Domino C-H Sulfonylation and Pyrazole Annulation for Fully

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Domino C-H Sulfonylation and Pyrazole Annulation for Fully Substituted Pyrazole Synthesis in Water Using Hydrophilic Enaminones Yanhui Guo, Guodong Wang, Li Wei, and Jie-Ping Wan J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02897 • Publication Date (Web): 04 Feb 2019 Downloaded from http://pubs.acs.org on February 4, 2019

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The Journal of Organic Chemistry

Domino C-H Sulfonylation and Pyrazole Annulation for Fully Substituted Pyrazole Synthesis in Water Using Hydrophilic Enaminones Yanhui Guo, Guodong Wang, Li Wei, Jie-Ping Wan* Collelge of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang 330022, P. R. China.

O R

15

the hydrophilic site

NH2

1

R

I2/TBHP

H O Ar

S

ArO2S

2

O

N N SO2Ar 20 examples up to 85% yield

NaHCO3, H2O, rt

NHNH2

R2

R1

> C(sp2)-H sulfenylation & pyrazole annulation > C-N cleavage confirmed by 15N labeling > Free of any metal reagent > Water as the sole medium > Efficient scale up synthesis

ABSTRACT. The cascade reactions between NH2-functionalized enaminones and sulfonyl hydrazines have been developed for the synthesis of fully substituted pyrazoles. By making use of the hydrophilic primary amino group in the enaminones, the reactions proceed well in the medium of pure water in the presence of molecular iodine, TBHP and NaHCO3 via cascade C-H sulfonylation and pyrazole annulation. The cleavage of the C-N bond in enaminones is confirmed by the experiment using 15N-labeled enaminone.

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The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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Pyrazole derivatives are ubiquitous in organic molecules with valuable biological functions.1-3 Over the recent years, a variety of new pyrazole derivatives have been discovered with enriched bioactivities such as the reversal activity to fluconazole resistance,4 antimicrobial activity,5 anticancer activity,6 antiproliferative activity,7 ALK5 kinase inhibitory activity,8 and antioxidation activity9. By making use of the chelating nitrogen atom, pyrazoles have also displayed application in the preparation of functional metal-organic complexes, high performance energetic materials, ultramicroporous materials, electroluminescent materials etc.10-12 Not surprisingly, the synthesis of pyrazoles and their derivatives keeps receiving interests.13-19 Over the last decade, different tactics have been developed for the synthesis of pyrazoles. For examples, the transition metal-catalyzed cross coupling reactions,20-22 [3+2] or [4+1] annulation using hydrazones,23-27 annulation of azodicarboxylates with dipoles,28 electrophilic cyclization of functionalized hydrazones,29-31 and annulation of diazo compounds32-33 have been reported as effective methods. Despite the availability of the these enriched synthetic pathways, the reaction of a hydrazine with a 1,3-electrophilic substrate such as 1,3-dicarbonyl substrates,34-37 Michael acceptors,38-40 tertiary enamines,41 and related multicomponent variants42-43 remain as the predominant options. The advantages of such methods cover not only the stable and easily available substrates, but also the fast generation of high molecular diversity from the varied reactions partners of hydrazines. More notably, because these synthetic methods usually involve in the carbonyl condensation and/or nucleophilic addition as key transformations, the catalytic conditions are always simple and economical. Therefore, developing new synthetic methods via the hydrazine-based annulation with stable and simple reaction partners is yet the mainstream direction for pyrazole synthesis.


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As easily accessible and stable building blocks, enaminones have been widespread employed to construct aryl rings and other functional compounds.44-52 In those known enaminone-based reactions providing pyrazole scaffolds,53-54 the N,N-disubstituted enaminones are unexceptionally used as the C=C-C fragment donors. The specific feature of enaminones, however, has not been adequately exploited. In this context, developing new enaminone-based pyrazole synthesis manifesting individual advantages of enaminones such as employing water as medium,55-60 is highly desirable. Herein, we report the synthesis of fully substituted pyrazoles via the hydrogen bond assisted reactions of NH2-functionalized enaminones and sulfonyl hydrazines in water medium free of any metal reagent. Aiming at developing water mediated synthetic method, the enaminone 1a and tosyl hydrazine 2a were tentatively employed with molecular iodine using water the sole medium, which provided pyrazole 3a with 35% yield at room temperature (entry 1, Table 1). Encouraged by this positive result, expanded investigation was then executed. First, notable improvement on the product yield was obtained by employing NaHCO3 as an additive (entry 2, Table 1), but NaHCO3 along was not able to initiate this reaction (entry 3, Table 1). Later, using KI or KIO3 as alternative iodine-based catalyst didn’t give better result (entries 4-5, Table 1). Et3N could also assist the synthesis of 3a with good result (entry 6, Table 1). Considering the ecofriendliness of NaHCO3, it was fixed as the additive in the subsequent experiments. In the reaction employing other oxidants, much higher yield occurred in the reaction with TBHP (entries 7-10, Table 1). At elevated temperature, lower yield of 3a was observed (entries 11-12, Table 1). Later on, the parallel reaction with different stirring time suggested that 6 h was most favorable (entries 13-14, Table 1). After that, this reaction was also carried out in EtOH and DMF, respectively. The results proved that water was actually a better medium (entries 15-16,


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Table 1). Additionally, reducing the volume of water led to the formation of 3a with even higher yield (entry 17, Table 1). A control experiment by varying the ratio of 1a/2a to 2:1 afforded 3a as the only product, no altered reaction pathway was observed (entry 18, Table 1). The extra entry performed parallel in MeCN provided also inferior yield of 3a (entry 19, Table 1). Table 1 Optimization on reaction conditionsa O

NH2

Ts NHNH2

Ph 1a

cat./additive H2O, temp.

N N Ts Ts

2a

3a Ph

entry

catalyst/addtive

oxidant

temp.(oC)

Yield (%)b

1

I2/-

air

rt

35

2

I2/NaHCO3

air

rt

50

3

-/NaHCO3

air

rt

nr

4

KI/NaHCO3

air

rt

30

5

KIO3/NaHCO3

air

rt

trace

6

I2/Et3N

air

rt

50

7

I2/NaHCO3

TBHP

rt

72

8

I2/NaHCO3

H2O2

rt

58

9

I2/NaHCO3

DDQ

rt

53

10

I2/NaHCO3

DTBP

rt

64

11

I2/NaHCO3

TBHP

60

40

12

I2/NaHCO3

TBHP

90

32

13c

I2/NaHCO3

TBHP

rt

60

14d

I2/NaHCO3

TBHP

rt

55

15e

I2/NaHCO3

TBHP

rt

60

16f

I2/NaHCO3

TBHP

rt

68

17g

I2/NaHCO3

TBHP

rt

80

18g,h

I2/NaHCO3

TBHP

rt

70


4

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19g,i

I2/NaHCO3

TBHP

rt

58

aGeneral

conditions: 1a (0.2 mmol), 2a (0.5 mmol), catalyst (20 mol%), additives (0.5 equiv) and oxidant (3.0 equiv) in 2.0 mL water, stirred for 6 h. bYield of isolated product based on 1a. cReaction time was 3 h. d Reaction time was 12 h.eReaction in EtOH. fReaction in DMF. gReaction in 1 mL water. hThe loading of 2a was 0.1 mmol, and yield was based on 2a. iReaction in MeCN Following the optimization, the synthetic scope of this synthetic method was then examined. The synthesized pyrazoles 3 were collected in Scheme 1. Generally, the aryl sulfonyl hydrazines were well tolerated for the synthesis by affording the products 3a-3r with good to excellent yields. The alkyl-based sulfonyl hydrazine, such as methyl sulfonyl hydrazine, however, was not successful. As for the enaminone component 1, even broader compatibility was identified. The aryl, alkyl (R1 = aryl, R2 = methyl) functionalized enaminones reacted with various aryl sulfonyl hydrazines to afford corresponding products all with satisfactory yield (3a-3h, Scheme 1) regardless the property of the substituent in both substrates. In addition, the double alkyl (R1, R2 = alkyl) functionalized enaminones could also participate the synthesis with fine results (3i-3r, Scheme 1). One notable point was that the 1,4,6-trimethylphenyl functionalized sulfonyl hydrazine reacted smoothly to afford product 3m (Scheme 1), its slightly lower yield might be attributed to the steric hindrance of the 2,4-dimethyl substitution. On the other hand, the reaction employing double ethyl functionalized enaminone (R1 = R2 = ethyl) led to the formation of the expected products with lower yield than equivalent products (3p, 3q and 3r vs 3k, 3i and 3l, Scheme 1), suggesting that the more bulky group R2 undermined the reaction efficiency. Furthermore, sulfonyl hydrazine bearing trifluoromethyl- and fluorinated phenyl substructure participated the synthesis with satisfactory results (3s and 3t, Scheme 1). In expanded study, the N,N-dimethyl enaminone 1f reacted with tosyl hydrazine 2a to give corresponding pyrazole 3u with 23% yield (Scheme 1), suggesting that the free NH2 was crucial under the present conditions. Actually, an enaminone containing the electron withdrawing effect phenyl in the


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amino group (NH-enaminone) didn’t take part in the expected reaction. On the other hand, simultaneously subjecting 2a and p-chlorophenyl sulfonyl hydrazine together with enaminone 1a led to the formation of complex mixture containing various homo- and cross-condensed products. Finally, when the reaction of aryl/aryl enaminone (R1 = R1 = Ph) and 2a was performed, no formation of product 3 was observed. Scheme 1 Scope on the synthesis fully substituted pyrazolesa,b

O

NH2

R1

O

R2

Ar

1 Ar O Ph

S

O

N N O S O Ar

R2 S

I2/TBHP

O

O NHNH2 NaHCO3, H2O, rt S Ar O 2

Ar = 4-MeC4H4, 3a, 80% Ar = C6H5, 3b, 76% Ar = 4-FC4H4, 3c, 82% Ar = 4-ClC4H4, 3d, 85% Ar = 4-BrC4H4, 3e, 82% Ar = 2-MeC4H4, 3f, 78%

S

O

Ar

N Ts

Ar = 4-MeOC4H4, 3g, 78% N Ar = 4-ClC6H4, 3h, 75%

R = Et,, Ar = 4-ClC4H4, 3p, 68% R = Et, Ar = 4-MeC4H4, 3q, 65% R = Et, Ar = 4-MeOC4H4, 3r, 70% R = Me, Ar = 4-CF3C4H4, 3s, 70% R = Me, Ar = 4-FC4H4, 3t, 77% Ts

O N 1f

1 3 R

Ts

R = Me, Ar = 4-MeC6H4, 3i, 75% R R = Me, Ar = naphth-2-yl, 3j, 82% O R = Me, Ar = 4-ClC6H4, 3k, 83% N R = Me, Ar = 4-MeOC6H4, 3l, 78% R N R = Me, Ar = 2,4,6-Me3C6H2, 3m, 67% O S O R = Me, Ar = 2-MeC H , 3n, 74% 6 4 Ar R = Me, Ar = Ph, 3o, 71% Ar

N N SO2Ar

+ TsNHNH2

N N

standard conditions

2a

Ts 3u, 23%

aGeneral

conditions: enaminone 1 (0.2 mmol), sulfonyl hydrazine 2 (0.5 mmol), I2 (0.04 mmol), NaHCO3 (0.1 mmol), TBHP (0.6 mmol) in water (1 mL), stirred at rt for 6 h. bYield of isolated product based on 1. Notably, the scale-up reaction of 3a with 2a in 12 mmol scale gave 3i with 65% yield (3.15g), demonstrating the practical application of the method in large scale synthesis (Eq 1).


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O

NH2

1d, 12 mmol

I2 (0.2 equiv) NaHCO3 (0.5 equiv)

3i TBHP (3.0 equiv) 65%, 3.151g H2O, rt., 6h 2a, 30 mmol

+ TsNHNH2

(1)

Successively, to exploit possible reaction mechanism, several control experiments were performed. First, the enaminoester 4 was utilized to react with 2a under the standard reaction conditions. The production of 5 was observed (Eq 2), which suggested that the α-sulfonylation of enaminone/enaminoester might take place before the annulation. In addition, employing the prior synthesized pyrazole 6 and 2a did not provide desired product (Eq 3), implying that the C(sp2)-H bond in the pyrazole ring was inactive toward the sulfonylation, supporting that that the reaction proceeded via the sequence of sulfonylation and pyrazole annulation. Finally, the N15 labeled enaminone 1a-N15 was prepared (see SI) and employed to react with 2a (Eq 4). However, not any N15-labeled pyrazole product was observed, confirming that the C-N bond in enaminone was cleaved during the reaction. Finally, the radical scavenger BHT evidently inhibited the formation of 3a (Eqs 5 and 6), indicating that the reaction should proceed via free radical pathway. A parallel reaction employing TEMPO (4 equiv) gave product 3a with 73% yield, suggesting that TEMPO was not the proper scavenger of the present reaction. Furthermore, employing only 1a under the standard reaction condition did not provide the 1-phenylbutane-1,3-dione 7 (Eq 7), indicating that the direct hydrolysis of enaminone was not the possible transformation step. Alternatively, employing 7 to react with 2a provided 3a only in 45% yield (Eq 8), confirming the specific advantage of the enaminone substrate in the present system. Moreover, addition of NH4OAc together with these substrates gave rise to evidently enhanced yield of 3a (Eq 9), supporting that the formation of NH2 enaminone was positive.


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O EtO

NH2

+ TsNHNH2 2a

4 N

N Ts

+ TsNHNH2

15

NH2

Ph 1a-N

N

H N

Ts (2)

EtO 5 Ts

standard conditions

NR

Ts

77%

3a Ph

standard conditions BHT

NH2

3a

45% (BHT, 2 equiv)

(5)

20% (BHT, 4 equiv)

(6)

O

standard conditions

O (7)

Ph

Ph

1a O

(3)

N N Ts (4)

standard conditions

2a

2a

O

Ph

+ TsNHNH2

15

1a

60%

O

2a

6 Ph O

standard conditions

Page 8 of 26

7, not formed O

2a

standard conditions

45% 3a

(8)

52% (with 1 equiv. NH4OAc) (9)

7

Following these clues, the possible mechanism of the reaction is proposed (Scheme 2). First, molecular iodine reacts with TBHP to provide t-BuOO۰ free radical in the presence of base. The resulting iodine anion can be regenerated to molecular iodine via the oxidation of TBHP and produces t-BuO·. Subsequently, in the presence of the in situ generated free radical species, tosyl hydrazine undergoes well documented transformations of dehydrogenation and nitrogen gas extrusion to provide sulfonyl radical A.61-64 The free radical addition of A to the enaminone C=C double bond leads to the production of free radical intermediate B. The coupling of B with molecular iodine then affords intermediate C which is transformed into the sulfonyl enaminone D by featured β-elimination of HI. The successive hydrolysis of enamine fragment and the tandem condensation with another tosyl hydrazine yields intermediate E. The intramolecular addition of the nucleophilic nitrogen to the ketone carbonyl gives rise to the hydroxypyrazoline F, and the final dehydration on F yields the target product.


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t-BuOO + H2O

t-BuOOH + OH-

I-

I2

t-BuOOH

t-BuO + OH-

1a t-BuOO or t-BuO

TsNHNH2 ref. 21

O

Ts

NH2

Ph C

Ts

I

Ts B

O

N Ph HO Ts H F

NH2

TsNHNH2

Ts D

HI

Ph H 2O

Ts NH N

O Ph

Ph

Ts N

I

Ph

A

t-BuOOH or + N2 t-BuOH O

I2

NH2

Ts N

NH3

Ts E

N

Ts

Scheme 2 The proposed reaction mechanism In summary, by employing NH2 functionalized enaminones and sulfonyl hydrazines in water, a green synthetic method affording fully substituted pyrazoles is accomplished. Without using any metal catalyst, the reactions proceed with fine substrate tolerance and good to excellent yields. Isotope labeling experiment confirms the C-N bond cleavage of enaminone, disclosing the sole role of this amino group as the hydrogen bond donor to assist the reaction in water. EXPERIMENTAL SECTION General experimental information All experiments were carried out under air atmosphere. Enaminones 165 and sulfonyl hydrazines (expect tosyl hydrazine 2a) 266 were synthesized following literature process. All other chemicals used in the experiments were obtained from commercial sources and used


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directly without further treatment. The 1H and

13C

apparatus and the frequencies for 1H NMR and

Page 10 of 26

NMR spectra were recorded in 400 MHz

13C

NMR test are 400 MHz and 100 MHz,

respectively. The chemical shifts were reported in ppm with reference to TMS internal standard. Melting points for all solid products were tested in X-4A instrument without correcting temperature. The HRMS were obtained under ESI model in a mass spectrometry equipped with TOF analyzer. General procedure for the synthesis of product 3 To a 25 mL round-bottom flask were added enaminone 1 (0.2 mmol), arylsulfonyl hydrazine 2 (0.5 mmol), NaHCO3 (0.1 mmol), molecular iodine (0.04 mmol), TBHP (0.6 mmol, 70 % solution in water) and H2O (1.0 mL). The mixture was stirred at the room temperature for 6 h (TLC). Upon completion, 5 mL of water was added, and the resulting mixture was extracted with ethyl acetate (3 × 10 mL). The organic phases were combined and washed with small amount of water for three times. After drying with anhydrous Na2SO4, the solid was filtered. The solvent in the acquired solution was removed under reduced pressure. The resulting residue was subjected to flash silica gel column chromatography to provide pure products with the elution of mixed petroleum ether/ethyl acetate (v/v = 10:1 or 5:1). Scale up synthesis of pyrazole 3i To a 100 mL round-bottom flask were charged enaminone 1d (12 mmol), tosyl hydrazine 2a (30 mmol), NaHCO3 (6.0 mmol), molecular iodine (2.4 mmol), TBHP (1.8 mmol, 70 % solution in water) and H2O (10 mL). The mixture was stirred at the room temperature for 6 h (TLC). Upon completion, 10 mL water was added to the flask, and the resulting mixture was extracted with ethyl acetate (3 × 15 mL). The organic phases were combined and washed with small amount of water for three times. After drying with anhydrous Na2SO4, the solid was filtered and


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the solvent in the acquired solution was removed under reduced pressure. The residue acquired therein was subjected to flash silica gel column chromatography to provide pure products 3i (3.151g, 65%) with the elution of mixed petroleum ether/ethyl acetate (v/v = 5:1). 3-Methyl-5-phenyl-1,4-ditosyl-1H-pyrazole (3a).35 Yield: 75 mg (80 %); white solid; m.p. 212-213 oC; 1H NMR (400 MHz, CDCl3): δ 7.58-7.47 (m, 3 H), 7.37 (t, J = 7.6 Hz, 2 H), 7.307.22 (m, 4 H), 7.14-7.04 (m, 4 H), 2.56 (s, 3 H), 2.42 (s, 3 H), 2.36 (s, 3 H); 13C{1H} NMR (100 MHz, CDCl3): 151.1, 147.9, 146.5, 144.3, 138.6, 134.0, 130.8, 130.2, 130.0, 129.4, 128.4, 127.4, 127.2, 126.3, 124.2, 21.8, 21.6, 14.1. 3-Methyl-5-phenyl-1,4-bis(phenylsulfonyl)-1H-pyrazole (3b). Yield: 67 mg (76 %); white solid; m.p. 123-124 oC; 1H NMR (400 MHz, CDCl3): δ 7.68-7.61 (m, 3 H), 7.56 -7.43 (m, 4 H), 7.41-7.28 (m, 6 H), 7.04 (d, J = 7.6 Hz, 2 H), 2.59 (s, 3 H); 13C{1H} NMR (100 MHz, CDCl3): 151.3, 148.3, 141.5, 137.0, 135.0, 133.3, 130.7, 130.3, 129.4, 128.8, 128.4, 127.5, 127.1, 126.0, 124.0, 14.1; ESI-HRMS: Calcd for C22H19N2O4S2 [M+H]+ 439.0781, found 439.0783. 1,4-Bis(4-fluorophenylsulfonyl)-3-methyl-5-phenyl-1H-pyrazole (3c). Yield: 78 mg (82 %); white solid; m.p. 169-170 oC; 1H NMR (400 MHz, CDCl3): δ 7.74-7.67 (m, 2 H), 7.56-7.50 (m, 1 H), 7.43-7.34 (m, 4 H), 7.15 (t, J = 8.4 Hz, 2 H), 7.05 (d, J = 7.6 Hz, 2 H), 6.97 (t, J = 8.4 Hz, 2 H), 2.59 (s, 3 H); 13C{1H} NMR (100 MHz, CDCl3): 166.5 (d, J =258 Hz), 165.4 (d, J =255 Hz), 151.2, 148.0, 137.4 (d, J =3 Hz), 132.8 (d, J =3 Hz), 131.5 (d, J =10 Hz), 130.6, 130.5, 130.1 (d, J =10 Hz), 127.7, 125.9, 124.0, 116.9 (d, J =23 Hz), 116.1 (d, J =23 Hz), 14.2; ESI-HRMS: Calcd for C22H17F2N2O4S2 [M+H]+ 475.0592, found 475.0597. 1,4-Bis(4-chlorophenylsulfonyl)-3-methyl-5-phenyl-1H-pyrazole (3d). Yield: 86 mg (85 %); white solid; m.p. 179-180 oC; 1H NMR (400 MHz, CDCl3): δ 7.61 (d, J = 8.8 Hz, 2 H), 7.54 (t, J = 7.4 Hz, 1 H), 7.45 (d, J = 8.8 Hz, 2 H), 7.39 (t, J = 7.6 Hz, 2 H), 7.33-7.23 (m, 4 H), 7.05


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(d, J = 7.2 Hz, 2 H), 2.58 (s, 3 H); 13C{1H} NMR (100 MHz, CDCl3): 151.4, 148.2, 142.1, 140.1, 139.8, 135.2, 130.6, 130.5, 129.9, 129.8, 129.1, 128.7, 127.7, 125.8, 123.9, 14.2; ESI-HRMS: Calcd for C22H17Cl2N2O4S2 [M+H]+ 507.0001, found 507.0003. 1,4-Bis(4-bromophenylsulfonyl)-3-methyl-5-phenyl-1H-pyrazole (3e). Yield: 97 mg (82 %); white solid; m.p. 219-220 oC; 1H NMR (400 MHz, CDCl3): δ 7.63 (d, J = 8.8 Hz, 2 H), 7.587.50 (m, 3 H), 7.47-7.35 (m, 4 H), 7.21 (d, J = 8.4 Hz, 2 H), 7.05 (d, J = 7.2 Hz, 2 H), 2.58 (s, 3 H); 13C{1H} NMR (100 MHz, CDCl3): 151.5, 148.2, 140.3, 135.7, 132.8, 132.1, 130.8, 130.6, 130.6, 129.8, 128.7, 128.7, 127.7, 125.8, 123.9, 14.2; ESI-HRMS: Calcd for C22H17Br2N2O4S2 [M+H]+ 594.8991, found 594.9003. 3-Methyl-5-phenyl-1,4-bis(o-tolylsulfonyl)-1H-pyrazole (3f). Yield: 73 mg (78 %); white solid; m.p. 114-115 oC; 1H NMR (400 MHz, CDCl3): δ 7.44 (t, J = 7.6 Hz, 1 H), 7.32-7.21 (m, 4 H), 7.18 (d, J = 8.0 Hz, 1 H), 7.12 (d, J = 7.6 Hz, 1 H), 7.09-6.99 (m, 3 H), 6.85 (t, J = 7.6 Hz, 1 H), 6.73 (d, J = 7.2 Hz, 2 H), 2.61 (s, 3 H), 2.43 (s, 3 H), 2.33 (s, 3 H); 13C{1H} NMR (100 MHz, CDCl3): 150.4, 147.2, 139.1, 138.8, 137.3, 135.3, 134.9, 133.2, 132.7, 132.1, 130.5, 129.8, 129.0, 127.3, 126.3, 125.6, 125.2, 123.2, 20.1, 19.6, 14.2; ESI-HRMS: Calcd for C24H23N2O4S2 [M+H]+ 467.1094, found 467.1112. 5-(4-Methoxyphenyl)-3-methyl-1,4-ditosyl-1H-pyrazole (3g). Yield: 77 mg (78 %); white solid; m.p. 223-224 oC; 1H NMR (400 MHz, CDCl3): δ 7.53 (d, J = 8.4 Hz, 2 H), 7.31-7.22 (m, 4 H), 7.12 (d, J = 8.4 Hz, 2 H), 7.01 (d, J = 8.8 Hz, 2 H), 6.89 (d, J = 8.8 Hz, 2 H), 3.90 (s, 3 H), 2.55 (s, 3 H), 2.43 (s, 3 H), 2.36 (s, 3 H); 13C{1H} NMR (100 MHz, CDCl3): 161.1, 151.1, 148.2, 146.3, 144.2, 138.8, 134.0, 132.3, 129.9, 129.4, 128.4, 127.1, 124.1, 117.9, 112.9, 55.4, 21.8, 21.6, 14.2; ESI-HRMS: Calcd for C25H25N2O5S2 [M+H]+ 497.1199, found 497.1201.


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5-(4-Chlorophenyl)-3-methyl-1,4-ditosyl-1H-pyrazole (3h). Yield: 75 mg (75 %); white solid; m.p. 185-186 oC; 1H NMR (400 MHz, CDCl3): δ 7.56 (d, J = 8.4 Hz, 2 H), 7.36 (d, J = 8.4 Hz, 2 H), 7.33-7.27 (m, 4 H), 7.15 (d, J = 8.4 Hz, 2 H), 7.03 (d, J = 8.4 Hz, 2 H), 2.55 (s, 3 H), 2.44 (s, 3 H), 2.38 (s, 3 H); 13C{1H} NMR (100 MHz, CDCl3): 151.2, 146.7, 146.6, 144.6, 138.5, 136.7, 133.8, 132.1, 130.1, 129.5, 128.4, 127.8, 127.1, 124.7, 124.4, 21.8, 21.6, 14.0; ESIHRMS: Calcd for C24H22ClN2O4S2 [M+H]+ 501.0704, found 501.0706. 3,5-Dimethyl-1,4-ditosyl-1H-pyrazole (3i).35 Yield: 61 mg (75 %); white solid; m.p. 92-93 oC; 1H

NMR (400 MHz, CDCl3): δ 7.86 (d, J = 8.0 Hz, 2 H), 7.73 (d, J = 8.0 Hz, 2 H), 7.35 (d, J

= 8.0 Hz, 2 H), 7.31 (d, J = 8.0 Hz, 2 H), 2.84 (s, 3 H), 2.42 (d, J = 10.8 Hz, 6 H), 2.36 (s, 3 H); 13C{1H}

NMR (100 MHz, CDCl3): 151.2, 146.7, 146.5, 144.5, 139.4, 134.1, 130.3, 129.9, 128.2,

126.7, 121.8, 21.8, 21.6, 13.7, 11.7. 3,5-Dimethyl-1,4-bis(naphthalen-2-ylsulfonyl)-1H-pyrazole (3j).35 Yield: 78 mg (82 %); white solid; m.p. 222-223 oC; 1H NMR (400 MHz, CDCl3): δ 8.61 (s, 1 H), 8.46 (s, 1 H), 8.047.83 (m, 7 H), 7.77-7.56 (m, 5 H), 2.95 (s, 3 H), 2.40 (s, 3 H); 13C{1H} NMR (100 MHz, CDCl3): 151.5, 147.2, 139.0, 135.8, 135.1, 133.8, 132.1, 131.9, 130.5, 130.2, 130.1, 129.8, 129.7, 129.4, 129.3, 128.2, 128.1, 128.0, 128.0, 127.8, 122.1, 121.6, 121.6, 13.8 11.9. 1,4-Bis(4-chlorophenylsulfonyl)-3,5-dimethyl-1H-pyrazole (3k).35 Yield: 74 mg (83 %); white solid; m.p. 209-210 oC; 1H NMR (400 MHz, CDCl3): δ 7.94 (d, J = 8.4 Hz, 2 H), 7.79 (d, J = 8.4 Hz, 2 H), 7.59-7.47 (m, 4 H), 2.86 (s, 3 H), 2.35 (s, 3 H); 13C{1H} NMR (100 MHz, CDCl3): 151.6, 147.3, 142.2, 140.6, 140.3, 135.2, 130.0, 129.7, 128.2, 121.4, 13.7, 11.8. 1,4-Bis(4-methoxyphenylsulfonyl)-3,5-dimethyl-1H-pyrazole (3l).35 Yield: 68 mg (78 %); white solid; m.p. 107-108 oC; 1H NMR (400 MHz, CDCl3): δ 7.92 (d, J = 9.2 Hz, 2 H), 7.78 (d, J = 8.8 Hz, 2 H), 6.99 (dd, J = 13.2 Hz, 9.2 Hz, 4 H), 3.91-3.87 (m, 3 H), 3.87-3.84 (m, 3 H), 2.84


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(s, 3 H), 2.35 (s, 3 H); 13C{1H} NMR (100 MHz, CDCl3): 164.8, 163.5, 151.0, 146.2, 133.9, 130.6, 128.9, 128.2, 122.0, 114.9, 114.5, 55.9, 55.7, 13.7, 11.7. 1,4-Bis(mesitylsulfonyl)-3,5-dimethyl-1H-pyrazole (3m). Yield: 62 mg (67 %); white solid; m.p. 123-125 oC; 1H NMR (400 MHz, CDCl3): δ 6.99 (s, 2 H), 6.93 (s, 2 H), 2.69 (s, 3 H), 2.55 (s, 6 H), 2.53 (s, 6 H), 2.33 (s, 3 H), 2.30 (s, 3 H), 2.04 (s, 3 H);

13C{1H}

NMR (100 MHz,

CDCl3): 149.7, 145.6, 145.2, 143.4, 141.2, 139.4, 135.1, 132.3, 131.6, 122.6, 22.6, 22.0, 21.2, 21.0, 13.0, 11.5; ESI-HRMS: Calcd for C23H29N2O4S2 [M+H]+ 461.1563, found 461.1563. 3,5-Dimethyl-1,4-bis(o-tolylsulfonyl)-1H-pyrazole (3n).35 Yield: 60 mg (74 %); white solid; m.p. 94-96 oC; 1H NMR (400 MHz, CDCl3): δ 8.14-8.00 (m, 2 H), 7.63-7.54 (m, 1 H), 7.55-7.46 (m, 1 H), 7.44-7.32 (m, 3 H), 7.29 (s, 1 H), 2.75 (s, 3 H), 2.58 (s, 3 H), 2.43 (s, 3 H), 2.19 (s, 3 H); 13C{1H} NMR (100 MHz, CDCl3): 150.8, 147.1, 139.3, 139.3, 137.7, 135.5, 135.2, 133.7, 133. 2, 132.9, 130.3, 128.9, 126.8, 126.3, 20.3, 19.5, 13.5, 11.9. 3,5-Dimethyl-1,4-bis(phenylsulfonyl)-1H-pyrazole (3o).35 Yield: 53 mg (71 %); white solid; m.p. 46-47 oC; 1H NMR (400 MHz, CDCl3): δ 7.99 (d, J = 7.6 Hz, 2 H), 7.85 (d, J = 7.6 Hz, 2 H), 7.70 (t, J = 7.2 Hz, 1 H), 7.63-7.47 (m, 5 H), 2.87 (s, 3 H), 2.37 (s, 3 H); 13C{1H} NMR (100 MHz, CDCl3): 151.5, 147.1, 142.2, 137.0, 135.1, 133.5, 129.7, 129.4, 128.2, 126.7, 121.6, 13.7, 11.8. 1,4-Bis(4-chlorophenylsulfonyl)-3,5-diethyl-1H-pyrazole (3p). Yield: 64 mg (68 %); white solid; m.p. 141-142 oC; 1H NMR (400 MHz, CDCl3): δ 7.98 (d, J = 8.4 Hz, 2 H), 7.80 (d, J = 8.4 Hz, 2 H), 7.52 (dd, J1= 19.2 Hz, J2 = 8.4 Hz, 4 H), 3.34 (q, J = 7.2 Hz, 2 H), 2.74 (q, J = 7.2 Hz, 2 H), 1.27 (t, J = 7.2 Hz, 3 H), 1.16 (t, J = 7.4 Hz, 3 H); 13C{1H} NMR (100 MHz, CDCl3): 156.3, 153.4, 142.0, 140.8, 140.2, 135.4, 130.0, 129.8, 129.7, 128.3, 119.8, 21.0, 19.0, 14.9, 11.8; ESI-HRMS: Calcd for C19H19Cl2N2O4S2 [M+H]+ 473.0158, found 473.0159.


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3,5-Diethyl-1,4-ditosyl-1H-pyrazole (3q).35 Yield: 56 mg (65 %); white solid; m.p. 146-147 oC; 1H

NMR (400 MHz, CDCl3): δ 7.89 (d, J = 8.0 Hz, 2 H), 7.73 (d, J = 8.0 Hz, 2 H), 7.32 (dd,

J1 = 17.2 Hz, J2 = 8.0 Hz, 4 H), 3.34 (q, J = 7.2 Hz, 2 H), 2.75 (q, J = 7.4 Hz, 2 H), 2.43 (d, J = 10.8 Hz, 6 H), 1.24 (t, J = 7.4 Hz, 3 H), 1.16 (t, J = 7.4 Hz, 3 H); 13C{1H} NMR (100 MHz, CDCl3): 156.0, 152.8, 146.3, 144.4, 139.6, 134.3, 130.0, 129.9, 128.5, 126.8, 120.2, 21.8, 21.6, 21.0, 18.9, 14.8, 12.0. 3,5-Diethyl-1,4-bis(4-methoxyphenylsulfonyl)-1H-pyrazole (3r). Yield: 65 mg (70 %); white solid; m.p. 123-124 oC; 1H NMR (400 MHz, CDCl3): δ 7.95 (d, J = 9.2 Hz, 2 H), 7.79 (d, J = 8.8 Hz, 2 H), 6.98 (dd, J = 11.6, 9.2 Hz, 4 H), 3.87 (d, J = 10.0 Hz, 6 H), 3.33 (q, J = 7.4 Hz, 2 H), 2.75 (q, J = 7.4 Hz, 2 H), 1.24 (t, J = 7.2 Hz, 3 H), 1.16 (d, J = 7.6 Hz, 3 H); 13C{1H} NMR (100 MHz, CDCl3): 156.0, 158.7, 151.0, 147.5, 129.4, 126.1, 124.3, 123.7, 115.6, 109.8, 109.7, 51.1, 50.9, 16.2, 14.2, 10.0, 7.3; ESI-HRMS: Calcd for C21H25N2O6S2 [M+H]+ 465.1149, found 465.1150. 3,5-Dimethyl-1,4-bis(4-(trifluoromethyl)phenylsulfonyl)-1H-pyrazole (3s).35 Yield: 71 mg (70 %); white solid; m.p. 245-246 oC; 1H NMR (400 MHz, CDCl3): δ 8.16 (d, J = 8.0 Hz, 2 H), 7.99 (d, J = 8.4 Hz, 2 H), 7.86 (d, J = 8.0 Hz, 2 H), 7.81 (d, J = 8.4 Hz, 2 H), 2.90 (s, 3 H), 2.38 (s, 3 H); 13C{1H} NMR (100 MHz, CDCl3): 152.0, 148.0, 145.4, 140.2, 137.2, 136.9, 136.6, 136.2, 135.9, 135.5, 135.2, 134.9, 129.0, 127.3, 126.9, 126.9, 126.8, 126.8, 126.7, 126.7, 126.6, 126.6, 124.3, 124.1, 121.6, 121.4, 121.1, 13.8, 11.9. 1,4-Bis(4-fluorophenylsulfonyl)-3,5-dimethyl-1H-pyrazole (3t).35 Yield: 63 mg (77 %); white solid; m.p. 187-189 oC; 1H NMR (400 MHz, CDCl3): δ 8.07-8.00 (m, 2 H), 7.93-7.83 (m, 2 H), 7.31-7.12 (m, 4 H), 2.87 (s, 3 H), 2.36 (s, 3 H); 13C{1H} NMR (100 MHz, CDCl3): 166.6 (d,


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Page 16 of 26

J = 258 Hz), 165.6 (d, J = 255 Hz), 151.5, 147.1, 138.2 (d, J = 3 Hz), 132.8 (d, J = 3 Hz), 131.4 (d, J = 10 Hz), 129.6 (d, J = 10 Hz), 121.5, 117.2 (d, J = 23 Hz), 116.7 (d, J = 23 Hz), 13.7, 11.8. 5-Phenyl-1,4-ditosyl-1H-pyrazole (3u). Yield: 21 mg (23 %); white solid; m.p. 188-189 oC; 1H

NMR (400 MHz, CDCl3): δ 8.15 (s, 1 H), 7.59-7.49 (m, 3 H), 7.37 (t, J = 7.8 Hz, 2 H), 7.29-

7.18 (m, 4 H), 7.10-7.03 (m, 4 H), 2.41 (s, 3 H), 2.34 (s, 3 H). 13C{1H} NMR (100 MHz, CDCl3): 146.8, 146.4, 144.5, 141.6, 137.9, 133.6, 131.0, 130.4, 130.1, 129.4, 128.5, 127.6, 127.5, 126.9, 125.4, 21.8, 21.6; ESI-HRMS: Calcd for C23H21Cl2N2O4S2 [M+H]+ 453.0937, found 453.0939. (E)-ethyl 2-tosyl-3-(2-tosylhydrazono)butanoate (5).35 Yield: 54 mg (60 %); white solid; m.p. 182-183 oC; 1H NMR (400 MHz, DMSO-d6): δ 10.75 (s, 1 H), 7.66-7.61 (m, 4 H), 7.407.22 (m, 4 H), 5.32 (s, 1 H), 4.02 (dd, J = 7.2, 4.8 Hz, 2 H), 2.38 (d, J = 6.4 Hz, 6 H), 2.03 (s, 3 H), 1.03 (t, J = 7.0 Hz, 3 H). 13C{1H} NMR (100 MHz, DMSO-d6) δ 163.4, 147.1, 145.5, 143.7, 136.6, 135.2, 129.9, 129.8, 129.3, 127.7, 76.2, 62.4, 21.6, 21.5, 16.7, 14.0. ASSOCIATED CONTENT Supporting Information. The Supporting Information is available free of charge on the ACS Publications website at DOI: The following files are available free of charge. HMRS spectra of 15N labeled enaminone 1a-N15 and the product from Eq 4, as well as all new products, 1H and 13C NMR spectra of all products (PDF) AUTHOR INFORMATION Corresponding Author Email: [email protected]


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Notes The authors declare no competing financial interest. ACKNOWLEDGMENT This work is financially supported by the National Natural Science Foundation of China (21861019 and 21562025). REFERENCES 1 Xu, Z.; Gao, G.; Ren, Q.-C.; Song, X.-F.; Feng, L.-S.; Lv, Z.-S. Recent advances of pyrazole-containing derivatives as anti-tubercular agents. Eur. J. Med. Chem. 2017, 139, 429440. 2 Faria, J. V.; Vegi, P. F.; Miguita, A. G. C.; dos Santos, M. S.; Boechat, N.; Bernardino, A. M. Recently reported biological activities of pyrazole compounds. Bioorg. Med. Chem. 2017, 25, 5891-5903. 3 Küçükgüzel, Ş.G.; Şenkardeş, S. Recent advances in bioactive pyrazoles. Eur. J. Med. Chem. 2015, 97, 786-815. 4 Cui, C.-Y.; Liu, J.; Zheng, H.-B.; Jin, X.-Y.; Zhao, X.-Y.; Chang, W.-Q.; Sun, B.; Lou, H.-X. Diversity-oriented synthesis of pyrazoles derivatives from flavones and isoflavones leads to the discovery of promising reversal agents of fluconazole resistance in Candida albicans. Bioorg. Med. Chem. Lett. 2018, 28, 1545-1549. 5 Sowmya, D. V.; Teja, G. L.; Padmaja, A.; Prasad, V. K.; Padmavathi, V. Green approach for the synthesis of thiophenyl pyrazoles and isoxazoles by adopting 1,3-dipolar cycloaddition methodology and their antimicrobial activity. Eur. J. Med. Chem. 2018, 143, 891-898.


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Zinc-promoted

cyclization

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tosylhydrazones

and

2-


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Domino C-H Sulfonylation and Pyrazole Annulation for Fully

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