Synthesis of 2,2-di(pyrazol-1-yl)enones via the 2:1 coupling of pyrazoles and acylbromoacetylenes in solid alumina

Article abstract of DOI:10.1016/j.tetlet.2018.10.033

Pyrazoles were reacted with acylbromoacetylenes in solid Al₂O₃ at room temperature to afford 2,2-di(pyrazol-1-yl)enones in 22–69% yield. The reaction proceeds via isolable intermediates, (Z)-2-bromo-2-(pyrazol-1-yl)enones. This unexpected 2:1 coupling is in contrast to similar reactions of pyrroles, furans and thiophenes, which give the corresponding acylethynyl derivatives. This reaction opens a one-pot route to inaccessible gem-dipyrazolylenones, which have potential applications as bidentate chelating ligands and building blocks for drug design.

Full text of DOI:10.1016/j.tetlet.2018.10.033

Accepted Manuscript
Synthesis of 2,2-di(pyrazol-1-yl)enones via the 2:1 coupling of pyrazoles and
acylbromoacetylenes in solid alumina
Maxim D. Gotsko, Lyubov' N. Sobenina, Alexander V. Vashchenko, Boris A.
Trofimov
PII:
S0040-4039(18)31251-6
https://doi.org/10.1016/j.tetlet.2018.10.033
TETL 50343
DOI:
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
18 September 2018
16 October 2018
18 October 2018
Please cite this article as: Gotsko, M.D., Sobenina, L.N., Vashchenko, A.V., Trofimov, B.A., Synthesis of 2,2-
di(pyrazol-1-yl)enones via the 2:1 coupling of pyrazoles and acylbromoacetylenes in solid alumina, Tetrahedron
Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.10.033
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Synthesis of 2,2-di(pyrazol-1-yl)enones via the 2:1 coupling of pyrazoles and
acylbromoacetylenes in solid alumina
Maxim D. Gotsko, Lyubov’ N. Sobenina, Alexander V. Vashchenko, Boris A. Trofimov
*
A.E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences, 1
Favorsky St., Irkutsk 664033, Russian Federation
Abstract
Pyrazoles were reacted with acylbromoacetylenes in solid Al O at room temperature to afford
2
3
2
,2-di(pyrazol-1-yl)enones in 22-69% yield. The reaction proceeds via isolable intermediates, (Z)-2-
bromo-2-(pyrazol-1-yl)enones. This unexpected 2:1 coupling is in contrast to similar reactions of
pyrroles, furans and thiophenes, which give the corresponding acylethynyl derivatives. This reaction
opens a one-pot route to inaccessible gem-dipyrazolylenones, which have potential applications as
bidentate chelating ligands and building blocks for drug design.
R1
R1
R1
N
N
O
Al O
2
3
Br
R1
N
+
R1
N
R2
R1
N
H
o
N
2
0-25 C, 24 h
O
R2
1
2
22-69%
R = H, Me; R = Me, Ph, 2-furyl, 2-thienyl
Keywords: pyrazoles; acylbromoacetylenes; di(pyrazol-1-yl)enones; transition metal-free synthesis;
Al O
2
3
Introduction
Functionalized pyrazoles have attracted significant attention as promising building blocks for
pharmaceuticals and ligands of metallocomplexes. The pyrazole scaffold is common in many
1
2
commercial drugs, e.g. nonsteroidal anti-inflammatory and anti-cancer medicines. They are also
3
4
5
exploited in fine chemical synthesis, metal complex catalysis, and the design of liquid crystals and
6
polymer materials. Therefore the advanced synthesis of functionalized pyrazoles remains a topical
issue in this area of heterocyclic chemistry. In order to develop a new approach to the synthesis of
acetylenic derivatives of pyrazoles we have extended the previously reported ethynylation reactions of
7
selected five-membered aromatic heterocycles with electron-deficient haloacetylenes. For example,
pyrroles7a-f are easily ethynylated with acylbromoacetylenes in the absence of transition metals in solid
metal oxides and salts (e.g. Al O , ZnO, BaO, K CO ) (Scheme 1).
2
3
2
3
R3
R3
O
Al O
2
3
R2
+ Br
N
R1
R4 20-25 C
o
R2
O
N
R1
R4
Scheme 1. Reaction of pyrroles with acylbromoacetylenes.7a-f
It was also shown that furans7c, 7g and thiophenes are capable of being ethynylated under similar
conditions. A logical evolution of these investigations is to examine whether pyrazoles can be
similarly cross-coupled with acylhaloacetylenes.
7f
Results and Discussion
Initially, we examined the model reaction of unsubstituted pyrazole 1a with
benzoylbromoacetylene 2a under conditions typical for the ethynylation of pyrroles. The reactants
were intensively ground (5-10 min) in excess solid Al O and allowed to stand at room temperature for
2
3
2
4 h. The conversion of pyrazole 1a, acylbromoacetylene 2a, and the product ratios were monitored by

1
H NMR spectroscopy of the CDCl extracts. The reaction was stopped after the complete
3
consumption of acylbromoacetylene 2a.
Using an equimolar ratio of the reactants, dipyrazolylenone 3a (instead of the expected ethynyl
derivative 4) was formed in 18% yield (Scheme 2, Table 1, entry 4) which was in contrast to the
previous results for the same reaction with pyrroles7a-f and furans.7c, 7g
N
N
Br
Br
Br
N
N
N
O
Al O
N
2
3
N
+
+
Br
N
N
+
O
O
N
H
R
o
O
2
0-25 C, 24 h
R
2a-c
R
R
R
O
1a
3
a-c
5a-c
6a-c
4
R = Ph (a), 2-furyl (b), 2-thienyl (c)
Scheme 2. Reaction of pyrazole 1a with acylbromoacetylenes 2a-c
The reaction proceeds via the intermediate (Z)-2-bromo-2-(pyrazol-1-yl)enone 5a and is
accompanied by the formation of 2,2-dibromoenone 6a. Modest yields (22-35%) of dipyrazolylenones
3
a-c were obtained using a two-fold molar excess of pyrazole 1a relative to acylbromoacetylenes 2a-c,
with the yields of bromopyrazolylenones 5a-c and dibromoenones 6a-c being 10-18% and 8-14%,
respectively (Table 1).
Table 1. Reaction of pyrazole 1a with acylbromoacetylenes 2a-c.a-c
N
N
Br
Br
Br
O
R
N
Al O
2
3
N
N
N
+
Br
N
+
+
N
H
O
o
O
20-25 C, 24 h
O
2a-c
R
R
R
1a
3a-c
5a-c
6a-c
Dipyrazolylenone 3
Bromopyrazolylenone 5
Dibromoenone 6
Entry
Acetylene 2
d
e
e
(%)
(%)
(%)
N
N
Br
Br
Br
N
N
N
O
N
O
O
Br
O
1
2a
a
b
a
b
6a (14 , 6 )
5
a (10 , 7 )
a
b
3
a (32 , 42 )
N
N
Br
Br
Br
N
N
N
O
N
O
O
Br
O
2
O
O
2b
O
O
a
b
a
b
a
b
5b (13 , 8 )
6
b (8 , 5 )
3
b (22 , 34 )

N
N
Br
Br
N
Br
N
N
N
O
O
O
O
Br
3
S
S
S
S
2c
a
b
a
b
6c (12 , 7 )
a
b
5c (18 , 13 )
3
c (35 , 43 )
N
N
Br
Br
Br
N
N
N
N
O
O
O
O
Br
4
2a
6a (25c)
5a (22c)
a (18c)
3
a
Reagents and conditions: 1a (2 mmol), 2 (1 mmol), Al
2
O
3
(10-fold amount by weight with respect to the total mass of
(10-fold amount by weight with respect to the total mass of
(10-fold amount by weight with respect to the total mass of
reagents); r.t., 24 h;
b
Reagents and conditions: 1a (3 mmol), 2 (1 mmol), Al
2
O
3
reagents); r.t., 24 h;
c
Reagents and conditions: 1a (1 mmol), 2 (1 mmol), Al
2
O
3
reagents); r.t., 24 h;
d
Isolated yield (column chromatography, SiO
2
, n-hexane-diethyl ether, 1:1);
, n-hexane).
e
Isolated yield (column chromatography, SiO
2
Surprisingly, no traces of ethynylpyrazoles 4 were detectable in the reaction mixture, implying
that dipyrazolylenones 3a-c are not adducts from the reaction of pyrazole 1a with the intermediate
ethynylated pyrazoles 4.
The structure of the intermediate (Z)-2-bromo-2-(pyrazol-1-yl)enones 5a-c was established by
1
13
X-ray crystallographic analysis (5c, Fig. 1) and supported by H and C NMR spectroscopy.
Figure 1. Single crystal X-ray structure of (Z)-3-bromo-3-(1H-pyrazol-1-yl)-1-(thiophen-2-yl)prop-2-
en-1-one (5c).
3
,5-Dimethylpyrazole 1b reacts with acylbromoacetylenes 2a-d in a 2:1 ratio to form
dipyrazolylenones 7a-d in 42-55% yield (Table 2). Remarkably, in this case, the bromopyrazolylenone
1
of type 5 was not discernible in the reaction mixture. For example, H NMR monitoring of the reaction
between pyrazole 1b and benzoylbromoacetylene 2a (reactant molar ratio 1b : 2a, 2:1) showed no
other products except for dipyrazolylenone 7a and dibromoenone 6a (Table 3).

Better yields of dipyrazolylenones 3a-c (34-43%, Table 1) and 7a-d (55-69%, Table 2) were
attained using a three-fold molar excess of pyrazoles 1a,b relative to acylbromoacetylenes 2a-d, with
the yields of dibromoenones 6a-d being 5-10% (Tables 1, 2).
It is noteworthy, that a 3-fold molar excess of acetylene 2a, resulted in the formation of
dipyrazolylenone 7a in 18% yield, while the expected intermediate bromopyrazolylenone of type 5
was not present in the reaction mixture. The yield of dibromoenone 6a was predictably increased to
6
0% (c.f. Table 2, entry 5). The latter result means that under the conditions studied,
acylbromoacetylenes 2a-d undergo a parallel transformation to dibromoenones 6a-d by the addition of
HBr to the triple bond.
Table 2. Reaction of pyrazole 1b with acylbromoacetylenes 2a-d.a-c
N
N
Br
O
R
Br
Al O
2
3
Br
N
N
+
+
O
N
N
H
o
2
0-25 C, 24 h
O
2a-d
R
R
1b
7a-d
6a-d
Entry Acetylene 2
Dipyrazolylenone 7 (%)d Dibromoenone 5 (%)e
Br
N
N
Br
N
O
N
O
O
Br
1
2a
6
a
7
a
a
b
(
18 , 10 )
a
b
(
55 , 68 )
N
Br
O
Br
N
N
N
O
O
Br
2
O
2b
O
O
6
b
a
b
7
b
(12 , 8 )
a
b
(
48 , 64 )
N
N
Br
O
Br
N
N
O
O
Br
3
S
S
S
2c
6
c
a
b
7
c
(14% , 10 )
a
b
(
52 , 69 )

a
Reagents
conditions: 1b (2 mmol),
2 (1 mmol), Al (10-
and
Br
N
N
Br
2
O
3
N
O
O
N
fold amount by weight
with respect to the total
mass of reagents); r.t., 24
Br
4
5
O
Me
Me
2d
Me
6
a
d
h;
7
d
b
b
(
12 , 7 )
Reagents
and
a
b
(42 , 55 )
conditions: 1b (3 mmol),
(1 mmol), Al (10-
2
2 3
O
fold amount by weight
with respect to the total
mass of reagents); r.t., 24
h;
Br
O
N
N
Br
N
O
N
Br
O
c
Reagents
conditions: 1b (1 mmol),
(3 mmol), Al (10-
and
2a
2
2 3
O
6
a
fold amount by weight
with respect to the total
mass of reagents); r.t., 24
7
a
c e
(
60 )
c d
(18 )
h;
d
Isolated yield (column chromatography, SiO
2
, n-hexane-diethyl ether, 1:1);
, n-hexane).
e
Isolated yield (column chromatography, SiO
2
1
a
Table 3. H NMR-monitoring of the reaction between pyrazole 1b and benzoylbromoacetylene 2a
a
Reagents and
Composition of the reaction mixture (%)
conditions: 1b (2
Compound
mmol), 2a (1 mmol),
1
4
2
2
4
h
3 h
36
13
45
6
6 h
27
9
24 h
22
1
2 3
Al O (10-fold amount
1
2
7
6
b
a
a
a
8
by weight with respect
to total mass of
8
0
reagents); r.t.
56
8
62
15
The
structure of dipyrazolylenones 7a-d was established by X-ray crystallographic analysis (7b, Fig. 2) and
1
13
supported by H and C NMR spectroscopy.
Figure 2. Single crystal X-ray structure of 3,3-di(3,5-dimethyl-1H-pyrazol-1-yl)-1-(furan-2-yl)prop-2-
en-1-one (7b).
It should be noted that when the reaction of pyrazole 1a with benzoylbromoacetylene 2a was
conducted without Al O (rt, 24 h) it proceeded much more slowly (the conversion of acetylene 2a was
2
3
1
about 30%), although the products formed in minor quantities were the same ( H NMR).
Basing on the results obtained and previous mechanistic rationalizations concerning the reactions
of pyrroles with haloacetylenes7a-f it may be suggested that the synthesis of dipyrazolylenones 3a-c and
7
a-d is triggered by the nucleophilic addition of pyrazoles 1a,b to the triple bond of
acylbromoacetylenes 2a-d to form the intermediate zwitterion (Scheme 3), which converts via proton

transfer from the pyrazole moiety to its carbanionic center to give isolable intermediate 5. Subsequent
nucleophilic substitution of the bromine atom by a second molecule of pyrazole 1a affords
dipyrazolylenone 3. The released HBr is scavenged by another molecule of bromoacetylene to produce
dibromoenone 6. Presumably, substitution of the bromine atom in the intermediate and hence the
release of HBr is faster than its consumption by bromoacetylene for the formation of dibromoenone 6
which explains why in some cases the yield of the product exceeds 50%. Additionally, this also can
take place because HBr may be partially consumed by Al O .
2
3
O
O
Br
R
Br
R
O
R
N
+
Br
N
N
H
N
H
N
NH
2a-c
5
1a
N
O
N
H
O
Br
R
N N
N
R
1a
+
HBr
N
H
H
N
N
5
3a-c
Br
Br
O
HBr
Br
O
R
2a-c
R
6a-c
Scheme 3. Proposed mechanism for dipyrazolylenones 3a-c formation.
Unlike the ethynylation of pyrroles, where the initial zwitterion releases a halogen anion to
restore the triple bond, for pyrazole, rapid intramolecular neutralization of the carbanionic site of the
intermediate zwitterion occurs which precludes formation of the ethynyl derivatives. Such a change of
the reaction mechanism is likely due to the higher acidity of pyrazoles compared with pyrroles (pk of
a
pyrazole is 14.2 whereas pk of pyrrole is 17.5).
a
This mechanism has been experimentally proven by the reaction between bromopyrazolylenone
5
3
a and pyrazole 1a (under the same conditions), which led to the reaction mixture containing product
1
a. According to H NMR monitoring the composition of the mixture was 3a : 5a : 1a = 0.94 : 0.87 : 1.
Intramolecular proton transfer in the initial zwitterion is supported by the (Z)-configuration of
intermediates 5 which is stabilized in a five-membered ring transition state (Scheme 2). This is also
consistent with the fact that 1,3,5-trimethyl-1H-pyrazole 1c, which has no proton at position 1
available for intramolecular transfer, does not react with acetylbromoacetylene 2d under the conditions
studied.
The assumption that dipyrazolylenones 3a-c and 7a-d may result from double nucleophilic
substitution of the bromine atom in dibromoenones 6a-d was not confirmed by the following
experiment: when dibromoenone 6a was allowed contact (120 h, Al O , room temperature) with
2
3

1
pyrazole 1a, only a small amount of dipyrazolylenone 3a (5%) was detected ( H NMR) in the reaction
mixture.
In conclusion, a transition metal-free one-pot synthesis of dipyrazolylenones via the reaction of
pyrazoles with acylbromoacetylenes in solid Al O at room temperature has been developed. This
2
3
facile synthesis of dipyrazolylenones can be considered as a novel contribution to the chemistry of
pyrazoles and their applications.
Acknowledgements
Authors acknowledge the Baikal Analytical Center for collective use SB RAS for the equipment.
References and notes
1
. (a) Friedrich, G., Rose, T., Rissler, K. J. Chromatogr. B. 2002; 786: 295-305; (b) Teranisi, K. J. P.
W. O. Patent 2004,014,932, 2004; Chem. Abstr. 2004, 140, 199632; (c) Chimenti, F.,
Fioravanti, R., Bolasco, A., Manna, F., Chimenti, P., Secci, D., Befani, O., Turini, P., Ortuso,
F., Alcaro, S. J. Med. Chem. 2007; 50: 425-428; (d) Pantel, J., Williams, S. Y., Sebag, J. D.,
Corbin, J. D., Weaver, C. D., Cone, R. D. Eur. J. Pharmacol. 2011; 660: 139-147; (e) Kumar,
K. A., Jayaroopa, P. Int. J. PharmTech Res. 2013; 5: 1473-1486.
2
3
. (a) Kumari, S., Paliwal, S., Chauhan, C. Synth. Commun. 2014; 44: 1521-1578; (b) Shamsuzzaman,
Siddiqui, T., Alam, M. G., Dar, A. M. J. Saudi Chem. Soc. 2015; 19: 387-391.
. (a) Noshiranzadeha, N., Ramazani, A., Mahyari, A. T., Slepokura, K., Lis, T. Z. Naturforsch., B:
Chem. Sci. 2008; 63: 65-70; (b) Azpiroz, R., Rubio-Perez, L., Giuseppe, A., Passarelli, V.,
Lahoz, F., Castarlenas, R., Perez-Torrente, J., Oro, L. ACS Catal. 2014; 4: 4244-4253; (c)
Azpiroz, R., Passarelli, V., Castarlenas, R., Perez-Torrente, J., Oro, L. J. Mex. Chem. Soc.
2
017; 61: 138-145.
4
5
. (a) Pal, A., Ghosh, R., Adarsh, N., Sarkar, A. Tetrahedron. 2010; 66: 5451-5458; (b) Huertas-
Sanchez, A., Luna-Giles, F., Vinuelas-Zahinos, E., Barros-Garcia, F., Bernalte-García, A.
Polyhedron. 2015; 102: 394-400.
. (a) Thaker, B., Solanki, D., Patel, B., Vansadia, A., Dhimmar, Y. Mol. Cryst. Liq. Cryst. 2012; 552:
1
34-146; (b) Soria, L., Ovejero, P., Cano, M., Campo, J. A., Torres, M. R., Nunez, C., Lodeiro,
C. Dyes and Pigments. 2014; 110: 159-168.
6
7
. Mukundam, V., Kumar, A., Dhanunjayarao, K., Ravi, A., Peruncheralathana, S., Venkatasubbaiah,
K. Polym. Chem. 2015; 6: 7764-7770.
. (a) Trofimov, B. A., Stepanova, Z. V., Sobenina, L. N., Mikhaleva, A. I., Ushakov, I. A.
Tetrahedron Lett. 2004; 45: 6513-6516; (b) Trofimov, B. A., Sobenina, L. N. Targets in
Heterocyclic Systems. 2009; 13: 92-119; (c) Sobenina, L. N., Petrova, O. V., Tomilin, D. N.,
Gotsko, M. D., Ushakov, I. A., Klyba, L. V., Mikhaleva, A. I., Trofimov, B. A. Tetrahedron.
2
014; 70: 9506-9511; (d) Gotsko, M. D., Sobenina, L. N., Tomilin, D. N., Ushakov, I. A.,
Dogadina, A. V., Trofimov, B. A. Tetrahedron Lett. 2015; 56: 4657-4660; (e) Gotsko, M. D.,
Sobenina, L. N., Tomilin, D. N., Markova, M. V., Ushakov, I. A., Vakul’skaya, T. I.,
Khutsishvili, S. S., Trofimov, B. A. Tetrahedron Lett. 2016; 57: 4961-4964; (f) Tomilin, D. N.,
Petrushenko, K. B., Sobenina, L. N., Gotsko, M. D., Ushakov, I. A., Skitnevskaya, A. D.,
Trofimov, A. B., Trofimov, B. A. Asian J. Org. Chem. 2016; 5: 1288-1294; (g) Sobenina, L.
N., Tomilin, D. N., Gotsko, M. D., Ushakov, I. A., Trofimov, B. A. Tetrahedron. 2018; 74:
1
565-1570.
2
,2-Di(pyrazol-1-yl)enones via 2:1 cross-coupling of pyrazoles and acylhaloacetylenes
This reaction differs essentially from pyrrole behavior under the same conditions
The mechanism involves substitution of bromine in intermediate pyrazolylbromoenones