Green and complementary regioselective synthesis of 3-(1 –substituted pyrazol-3(or 5)-yl)indoles from β-ethyltho-β-indolyl-α,β-unsaturated ketones in water

Article abstract of DOI:10.1080/00397911.2020.1801747

Eco-friendly and practical methods for the complementary regioselective synthesis of 3-(1-substituted pyrazol-3-yl) indoles and 3-(1-substituted pyrazol-5-yl) indoles, from DBSA-mediated regioselective cyclocondensation reaction of β-ethyltho-β-indolyl-α,

Full text of DOI:10.1080/00397911.2020.1801747

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Green and complementary regioselective
synthesis of 3-(1 –substituted pyrazol-3(or
5)-yl)indoles from β-ethyltho-β-indolyl-α,β-
unsaturated ketones in water
Xiao-Bo Zhao , Si-Ao Jiang , Nan Wang & Hai-Feng Yu
To cite this article: Xiao-Bo Zhao , Si-Ao Jiang , Nan Wang & Hai-Feng Yu (2020): Green
and complementary regioselective synthesis of 3-(1 –substituted pyrazol-3(or 5)-yl)indoles
from β-ethyltho-β-indolyl-α,β-unsaturated ketones in water, Synthetic Communications, DOI:
10.1080/00397911.2020.1801747
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SYNTHETIC COMMUNICATIONSV
https://doi.org/10.1080/00397911.2020.1801747
Green and complementary regioselective synthesis of 3-(1
–substituted pyrazol-3(or 5)-yl)indoles from b-ethyltho-
b-indolyl-a,b-unsaturated ketones in water
Xiao-Bo Zhao, Si-Ao Jiang, Nan Wang, and Hai-Feng Yu
College of Chemistry, Baicheng Normal University, Baicheng, China
ABSTRACT
ARTICLE HISTORY
Received 5 June 2020
Eco-friendly and practical methods for the complementary regiose-
lective synthesis of 3-(1-substituted pyrazol-3-yl) indoles and 3-(1-
substituted pyrazol-5-yl) indoles, from DBSA-mediated regioselective
cyclocondensation reaction of b-ethyltho-b-indolyl-a, b-unsaturated
ketones and monosubstituted hydrazines in water through simply
varying the appropriate reaction way, had been developed. The
methods not only efficiently avoided the use of organic solvent but
also exhibited attractive characteristics such as operational simplicity,
broad substrate scope, easy separation of products and ease of
scale-up.
KEYWORDS
b-ethylthio-b-indolyl-a;
b-unsaturated ketones; 3-
pyrazolindoles; hydrazines;
aqueous synthesis;
regioselectivity
GRAPHICAL ABSTRACT
O
Ar
N
Ar
N
R2
R2
R2
1) DBSA(1 equiv.)
H2O, reflux, 1h
2) R3NHNH2
reflux, 10 h
Ar
EtS
R3NHNH2
R3
N
R3
N
DBSA(1 equiv.)
H2O, reflux, 14 h
N
N
N
R1
R1
R1
Introduction
Over recent decades, the synthesis of 3-pyrazol indoles had attracted considerable atten-
tion due to many of them exhibiting a great diversity of good biological activities[1]
such as antimicrobial,[2] anti-inflammatory[3] and antioxidant.[4] Although their synthe-
sis had been well-documented, it remained a challenge to reach sufficient regio-selectiv-
ity for 3-(1-substituted pyrazol-3(or 5)-yl)indoles in the synthesis process. Recently,
with a view to the goal, some effort had been devoted toward some researches[5]. Ila
and coworkers investigated the cyclocondensation of arylhydrazines with 3-(1-methyl-
1H-indol-3-yl)-1-aryl-3-thioxopropan-1-one or 3-(1-methyl-1H-indol-3-yl)-3-(methyl-
thio)-1-arylprop-2-en-1-one, and isomeric 3-(pyrazol-5(or 3)-yl) ꢀ1-methyl-1H-indoles
were obtained with complete regioselectivity, respectively[5a]. Gupton and coworkers
regioselectively prepared isomeric 1-methyl-3-(1-aryl-1H-pyrazol-3(or 5)-yl)-1H-indoles
by cyclocondensation of arylhydrazines with indole chloroenals or indole
CONTACT Hai-FengYu
yuhf68105@sina.com
College of Chemistry, Baicheng Normal University, Baicheng
137000, China
Supplemental data for this article can be accessed on the publisher’s website.
ß 2020 Taylor & Francis Group, LLC

2
X.-B. ZHAO ET AL.
vinylogousamide[5b]. Usachev and coworkers achieved regio-controlled synthesis of 3-(1-
phenyl-1H-pyrazol-3(or 5)-yl)-2-(trifluoro-methyl)-1H-indoles by the Fischer reactions of
isomeric 1-phenyl-2-(1,1,1-trifluoro-3-(1-phenyl-1H-pyrazol-3(or 5)-yl)propan-2-ylidene)-
hydrazines, respectively.[5c] However, all the reported reactions are performed in organic
medium such as acetonitrile and dichloromethane, which can lead to serious environmen-
tal and safety problems. Therefore, the development of eco-friendly regioselective synthesis
of 3-(1-substituted pyrazol-3(or 5)-yl)indoles is highly desirable.
With concerning of environmental problems, green organic synthesis was getting a
full development in the past decades. As an important research topic in green synthesis,
the organic reaction in water without the use of organic solvents had received more and
more attention because water was noncorrosive, nonflammable, nontoxic, cheap and the
most abundant solvent in nature, and its usage could remarkably reduce the discharge
of a large amount of harmful organic solvents.[6] Therefore, we were interested in the
organic reaction in water, and a range of aqueous organic reactions, including thioace-
talization using ketene dithioacetals as odorless thiol equivalent,[7] Friedel-Crafts alkyl-
ation of cyclic ketene dithioacetals with alcohols[8] and hydrolysis of chain a-oxo ketene
dithioacetals,[9] had been realized in our group.
b-Ethyltho-b-indolyl-a, b-unsaturated ketones 1 had been emerging as versatile inter-
mediate in the synthesis of indole derivatives.[10] In view of the diverse good bio-activ-
ities of 3-pyrazol indole, we recently started to study its synthesis on the basis of 1, and
the catalyst free cyclocondensation reaction of 1 with hydrazine hydrate or semicarba-
zide hydrochloride as hydrazine equivalent efficiently giving 3-unsubstituted pyrazol
indoles[11,12] and the regioselective cyclocondensation of 1 with mono-substituted
hydrazines yielding the isomeric 3-(pyrazol-5-yl) indoles and 3-(pyrazol-3-yl)indoles by
simply varying the appropriate reaction conditions[13] had been realized (Scheme 1).
R2
Ar
N
N
H
N
O
R1
H2N
.
HCl
NH2
N
previous work
H
R2
Ar
H2O, reflux
O
AcOH, reflux
N
R2
R
Ar
N
.
R2
N2H4 H2O
t-BuOH, reflux
Ar
N
RNHNH2
previous work
R1
N
EtS
N
previous work
R2
Ar
H
N
AcOH
N
R1
(1equiv.)
R1
1
N
/EtOH, rflux
N
N
RNHNH2
R
this work
regioselective
synthesis
R1
DBSA/H2O
reflux
R2
R2
Ar
Ar
N
N
N
R
N
N
N
R
R1
R1
Scheme 1. The synthesis of 3-pyrazolyl indoles from b-ethyltho-b-indolyl-a, b-unsaturated ketones 1.

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SYNTHETIC COMMUNICATIONSV
3
Most recently, with a view to developing an eco-friendly and highly regioselective syn-
thesis of 3-pyrazol indoles, we studied in detail the cyclocondensation reaction of 1 and
monosubstituted hydrazines in the presence of 4-dodecylbenzene sulfonic acid (DBSA)
in water (Scheme 1), and found that the cyclocondensation reaction could regioselec-
tively produce the isomeric 3-(pyrazol-3-yl)indoles and 3-(pyrazol-5-yl) indoles by sim-
ply varying the appropriate reaction procedure. Herein, it is our pleasure to report
these results.
Results and discussion
b-Ethyltho-b-indolyl-a, b-unsaturated ketones 1[10a,14] 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.[15] On the Basis of our previous work,[7–9] commercially available p-dode-
cylbenzenesulfonic acid (DBSA) was chosen as surfactant-combined catalyst in the cur-
rent study.
Initially, the model reaction of (Z/E)-3-(ethylthio)-3-(1-methyl-1H-indol-3-yl)-1-phe-
nylprop-2-en-1-one 1a (0.25 mmol) with phenylhydrazine 2a (0.3 mmol) was performed
in the presence of DBSA (0.25 mmol) in boiling water (2 mL). It was found that a white
solid were precipitated from the reaction system when the reaction was refluxed for
14 h, and the pure white crystal, as 3-(1, 3-diphenyl-1H-pyrazol-3-yl)-1-methyl-1H-
indole 3a on the basis of the comparison of melting point and Rf with that reported[13]
,
was obtained in 78% yield by filtration and subsequent recrystallization with ethanol.
Further increasing the amount of DBSA, the yield of 3a was not improved markedly.
The results indicated that the cyclocondensation reactions favored the formation of 3a
when the reaction of 1a and 2a was performed in the presence of DBSA in boiling
water. Under the optimized conditions described above, the cyclocondensation reaction
of 1b-1o and phenylhydrazine 2a smoothly carried out to furnish 3-(1-substituted pyra-
zol-3-yl)indoles 3b-3o in medium to good yields (Table 1, entries 1–15). Similarly, the
reaction of 1a and mono-substituted hydrazines 2b–2e also gave satisfactory results, and
3-(1-substituted pyrazol-3-yl) indoles 3p–3s were produced in good yields (Table 1,
entries 16-19).
Next, we turned our attention to the aqueous synthesis of 3-(1-substituted pyrazol-5-
yl)indoles 4. We previously reported that 1 could occur the DBSA-mediated hydrolysis
reaction in water to produce 10,[10b] in which the electrophilicity of the carbon adjacent to
aryl group and the carbon adjacent to indole group was altered. Therefore, when we exam-
ined the model reaction of 1a and 2a, 2a was added to reaction system after the mixture
of 1a, DBSA and H2O was refluxed for 1 h to yield 1a0, and the reaction mixture was then
further refluxed for 10 hour. To our delight, the reaction, which was a one-pot, two-step
procedure, was very clean and only furnished 3-(1,3-diphenyl-1H-pyrazol-5-yl)-1-methyl-
1H-indole 4a in 92% yield by filtration and recrystallization with ethanol. As shown in
Table 2, this methodology was also successfully applied to the reactions of 1b–1o and 2a,
1a and 2b–2e, producing the desired products 4 b–4s in excellent yields, respectively.
Except for 4n and 4r, the products 3 and 4 were all white crystals, and were easily
obtained by filtration and recrystallization with ethanol. In these reactions, electron-

4
X.-B. ZHAO ET AL.
Table 1. The aqueous synthesis of 3-(1-substituted pyrazol-3-yl)indoles 3a.
aReagents and conditions: 1 (0.25 mmol), 2 (0.3 mmol), DBSA (0.25 mmol), H2O (2 mL), reflux, 14 h; bIsolated yield.

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SYNTHETIC COMMUNICATIONSV
5
Table 2. The aqueous synthesis of 3-(1-substituted pyrazol-5-yl) indoles 4a,b
O
Ar
R2
R2
DBSA(1 equiv.)
H2O, reflux, 1h
R2
OH
O
Ar
EtS
R3NHNH2
reflux, 10 h
2
N
N
Ar
R3
N
N
N
4
1'
R1
1
R1
R1
H3CO
Cl
N
N
N
Ph
N
N
N
N
Ph
N
N
Ph
N
N
N
Ph
N
N
Ph
N
4a, 92%
4b, 90%
4c, 91%
4d, 87%
4e, 90%
Br
S
N
N
Ph
4f, 91%
N
N
N
N
Ph
4g, 92%
N
N
Ph
4i, 90%
N
N
N
N
N
N
N
Ph
4h, 85%
Ph
4j, 91%
Br
H3CO
N
N
N
N
N
N
N
Ph
N
N
Ph
N
N
N
Ph
4k, 92%
N
N
N
Ph
Ph
Ph
4l, 92%
4n, 89%c
4o, 90%
4m, 90%
N
N
N
N
N
N
N
N
N
N
N
N
Ph
Cl
4q, 91%
4r, 90%c
4s, 92%
4p, 91%
aReagents and conditions: 1 (0.25 mmol), 2 (0.3 mmol), DBSA (0.25 mmol), H2O (2 mL), reflux; bIsolated yield; cthe iso-
lated yield by silica gel column chromatography (petroleum ether (60–90 ꢁC)/ethyl ether 4:1, v/v).
donating as well as electron-withdrawing substituents such as methyl, methoxy, chloro
and bromo on either phenyl or indolyl were well tolerated. In addition, the Z/E config-
uration of 1 did not affect formation of the desired product 3 and 4.
Furthermore, we used the model reaction of 1a (4 mmol) and 2a to assess the scal-
ability of the above two processes (Scheme 2). The result showed that the cycloconden-
sation reaction based on the above two processes described could efficiently furnish
gram-quantities of the desired product 3a in 72% yield and 4a in 88% yield,
respectively.
On the basis of the above results and our previous works,[11–13] a possible mechanism
for the synthesis of both 3 and 4 was proposed, asdepicted in Scheme 3. When 1a and
PhNHNH2 2a was added to reaction system together, the protonation of NH2 of 2a
firstly led to the formation of the cation 2a0 because of its higher basicity than that of
NH in the presence of DBSA, and an equilibrium was present between 2a and 2a0.
Then, 1a was protonated by Hþ released by 2a0 to form carbocation I, which was
attacked by NH2 of 2a to give intermediate II. Subsequently, the elimination of EtSH in
II resulted in the formation of intermediate III, which occurs intramolecular cyclization

6
X.-B. ZHAO ET AL.
O
Ph
N
Ph
1) DBSA(1 equiv.)
H2O, reflux, 1h
Ph
EtS
PhNHNH2 2a
Ph
N
N
N
DBSA(1 equiv.)
H2O, reflux, 14 h
2) PhNHNH2
2a
reflux, 10 h
Ph
N
N
N
3a, 72% (1.010g)
1a, 4 mmol (1.284g)
4a, 84% (1.1723g)
Scheme 2. The scalability of the process.
+
2a'
PhNHNH3
+ H+ -H+
O
OH
Ph
Ph
EtS
OH
O
H+
OH OH
Ph +
H2NHNPh 2a
hydrolysis
+
EtS
DBSA/H2O,
Ph
reflux, 1 h
I
IV
N
N
N
N
1a
1a'
PhNHNH2
Ph
NH
OH
Ph
H
SEt
HN
OH
N
Ph
N
Ph
H
V
II
HO
N
N
-H2O
-EtSH
Ph
O
Ph
Ph
NH
Ph
H
N
O
N
N
Ph
Ph
N
N
-H2O
-H2O
N
Ph
N
H
Ph
III
3a
N
N
N
VI
4a
N
Scheme 3. Proposed mechanisms for the formation of 3 and 4.
reaction to give 3a. In the absence of 2a, 1a occurred hydrolysis in the presence of
DBSA in refluxing water to generate hydrolysate 1a0, in which the carbonyl group fur-
ther was protonated to afford carbocation IV. At this time 2a was added to reaction
mixture, and intermediate V was obtained through the attack of NH2 of 2a tocarboca-
tion IV. Next, V occurred readily sequential dehydration and intramolecular cyclization
reaction, furnishing 4a.
In summary, for the first time, we had successfully developed the green and comple-
mentary regioselective synthesis of the isomeric 3-(1-substituted pyrazol-3-yl) indoles 3
and 3-(1-substituted pyrazol-5-yl)indoles 4 from DBSA-mediated cyclocon-densation of
b-ethyltho-b-indolyl-a, b-unsaturated ketones 1 with monosubstituted hydrazines 2 in
water by simply varying the appropriate reaction way. In sharp contrast to the reported
methods,[5,11,13] the method not only revealed good flexibility and high synthesis effi-
ciency because isomeric 3 and 4 could be obtained in good yield at will from the same
reactant but also opened up a new avenue for cheap, convenient, green synthesis of iso-
meric 3 and 4. In addition, except for 4n and 4r, 3 and 4 were all were easily obtained
by filtration and recrystallization with ethanol.

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SYNTHETIC COMMUNICATIONSV
7
Experimental
General considerations
1
A H and 13C 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.
Typical procedure for the preparation of 3
b-ethyltho-b-indolyl-a, b-unsaturated ketones 1 (0.25 mmol) and hydrazines 2 (0.3 mmol)
was added to water (2 mL) including 0.25 mmol DBSA, respectively. Then, the mixture
was refluxed for 14 h until the conversion of 1 was completed as evidenced by TLC, in
which a white solid was precipitated from the reaction system. After filtration and recrys-
tallization with ethanol, pure 3 as white crystal were obtained in good yields.
Typical procedure for the preparation of 4
After a mixture of 1 (0.25 mmol) and DBSA (0.25 mmol) in water (2 mL) was refluxed
for 1 h, hydrazines 2 was added to the reaction mixture. Then further refluxing 10 h
until the cyclocondensation reaction was completed as determined by TLC monitoring,
in which a white solid was precipitated from the reaction system except the formation
of 4n and 4r. After filtration and recrystallization with ethanol, pure 4a–m, 4o–q and
4s as white crystal were obtained in excellent yields. In the case of 4n and 4r, they
could be obtained in excellent yields after the reaction mixtures were extracted using
CH2Cl2 (3 ꢂ 10 mL) and subsequently purified by silica gel column chromatography
(petroleum ether (60–90 ꢁC)/ethyl ether 4:1, v/v).
The products 3 and 4 were the known compounds, and their spectra agreed well
1
with those reported in the literature.[13] The characterization data and copies of H and
13C NMR spectra for compounds of 3 and 4 can be found via the “Supporting
Information” section of this article’s webpage.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Funding
We are grateful to the Foundation of Jilin Province Department of Education [JJKH20200001KJ
and JJKH20180307KJ].
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