Catalyst free cyclocondensation of β-ethylthio-β-indolyl-α, β-unsaturated ketones with hydrazines: Efficient synthesis of 3-pyrazolyl indoles

Article abstract of DOI:10.1080/00397911.2019.1681001

Catalyst free cyclocondensation of β-ethylthio-β-indolyl-α,β-unsaturated ketones with hydrazines has been developed, and 3-pyrazolyl indoles were efficiently synthesized in excellent yields. The catalyst free protocol avoids the use of a large excess of catalysts such as acids and bases, eliminating the discharge of harmful chemicals.

Full text of DOI:10.1080/00397911.2019.1681001

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Catalyst free cyclocondensation of β-ethylthio-β-
indolyl-α, β-unsaturated ketones with hydrazines:
Efficient synthesis of 3-pyrazolyl indoles
Hai-Feng Yu & Wen-Ju Wang
To cite this article: Hai-Feng Yu & Wen-Ju Wang (2020): Catalyst free cyclocondensation of β-
ethylthio-β-indolyl-α, β-unsaturated ketones with hydrazines: Efficient synthesis of 3-pyrazolyl
indoles, Synthetic Communications, DOI: 10.1080/00397911.2019.1681001
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SYNTHETIC COMMUNICATIONSV
https://doi.org/10.1080/00397911.2019.1681001
Catalyst free cyclocondensation of b-ethylthio-b-indolyl-a,
b-unsaturated ketones with hydrazines: Efficient synthesis
of 3-pyrazolyl indoles
Hai-Feng Yu and Wen-Ju Wang
College of Chemistry, Baicheng Normal University, Baicheng, China
ABSTRACT
ARTICLE HISTORY
Received 11 June 2019
Catalyst free cyclocondensation of b-ethylthio-b-indolyl-a,b-unsat
urated ketones with hydrazines has been developed, and 3-pyrazolyl
indoles were efficiently synthesized in excellent yields. The catalyst
free protocol avoids the use of a large excess of catalysts such as
acids and bases, eliminating the discharge of harmful chemicals.
KEYWORDS
Cyclocondensation;
b-ethylthio-b-indolyl-a;
b-unsaturated ketones;
hydrazines; indole
derivatives; 3-pyra-
zolyl indoles
GRAPHICAL ABSTRACT
O
R3
R1
N
R3
R1
EtS
(CH3)3COH, 120 o
C
.
NH2NH2 H2O
N
H
+
4 h, sealed tube
N
N
R2
R4
R2
R4
Introduction
The synthesis of 3-pyrazolyl indoles had received more and more attention because of
their versatile synthetic values[1] and exhibiting a broad spectrum of biological
activities[2] such as antimicrobial[3], anti-inflammatory[4] and antioxidant.[5] As a result,
versatile synthetic routes have been developed for the synthesis of 3-pyrazolyl
indoles,[6–9] including the cyclocondensation of 1,3-diketones and related derivatives
with hydrazines,[6] the direct coupling of indole derivatives and pyrazole derivatives,[7]
acid-catalyzed intramolecular cyclization reaction of N-propargylation of N-acetyl-N-
tosylhydrazine,[8] and other procedures.[9] However, despite tremendous efforts to
develop more efficient strategies in these areas, the remarkable disadvantage of these
reactions was frequent use of a large number of catalysts such as acids and bases, which
can create serious environmental and safety problems. Thus, the development of catalyst
free approaches to 3-pyrazolyl indoles avoiding the use and release of the toxic and
hazardous materials which pollute the environment are highly desirable.
CONTACT Wen-Ju Wang
wangwj3309@163.com
College of Chemistry, Baicheng Normal University, P.O. Box:
137000, Baicheng, Jilin, China.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2020 Taylor & Francis Group, LLC

2
H.-F. YU AND W.-J. WANG
O
RNHNH2
R1
N
B(OH)2
t-BuOK or AcOH
R2
R1
t-BuOH, reflux
R2
N
R
previous work
Liebeskind-Srogl
coupling reaction
SEt
R2
R1
N
guanidine
NaOH/EtOH,
reflux
R4
N
O
H2N
previous work
R1
EtS
N
R3
R4
O
R5
R1=Me
SEt
O
R5
R4
NaOH(3eq)
EtOH/H2O
reflux
R5
N
N
R4
R1
EtS
R3
hydrolysis
R3
previous work
desulfitative C-C
coupling reaction
R4
O
O
R1=Me, Ar
N
R3
R5
R1
H2SO4(5 mol%)
N
R3
CH3CN/H2O
R5
.
N2H4 H2O
reflux
R1
free acids or
alkalis
this work
N
N
H
N
R5
R3
Scheme 1. Synthesis and application b-ethyltho-b-aryl-a,b-unsaturated ketones.
b-Ethyltho-b-aryl-a,b-unsaturated ketones could be regarded as versatile
organic synthesis intermediates due to their structural features of multi-reaction
center and multi-functional group (Scheme 1).[10,11] The condensation reactions of
b-ethyltho-b-indolyl-a,b-unsaturated ketones with guanidine affording alkaloids
meridianin derivatives 3-pyrimidyl indoles[10a] and hydrolysis reaction selective yielding
3-acetyl indoles and 3-acetoacetyl indoles[10b] had recently been realized (Scheme 1). In
addition, we also realized that potassium tert-butoxide or acetic acid mediated regiose-
lective cyclocondensation of b-ethyltho-b-phenyl-a,b-unsaturated ketones with hydra-
zines, affording only 1,3,5-trisubstituted pyrazoles in excellent yields.[11] As part of our
continuing research in the context, keeping in mind environmental requirements and
the significance of 3-pyrazolyl indoles, herein, we would like to report the catalyst free
cyclocondensation of b-ethyltho-b-indolyl-a,b-unsaturated ketones with hydrazine
hydrate to efficiently afford 3-pyrazolyl indoles. Unlike our previous work,[11] this work
concentrates on the study of green catalyst free synthesis of 3-pyrazolyl indoles.
Results and discussion
b-Ethyltho-b-indolyl-a,b-unsaturated ketones 1[10,12] were easily prepared in good yields
via acid mediated selective desulfitative carbon-carbon coupling reaction between
indoles and a-oxo ketene dithioacetals which are readily available and stable synthetic
intermediate.[13,14] The reactions of (Z/E)-3-(ethylthio)-3-(1-methyl-1H-indol-3-yl)-1-
phenylprop-2-en-1-one 1a with hydrazine hydrate 2a was selected as a model reaction
to screen the experimental conditions. We initially examined the cyclocondensation
reaction of 1a and 2a in refluxing EtOH (95%) when their molar ratio was 1:1, and
found the reactions gave a white solid product in 60% yield, which was characterized as
1-methyl-3-(3-phenyl-1H-pyrazol-5-yl)-1H-indole 3a on the basis of its spectral and

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SYNTHETIC COMMUNICATIONSV
3
Table 1. Screening of reaction conditionsa.
O
conditions
.
+
NH2NH2 H2O
EtS
N
N
N
H
N
2a
3a
1a
Entry
1a/2a(mol ratio)
Solvent
Temperature (oC)
Time (h)
Yield (%)b
1
2
3
4
5
6
7
1:1
2:3
1:2
1:3
1:2
1:2
1:2
1:2
1:2
1:2
CH3CH2OH (95%)
CH3CH2OH (95%)
CH3CH2OH (95%)
CH3CH2OH (95%)
CH3CH2OH
CH3CHOHCH3
(CH3)3COH
(CH3)3COH
(CH3)3COH
(CH3)3COH
reflux
reflux
reflux
reflux
reflux
reflux
reflux
100
20
18
15
14
15
13
8
7
4
3
60
63
74
77
79
81
82
90
94
93
8c
9c
10c
120
130
aReaction conditions: 1a (0.5 mmol), solvent (1 mL); bYield of isolated products; the reaction performed in sealed tube.
c
analytical data (Table 1, Entry1). The result showed that the cyclocondensation reaction
of 1a and 2a could effectively carry out without acids or bases catalysis to yield 3a.
Next, we studied the nonacid or alkali mediated reactions in detail under various condi-
tions to identify the optimal conditions. It was found that on changing the molar ratio
of 1a and 2a from 1:1 to 1:2, the yield of 3a was markedly increased, while further
reducing the ratio slightly improved the yield of 3a, which indicates that the prefect
ratio can be obtained when the reaction is proceeded with 1:2 molar ratio of 1a and 2a
(Table 1, Entries1–4). Subsequently, we tested the influence of reaction medium, and
found that the reaction proceeded more efficiently in tertbutyl alcohol ((CH3)3COH)
than in ethanol (CH3CH2OH) and isopropyl alcohol (CH3CHOHCH3). (Table 1,
Entries 5–7). The reaction efficiency was markedly improved by elevating the reaction
temperature, and the reaction could be completed in 4 h at 120 ꢀC to produce 3a in
94% yield (Table 1, Entries8–10). Accordingly, the optimal reaction conditions are a 1a/
2a ratio of 1:2, tert-butyl alcohol ((CH3)3COH) as the solvent, and run the reaction at
120 ꢀC (Table 1, Entry 9).
With the optimized conditions in hand, we examined the reaction of various b-ethyl-
tho-b-indolyl-a,b-unsaturated ketones 1 b-o with hydrazines 2 to define the scope of
the reaction, and the results are summarized in Table 2 and Scheme 2. The
compounds 1, such as (Z/E)-3-(ethylthio)-3-(1-methyl-1H-indol-3-yl)-1-arylprop-2-en-
1-ones 1a-1i (Table 2, Entry1-9), (Z/E)-3-(5-methyl/bromo/methoxy-1-methyl-1H-indol-
3-yl)-3-(ethylthio)-1-phenylprop-2-en-1-one 1j, 1k and 1 l (Table 2, Entry 10-12),
(Z/E)-3-(1-benzyl-1H-indol-3-yl)-3-(ethylthio)-1-phenylprop-2-en-1-one 1 m (Table 2,
Entry 13), (Z/E)-3-(ethylthio)-3-(2-methyl-1H-indol-3-yl)-1-phenylprop-2-en-1-one 1n
and (Z/E)-4-(ethylthio)-4-(1-methyl-1H-indol-3-yl)but-3-en-2-one 1o (Table 2,
Entries14 and 15), reacted smoothly with hydrazine hydrate 2a to efficiently give corre-
sponding 3-pyrazolyl indoles 3a-3o in excellent yields, respectively. Obviously, the elec-
tronic effects of both electron-withdrawing and-donating substitutents on phenyl or
indolyl in 1 are insignicant to the cyclocondensation reaction. However, the substituents

4
H.-F. YU AND W.-J. WANG
Table 2. synthesis of 3-pyrazolyl indoles 3a–3oa.
O
R3
R1
R3
R1
EtS
(CH3
)
3COH, 120 o
4 h, sealed tube
C N
.
N
H
+
NH2NH2 H2
O
N
N
R2
R4
R2
R4
1
3a-3n
2a
Entry
1
1
3
Yield(%)b
94
O
EtS
N
N
H
N
N
1a
1b
3a
3b
O
2
3
92
94
EtS
N
N
H
N
N
O
EtS
N
N
N
H
N
1c
3c
O
4
92
EtS
N
N
N
H
N
1d
3d
O
O
5
6
92
91
O
EtS
N
N
N
N
H
N
1e
3e
Cl
O
Cl
EtS
N
N
H
N
1f
3f
Br
O
7
8
9
95
91
90
Br
EtS
N
N
N
H
N
1g
3g
O
S
S
EtS
N
N
N
H
N
1h
3h
O
EtS
N
N
N
H
N
1i
3i
3j
3k
3l
10
11
12
93
94
95
1j
O
O
O
EtS
N
N
N
H
N
1k
1l
O
Br
Br
EtS
N
N
N
H
N
O
EtS
N
13
94
N
N
H
N
3m
1m
O
14c
15
90
93
N
EtS
N
H
NH
NH
1n
3n
O
N
N
H
EtS
N
N
3o
1o
aCondition: 1 (0.5 mmol), 2a (1 mmol), (CH3)3COH (1 mL), 120 ꢀC, 4 h; bIsolated yields; cThe reac-
tion takes 8 h to complete.

R
SYNTHETIC COMMUNICATIONSV
5
R
R
(CH3)3COH, 120 o
4 h, sealed tube
C
1a, 1e and 1g
+
PhNHNH2
+
N
N
2b
Ph
N
N
N
N
Ph
3p'-3r'
3p-3r
R = H (3p), 68%
R = OCH3 (3q), 74%
R = Br(3r), 57%
R = H(3p)', 26%
R = OCH3(3q'), 22%
R = Br(3r'), 38%
Scheme 2. The cyclocondensation reaction of 1a, 1e and 1 g and phenylhydrazine 2b.
at the 2-positions on the indole rings in 1 showed a significant impact on the reaction
due to the steric hindrance effect. For example, it took a longer time for the cyclocon-
densation reaction of 1n and 2a to afford 3n to complete (Table 2, Entry 14). It was
worth noting that the (E)/(Z)-configurations of 1 did not affect the cyclocondensation
of b- ethyltho-b-indolyl-a,b-unsaturated ketones 1 with hydrazines 2 to efficiently
afford 3-pyrazolyl indoles 3.
Furthermore, we explored the cyclocondensation reaction outcome of the substi-
tuted hydrazine phenylhydrazine 2 b and 1a under the optimized conditions, and
found that the reactions proceeded smoothly to offer 3-(1,5-diphenyl-1H-pyrazol-3-
yl)-1-methyl-1H-indole 3p in 65% yield and its tautomer 3-(1,3-diphenyl-1H-pyrazol-
5-yl)-1-methyl-1H-indole 3p0 in 30% yield. The result suggested that the reaction gave
3p in preference to 3p0. The isomeric 3p and 3p0 can be separated effectively because
they have different Rf values (petroleum ether/ethyl acetate10:1, v/v), in which the Rf
value of 3p0 is slightly smaller than that of 3p. The structure of 3p0 was confirmed
with the help of spectral and analytical data as well as alternative synthesis by
reported method11, while structural determination of 3q on the basis of spectral and
analytical data and by comparison of 3p0. Both 1e and 1 g efficiently underwent the
same reaction with 2 b to preferentially produce corresponding 3q and 3r in moderate
yield (Scheme 1).
In summary, the catalyst free cyclocondensation reaction of b-ethyltho-b-indolyl-
a,b-unsaturated carbonyl ketones and hydrazines could efficiently carried out in
(CH3)3COH at 120 ꢀC to afford 3-pyrazolyl indoles in excellent yields. The procedure is
characterized by reducing the discharge of chemical waste, which is of great
significance to the protection of the environment. Further investigation of the applica-
tion of b-ethyltho-b-indolyl-a,b-unsaturated ketones is ongoing in our group.
Experimental
General considerations
1
A H and 13 C NMR spectra were recorded on a Bruker DRX-600 spectrometer and the
chemical shift values refer to d TMS ¼ 0.00 ppm; The HRMS analysis was achieved on
Bruck micro Tof using ESI method. All the melting points were uncorrected. Analytical
TLC plates, Sigma-Aldrich silica gel 60F200 were viewed by UV light (254 nm).
Chromatographic purifications were performed on SDZF silica gel 160.

6
H.-F. YU AND W.-J. WANG
Typical procedure for the preparation of 3-pyrazolyl indoles 3
A mixture of b-ethyltho-b-indolyl-a,b-unsaturated ketones 1 (0.5 mmol), hydrazines 2
(1 mmol), and (CH3)3COH (1 mL) were stirred for 4 h in 120 ꢀC in sealed tube in which
the conversion of 1 was completed as evidenced by TLC. After cooling to room tem-
perature, the reaction mixture was purified by silica gel column chromatography (pet-
roleum ether (60–90 ꢀC)/ethyl acetate10:1, v/v) to give pure 3 as white crystal in
excellent yields.
Funding
Supported by the Foundation of Science and Technology Research Projects of the 13th Five-Year
Plan of Jilin Provincial Department of Education [2016037].
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