Domino C-H Sulfonylation and Pyrazole Annulation for Fully Substituted Pyrazole Synthesis in Water Using Hydrophilic Enaminones

Article abstract of DOI:10.1021/acs.joc.8b02897

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 proc

Full text of DOI:10.1021/acs.joc.8b02897

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Note
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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Domino C-H Sulfonylation and Pyrazole Annulation
for Fully Substituted Pyrazole Synthesis in Water
Using Hydrophilic Enaminones
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Yanhui Guo, Guodong Wang, Li Wei, Jie-Ping Wan*
Collelge of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang 330022,
P. R. China.
O
15NH2
R2
the hydrophilic site
> C(sp2)-H sulfenylation & pyrazole annulation
> C-N cleavage confirmed by 15N labeling
> Free of any metal reagent
R2
ArO2S
R1
I2/TBHP
H
R1
N
N
NaHCO3, H2O, rt
> Water as the sole medium
O
O
SO2Ar
Efficient scale up synthesis
>
S
20 examples
Ar
NHNH2
up to 85% yield
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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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 anti-
oxidation 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
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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.
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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 eco-
friendliness 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
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O
NH2
cat./additive
H2O, temp.
N
Ts NHNH2
Ts
N
Ph
Ts
1a
2a
Ph
3a
entry catalyst/addtive oxidant temp.(oC) Yield (%)b
1
I2/-
air
air
air
air
rt
rt
rt
rt
rt
rt
35
50
nr
2
I2/NaHCO3
-/NaHCO3
KI/NaHCO3
3
4
30
trace
50
72
58
53
64
40
32
60
55
60
68
80
70
5
KIO3/NaHCO3 air
6
I2/Et3N
air
7
I2/NaHCO3
I2/NaHCO3
I2/NaHCO3
I2/NaHCO3
I2/NaHCO3
I2/NaHCO3
I2/NaHCO3
I2/NaHCO3
I2/NaHCO3
I2/NaHCO3
I2/NaHCO3
TBHP rt
8
H2O2
DDQ
rt
rt
9
10
11
12
13c
14d
15e
16f
17g
DTBP rt
TBHP 60
TBHP 90
TBHP rt
TBHP rt
TBHP rt
TBHP rt
TBHP rt
TBHP rt
18g,h I2/NaHCO3
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19g,i I2/NaHCO3
TBHP rt
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aGeneral conditions: 1a (0.2 mmol), 2a (0.5 mmol), catalyst (20 mol%), additives (0.5 equiv)
5
6
7
8
b
and oxidant (3.0 equiv) in 2.0 mL water, stirred for 6 h. Yield of isolated product based on 1a.
d
f
cReaction time was 3 h. Reaction time was 12 h.eReaction in EtOH. Reaction in DMF.
gReaction in 1 mL water. hThe loading of 2a was 0.1 mmol, and yield was based on 2a. iReaction
in MeCN
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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.
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Scheme 1 Scope on the synthesis fully substituted pyrazolesa,b
R2
N
N
O
NH2
R2
O
I2/TBHP
O
SO2Ar
S
O
R1
NaHCO3, H2O, rt
NHNH2
Ar
S
Ar
R1
3
1
O
2
Ar
O
3a
Ar = 4-MeC4H4, , 80%
3b
Ar = C6H5, , 76%
3c
Ar = 4-FC4H4, , 82%
3d
Ar = 4-ClC4H4, , 85%
3e
Ar = 4-BrC4H4, , 82%
3f
Ar = 2-MeC4H4, , 78%
O
S
Ts
3g
Ar = 4-MeOC4H4, , 78%
3h
Ar = 4-ClC6H4, , 75%
N
N
Ph
Ar
N
N
O S O
Ar
Ts
3i
R = Me, Ar = 4-MeC6H4, , 75%
3j
R = Me, Ar = naphth-2-yl, , 82%
R
3k
R = Me, Ar = 4-ClC6H4, , 83%
3p
R = Et,, Ar = 4-ClC4H4, , 68%
3q
R = Et, Ar = 4-MeC4H4, , 65%
3r
R = Et, Ar = 4-MeOC4H4, , 70%
Ar
O
O
S
N
3l
R = Me, Ar = 4-MeOC6H4, , 78%
3s
R = Me, Ar = 4-CF3C4H4, , 70%
R
N
3m
3t
R = Me, Ar = 2,4,6-Me3C6H2,
, 67% R = Me, Ar = 4-FC4H4, , 77%
O S O
Ar
3n
R = Me, Ar = 2-MeC6H4, , 74%
3o
R = Me, Ar = Ph, , 71%
Ts
O
N
N
standard conditions
N
+
TsNHNH2
Ts
, 23%
2a
1f
3u
aGeneral conditions: enaminone 1 (0.2 mmol), sulfonyl hydrazine 2 (0.5 mmol), I2 (0.04
b
mmol), NaHCO3 (0.1 mmol), TBHP (0.6 mmol) in water (1 mL), stirred at rt for 6 h. Yield 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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6
I2 (0.2 equiv)
NaHCO3 (0.5 equiv)
O
NH2
3i
TsNHNH2
+
(1)
65%, 3.151g
TBHP (3.0 equiv)
H2O, rt., 6h
1d
2a
, 30 mmol
, 12 mmol
7
8
9
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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H
N
standard
conditions
O
N
NH2
Ts
O
N
Ts
+
TsNHNH2
(2)
(3)
EtO
60%
EtO
2a
4
5
Ts
NR
standard
conditions
N
+
TsNHNH2
2a
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Ph
6
N
N
standard
conditions
O
15NH2
(4)
Ts
+
TsNHNH2
Ts
Ph
77%
Ph
1a-N15
2a
3a
standard
conditions
(5)
(6)
45% (BHT, 2 equiv)
20% (BHT, 4 equiv)
3a
1a
2a
BHT
O
O
O
NH2
standard conditions
(7)
Ph
Ph
1a
7
, not formed
standard
conditions
(8)
(9)
45%
O
O
3a
2a
52% (with 1 equiv. NH4OAc)
Ph
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-BuOOH + OH-
t-BuOO + H2O
5
6
7
I2
I-
8
9
t-BuO + OH-
t-BuOOH
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1a
I2
I
O
NH2
t-BuOO
or
t-BuO
TsNHNH2
Ts
Ph
ref. 21
A
Ts
B
t-BuOOH
or
+
N2
t-BuOH
Ts
TsNHNH2
NH3
NH
O
NH2
O
NH2
O
N
Ph
Ph
Ph
I
Ts
Ts
Ts
E
HI
C
D
Ts
Ts
N
N
N
N
Ph
Ph
HO
Ts
H
Ts
H2O
F
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 H and 13C NMR spectra were recorded in 400 MHz
5
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1
apparatus and the frequencies for H NMR and 13C NMR test are 400 MHz and 100 MHz,
7
8
9
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.
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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), 7.30-
7.22 (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.
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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.
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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), 7.58-
7.50 (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; ESI-
HRMS: Calcd for C24H22ClN2O4S2 [M+H]+ 501.0704, found 501.0706.
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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 %);
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white solid; m.p. 222-223 C; H NMR (400 MHz, CDCl3): δ 8.61 (s, 1 H), 8.46 (s, 1 H), 8.04-
7.83 (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.
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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
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(s, 6 H), 2.53 (s, 6 H), 2.33 (s, 3 H), 2.30 (s, 3 H), 2.04 (s, 3 H); C{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;
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m.p. 46-47 C; H 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.
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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
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(s, 3 H); C{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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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.
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5-Phenyl-1,4-ditosyl-1H-pyrazole (3u). Yield: 21 mg (23 %); white solid; m.p. 188-189 C;
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;
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m.p. 182-183 C; H NMR (400 MHz, DMSO-d6): δ 10.75 (s, 1 H), 7.66-7.61 (m, 4 H), 7.40-
7.22 (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: wanjieping@jxnu.edu.cn
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Notes
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The authors declare no competing financial interest.
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ACKNOWLEDGMENT
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This work is financially supported by the National Natural Science Foundation of China
(21861019 and 21562025).
REFERENCES
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Diversity-oriented synthesis of pyrazoles derivatives from flavones and isoflavones leads to the
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the synthesis of thiophenyl pyrazoles and isoxazoles by adopting 1,3-dipolar cycloaddition
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