyrazole and

NH amide signals, into major and minor components, was

observed in the ¹H NMR spectrum at 600 MHz. Two sets of

broad signals were observed in the ¹³C NMR spectra for

pyrazoles 14a-e and 14g-i recorded in DMSO-d_6,indicative of

the 3-carboxylate and 5-carboxylate, however, comparison of

the ¹³C NMR spectra of pyrazoles 10 and 14 in DMSO-d₆

strongly suggests that the dynamic equilibrium shifts towards the

3-carboxylate on removal of the sulfur moiety at the C(4)

As pyrazoles 10g and 10q were insoluble in CDCl₃their NMR

spectra were recorded in DMSO-d₆with broad signals for both

tautomers observed in each instance. Considering this, the

solvent dependency on the position of equilibrium was studied

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position (see supplementary information for further details).

Therefore, similar solvent effects on the dynamic equilibrium are

observed for both the 3,5-substituted and 3,4,5-substituted

pyrazoles 10 and 14 respectively, however, with the 5-

carboxylate predominating for the 3,4,5-substuted pyrazoles 10

and the 3-carboxylate predominating for the 3,5-substituted

pyrazoles 14 in DMSO-d₆. Accordingly, the pyrazoles 14a-i are

characterised as the 3-carboxylate in this work (Figure 7).

[3+2]-dipolar cycloadditions at both the sulfoxide and sulfone

levels, C(4) substituted sulfoxide and sulfone pyrazole

derivatives can be accessed readily in synthetically useful

quantities in the same overall number of synthetic steps.

Regioselective N-alkylation using alkyl bromides and K₂CO₃in

DMSO^[30]afforded the alkylated products in high combined

yields, with the 5-carboxylate formed preferentially in all

instances, consistent with selective alkylation of the major

tautomer present in DMSO (Scheme 12). Hydrolysis of the ester

moiety to the carboxylic acid 20 and subsequent amide coupling

gave pyrazole 21 illustrating that the use of α-diazoacetates as

dipoles and α-sulfenyl-β-chloroacrylamides as dipolarophiles

allows access not only to the generation of highly functionalised

pyrazoles but importantly functionalised pyrazoles amenable to

significant further synthetic transformations. An overview of

these synthetic transformations is outlined in Scheme 13, with

the tabulated results included in the supplementary information

(Table S1-S2 and Scheme S1).

In the solid state, the 4-sulfonylpyrazole 16a exists as the

tautomer with the carboxylate at the C(3) position (Figure 4). As

is the case for the pyrazoles formed at sulfide oxidation level,

one set of ¹³C NMR signals is observed for the 4-

sulfonylpyrazoles 16 in the non-interacting solvent CDCl₃,

however the C(4) carbon is considerably sharper and more

deshielded for this set of compounds than for the sulfide

analogues. The C(3) and C(5) carbons remain very broad,

suggesting that the pyrazoles 17 are also in dynamic

equilibrium, with the 3-carboxylate the favoured tautomer, and

the 5-carboxylate tautomer undetectable in the ¹³C NMR spectra

as seen at the sulfide level of cycloaddition. The 4-

sulfonylpyrazoles 17 are assigned as the major 3-carboxylate

tautomer in this work (Figure 7).

Scheme 13. Overview of the synthetic potential of the densely functionalised

3,4,5-substituted pyrazoles 10; facile selective sulfur oxidation, regioselective

N-alkylation, ester hydrolysis and sequential amide coupling.

Figure 7. Principal tautomers of 3,4,5 substituted pyrazoles 10a-q and 16a-g,

and 3,5-substituted pyrazoles 14a-i illustrating the importance of solvent on

the dynamic equilibrium. Structures are named and numbered accordingly in

the experimental section/supplementary information.

Conclusions

Further Derivatisation of the Pyrazole Scaffold

In summary, we have presented herein highly regioselective

synthetic methodology leading to densely functionalised C(3),

C(4) and C(5) substituted pyrazoles 10a-q and 16a-g via

thermal [3+2]-dipolar cycloaddition, of α-diazoacetates and α-

thio-β-chloroacrylamides, at the sulfide, sulfoxide and sulfone

levels of oxidation. Significantly, this work allows access to C(4)-

sulfenyl or sulfonyl pyrazoles, through migration of the sulfur

substituent at the sulfide and sulfone oxidation levels, while

elimination of the sulfinyl group is observed, leading to 3,5-

The [3+2]-dipolar cycloaddition of α-diazoacetates is a powerful

synthetic methodology that has the advantage that it allows

incorporation of highly functionalised substituents at each the

C(3), C(4) and C(5) positions of the pyrazole core. As there are

very few examples of 3,4,5-trisubstituted pyrazoles (particularly

bearing

a sulfur moiety), with each substituent bearing

functionalisable groups investigation of the synthetic potential of

these compounds was briefly undertaken utilising pyrazole 10a

as a standard substrate.

disubstituted pyrazoles 14a-i.

Notably, use of highly

functionalised dipolarophiles, and in particular a chlorine which

can act as a leaving group, enables the key rearrangement

following cycloaddition to provide the synthetically versatile

pyrazoles, where each of the three substituents has the potential

for orthogonal functional group interconversion. While the sulfide

Notably, selective oxidation of sulfides 10 to either sulfoxides 19

or sulfones 16 can readily be achieved in high yields using

mCPBA. Therefore, despite the limitations associated with the

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Single-crystal X-ray analysis was performed on

a Bruker APEX II DUO

migration to the electron deficient carbon is readily rationalised,

the analogous carbon-carbon 1,2-sulfonyl migration is

unprecedented and mechanistically intriguing. Notably, we have

found that the [3+2]-dipolar cycloaddition is remarkably

insensitive to the nature of the substituent present on both the

amide and sulfide, with extension to esters also possible. While

moderate to good yields are obtained using the dipolarophiles at

the sulfide level of oxidation, efficiencies are decreased when

conducted using the sulfoxide or sulfone, reflecting the labile

nature of the reactants and products under the reaction

conditions.

diffractometer at room temperature using graphite monochromatic Mo Kα (λ =

0.7107 Å) radiation. All calculations and refinement were made using the

APEX software,^[31]containing the SHELX suite of programs^[32]and diagrams

prepared with Mercury 3.10.^[33]All nonhydrogen atoms were located and

refined with anisotropic thermal parameters. Hydrogen atoms were included in

calculated positions or were located and refined with isotropic thermal

parameters.

General procedure for the preparation for the formation of α-

chloroamides. 2-Chloro-N-(2′,2′-dimethylpropyl)propanamide (6d)

2-Chloropropionyl chloride (7.61 g, 59.94 mmol) in dichloromethane (50 ml)

was added dropwise over 20 min to a solution of 2,2-dimethylpropylamine

(5.17 g, 59.35 mmol) and triethylamine (6.07 g, 59.94 mmol) in

dichloromethane (100 ml) at 0°C, while stirring under nitrogen. On completion

of the addition, the reaction solution was removed from the ice bath and stirred

at room temperature for 4 h. Water (200 ml) was added and the layers

separated. The organic layer was washed with a saturated solution of sodium

bicarbonate (2 x 150 ml), water (200 ml), and brine (200 ml), dried, filtered and

concentrated under reduced pressure to give the α-chloroamide 6d as a white

solid (15.38 g, 97 %) which required no further purification; mp 79-81˚C;

In contrast to alternative synthetic methods leading to pyrazoles,

such as hydrazine condensation, this methodology offers distinct

synthetic advantage enabling access to highly substituted and

structurally diverse pyrazoles with functionality amenable to

further selective synthetic transformations.

_max/cm^-1(ATR) 3255 (NH), 3093 (CH), 2957 (CH), 1652 (CO), 1574, 1374

Isolation of the N-alkylated pyrazoles 11a and 12a as by-

products from the cycloaddition through further reaction of the

pyrazoles 10 with excess α-diazoacetate, proved useful in

rationalising the tautomeric behaviour evident in the NMR

spectra of the pyrazoles, with the position of tautomeric

equilibrium influenced by solvent and substituents.



(CN stretch); ¹H NMR (300 MHz, CDCl₃) δ = 0.94 [s, 9H, C(CH₃)₃], 1.75 [d, J =

7.1 Hz, 3H, C(3)H₃], 3.06 [dd, A of ABX system, J_AB= 13.3 Hz, J_AX= 6.3 Hz,

1H, one of CH₂NH], 3.13 [dd, B of ABX system, J_BA= 13.3 Hz, J_BX= 6.4 Hz,

1H, one of CH₂NH], 4.45 [q, J = 7.1 Hz, 1H, C(2)H], 6.70 (br s, 1H, NH) ppm;

¹³C NMR (75.5 MHz, CDCl₃) δ = 22.8 [CH₃, C(3)H₃], 27.0 [C(CH₃)₃], 31.9 [C,

C(CH₃)₃], 50.8 (CH₂NH), 56.3 [CH, C(2)H], 169.4 (C=O) ppm; HRMS (ES+):

Exact mass calculated for C₈H₁₆NO³⁵Cl [M+H]⁺178.0993. Found 178.0995;

m/z (ES+) 180.3 {[(C₈H₁₆NO³⁷Cl)+H⁺], 30%}, 178.3 {[(C₈H₁₆NO³⁵Cl)+H⁺],

100%}.

Experimental Section

General procedure for the preparation for the formation of α-thioamides.

N-(2′,2′-Dimethylpropyl)-2-(phenylthio)propanamide (7d)

General Procedures: Solvents were distilled prior to use as follows:

Dichloromethane was distilled from phosphorus pentoxide, ethyl acetate was

distilled from potassium carbonate; and hexane was distilled prior to use. For

[3+2]-dipolar cycloadditions HPLC grade toluene was used. All commercial

reagents were used without further purification unless otherwise stated.

Thiophenol (2.89 ml, 28.2 mmol) in ethanol (22 ml) was added to a solution of

aqueous sodium hydroxide (0.8 M, 78 ml, 54.20 mmol). Immediately,

a

solution of 2-chloro-N-(2′,2′-dimethylpropyl)propenamide 6d (4.80 g, 27.10

mmol) in ethanol (60 ml) was added gradually over 15 minutes to the reaction

mixture. Following heating under reflux for 1 h, the reaction was cooled in an

ice bath and was quenched by the addition of water (70 ml). The solid

precipitate was isolated by suction filtration to give pure N-(2′,2′-

dimethylpropyl)-2-(phenylthio)propenamide 7d as a white solid (6.67 g, 98 %);

mp 87-89˚C; _max/cm^-1(ATR) 3272 (NH), 2964 (CH), 2953 (CH), 1640 (C=O

amide), 1564, 1203; ¹H NMR (300 MHz, CDCl₃) δ = 0.78 [s, 9H, C(CH₃)₃],

1.56 [d, J = 7.3 Hz, 3H, C(2)H₃], 2.95 [dd, A of ABX system, J_AB= 13.3 Hz, J_AX

¹H NMR spectra were run at either 300, 400 or 600 MHz and ¹³C NMR spectra

were recorded at either 75.5, 100 or 150.9 MHz. All spectra were recorded at

room temperature (300K) in deuterated chloroform (CDCl₃), unless otherwise

stated using tetramethylsilane (TMS) as an internal standard. Chemical shifts

(δ_Hand δ_C) are reported in parts per million (ppm) relative to TMS, and

coupling constants are expressed in hertz (Hz). Splitting patterns in ¹H NMR

spectra are designated as s (singlet), br s (broad singlet), d (doublet), t (triplet),

q (quartet), dd (doublet of doublets) and m (multiplet). ¹³C NMR spectra were

calibrated using the solvent signal, i.e., CDCl₃δ_C77.0 ppm, DMSO-d₆39.5

ppm, toluene-d₈20.4 ppm. Assignments were made with the aid of DEPT

experiments and 2D NMR experiments including COSY, HSQC and HMBC.

= 6.0 Hz, 1H, one of CH₂NH], 3.06 [dd, B of ABX system, J_BA= 13.3 Hz, J_BX

=

6.7, 1H, one of CH₂NH], 3.91 [q, J = 7.4 Hz, 1H, C(2)H], 6.79 (br s, 1H, NH),

7.15-7.36 (m, 5H, ArH) ppm; ¹³C NMR (75.5 MHz, CDCl₃) δ = 18.3 [CH₃,

C(3)H₃], 26.9 [CH₃, C(CH₃)₃] 31.6 [C, C(CH₃)₃], 46.6 [CH, C(2)H], 50.6 (CH₂,

CH₂NH), 126.7 (CH, CH_Ar), 129.0 (CH, CH_Ar), 129.1 (CH, CH_Ar), 134.1 [C,

C_Ar(q], 171.5 (C=O) ppm; HRMS (ES+): Exact mass calculated for C₁₄H₂₁NOS

[M+H]⁺252.1422. Found 252.1428; m/z (ES+) 252.4 {[(C₁₄H₂₁NOS)+H⁺],

100%}.

Infrared spectra were measured using a FTIR UATR2 spectrometer or were

recorded as films on sodium chloride plates on a PerkinElmer Paragon 1000

FT-IR spectrometer. Flash column chromatography was carried out using

Kieselgel silica gel 60, 0.035−0.075 mm (Merck).

Thin-layer chromatography (TLC) was carried out on precoated silica gel

plates (Merck 60 PF254). Visualization was achieved by UV (254 nm) light

absorption.

Novel compounds 7e and 7l-m were similarly prepared, see supplementary

information for characterisation data.

The Microanalysis Laboratory, National University of Ireland, Cork, performed

elemental analysis using a PerkinElmer 240 and Exeter Analytical CE440

elemental analyser. Low-resolution mass spectra (LRMS) was recorded on a

Waters Quattro Micro triple quadrupole instrument in electrospray ionization

(ESI) mode using 50% acetonitrile−water containing 0.1% formic acid as

eluent. High resolution (precise) mass spectra (HRMS) were recorded on a

Waters LCT Premier Tof LC−MS instrument in electrospray ionization (ESI)

mode using 50% acetonitrile−water containing 0.1% formic acid as eluent.

High-resolution (precise) mass spectra (HRMS) were also recorded on an

General procedure for the preparation for the formation of α-thio-β-

chloroacrylamides.

N-(2′,2′-Dimethylpropyl)-Z-3-chloro-2-(phenylthio)propenamide (8d)

Unrecrystallised N-chlorosuccinimide (5.19 g, 38.90 mmol) was added in one

portion to a solution of N-(2′,2′-dimethylpropyl)-2-(phenylthio)propenamide 7d

(5.01 g, 19.95 mmol) in toluene (110 ml). The flask was immediately immersed

in an oil bath at 90 °C and heating was maintained with stirring for 3 h. The

reaction mixture was cooled to 0 °C and the succinimide by-product was

removed by filtration. The solvent was removed at reduced pressure to give

Agilent

6530B

Accurate

Mass

Q-TOF

LC/MS

instrument

in

electrosprayionisation mode using 50% acetonitrile− water containing 0.1%

formic acid as eluent. Samples were prepared for either LRMS or HRMS by

employing acetonitrile as solvent.

the crude product as

a brown solid. This was purified by column

chromatography on silica gel using hexane: ethyl acetate (95:5) as eluent to

give the pure α-thio-β-chloroacrylamide 8d as a white solid (4.13 g, 77%); mp

79-82°C; Found C, 59.39; H, 6.35; N, 4.96. C₁₄H₁₈NOSCl requires C, 59.25; H,

6.39; N, 4.94; _max/cm^-1(ATR) 3382 NH), 2955 (CH), 1646 (C=O amide), 1519,

1232; ¹H NMR (300 MHz, CDCl₃) δ = 0.68 [s, 9H, C(CH₃)₃], 3.02 (d, J = 6.4

Melting points were obtained using

a Unimelt Thomas−Hoover capillary

melting point apparatus and are uncorrected.

10.1002/ejoc.201900494

European Journal of Organic Chemistry

FULL PAPER

Hz, 2H, CH₂NH), 6.92 (br s, 1H, NH), 7.16-7.33 (m, 5H, ArH), 7.97 [s, 1H,

ClHC(3)=] ppm; ¹³C NMR (75.5 MHz, CDCl₃) δ = 26.8 [CH₃, C(CH₃)₃], 31.7 [C,

C(CH₃)₃], 51.1 (CH₂, CH₂NH), 127.0 (CH, CH_Ar), 127.8 (CH, CH_Ar), 129.5 (CH,

CH_Ar), 130.4 [C, SC(2)=], 133.0 (C, C_Ar(q)), 139.7 [CH, C(3)HCl=], 162.1 (C=O)

ppm; HRMS (ES+): Exact mass calculated for C₁₄H₁₈NOS³⁵Cl [M+H]⁺

284.0858. Found 284.0866; m/z (ES+) 286.3 {[(C₁₄H₁₈NOS³⁷Cl)+H⁺], 40%},

284.3 {[(C₁₄H₁₈NOS³⁵Cl)+H⁺], 100%}.

major and minor tautomers, CH_Ar), 132.7 (C, major tautomer, C_Ar(q)), 133.6 (C,

minor tautomer, C_Ar(q)), 135.3 (C, minor tautomer, C_Ar(q)), 136.2 (C, major

tautomer, C_Ar(q)),136.3 (C, major tautomer, C_Ar(q)), 136.8 (C, minor tautomer,

C_Ar(q)), 137.5 [C, major tautomer, one of C(3) or C(5)],142.1 [C, minor tautomer,

one of C(3) or C(5)], 144.8 [C, minor tautomer, one of C(3) or C(5)], 149.9 [C,

major tautomer, one of C(3) or C(5)], 156.2 (C, minor tautomer, C=O amide),

158.0 (C, major tautomer, C=O amide), 159.2 (C, major tautomer, C=O ester),

160.8 (C, minor tautomer, C=O ester) ppm; ¹³C NMR (150.9 MHz, Toluene-d₈)

δ = 14.1 (CH₃, OCH₂CH₃), 20.8 (CH₃, ArCH₃), 61.0 (CH₂, OCH₂CH₃), 109.6 [C,

br, C(4)], 120.2 (CH, CH_Ar), 126.8 (CH, CH_Ar), 129.4 (CH, CH_Ar), 129.9 (CH,

CH_Ar), 134.4 (C, C_Ar(q)), 135.4 (C, C_Ar(q)), 135.8 (C, C_Ar(q)), 140.9 [C, br, one of

C(3) or C(5)], 146.0 [C, br, one of C(3) or C(5)], 156.0 (C, C=O amide), 160.5

(C, C=O ester) ppm; HRMS (ES+): Exact mass calculated for C₂₀H₁₉N₃O₃S

[M+H]⁺382.1208. Found 382.1215; m/z (ES+) 382.2 {[(C₂₀H₁₉N₃O₃S)+H⁺],

48%}, 782.7 (100%).

Novel compounds 8e and 7l-m were similarly prepared, see supplementary

information for characterisation data.

General procedure for the preparation for the formation of α-sulfinyl-β-

chloroacrylamides.

N-(2′,2′-Dimethylpropyl)-Z-3-chloro-2-(benzenesulfinyl)propenamide (9d)

Note: 4 x CH_Arsignals observed for 5 x CH_Arsignals in ¹³C NMR spectrum of

pyrazole 10a in toluene-d_8.1 CH_Arsignal overlapping with toluene-d₈residual

solvent peaks.

A solution of Oxone® (6.69 g, 21.76 mmol) in water (40 ml) was added

dropwise to

(phenylthio)propenamide 8d (3.08 g, 10.88 mmol) in acetone (120 ml) at room

temperature. colourless precipitate formed immediately. The reaction

a stirring solution of N-(2′,2′-dimethylpropyl)-Z-3-chloro-2-

A

Compounds 10b-q were similarly prepared, see supplementary information for

mixture was stirred overnight at which point water (200 ml) was added. The

layers were separated and the aqueous layer was extracted with

dichloromethane (3 x 70 ml). The combined organic extracts were washed

with water (2 x 100 ml) and brine (100 ml), dried, filtered and concentrated to

give the pure sulfoxide 9d as a clear oil (3.13 g, 96 %); _max/cm^-1(ATR) 3267

(NH stretch), 3059 (CH stretch), 2957 (CH), 1668 (C=O amide), 1556 (NH

bend), 1030 (SO); ¹H NMR (300 MHz, CDCl₃) δ = 0.82 [s, 9H, C(CH₃)₃], 2.91-

3.00 [dd, A of ABX system, J_AB= 13.3 Hz, J_AX= 5.5 Hz, 1H one of CH₂NH],

3.10-3.19 [dd, B of ABX system, J_BA= 13.3 Hz, J_BX= 6.5 Hz, 1H, one of

characterisation data.

General procedure for the [3+2]-dipolar cycloaddition of α-diazoacetetes

and α-sulfinyl-β-chloroacrylamides.

Ethyl 5-(4′-methylphenylcarbamoyl)-1H-pyrazole-3-carboxylate (14a)

Ethyl diazoacetate (0.97 ml, >87% in dichloromethane, 8 mmol) was added in

one portion to

a stirring solution of N-(4′-methylphenyl)-Z-3-chloro-2-

(benzenesulfinyl)propenamide 9a (319 mg, 1 mmol) in toluene (2 ml) at room

temperature. The reaction mixture was heated gradually to 100˚C and was

stirred at this temperature under nitrogen for 48 h. Upon completion, the

reaction mixture was cooled to room temperature during which a precipitate

formed. The reaction mixture was further cooled in an ice bath for 1 h. The

precipitate was collected by filtration through a sintered glass funnel (grade 4),

and was washed thoroughly with diethyl ether until all the yellow impurity had

been removed to give the pyrazole 14a as a white solid (128 mg, 47%); mp

216-218°C; _max/cm^-1(ATR) 3341 (NH stretch), 3213 (NH) 3000 (CH), 1692

(C=O ester), 1667 (C=O amide), 1509, 826; ¹H NMR (300 MHz, CDCl₃) δ =

1.41 (t, J = 7.1 Hz, 3H, OCH₂CH₃), 2.34 (s, 3H, ArH), 4.43 (q, J = 7.1 Hz, 2H,

OCH₂CH₃), 7.17 (d, J = 8.2 Hz, 2H, ArH), 7.42 [s, 1H, C(4)H], 7.56 (d, J = 8.3

Hz, 2H, ArH), 8.61 (br s, 1H, NH amide), 11.33 (br s, 1H, NH pyrazole) ppm;

¹H NMR (600 MHz, DMSO-d₆) δ = 1.32 (t, J = 7.1 Hz, 3H, OCH₂CH₃), 2.27 (s,

3H, ArCH₃), 4.32 (q, J = 7.1 Hz, 2H, OCH₂CH₃), 7.15 (d, J = 8.2 Hz, 2H, ArH),

7.48 [br s, 1H, C(4)H], 7.65 (d, J = 8.3 Hz, 2H ArH), 10.18 (br s, 1H, NH

amide), 14.47 (br s, 1H, NH pyrazole) ppm; ¹³C NMR (150.9 MHz, DMSO-d₆)

14.2 (CH₃, ArCH₃), 20.5 (CH₃, OCH₂CH₃), 60.7 (CH₂, OCH₂CH₃), 108.6 [CH,

C(3)H], 120.3 (CH, CH_Ar), 129.1 (CH, CH_Ar), 133.0 (C, C_Ar(q)), 135.9 (C, C_Ar(q)),

157.6 (C, br, C=O amide), 160.3 (C, br, C=O ester) ppm; HRMS (ES+): Exact

mass calculated for C₁₄H₁₅N₃O₃[M+H]⁺274.1196. Found 274.1196.

CH₂NH], 7.47-7.70 (m, 5H, ArH), 7.80 (s, 1H, ClHC(3)=), 8.34 (C=O) ppm; ¹³

C

NMR (75.5 MHz, CDCl₃) δ = 27.2 [CH₃, C(CH₃)₃], 31.7 [C, C(CH₃)₃], 50.8 (CH₂,

CH₂NH), 124.2 (CH, CH_Ar), 129.6 (CH, CH_Ar), 131.6 (CH, CH_Ar), 137.5 [CH,

C(3)HCl=], 138.7 [C, SC(2)=], 141.2 (C, C_Ar(q)), 160.8 (C=O) ppm; HRMS

(ES+): Exact mass calculated C₁₄H₁₈NO₂S³⁵Cl [M+H]⁺300.0820. Found

300.0827; m/z (ES+) 302.2 {[(C₁₄H₁₈NO₂S³⁷Cl)+H⁺], 40%} 300.2

{[(C₁₄H₁₈NO₂S³⁵Cl)+H⁺], 100%}.

Novel compounds 9e and 9h were similarly prepared, see supplementary

information for characterisation data.

General procedure for the [3+2]-dipolar cycloaddition of α-diazoacetetes

and α-sulfenyl-β-chloroacrylamides.

Ethyl 4-(phenylthio)-5-(4′-methylphenylcarbamoyl)-1H-pyrazole-3-

carboxylate (major tautomer) and ethyl 4-(phenylthio)-3-(4′-

methylphenylcarbamoyl)-1H-pyrazole-5-carboxylate (minor tautomer)

(10a)

Ethyl diazoacetate (0.97 ml, 8 mmol, 87% in dichloromethane) was added in

one

portion

to

a

solution

of

N-(4′-methylphenyl)-Z-3-chloro-2-

Note: In the ¹³C NMR spectrum of pyrazole 14a at 150.9 MHz the C(3) and

(phenylthio)propenamide 8a (303 mg, 1 mmol) in toluene (5 ml) at room

temperature. The solution was heated gradually to 100 °C and stirred under

nitrogen for 24h. The cooled reaction mixture in toluene was transferred

directly onto a silica gel column to prevent any potential degradation of

unreacted EDA if concentrated. Purification by column chromatography using

hexane-ethyl acetate (gradient elution 20-30% ethyl acetate) as eluent,

followed by trituration with diethyl ether gave the pyrazole 10a as a white solid

(245 mg, 64 %); mp 155-158 °C; _max/cm^-1(ATR) 3188 (NH), 1717 (C=O ester),

1661 (C=O amide), 1235, 817, 737; ¹H NMR (600 MHz, CDCl₃) δ = 1.28 (t, J =

7.1 Hz, 3H, OCH₂CH₃), 2.32 (s, 3H, ArCH₃), 4.35 (q, J = 7.1 Hz, 2H,

OCH₂CH₃), 7.15 (d, J = 8.3 Hz, 2H, ArH), 7.17-7.30 (m, 5H, ArH), 7.49 (d, J =

8.3 Hz, 2H, ArH), 9.95 (br s, 1H, NH amide), 13.08 (br s, 1H, NH pyrazole)

ppm; ¹H NMR (600 MHz, DMSO-d₆) δ = 1.13 (t, J = 7.1 Hz, 3H, OCH₂CH₃),

2.25 (s, 3H, ArCH₃), 4.20 (q, J = 7.0 Hz, 2H, OCH₂CH₃), 7.11 (app. t,

unresolved coupling, 5H, ArH), 7.23 (app. t, unresolved coupling, 2H, ArH),

7.51-7.61 (m, 2H, ArH), 10.27 (br s, 1H, NH amide), 14.80 (br s, 1H, NH

pyrazole) ppm; ¹H NMR (600 MHz, Toluene-d₈) δ = 1.01 (t, J = 7.1 Hz, 3H,

OCH₂CH₃), 2.04 (s, 3H, ArCH₃), 4.07 (q, J = 7.1 Hz, 2H, OCH₂CH₃), 6.74-6.92

(m, 5H, ArH), 7.12-7.17 (m, 2H, ArH), 7.55-7.60 (m, 2H, ArH), 9.83 (s, 1H, NH

amide), 12.63 (br s, 1H, NH pyrazole) ppm; ¹³C NMR (150.9 MHz, CDCl₃) δ =

14.0 (CH₃, OCH₂CH₃), 20.9 (CH₃, ArCH₃), 61.5 (CH₂, OCH₂CH₃), 109.1 [C, br,

C(4)], 120.3 (CH, CH_Ar), 126.8 (CH, CH_Ar), 127.4 (CH, CH_Ar), 129.3 (CH, CH_Ar),

129.6 (CH, CH_Ar), 134.1 (C, C_Ar(q)), 134.7 (C, C_Ar(q)), 135.0 (C, C_Ar(q)), 140.4 [C,

br, one of C(3) or C(5)], 145.8 [C, br, one of C(3) or C(5)], 156.0 (C, C=O

amide), 160.5 (C, C=O ester) ppm; ¹³C NMR (150.9 MHz, DMSO-d₆) δ = 13.8

(CH₃, OCH₂CH₃), 20.5 (CH₃, ArCH₃), 60.5 (CH₂, minor tautomer, OCH₂CH₃),

61.3 (CH₂, major tautomer, OCH₂CH₃), 108.5 [C, minor tautomer, C(4)], 111.4

[C, major tautomer, C(4)], 120.0 (CH, CH_Ar), 125.5 (CH, CH_Ar), 125.9 (CH,

CH_Ar), 126.7 (CH, CH_Ar), 128.9, 129.0 129.3 (CH, overlapping broad signals,

C(5) carbons were not readiliy observed (10s delay time). Signals for the

minor

tautomer,

ethyl

3-(4′-methylphenylcarbamoyl)-1H-pyrazole-5-

carboxylate were not observed.

Compounds 14b-i were similarly prepared, see supplementary information for

characterisation data.

Purification of commercial mCPBA^[34]

In a 1L volumetric flask sodium hydroxide (0.1 M, 410 ml) and potassium

phosphate monobasic (0.2 M, 250 ml) were mixed. The flask was filled up to 1

L with deionised water and the solution was stirred vigorously for 2 min to

generate the buffer solution (pH 7.5). Commercial mCPBA (10 g, 65-77 %)

was dissolved in diethyl ether (150 ml), and washed three times with buffer

solution (pH 7.5, 150 ml). The ether layer was dried with MgSO₄, filtered and

carefully evaporated under reduced pressure to give 6.88 g pure mCPBA as a

white solid. The peracid was transferred to a plastic container and stored in

the refridgerator for

3 months without decomposition. The purity was

determined by ¹H NMR spectroscopy.

Caution: It has been determined that 95-100% mCPBA can be detonated by

shock or sparks, whereas commercial 70-85 % mCPBA is not shock sensitive.

It should be stored in a refridgerator in tightly closed containers.

General procedure for the [3+2]-dipolar cycloaddition of α-diazoacetetes

and α-sulfonyl-β-chloroacrylamides.

Ethyl

4-(phenylsulfonyl)-5-(4′-methylphenylcarbamoyl)-1H-pyrazole-3-

carboxylate (16a)

10.1002/ejoc.201900494

European Journal of Organic Chemistry

FULL PAPER

1531 (NH bend), 1270; ¹H NMR (600 MHz, CDCl₃) δ = 1.15 [t, J = 7.1 Hz, 3H,

one of C(5)CO₂CH₂CH₃or NCH₂CO₂CH₂CH₃], 1.28 [t, J = 7.2 Hz, 3H, one of

C(5)CO₂CH₂CH₃or NCH₂CO₂CH₂CH₃], 2.29 (s, 3H, ArCH₃), 4.21 and 4.24

[overlapping quartets, 4H, J = 7.1 Hz, C(5)CO₂CH₂or NCH₂CO₂CH₂], 5.38 (s,

2H, NCH₂CO), 7.03-7.26 (m, 7H, ArH), 7.49 (d, J = 8.5 Hz, 2H, ArH), 9.09 (s,

1H, NH amide) ppm; ¹³C NMR (150.9 MHz, CDCl₃) δ = 13.6 [CH₃, one of

C(5)CO₂CH₂CH₃or NCH₂CO₂CH₂CH₃], 13.9 [CH₃, one of C(5)CO₂CH₂CH₃or

NCH₂CO₂CH₂CH₃], 20.7 (CH₃, ArCH₃), 55.0 (CH₂, NCH₂CO], 62.0 (CH_2,

overlapping C(5)CO₂CH₂or NCH₂CO₂CH₂], 113.7 [C, C(4)], 119.8 (CH, CH_Ar),

125.9 (CH, CH_Ar), 126.8 (CH, CH_Ar), 128.9 (CH, CH_Ar), 129.3 (CH, CH_Ar),

133.9 (C, C_Ar(q)), 134.9 (C, C_Ar(q)), 136.4 (C, C_Ar(q)), 137.1 [C, C(5)], 146.6 [C,

C(3)], 157.6 (C, C=O amide), 158.8 [C, C(5)C=O], 166.7 [C, NCH₂C=O] ppm;

¹H NMR (600 MHz, DMSO-d₆) δ = 1.06 [t, J = 7.1 Hz, 3H, C(5)CO₂CH₂CH₃],

1.21 [t, J = 7.1 Hz, 3H, NCH₂CO₂CH₂CH₃], 2.25 (s, 3H, ArCH₃), 4.14 [q, J =

7.1 Hz, 2H, C(5)CO₂CH₂], 4.19 [q, J = 7.1 Hz, 2H, NCH₂CO₂CH₂], 5.44 (s, 2H,

NCH₂CO), 7.06-7.15 (m, 5H, ArH), 7.21-7.28 (m, 2H, ArH), 7.56 (d, J = 8.5 Hz,

2H, ArH), 10.34 (s, 1H, NH amide) ppm; ¹³C NMR (150.9 MHz, DMSO-d₆) δ =

13.5 [CH₃, C(5)CO₂CH₂CH₃], 14.0 [CH₃, NCH₂CO₂CH₂CH₃], 20.5 (CH₃,

ArCH₃), 54.8 (CH₂, NCH₂CO), 61.5 [CH₂, C(5)CO₂CH₂], 61.7 [NCH₂CO₂CH₂],

111.3 [C, C(4)], 119.9 (CH, CH_Ar), 125.7 (CH, CH_Ar), 126.6 (CH, CH_Ar), 128.9

(CH, CH_Ar), 129.0 (CH, CH_Ar), 132.9 (C, C_Ar(q)), 135.9 (C, C_Ar(q)), 136.1 (C,

C_Ar(q)), 137.0 [C, C(5)], 148.6 [C, C(3)], 158.1 [C, C(5)C=O], 158.6 (C, C=O

amide), 167.3 [C, NCH₂C=O] ppm; ¹H NMR (600 MHz, Toluene-d₈) δ = 0.83 [t,

J = 7.1 Hz, 3H, one of C(5)CO₂CH₂CH₃or NCH₂CO₂CH₂CH₃], 0.89 [t, J = 7.1

Hz, 3H, one of C(5)CO₂CH₂CH₃or NCH₂CO₂CH₂CH₃], 2.06 (s, 3H, ArCH₃),

3.86 [q, J = 7.1 Hz, 2H, C(5)CO₂CH₂], 3.88 [q, J = 7.1 Hz, 2H, NCH₂CO₂CH₂],

5.03 (s, 2H, NCH₂CO), 6.80 (t, unresolved coupling, 1H, ArH), 6.87 (d, J = 8.3

Hz, 2H, ArH), 6.92 (t, J = 7.8 Hz, 2H, ArH), 7.27 (d, J = 7.5 Hz, 2H, ArH), 7.49

(d, J = 8.3 Hz, 2H, ArH), 8.60 (s, 1H, NH amide) ppm; ¹³C NMR (150.9 MHz,

Toluene-d₈) δ = 13.6 [CH₃, one of C(5)CO₂CH₂CH₃] or NCH₂CO₂CH₂CH₃],

13.9 [CH₃, one of C(5)CO₂CH₂CH₃or NCH₂CO₂CH₂CH₃], 20.7 (CH₃,

overlapping with residual toluene-d₈signal, ArCH₃), 54.9 (CH₂, NCH₂CO), 61.7

[CH₂, C(5)CO₂CH₂], 61.8 [NCH₂CO₂CH₂], 115.9 [C, C(4)], 119.7 (CH, CH_Ar)*,

125.8 (CH, CH_Ar), 127.8 (CH, CH_Ar), 129.6 (CH, CH_Ar), 133.2 (C, C_Ar(q)), 136.3

(C, C_Ar(q)), 137.2 (C, C_Ar(q)), 138.3 [C, C(5)], 147.5 [C, C(3)], 157.4 (C, C=O

amide), 159.5 [C, C(5)C=O], 166.8 [C, NCH₂C=O] ppm; * 1 x CH_Arsignal in

toluene-d₈spectrum overlapping with residual solvent signal; HRMS (ES+):

Exact mass calculated for C₂₄H₂₅N₃O₅S [M+H]⁺468.1588. Found 468.1587;

m/z (ES+) 468.2 {[(C₂₄H₂₅N₃O₅S)+H⁺], 100%}. The regiochemistry was

m-CPBA (77%, 448 mg, 2 mmol) in dichloromethane (15 ml) was added

dropwise over 2 minutes to a stirring solution of N-(4′-methylphenyl)-Z-3-

chloro-2-(benzenesulfinyl)propenamide 9a (319 mg,

1

mmol) in

dichloromethane (5 ml) at room temperature. The reaction progress was

monitored by ¹H NMR spectroscopy. Once the impurity profile of the reaction

was observed to increase relative to the increase in sulfoxide 9a to sulfone

15a oxidation the reaction mixture was concentrated under reduced pressure

to an approximate volume of 10 ml in dichloromethane. Ethyl diazoacetate

(0.49 ml, 4 mmol, >87% in dichloromethane) was added in one portion to the

crude sulfone and the reaction mixture was stirred overnight at room

temperature under nitrogen. Repeated purification by column chromatography

on silica gel using hexane: ethyl acetate (60:40) as eluent, followed by

dichloromethane: ethyl acetate (80:20) gave the pure pyrazole 16a as a white

solid (67 mg, 16 % over 2 steps); mp 179-181˚C; _max/cm^-1(ATR) 3193 (NH),

1736 (C=O ester), 1659 (C=O amide), 1311 (asymmetric SO₂), 1241, 1148

(symmetric SO₂); ¹H NMR (600 MHz, CDCl₃) δ = 1.37 (t, J = 7.1 Hz, 3H,

OCH₂CH₃), 2.35 (s, 3H, ArCH₃), 4.41 (q, J = 7.1 Hz, 2H OCH₂CH₃), 7.20 (d, J

= 8.1 Hz, 2H, ArH), 7.53 (d, J = 7.8 Hz, 2H, ArH), 7.59-7.70 (m, 3H, ArH), 8.07

(d, J = 7.8 Hz, 2H, ArH), 11.20 (br s, 1H, NH amide) ppm; ¹³C NMR (150.9

MHz, CDCl₃) δ = 14.0 (CH₃, OCH₂CH₃), 21.0 (CH₃, ArCH₃), 62.5 (CH₂,

OCH₂CH₃), 120.0 [C, C(4)], 120.3 (CH, CH_Ar), 127.5 (CH, CH_Ar), 129.2 (CH,

CH_Ar), 129.8 (CH, CH_Ar), 134.0 (CH, CH_Ar), 134.3 (C, C_Ar(q)), 135.5 (C, C_Ar(q)),

138.6 [C, one of C(3) or C(5)], 140.7 (C, C_Ar(q)), 145.2 [C, one of C(3) or C(5)],

154.0 (C, C=O amide), 160.3 (C, C=O ester) ppm; HRMS (ES+): Exact mass

calculated for C₂₀H₁₉N₃O₅S [M+H]⁺414.1118. Found 414.1123; m/z (ES-)

412.2 {[(C₂₀H₁₉N₃O₅S)-H⁺], 100%}. The regiochemistry was determined by

single X-ray diffraction on a crystalline sample of 16a recrystallised from

dichloromethane. Crystals of 16a are triclinic, space group P, formula

C₂₀H₁₉N₃O₃S, MW = 413.44 g mol^-1, a = 7.6015(5) Å, b = 8.4522(6) Å, c =

15.5976(11) Å, α = 81.209(2)°, β = 81.359(2)°, γ = 70.921(2)°, U = 930.55(11)

Å3 , F(000) = 432, (Mo K) = 0.214 mm-1 , R₁(F) = 0.0560 and S = 1.019 for

4588 observed reflections with I > 2(I), wR₂(F²) = 0.1698 for all 7982 unique

reflections.

CCDC 1906490 (for pyrazole 16a) contains the supplementary

crystallographic data for this paper. These data can be obtained free of charge

from The Cambridge Crstallographic Data Centre.

determined by single X-ray diffraction on

recrystallised from dichloromethane. Crystals of pyrazole 11a are triclinic,

a crystalline sample of 11a

Compounds 16b-g were similarly prepared, see supplementary information for

characterisation data.

-

1

space group P , formula C₂₄H₂₅N₃O₅S, MW = 467.53 g mol^-1, a = 9.456(2) Å,

The title compound 16a was also prepared by addition of m-CPBA (113 mg,

b = 11.142(3) Å, c = 12.695(3) Å, α = 70.288(8)°, β = 81.753(8)°, γ =

70.999(8)°, U = 1189.7(5) Å³, F(000) = 492, m(Mo Ka) = 0.176 mm^-1, R₁(F) =

0.0546 and S = 1.031 for 2701 observed reflections with I > 2σ(I), wR₂(F²) =

0.1564 for all 4552 unique reflections.

0.655 mmol, 100%) to

a

stirring solution of 4-(phenylthio)-5-(4′-

methylphenylcarbamoyl)-1H-pyrazole-3-carboxylate 10a (100 mg, 0.262

mmol) in dichloromethane (5 ml) at room temperature. The reaction solution

was heated to reflux and stirred overnight. Sodium thiosulfate (10 ml, 10%

w/v) was added to the cooled reaction mixture and the layers were separated.

The organic layer was washed with sodium thiosulfate (2 x 10 ml, 10% w/v),

CCDC 1906489 (for pyrazole 11a) contains the supplementary

crystallographic data for this paper. These data can be obtained free of charge

from The Cambridge Crstallographic Data Centre.

sat. sodium bicarbonate (3

x 10 ml), brine (10 ml), dried, filtered and

concentrated under reduced pressure to give the pure pyrazole 16a as a white

solid (89 mg, 82%). Spectroscopic characteristics were consistent with those

outlined previously.

Pyrazole 12a; less polar; mp 124-127°C; _max/cm^-1(ATR) 3301 (NH stretch),

1741 (C=O ester), 1732 (C=O ester), 1650 (C=O amide), 1539 (NH bend),

1216, 1057; ¹H NMR (600 MHz, CDCl₃) δ = 1.27 [t, J = 7.2 Hz, 3H,

NCH₂CO₂CH₂CH₃], 1.29 [t, J = 7.2 Hz, 3H, C(3)CO₂CH₂CH₃], 2.31 (s, 3H,

ArCH₃), 4.24 [q, J = 7.1 Hz, 2H, NCH₂CO₂CH₂], 4.36 [q, J = 7.1 Hz, 2H,

C(3)CO₂CH₂], 5.58 (s, 2H, NCH₂CO), 7.11 (d. J = 8.4 Hz, 2H, ArH), 7.16-7.23

(m, 3H, ArH), 7.24-7.30 (m, 2H, ArH), 7.35 (d, J = 8.4 Hz, ArH), 10.04 (br s, 1H,

NH amide) ppm; ¹³C NMR (150.9 MHz, CDCl₃) δ = 14.0 (CH_3,one of

C(3)CO₂CH₂CH₃or NCH₂CO₂CH₂CH₃), 14.1 (CH_3,one of C(3)CO₂CH₂CH₃or

NCH₂CO₂CH₂CH₃), 20.8 (CH₃, ArCH₃), 55.8 (CH₂, NCH₂CO), 61.5 [CH₂,

C(3)CO₂CH₂], 61.9 [CH₂, NCH₂CO₂CH₂], 110.3 [C, C(4)], 120.5 (CH, CH_Ar),

126.8 (CH, CH_Ar), 127.0 (CH, CH_Ar), 129.4 (CH, CH_Ar), 129.5 (CH, CH_Ar),

134.2 (C, C_Ar(q)), 134.6 (C, C_Ar(q)), 134.9 (C, C_Ar(q)), 138.8 [C, C(5)], 144.6 [C,

C(3)], 155.9 (C, C=O amide), 160.4 [C, C(3)C=O], 167.0 [C, NCH₂C=O] ppm;

¹H NMR (600 MHz, DMSO-d₆) δ = 1.14 [t, J = 7.1 Hz, 3H, NCH₂CO₂CH₂CH₃],

1.17 [t, J = 7.1 Hz, 3H, C(3)CO₂CH₂CH₃], 2.26 (s, 3H, ArCH₃), 4.15 [q, J = 7.1

Hz, 2H, NCH₂CO₂CH₂], 4.19 [q, J = 7.1 Hz, 2H, C(3)CO₂CH₂], 5.40 (s, 2H,

NCH₂CO), 6.96-7.27 (m, 7H, ArH), 7.47-7.50 (m, 2H, ArH), 10.56 (s, 1H, NH

General procedure for the N-alkylation of pyrazole 10a.

Ethyl 1-(2-ethoxy-2-oxoethyl)-4-(phenylthio)-3-(4′-

methylphenylcarbamoyl)-1H-pyrazole-5-carboxylate (11a) and ethyl 1-(2-

ethoxy-2-oxoethyl)-4-(phenylthio)-5-(4′-methylphenylcarbamoyl)-1H-

pyrazole-3-carboxylate (12a)

Ethyl 4-(phenylthio)-5-(4′-methylphenylcarbamoyl)-1H-pyrazole-3-carboxylate

10a (150 mg, 0.393 mmol), potassium carbonate (71 mg, 0.512 mmol) and a

stirrer bar were placed in a vial. Anhydrous dimethylsulfoxide (3 ml) was

added and the resultant mixture was stirred at room temperature under

nitrogen. Ethyl bromoacetate (0.06 ml, 0.472 mmol) was added and the

resulting mixture was stirred at room temperature for 24 h. The reaction

mixture was quenched with iced water (10 ml). The resulting mixture was

extracted with ethyl acetate (2 x 15 ml). The combined organic layers were

washed with brine (20 ml), dried over magnesium sulfate, and concentrated

under reduced pressure to give the crude product as a yellow oil which

contained a mixture of N-alkylated pyrazoles 11a:12a in a ratio of 72:28.

Purification by column chromatography on silica gel using hexane: ethyl

acetate (80:20) as eluent gave pure pyrazole 11a as a clear oil which solidified

overnight to give a white solid (112 mg, 61 %), pure pyrazole 12a as a white

solid (46 mg, 25 %), and a mixed fraction of 11a and 12a as a clear oil which

solidified overnight to give a white solid (11 mg, 6 %) to give a combined yield

of 92 %.

amide) ppm;

¹³C NMR (150.9 MHz, DMSO-d₆)

δ = 13.88 [CH₃,

NCH₂CO₂CH₂CH₃], 13.90 [t, J = 7.1 Hz, 3H, C(3)CO₂CH₂CH₃], 20.5 (CH₃,

ArCH₃), 53.6 (CH₂, NCH₂CO), 60.8 [CH₂, C(3)CO₂CH₂], 61.5 [CH₂,

NCH₂CO₂CH₂], 110.7 [C, C(4)], 119.9 (CH, CH_Ar), 125.9 (CH, CH_Ar), 126.6

(CH, CH_Ar), 129.1 (CH, CH_Ar), 129.2 (CH, CH_Ar), 133.7 (C, C_Ar(q)), 135.3 (C,

C_Ar(q)), 136.9 (C, C_Ar(q)), 142.4 (C, C(5)], 143.2 (C, C(3)], 156.1 (C, C=O amide),

160.2 [C, C(3)C=O], 167.0 [C, NCH₂C=O] ppm; ¹H NMR (600 MHz, Toluene-

d₈) δ = 0.87 [t, J = 7.1 Hz, 3H, NCH₂CO₂CH₂CH₃], 0.97 [t, J = 7.1 Hz, 3H,

C(3)CO₂CH₂CH₃], 2.02 (s, 3H, ArCH₃), 3.86 [q, J = 7.1 Hz, 2H, NCH₂CO₂CH₂],

4.05 [q, J = 7.1 Hz, 2H, C(3)CO₂CH₂], 5.31 (s, 2H, NCH₂CO), 6.72-6.77 (m,

Pyrazole 11a; more polar; mp 107-109°C; _max/cm^-1(ATR) 3340 (NH stretch),

2993 (CH stretch), 1736 (C=O ester), 1708 (C=O ester), 1682 (C=O amide),

10.1002/ejoc.201900494

European Journal of Organic Chemistry

FULL PAPER

1H, ArH), 6.79-6.86 (m, 4H, ArH), 7.15-7.19 (m, 2H, ArH), 7.44-7.49 (m, 2H,

ArH), 10.09 (s, 1H, NH amide) ppm; ¹³C NMR (150.9 MHz, Toluene-d₈) δ =

13.9 [CH₃, NCH₂CO₂CH₂CH₃], 14.1 [CH₃, C(3)CO₂CH₂CH₃], 20.7 (CH₃,

overlapping with residual toluene-d₈signal, ArCH₃), 55.9 (CH₂, NCH₂CO), 60.9

[CH₂, C(3)CO₂CH₂], 61.5 [CH₂, NCH₂CO₂CH₂], 110.6 [C, C(4)], 120.2 (CH,

CH_Ar), 126.8 (CH, CH_Ar), 127.6 (CH, CH_Ar), 129.5 (CH, CH_Ar), 129.8 (CH, CH_Ar),

134.3 (C, C_Ar(q)), 135.5 (C, C_Ar(q)), 135.7 (C, C_Ar(q)), 138.8 [C, C(5)], 145.2 [C,

C(3)], 156.2 (C, C=O amide), 160.6 [C, C(3)C=O], 167.0 [C, NCH₂C=O] ppm;

HRMS (ES+): Exact mass calculated for C₂₄H₂₅N₃O₅S [M+H]⁺468.1588.

Found 468.1583; m/z (ES+) 468.2 {[(C₂₄H₂₅N₃O₅S)+H⁺], 68%}, 721.1 (100%).

Note: C(3) and C(5) not observed at 600 MHz

N³-(4′-Methoxyphenyl)-4-(phenylthio)-N⁵-(4′-methylphenyl)-1H-pyrazole-

3,5-dicarboxamide (21)

4-Dimethylaminopyridine (7 mg, 0.06 mmol) and p-anisidine (150 mg, 1.22

mmol) were added to

a

stirring solution of 4-(phenylthio)-5-(4-

methylphenylcarbamoyl)-1H-pyrazole-3-carboxylic acid 20 (195 mg, 0.55

mmol) in dichloromethane (25 ml) at 0˚C. The solution was stirred at this

temperature for 2 minutes at which point N′,N′-diisopropylcarbodiimide (105

mg, 0.83 mmol) was added in dichloromethane (5 ml). The reaction mixture

was immediately heated to reflux and was stirred at this temperature for 12 h.

The cooled reaction mixture was washed with water (30 ml) and the layers

separated. The organic layer was washed with 2M hydrochloric acid (2 x 30

ml) and brine (30 ml), dried, and concentrated under reduced pressure to give

the crude product as a grey/brown solid. Purification by recrystallistation using

ethyl acetate: heptane gave the pure product as a grey solid (162 mg, 64 %);

mp 237-239°C; _max/cm^-1(ATR) 3211 (NH stretch), 2917 (CH), 1682, (C=O

amide), 1666 (C=O amide), 1320, 1161; ¹H NMR (300 MHz, DMSO-d₆) δ =

2.26 (s, 3H, ArCH₃), 3.73 (s, 3H, ArOCH₃), 6.58-7.87 (m, 13H, ArH), 10.18 (s,

1H, NH amide), 10.22 (s, 1H, NH amide),14.67 (br s, NH pyrazole) ppm; ¹H

NMR (600 MHz, DMSO-d₆) δ = 2.27 (s, 3H, ArCH₃), 3.73 (s, 3H, ArOCH₃),

6.62-7.90 (m, 13H, ArH), 10.22 (s, 1H, NH amide), 10.26 (s, 1H, NH amide),

14.70 (br s, 1H, NH pyrazole) ppm; ¹³C NMR (150.9 MHz, DMSO-d₆) δ = 20.5

(CH₃, ArCH₃), 55.2 (CH₃, ArOCH₃), 106.5 [C, C(4)], 113.9 (CH, CH_Ar), 119.9

(CH, CH_Ar), 121.4 (CH, CH_Ar), 125.8 (CH, CH_Ar), 126.7 (CH, CH_Ar), 129.1 (CH,

CH_Ar), 129.2 (CH, CH_Ar), 131.3 (C, br, C_Ar(q)), 133.1 (C, br, C_Ar(q)), 135.7 (C, br,

C_Ar(q)), 136.9 (C, C_Ar(q)), 142.2 [C, br, one of C(3) or C(5)], 148.0 [C, br, one of

C(3) or C(5)], 155.8 (C, C_Ar(q)OMe), 157.6 (C, br, overlapping C=O amides)

ppm; HRMS (ES+): Exact mass calculated for C₂₅H₂₂N₄O₃S [M+H]⁺459.1485.

Found 459.1486.

Note: The title compounds 11a and 12a were also isolated as byproducts in

the [3+2]-dipolar cycloaddition of α-thio-β-chloroacrylamide 8a and ethyl

diazoacetate, through competing N–H insertion. Spectroscopic data are

consistent with that outlined previously.

Compounds 17a-c and 18a-b were similarly prepared, see supplementary

information for characterisation data.

General procedure for the selective oxidation of pyrazoles 10.

Ethyl 4-(phenylsulfinyl)-5-(4′-methylphenylcarbamoyl)-1H-pyrazole-3-

carboxylate (19a)

mCPBA (35 mg, 0.2 mmol, 100%) was added in one portion to a stirring

solution

of

4-(phenylthio)-5-(4′-methylphenylcarbamoyl)-1H-pyrazole-3-

carboxylate 10a (40 mg, 0.1 mmol) in dichloromethane (10 ml) at room

temperature. After stirring overnight sodium thiosulfate (10 ml, 10% w/v) was

added and the layers were separated. The organic layer was washed with

sodium thiosulfate (2 x 10 ml, 10% w/v), sat. sodium bicarbonate (3 x 10 ml)

and brine, dried with magnesium sulfate and concentrated under reduced

pressure to give the crude product as a white solid. ¹H NMR analysis of the

crude product indicated complete consumption of the starting material with

evidence for both the sulfoxide 19a and sulfone 16a present (approx. 85:15).

Purification by column chromatography using hexane: ethyl acetate as eluent

(gradient elution 20-30% ethyl acetate) gave sulfoxide 19a as a white solid (26

mg, 66 %); mp 187-189°C; _max/cm^-1(ATR) 3096 (NH stretch), 2994 (CH),

Acknowledgments

2918 (CH), 1699 (C=O ester), 1669 (C=O amide), 1235, 1029 (S=O), 980; ¹

H

NMR (300 MHz, CDCl₃) δ = 1.43 (t, J = 7.1 Hz, 3H, OCH₂CH₃), 2.34 (s, 3H,

ArCH₃), 4.36-4.57 (m, 2H, OCH₂CH₃), 7.18 (d, J = 8.1 Hz, 2H, ArH), 7.37-7.51

(m, 3H, ArH), 7.63-7.83 (m, 4H, ArH), 12.36 (br s, 1H, NH amide), 12.79 (br s,

1H, NH pyrazole) ppm; ¹³C NMR (75.5 MHz, CDCl₃) δ = 14.2 (CH₃, OCH₂CH₃),

21.0 (CH₃, ArCH₃), 62.3 (CH₂, OCH₂CH₃), 120.3 (CH, CH_Ar), 124.1 [C, C(4)],

125.1 (CH, CH_Ar), 129.6 (CH, 2 overlapping CH_Arsignals), 131.7 (CH, CH_Ar),

134.8 (C, C_Ar(q)) 135.1 (C, C_Ar(q)), 139.6 [C, one of C(3) or C(5)], 142.8 [C, one

of C(3) or C(5)], 143.4 (C, C_Ar(q)), 154.8 (C, C=O amide), 161.2 (C, C=O ester)

ppm; HRMS (ES+): Exact mass calculated for C₂₀H₁₉N₃O₄S [M+H]⁺398.1169.

Found 398.1183.

Financial support from the Synthesis and Solid State

Pharmaceutical Centre supported by Science Foundation

Ireland, co-funded under the European Regional Development

Fund (grant number: 12/RC/2275) and with use of equipment

provided by Science Foundation Ireland through a research

infrastructure award for process flow spectroscopy (Prospect)

(grant number: SFI 15/RI/3221) are gratefully acknowledged.

The authors would like to acknowledge Dr. Denis Lynch for

enabling access to ProSpect.

Compounds 16a, 16e and 19b were similarly prepared, see supplementary

information for characterisation data.

4-(Phenylthio)-5-(4-methylphenylcarbamoyl)-1H-pyrazole-3-carboxylic

acid (20)

Keywords: [3+2]-dipolar cycloaddition • sulfonyl migration •

pyrazole • tautomers• α-thio-β-chloroacrylamide

Sodium hydroxide (97 mg, 2.43 mmol) in water (15 ml) was added in one

portion

to

a

stirring

solution

of

ethyl

4-(phenylthio)-5-(4’-

[1]

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a) J. A. Joule, K. Mills in Heterocyclic Chemistry, John Wiley & Sons,

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methylphenylcarbamoyl)-1H-pyrazole-3-carboxylate 10a (232 mg, 0.61 mmol)

in methanol (5 ml) at room temperature. The heterogenous reaction mixture

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concentrated under reduced pressure to dryness. Water (15 ml) and ethyl

acetate (15 ml) was added, and the layers separated. Concentrated HCl was

added until a pH of 2 was achieved, which caused the carboxylic acid 20 to

precipitate out of solution. Ethyl acetate (15 ml) was added and the layers

separated. The aqueous layer was further extracted with ethyl acetate (2 x 15

ml). The combined organic layers were washed with brine (15 ml), dried, and

concentrated under reduced pressure to give the pure pyrazole 20 (195 mg,

91 %) as a white solid; mp 226-229°C; _max/cm^-1(ATR) 3126 (OH stretch),

3025 (NH), 2953 (CH), 1690 (C=O carboxylic acid), 1648 (C=O amide), 1606,

1474, 1235; ¹H NMR (300 MHz, DMSO-d₆) δ = 2.26 (s, 3H, ArCH₃), 3.40 (br s,

1H, COOH), 7.04-7.30 (m, 7H, ArH), 7.55 (d, J = 8.1 Hz, 2H, ArH), 10.18 (s,

1H, NH amide), 14.64 (br s, 1H, NH pyrazole) ppm; ¹H NMR (600 MHz,

DMSO-d₆) δ = 2.25 (s, 3H, ArCH₃), 3.38 (br s, 1H, COOH), 7.02-7.28 (m, 7H,

ArH), 7.46-7.64 (d, J = 8.1 Hz, 2H, ArH), 10.20 (s, 1H, NH amide), 14.67 (br s,

1H, NH pyrazole) ppm; ¹³C NMR (600 MHz, DMSO-d₆) δ = 20.9 (CH₃, ArCH₃),

110.8 [C, C(4)], 120.3 (CH, CH_Ar), 125.7 (CH, CH_Ar), 126.9 (CH, CH_Ar), 129.3

(CH, CH_Ar), 129.5 (CH, CH_Ar), 133.1 (C, C_Ar(q)), 136.5 (C, C_Ar(q)), 138.0 (C,

C_Ar(q)), 150.2 (C, C=O carboxylic acid), 159.7 (C, C=O amide) ppm; HRMS

(ES+): Exact mass calculated for C₁₈H₁₅N₃O₃S [M+H]⁺354.0907. Found

354.0901.

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10.1002/ejoc.201900494

European Journal of Organic Chemistry

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Key Topic*

Highly regioselective synthetic

Aaran J. Flynn, Alan Ford, U. B. Rao

Khandavilli, Simon E. Lawrence, Anita R.

Maguire*

methodology leading to densely

functionalised C(3), C(4) and C(5)

substituted pyrazoles via thermal [3+2]-

dipolar cycloaddition, of α-diazoacetates

and α-thio-β-chloroacrylamides, at the

sulfide, sulfoxide and sulfone levels of

oxidation, is described. This method

allows access to C(4)-sulfenyl or

sulfonyl pyrazoles, through migration of

the sulfur substituent at the sulfide and

sulfone oxidation levels, while

Page No. – Page No.

Regioselective Thermal [3+2]-Dipolar

Cycloadditions of α-Diazoacetates with α-

Sulfenyl/Sulfinyl/Sulfonyl-β-

Chloracrylamide Derivatives to form

Densely Functionalised Pyrazoles.

elimination of the sulfinyl group leading

to 3,5-disubstituted pyrazoles, is

observed.

*[3+2]-dipolar cycloaddition, pyrazoles, tautomers, α-thio-β-chloroacylamides, sulfonyl shift

Article Doi

Regioselective Thermal [3+2]-Dipolar Cycloadditions of α-Diazoacetates with α-Sulfenyl/Sulfinyl/Sulfonyl-β-Chloroacrylamide Derivatives to Form Densely Functionalised Pyrazoles

DOI: 10.1002/ejoc.201900494

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