Base-promoted ecofriendly synthesis of trisubstituted pyrazoles from α,β-alkynyl N-tosylhydrazones under metal- and solvent-free conditions

Article abstract of DOI:10.1055/s-0035-1561853

A simple and green method is described for the synthesis of trisubstituted pyrazoles from α,β-alkynyl N-tosylhydrazones under metal- and solvent-free conditions. Notably, only diisopropylamine is required as a promoter, and the reaction can be easily perf

Full text of DOI:10.1055/s-0035-1561853

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–E
letter
A
N. Li et al.
Letter
Synlett
Base-Promoted Ecofriendly Synthesis of Trisubstituted Pyrazoles
from α,β-Alkynyl N-Tosylhydrazones under Metal- and Solvent-
Free Conditions
Ning Li
Ts
NNHTs
iPr2NH (2 equiv)
N
N
Baoguo Li
Shufeng Chen*
R1
R1
R2
grinding
R2
Inner Mongolia Key Laboratory of Fine Organic Synthesis,
Department of Chemistry and Chemical Engineering, Inner
Mongolia University, Hohhot 010021, P. R. of China
shufengchen@imu.edu.cn
23 examples, 61–94% yield
gram scale
metal- and solvent-free conditions
R1 = aryl, alkyl; R2 = H, aryl, alkyl, TMS
Received: 16.01.2016
Accepted after revision: 26.02.2016
Published online: 16.03.2016
explored as good precursors for the synthesis of polyfunc-
tionalized pyrazoles with high efficiencies and high regio-
selectivities. However, these syntheses have several draw-
backs, including the use of hazardous transition metals,
harsh reaction conditions, poor regioselectivity, and labori-
ous workup procedures. In particular, it is desirable that
polyfunctionalized pyrazoles prepared for their biological
or pharmaceutical activities are free of residues of metal
catalysts in the final products; consequently, considerable
attention has to be paid to product purification and to the
detection of impurities. To overcome these drawbacks,
more convenient and more environmentally benign ap-
proaches to these N-heterocycles are required.15
As a continuation of our ongoing efforts to develop envi-
ronmentally benign synthetic reactions16 and our interest
in the synthesis of heterocycles,17 we developed a simple
and green method for the synthesis of trisubstituted pyra-
zoles from α,β-alkynyl N-tosylhydrazones under metal- and
solvent-free conditions (Scheme 1). Only diisopropylamine
is required as a promoter, and the reaction can be easily
performed at room temperature and on a gram scale. This
approach has several advantages over the conventional
methods, such as a shorter reaction time, mild reaction
temperatures, high isolated yields, and ease of purification
of the products.
DOI: 10.1055/s-0035-1561853; Art ID: st-2016-w0032-l
Abstract A simple and green method is described for the synthesis of
trisubstituted pyrazoles from α,β-alkynyl N-tosylhydrazones under met-
al- and solvent-free conditions. Notably, only diisopropylamine is re-
quired as a promoter, and the reaction can be easily performed at room
temperature and on a gram scale.
Keywords hydrazones, green chemistry, pyrazoles, cyclizations
Pyrazoles are among the most important N-heterocy-
cles and are found in many natural products and pharma-
ceutically active molecules; they are also frequently used as
ligands for metal-catalyzed cross-coupling reactions in ma-
terials science and in organic synthesis.1 Substituted pyra-
zoles, for example, are associated with a broad range of bio-
logical activities, such as antiviral,2 antidiabetic,3 antibacte-
rial,4 antiobesity,5 antiinflammatory,6 and antitumor
activities.7 In addition, some pyrazole derivatives are pres-
ent as core frameworks in a wide variety of leading drugs
and pesticides, such as celecoxib (Celebrex), sildenafil
(Viagra), zometapine, cyenopyrafen, and fenpyroximate.8
Their diverse pharmacological and biological activities have
stimulated substantial interest in the preparation of these
important heterocycles.
iPr2NH (2 equiv)
In recent decades, several methods have been devel-
oped for the synthesis of substituted pyrazoles.9 Typical
strategies for the synthesis of pyrazoles involve a 1,3-dipo-
lar cycloaddition reaction of diazo compounds and
alkynes,10 the cyclocondensation of hydrazines with 1,3-di-
carbonyl compounds or their equivalents,11 transition-met-
al-catalyzed C–N or C–C cross-coupling reactions,12 or one-
pot reactions through a propargylic substitution–cycliza-
tion cascade sequence from propargylic alcohols and hy-
drazines.13 Recently, α,β-alkynyl hydrazones14 have been
Ts
NNHTs
grinding
N
N
R1
R1
R2
metal-free
solvent-free
R2
Scheme 1 Synthesis of pyrazoles under metal- and solvent-free condi-
tions
Because solvent-free synthesis has attracted a great deal
of interest, it was imperative to investigate the reaction un-
der solvent-free conditions. First, we employed the α,β-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

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N. Li et al.
Letter
Synlett
alkynyl N-tosylhydrazone 1a as a substrate and investigated
its electrophilic cyclization reaction under metal- and sol-
vent-free conditions. The reaction proceeded successfully
in a porcelain mortar and pestle with K2CO3 as the promot-
er, without any catalyst, to give the corresponding pyrazole
2a in 79% yield at room temperature in 30 minutes (Table 1,
entry 1). Next, we carefully examined the effectiveness of
various bases in the reaction. The inorganic bases Cs2CO3,
Na2CO3, and KOH behaved similarly to K2CO3, giving the cor-
responding pyrazole 2a in 48, 27, and 44% yield, respective-
ly (entries 2–4). However, only a trace of 2a was detected
when t-BuOK was used under the same reaction conditions
(entry 5). Interestingly, when DBU was used as the promot-
er, a 78% yield of 2a was obtained (entry 6). Although
the use of Et3N resulted in an increased yield of 2a (entry 7),
i-Pr2NH was found to be the most effective base for this re-
Ts
NNHTs
iPr2NH (2 equiv)
N
N
R1
1a–u
grinding
r.t.
R1
R2
R2
2a–u
Ts
Ts
Ts
N
N
N N
N
N
Me
MeO
2b, 75%
2c, 83%
Ts
2a, 92%
Ts
Ts
N
N
N N
N
N
Cl
Br
F
2d, 73%
2e, 89%
2f, 74%
Ts
Ts
Ts
F
N
N
N
N
N
N
Cl
Cl
Cl
2g, 81%
2h, 87%
Ts
2i, 74%
Ts
Ts
N
N
N
N
N
N
nC5H11
Ph
F
2j, 91%
2k, 91%
2l, 80%
Ts
N
Ts
Ts
N
N
N
N N
Et
2m, 79%
2n, 77%
Ts
2o, 90%
Ts
Ts
N
N
N
N
N N
Cl
Br
F
2p, 84%
Ts
2q, 87%
Ts
2r, 84%
F
Ts
N
N
N
N
Br
N
N
Et
2s, 80%
2t, 94%
2u, 90%
Scheme 2 Diisopropylamine-promoted metal- and solvent-free synthesis of pyrazoles. All the reactions were carried out on a 0.3 mmol scale of 1 in
the presence of 0.6 mmol of i-Pr2NH under air at room temperature with grinding for 30 minutes. Isolated yields are reported.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

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action (entry 8). Increasing the loading of i-Pr2NH did not
improve the yield of the product (entry 9). Finally, for com-
parison, we attempted the reaction in the absence of a base,
but no reaction occurred under these conditions (entry 10).
excellent yield. Moreover, note that the reaction proceeded
readily when fluoro-containing substrates were used in this
transformation (2d, 2g, 2k, 2r, and 2s).
More interestingly, when an α,β-alkynyl N-tosylhydra-
zone 1v with a terminal alkyne moiety was used in the re-
action, the corresponding pyrazole 2v was successfully ob-
tained in excellent yield (Scheme 3, eq 1). Furthermore,
substrate 1w, bearing a trimethylsilyl substituent at the
alkyne terminus, also reacted smoothly, with concomitant
elimination of the TMS group, to afford product 2w in mod-
erate yield (Scheme 3, eq 2).
Table 1 Effect of the Base on the Electrophilic Cyclization Reaction of
the α,β-Alkynyl N-Tosylhydrazone 1a under Metal- and Solvent-Free
Conditionsa
Ts
NNHTs
N
N
base
Ph
neat, r.t.
Ph
Ph
Ph
1a
2a
Ts
NNHTs
iPr2NH (2 equiv)
N
N
Yieldb (%)
(1)
Entry
Base (mol%)
Time (min)
grinding
r.t., 30 min
H3C
2v, 90% yield
H
1
2
K2CO3 (200)
Cs2CO3 (200)
Na2CO3 (200)
KOH (200)
t-BuOK (200)
DBU (200)
Et3N (200)
i-Pr2NH (200)
i-Pr2NH (300)
–
30
30
60
60
30
30
30
30
30
60
79
1v
48
Ts
3
27
NNHTs
iPr2NH (2 equiv)
N
N
4
44
(2)
Ph
grinding
r.t., 30 min
Ph
2w, 61% yield
H
5
trace
78
TMS
1w
6
Scheme 3
7
88
8
92
To examine the practical utility of this reaction, we per-
formed it on a large scale. When we chose the α,β-alkynyl
N-tosylhydrazone 1a as a substrate for a gram-scale synthe-
sis, the reaction proceeded smoothly to give the pyrazole 2a
in 81% isolated yield under metal- and solvent-free condi-
tions (Scheme 4).
9
92
10
NRc
a Reactions conditions: 1a (0.15 mmol), r.t.
b Yield of the isolated pure product.
c No reaction; the starting materials were recovered.
To examine the scope of the present procedure, we per-
formed the reaction with a variety of α,β-alkynyl N-tosyl-
hydrazones 1 under metal- and solvent-free conditions
(Scheme 2).18 We found that the reaction proceeded
smoothly with a wide range of substrates to give the corre-
sponding pyrazoles 2 in high yields. Among the R1 groups
on the α,β-alkynyl N-tosylhydrazones 1, substituents con-
taining a phenyl ring bearing an electron-donating group or
halogen were tolerated and generally gave the desired
products 2 in high yields (2b–i). Interestingly, the reaction
proceeded smoothly with α,β-alkynyl N-tosylhydrazone
bearing a 2-naphthyl substituent, affording the correspond-
ing product 2j in excellent yield. In addition, replacement of
the aryl groups R1 with alkyl groups also led to the desired
2k–m in good yields. Next, we investigated effects of a sub-
stituent at the alkyne terminus (2n–t). The reaction was
not significantly affected by the presence of substituents on
the aromatic ring of the R2 group of α,β-alkynyl N-tosylhy-
drazones 1n–t; both electron-donating and halogen groups
were tolerated under the reaction conditions. Besides, we
were pleased to discover that substrate 1u, in which both R1
and R2 are alkyl groups, was also compatible with this
transformation, giving the desired pyrazole product 2u in
Ts
NNHTs
iPr2NH (2 equiv)
N
N
grinding
r.t., 60 min
Ph
Ph
Ph
Ph
1a (1.12 g)
2a, 81%
Scheme 4 Large-scale reaction
Scheme 5 shows our proposed mechanism for the for-
mation of pyrazole 2a through an intramolecular electro-
philic cyclization process. An initial base-promoted depro-
tonation of alkyne 1a gives intermediate A, which then un-
dergoes intramolecular electrophilic cyclization to provide
intermediate B. Protonation of intermediate B affords the fi-
nal product 2a.
In conclusion, we have developed a straightforward and
green method for the synthesis of pyrazoles in good to ex-
cellent yields from α,β-alkynyl N-tosylhydrazones, promot-
ed by i-Pr2NH under metal- and solvent-free reactions at
room temperature. This metal- and solvent-free reaction
readily permits the ecofriendly synthesis of novel trisubsti-
tuted pyrazole derivatives that might have widespread ap-
plications in the synthesis of bioactive natural products or
pharmaceuticals. Additionally, this method can be per-
formed on a large scale without any problems.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

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intramolecular
electrophilic
cyclization
Ts
Ts
NNHTs
NNTs
H+
N
N
N N
base
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
A
1a
B
2a
Scheme 5 Possible mechanism for the formation of pyrazole 2a by an intramolecular electrophilic cyclization reaction
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1521. (d) Janin, Y. L. Chem. Rev. 2012, 112, 3924. (e) Stanovnik,
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Acknowledgements
This project was generously supported by the National Natural Sci-
ence Foundation of China (No. 21262023) and the Natural Science
Foundation of Inner Mongolia of China (No. 2014JQ02).
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S
u
p
p
ortioInfgrmoaitn
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(18) Pyrazoles 2; General Procedure
i-Pr2NH (0.6 mmol) and the appropriate N-tosylhydrazone 1
(0.3 mmol) were thoroughly ground with a pestle and mortar
for 30 min. When the reaction was complete, the mixture was
purified by crystallization from CH2Cl2 or by column chroma-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

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tography (silica gel, EtOAc–PE) to give the pure pyrazole
product 2.
3,5-Diphenyl-1-tosyl-1H-pyrazole (2a)
δ = 2.35 (s, 3 H), 6.60 (s, 1 H), 7.19 (d, J = 8.0 Hz, 2 H), 7.35–7.45
(m, 8 H), 7.62 (d, J = 8.0 Hz, 2 H), 7.84 (d, J = 7.0 Hz, 2 H). 13C
NMR (125 MHz, CDCl3): δ = 21.69, 109.54, 126.48, 127.84,
128.04, 128.72, 129.33, 129.49, 129.62, 129.67, 130.02, 131.37,
134.88, 145.35, 149.48, 155.21. HRMS (ESI): m/z [M + H]+ calcd
for C22H19N2O2S: 375.1167; found: 375.1161.
White solid; yield: 103 mg (92%; gram scale: 81%); mp 122–
124 °C. IR (KBr): 3029, 2921, 2855, 1594, 1558, 1459, 1382,
1195, 1177, 761, 660, 598 cm–1 1H NMR (500 MHz, CDCl3):
.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E