1,3-Dipolar cycloaddition of azomethine imines to ethynyl hetarenes: A synthetic route to 2,3-dihydropyrazolo[1,2-a]pyrazol-1(5H)-one based heterobiaryls

Article abstract of DOI:10.1016/j.tet.2018.01.046

π-Deficient ethynyl hetarenes were used as dipolarophiles in a 1,3-dipolar cycloaddition reaction with azomethine imines (2-arylidene-5-oxopyrazolidin-2-ium-1-ides). Both CuI-catalyzed and catalyst-free thermally induced reactions proceeded with high regioselectivity providing 6-hetaryl-5-aryl-2,3-dihydropyrazolo[1,2-a]pyrazol-1(5H)-ones in moderate to excellent yields. The ethynyl hetarenes (pyridines, pyrazines, quinoxalines, pteridines and pyrimido[4,5-c]pyridazines) with ortho-methyl, ortho-cyano and ortho-alkynyl substituents were applicable to this reaction. 1,3-Dipolar cycloaddition reactions of alkynyl hetarenes with azomethine imines or other 1,3-dipole reagents can be considered as an alternative synthetic approach to heterobiaryls.

Full text of DOI:10.1016/j.tet.2018.01.046

Tetrahedron xxx (2018) 1e9
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
1,3-Dipolar cycloaddition of azomethine imines to ethynyl hetarenes:
A synthetic route to 2,3-dihydropyrazolo[1,2-a]pyrazol-1(5H)-one
based heterobiaryls
,
Julia I. Nelina-Nemtseva a, Anna V. Gulevskaya a *, Vitaliy V. Suslonov b,
Alexander D. Misharev b
a Department of Organic Chemistry, Southern Federal University, Zorge 7, Rostov-on-Don, 344090, Russian Federation
b Center for X-ray Diffraction Studies and Chemical Analysis and Materials Research Centre, Saint Petersburg State University, Universitetskii Pr., 26,
Peterhof, 198504, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
p
-Deficient ethynyl hetarenes were used as dipolarophiles in a 1,3-dipolar cycloaddition reaction with
Received 9 December 2017
Received in revised form
24 January 2018
Accepted 25 January 2018
Available online xxx
azomethine imines (2-arylidene-5-oxopyrazolidin-2-ium-1-ides). Both CuI-catalyzed and catalyst-free
thermally induced reactions proceeded with high regioselectivity providing 6-hetaryl-5-aryl-2,3-
dihydropyrazolo[1,2-a]pyrazol-1(5H)-ones in moderate to excellent yields. The ethynyl hetarenes (pyr-
idines, pyrazines, quinoxalines, pteridines and pyrimido[4,5-c]pyridazines) with ortho-methyl, ortho-
cyano and ortho-alkynyl substituents were applicable to this reaction. 1,3-Dipolar cycloaddition reactions
of alkynyl hetarenes with azomethine imines or other 1,3-dipole reagents can be considered as an
alternative synthetic approach to heterobiaryls.
Keywords:
1,3-Dipolar cycloaddition
Azomethine imines
Ethynyl hetarenes
© 2018 Published by Elsevier Ltd.
6-Hetaryl-5-aryl-2,3-dihydropyrazolo[1,2-a]
pyrazol-1(5H)-ones
Heterobiaryls
1. Introduction
using asymmetric acetylenes led to mixtures of regioisomers in
variable yields.5b,c,f In most cases, strongly activated esters of ace-
Tetrahydropyrazolo[1,2-a]pyrazolones have been studied since
the late 1980s as analogues of penicillin and cephalosporin anti-
biotics1a-f and have been developed as herbicides and pesticides,1g,h
antitumor agents,1i calcitonin agonist1j and as potent drugs for
treatment of cognitive dysfunctions such as Alzhheimer's disease.
Among a variety of reported synthetic approaches to these com-
pounds,2 1,3-dipolar cycloaddition3 of azomethine imines with al-
kynes is one of the most useful and straightforward tool. Dorn an
Otto were the first to report on the synthesis of dimethyl 3,3-
dimethyl-7-oxo-3,5,6,7-tetrahydropyrazolo[1,2-a]pyrazole-1,2-
dicarboxylate by refluxing 5-oxo-2-(propan-2-ylidene)pyrazolidin-
2-ium-1-ide with dimethyl acetylenedicarboxylate (DMAD) in
CH2Cl2 (Scheme 1, a).4 The method was very useful,5 however, the
reaction with other azomethine imines required rather harsh
conditions (refluxing in toluene, xylenes, anisole etc.)5b-g and at
tylenedicarboxylic, propiolic and tetrolic acids were used as dipo-
larophiles. Thermal cycloaddition of 2-benzylidene-3-methyl-5-
oxopyrazolidin-2-ium-1-ide with less electron-deficient acety-
lenic sulfones gave poor yields of the cycloaddition products
(Scheme 1, b).5h In 2003 Fu's group demonstrated that 1,3-dipolar
cycloaddition of azomethine imines with 1-alkynes can be cata-
lyzed by CuI (Scheme 1, c).6a,b Moreover, the reaction afforded a
single regioisomer and, at using a chiral ligand, generated the
product in very good enantiomeric excess. Since then, various
copper catalysts, including heterogeneous, ligand-free Cu(I) zeoli-
tes,6c [Cu( -OH)(TMEDA)2Cl2],6d (Bun4Nþ)4[
m g-H2SiW10O36Cu2(m-
1,1-N3)2],6e ligand-free, heterogeneous supported Cu(OH)x/Al2O3,6f
CuHMDS/(S)-DIP-BINAP,6g,h and some others.6i-l Notably, CuHMDS/
(S)-DIP-BINAP6g,h system afforded the cycloadducts in an unique
5,7-disubstituted manner (Scheme 1, d). The catalytic reaction
presumably involves the transient formation of a copper acetylide
to enhance the reactivity of the dipolarophile. That is why all the
catalytic methods are limited to the use of terminal alkynes. 1,3-
Dipolar cycloaddition of azomethine imines with internal alkynes,
* Corresponding author.
E-mail address: аgulevskaya@sfedu.ru (A.V. Gulevskaya).
https://doi.org/10.1016/j.tet.2018.01.046
0040-4020/© 2018 Published by Elsevier Ltd.
Please cite this article in press as: Nelina-Nemtseva JI, et al., 1,3-Dipolar cycloaddition of azomethine imines to ethynyl hetarenes: A synthetic
route to 2,3-dihydropyrazolo[1,2-a]pyrazol-1(5H)-one based heterobiaryls, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.01.046

2
J.I. Nelina-Nemtseva et al. / Tetrahedron xxx (2018) 1e9
Surprisingly, only one example6a of using alkynyl hetarene, i.e.
2-ethynylpyridine, as a dipolarophile in the above reactions was
reported (for a review on 1,3-cycloaddition of azomethine imines,
see ref.3o). In general, there are many examples of the use of
alkynyl hetarenes as dipolarophiles in the azide-alkyne Huisgen
cycloaddition.11 The reactions of alkynyl hetarenes with dipoles of
other types (nitrones,12a azomethine ylides,12b nitrile oxides,12c,d
diazoalkanes,12e-g) are rare.
Herein, we wish to describe 1,3-dipolar cycloaddition reactions
of ethynyl derivatives of some
p-deficient hetarenes with azome-
thine imines, i.e. 2-arylidene-5-oxopyrazolidin-2-ium-1-ides,
allowing the synthesis of tetrahydropyrazolo[1,2-a]pyrazole based
heterobiaryls. Heteroaryl-heteroaryl or heteroaryl-aryl motifs are
frequently present in the naturally occurring compounds, phar-
maceuticals, ligands and functional materials.13 It was additional
motivation for this study.
2. Results and discussion
Ethynyl derivatives of quinoxaline 1, pyrazine 2, pyridine 3, 1,3-
dimethylpteridine-2,4(1H,3H)-dione 4 and 6,8-dimethylpyrimido
[4,5-c]pyridazine-5,7(6H,8H)-dione 5 have been chosen to be
dipolarophiles (Fig. 1). All these heterocycles constitute the core
structures of many biologically active compounds.14 Moreover,
compounds 1e5 are ready available via the Sonogashira coupling of
the corresponding halides with trimethylsilylacetylene and sub-
sequent desilylation (see Experimental Section). 2-Arylidene-5-
oxopyrazolidin-2-ium-1-ides 6a-c were synthesized in accor-
dance with the reported procedure.15
For our initial experiment, azomethine imine 6a was exposed to
6a,b
2-ethynylquinoxaline 1a under conditions described in Ref.
(CuI, Cy2NMe, CH2Cl2, rt) without chiral ligand. The reaction
afforded 5-phenyl-6-(quinoxalin-2-yl)-2,3-dihydropyrazolo[1,2-a]
pyrazol-1(5H)-one 7a in 13% yield for 48 h (Table 1, Entry 1). The
use of acetonitrile as solvent led to decrease in yield (Entry 2). The
CuI/Et3N/DMSO catalytic system was also less effective (Entry 3). In
Scheme 1.
i.e. propiolylpyrazoles, using chiral Cu(II) complex of 3-(2-
naphthyl)- -alanine amide as a Lewis acid catalyst has been re-
L
ported by Ishihara group (Scheme 1, e).7 Although good regio- and
enantioselectivity have been reached, the yields of the cycloaddi-
tion products did not exceed 15%. Two-step synthesis of pyr-
azolopyrazolones, including [3þ2] cycloaddition of azomethine
imines with 1-alkynyl Fisher carbene complexes and subsequent
oxidative demetalation, has been elaborated.8 Recently, thermal
1,3-dipolar cycloaddition of azomethine imines with internal aroyl
alkynes under microwave irradiation has also been realized.9
Lithium ynolates has also been used as dipolarophiles (Scheme 1,
e).10
Fig. 1. Dipolarophiles and dipoles used in this study.
Please cite this article in press as: Nelina-Nemtseva JI, et al., 1,3-Dipolar cycloaddition of azomethine imines to ethynyl hetarenes: A synthetic
route to 2,3-dihydropyrazolo[1,2-a]pyrazol-1(5H)-one based heterobiaryls, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.01.046

J.I. Nelina-Nemtseva et al. / Tetrahedron xxx (2018) 1e9
3
Table 1
Screening of reaction conditions.a
Entry
R
Base
Catalyst
Solvent
Reaction conditions
Yield 7a, %
Recov. 1a, %
1
2
3
4
5
6
H
H
H
H
H
H
Cy2NMe
Cy2NMe
Et3N (1 equiv.)
Cy2NMe
Cy2NMe
CuI
CuI
CuI
CuI
CuI
e
CH2Cl2
MeCN
DMSO
CH2Cl2
CHCl3
CHCl3
rt, 48 h
rt, 48 h
rt, 48 h
reflux, 48 h
reflux, 22 h
reflux, 144 h
13
3
9
38
96
trace
65
24
41
60
e
Cy2NMe
87
a
The reaction was carried out in 0.3 mmol scale. In all cases, with the exception of Entry 3, 0.5 equiv. of a base and 5 mol.% of a catalyst were used.
both cases, complicated reaction mixtures were obtained, which
made the chromatographic separation of the products difficult.
Refluxing of the reaction mixture in CH2Cl2 improved the yield of
7a (Entry 4). The best result in terms of yield (98%) was obtained at
using chloroform as solvent under reflux (Entry 5). Blank experi-
ment without catalyst gave 7a in trace amounts even after pro-
longed heating (Entry 6). This indicates the presence of CuI catalyst
is essential for this transformation.
ethynylnicotinonitrile 3 were used as dipolarophiles, the desired
cycloadducts 7k and 7l were obtained in 73 and 79% yields,
respectively (Entry 10, 11).
We also tested catalyst-free thermally induced 1,3-dipolar
cycloaddition of azomethine imines to ethynyl hetarenes. Heating
2-ethynylqinoxaline 1a with azomethine imine 6a in p-xylene
(130 ꢀC, 7 h) gave cycloadduct 7a in 35% yield. Similar reaction of 3-
ethynylquinoxaline-2-carbonitrile 1d with 6a provided product 7f
in 35% yield. It should be noted that in contrast to the previously
described thermal reactions of azomethine imines with alkyl pro-
piolates or other asymmetric acetylenes5b,c,f both above reactions
proceeded regioselectively. It is known that 1,3-dipolar cycloaddi-
tion to acetylenes can be concerted or stepwise.16 It is known that
1,3-dipolar cycloaddition to acetylenes can be concerted or step-
Having identified the optimal reaction conditions for the dipolar
cycloaddition, we then examined other azomethine imines and
alkynes in this reaction. As shown in Table 2, azomethine imine 6b,
derived from 4-nitrobenzaldehyde, reacted with 1a giving rise
cycloadduct 7b in quantitative yield (Entry 1). Evidently, in this case
electron-withdrawing 4-nitrophenyl substituent is located at the
positive end of the dipole making it more reactive. On the contrary,
azomethine imine 6c bearing electron-releasing 4-methoxyphenyl
substituent at the positive end of the dipole afforded compound 7c
in significantly reduced yield (Entry 2). The reaction was sensitive
to the presence and nature of the ortho-substituent on the hetaryl
moiety of the starting alkyne. Alkyne 1b bearing 2-
methylquinoxalinyl substituent provided cycloadduct 7d in 37%
yield only (Entry 3). The reaction of dipole 6a with 2-chloro-3-
ethynylquinoxaline 1c was accompanied by tarring; we were un-
able to isolate either the starting material or the product (Entry 4).
3-Ethynylquinoxaline-2-carbonitrile 1d and 2-ethynyl-3-(phenyl-
ethynyl)quinoxaline 1e were both suitable substrates affording
corresponding products in 79% and 78% yields, respectively (Entries
5, 6). It should be noted that the cyano group of 1d remained intact,
although the reaction of 1,3-dipolar cycloaddition between potas-
sium cyanide and dipole similar to 6 was described earlier.5d
Exposure of 2,3-diethynylquinoxaline 1f to the reaction with 2
equivalents of azomethine imine 6a delivered pyrazolo[1,2-a]pyr-
azol-1(5H)-one 7h in 51% yield (Entry 7), which is significantly
lower than in the two previous cases. No product of double cyclo-
addition was observed. It is easy to see that in all cases the presence
of an ortho substituent in the quinoxaline nucleus of the hetaryl
acetylene 1 led to a decrease in the yield of the cycloaddition
product 7 (Entries 3, 5e7), which is particularly noticeable in the
case of the methyl derivative 1b (Entry 3). Apparently, the reason
wise.16 On the one hand,
p-deficient hetaryl moiety activates the
C≡C bond of 1 towards nucleophilic attack and can stabilize zwit-
terionic intermediate 8 via delocalization of the negative charge
favoring a stepwise mechanism and regioselective formation of
compounds 7a and 7f (Scheme 2). However, recently mechanism of
[3þ2]-cycloaddition of azomethine imines to methyl propiolate
was evaluated by computational and experimental methods (which
is especially important) supporting a polar concerted cycloaddition
mechanism with high asynchronicity.16c
The structures of synthesized compounds 7 were supported by a
combination of elemental analysis, mass-spectrometry, IR, UVevis,
1H and 13C NMR spectroscopic measurements. All of the com-
pounds are yellow-colored with lmax 359e407 nm. Their IR spectra
indicated the presence of C¼O group (
n
1685ꢁ1719 cmꢁ1). In cases
of alkynyl derivatives 7g,h,k the characteristic nC≡C band at
2105ꢁ2207 cmꢁ1 was also registered. The spectra of nitriles 7f,l
included a nC≡N band at 2220ꢁ2232 cmꢁ1. In the 1H NMR spectra
the H(5) proton of 7 appeared as a doublet at 5.6e5.8 ppm with a
coupling constant J ¼ 1.3e1.4 Hz or as a broad singlet. This corre-
sponds to the regioisomers depicted in Table 2. The structure of 7f
was proved by X-ray single crystal study (Fig. 2).
3. Conclusions
We have described regioselective CuI-catalyzed and catalyst-
for this is the steric factor. The
attached to the C≡C bond also affects the reaction outcome. The
reaction of dipole 6a with 6-ethynyllumazine 4, which is less
deficient than compound 1a, gave the corresponding cycloadduct
7i in moderate yield (Entry 8). However, isomeric to 3-
p-deficiency of the heterocyclic ring
free thermally induced 1,3-dipolar cycloaddition reactions of
p-
deficient ethynyl hetarenes and 2-arylidene-5-oxopyrazolidin-2-
ium-1-ides, which are expected to be a general route for the
facile synthesis of a wide range of 2,3-dihydropyrazolo[1,2-a]pyr-
azole based heterobiaryls. The 1,3-dipolar cycloaddition process
operates efficiently with ethynyl derivatives of pyridine, pyrazine,
quinoxaline, pteridine and pyrimido[4,5-c]pyridazine. The ethynyl
hetarenes with ortho-methyl, ortho-cyano and ortho-alkynyl
p-
4
ethynylpyridazinopyrimidine 5 was a more successful dipolar-
ophile providing cycloaddition product 7j in 72% yield (Entry 9).
When
2-ethynyl-3-(phenylethynyl)pyrazine
2
and
2-
Please cite this article in press as: Nelina-Nemtseva JI, et al., 1,3-Dipolar cycloaddition of azomethine imines to ethynyl hetarenes: A synthetic
route to 2,3-dihydropyrazolo[1,2-a]pyrazol-1(5H)-one based heterobiaryls, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.01.046

4
J.I. Nelina-Nemtseva et al. / Tetrahedron xxx (2018) 1e9
Table 2
Synthesis of 6-hetaryl-3-R-2,3-dihydropyrazolo[1,2-a]pyrazol-1(5H)-ones 7.
Entry
1
Ylide, R
Alkyne
Product 7
Yield 7%
Recov. alkyne %
6b,
1a
7b
7c
7d
7e
98
e
R ¼ 4-NO2C6H4
2
3
4
6c,
1a
1b
1c
56
37
e
35
R ¼ 4-MeOC6H4
6a
6a
60
tarring
5
6
6a
6a
1d
1e
7f
79
78
trace
trace
7g
7
8
6a
6a
1f
7h
51
56
28
4
7i
trace
9
6a
5
7j
72
18
Please cite this article in press as: Nelina-Nemtseva JI, et al., 1,3-Dipolar cycloaddition of azomethine imines to ethynyl hetarenes: A synthetic
route to 2,3-dihydropyrazolo[1,2-a]pyrazol-1(5H)-one based heterobiaryls, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.01.046

J.I. Nelina-Nemtseva et al. / Tetrahedron xxx (2018) 1e9
Product 7
5
Table 2 (continued )
Entry
10
Ylide, R
Alkyne
Yield 7%
Recov. alkyne %
21
6a
2
7k
73
11
6a
3
7l
79
20
Mass spectra were measured on a Finnigan MAT INCOS 50 spec-
trometer. The HR-ESI mass-spectra were obtained on a BRUKER
maXis spectrometer equipped with an electrospray ionization (ESI)
source. The instrument was operated in positive mode using an m/z
range of 50e1200. The capillary voltage of the ion source was set at
4000 V. The nebulizer gas pressure was 1.0 bar, and the drying gas
flow was 4.0 L/min. CHN analysis was accomplished by combustion
analysis (Dumas and Pregl method). Melting points were deter-
mined in glass capillaries using a Stuart SMP30 device and are
uncorrected. Flash column chromatography was performed on
silica gel. All commercial reagents were purchased from Acros and
Aldrich.
Scheme 2.
4.2. X-ray structure determination
Atomic coordinates, bond lengths, bond angles and thermal
parameters have been deposited at the Cambridge Crystallographic
Data Centre (CCDC) and allocated the deposition numbers CCDC
1590043 (7f).
4.3. Synthesis of the starting compounds
2,3-Dichloropyrazine, 2-chloro- and 2,3-dichloroquinoxalines
were purchased from Aldrich. 2-Chloro-3-methylquinoxaline,17 2-
chloro-3-(phenylethynyl)quinoxaline,18
3-chloroquinoxaline-2-
carbonitrile,19 6-chloro-1,3-dimethylpteridine-2,4(1H,3H)-dione,20
3-chloro-6,8-dimethylpyrimido[4,5-c]pyridazine-5,7(6H,8H)-
dione,21
2-chloro-3-(phenylethynyl)pyrazine,12
2-
Fig. 2. X-Ray crystal structure of 7f (a pair of (R)- and (S)-enantiomers of 7f connected
by inversion centre are present in the crystal unit cell).
chloronicotinonitrile,22 2-ethynylquinoxaline 1a,23 2-chloro-3-
ethynylquinoxaline 1c24 were synthesized in accordance with
literature procedures.
substituents are well-tolerated. Considering the importance of 2,3-
dihydropyrazolo[1,2-a]pyrazoles as core structures in pharmaco-
logically active substances, this method may became attractive for
both synthetic and medicinal chemistry.
4.4. General procedure for the synthesis of alkynyl azines
A mixture of azine chloride (0.50 mmol), Pd(PPh3)2Cl2 (42 mg,
0.06 mmol), CuI (6 mg, 0.03 mmol) and Et3N (6 mL) was stirred
under argon for 20 min at room temperature. Then a solution of
ethynyltrimethylsilane (63 mg, 0.09 mL, 0.64 mmol) was added
dropwise. The flask was closed tightly. The resulting mixture was
stirred for 24 h at 50e55 ꢀC. The reaction mixture was evaporated
to dryness without heating. The residue was mixed with silica gel
and purified by flash column chromatography on silica gel
(3 ꢂ 30 cm) with CHCl3 as the eluent.
4. Experimental
4.1. General
Proton (1H) and carbon (13C) nuclear magnetic resonance (NMR)
spectra were recorded on a Bruker DPXꢁ250 spectrometer (250
and 62.9 MHz, respectively). 1H and 13C NMR chemical shifts are in
parts per million relative to Me4Si. Coupling constants are in Hertz.
The IR spectra were recorded on a FT FSM-1202 spectrometer
(http://infraspek.ru) using KBr or Nujol. The UVevis spectra were
recorded on a Varian Cary 50 Probe spectrophotometer in CHCl3.
We were unable to obtain by chromatography pure samples of
(trimethylsilyl)ethynyl derivatives because of their partial desily-
lation. Thus, pure (trimethylsilyl)ethynyl derivatives or partially
desilylated products were subjected to desilylation according to the
Please cite this article in press as: Nelina-Nemtseva JI, et al., 1,3-Dipolar cycloaddition of azomethine imines to ethynyl hetarenes: A synthetic
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6
J.I. Nelina-Nemtseva et al. / Tetrahedron xxx (2018) 1e9
following procedure. To a solution of (trimethylsilyl)ethynyl azine
(0.5 mmol) in methanol (5 mL), KF,2H2O (56 mg, 0.6 mmol) was
added. The reaction mixture was stirred for 24 h at room temper-
ature and then evaporated to dryness. The residue was purified by
flash column chromatography on silica gel with CH2Cl2 as the
eluent. Rf, yield and characteristics for each compound are given
below. All alkynes decompose when stored.
79.9, 84.0, 85.5, 96.5, 121.5, 128.5, 129.8, 132.3, 140.8, 142.3, 142.4,
143.1; IR, cmꢁ1: 2199, 2220 (С≡C); MS (ESI) m/z: found 205.0768
[MþH]þ, calcd for C14H8N2 205.0760 [MþH]þ.
4.4.8. 2-Ethynylnicotinonitrile (3)
Rf 0.5, 89%. Off-white solid, with mp 115e117 ꢀC (125 ꢀC26); 1H
NMR (CDCl3)
d
ppm: 3.56 (s, 1H), 7.39 (dd, J ¼ 8.0, 4.9 Hz, 1H), 7.96
(dd, J ¼ 8.0, 1.7 Hz, 1H), 8.75 (dd, J ¼ 4.9, 1.7 Hz, 1H); 13C NMR
4.4.1. 2-Methyl-3-((trimethylsilyl)ethynyl)quinoxaline
(CDCl3) d ppm: 79.4, 83.8, 113.4, 115.6, 123.0, 140.0, 144.7, 152.9; IR,
Rf 0.3, 38%. Brown solid with mp 45e48 ꢀC; 1H NMR (CDCl3)
cmꢁ1: 2114 (С≡C), 2239 (С≡N); MS (ESI) m/z: found 129.0451
[MþH]þ, calcd for C8H4N2 129.0447 [MþH]þ.
d
ppm: 0.35 (s, 9H), 2.89 (s, 3H), 7.68e7.75 (m, 2H), 7.99 (dd, J ¼ 7.7,
1.8 Hz, 1H), 8.05 (dd, J ¼ 7.7, 1.8 Hz, 1H); 13C NMR (CDCl3)
d
ppm: ꢁ0.4, 23.2, 101.6, 102.5, 128.4, 128.9, 129.5, 130.5, 139.3,
4.4.9. 1,3-Dimethyl-6-((trimethylsilyl)ethynyl)pteridine-
2,4(1H,3H)-dione
140.6, 140.7, 155.3; IR, cmꢁ1: 2161 (С≡C); MS (ESI) m/z: found
241.1163 [MþH]þ, calcd for C14H16N2Si 241.1156 [MþH]þ.
Rf 0.2, 74%. Off-white solid with mp 115e117 ꢀC (decomp.)
(112e115 ꢀC27); 1H NMR (CDCl3)
d ppm: 0.26 (s, 9H), 3.51 (s, 3H),
4.4.2. 2-Ethynyl-3-methylquinoxaline (1b)
3.68 (s, 3H), 8.65 (s, 1H); 13C NMR (CDCl3)
d
ppm: ꢁ0.5, 29.1, 29.5,
Rf 0.4, 89%. Brown solid with mp 97e99 ꢀC; 1H NMR (CDCl3)
99.7, 100.5, 127.1, 135.1, 146.4, 150.3, 150.6, 159.2; IR, cmꢁ1: 1653,
1724 (C¼O), 2167 (С≡C); MS m/z: 288 ([Mþ], 43), 273 (100), 108
(11), 81 (13), 67 (11), 56 (13), 43 (22), 15 (33). Anal. calcd for
d
ppm: 2.90 (s, 3H), 3.58 (s, 1H), 7.70e7.77 (m, 2H), 8.00 (dd, J ¼ 7.9,
1.5 Hz, 1H), 8.05 (dd, J ¼ 7.9, 1.5 Hz, 1H); 13C NMR (CDCl3)
d ppm:
23.1, 80.9, 83.2, 128.5, 128.9, 129.6, 130.8, 138.6, 140.7, 140.9, 155.2;
IR, cmꢁ1: 2098 (С≡C); MS (ESI) m/z: found 169.0767 [MþH]þ, calcd
for C11H8N2 169.0760 [MþH]þ.
C13H16N4O2Si: C, 54.14; H, 5.59; N,19.43; Si, 9.74. Found: C, 54.34; H,
5.63; N, 19.17.
4.4.10. 6-Ethynyl-1,3-dimethylpteridine-2,4(1H,3H)-dione (4)
Rf 0.1, 83%. Off-white solid, decomp. >230 ꢀC (decomp.)
4.4.3. 3-Ethynylquinoxaline-2-carbonitrile (1d)
Rf 0.6, 74%. Off-white solid with mp 163e165 ꢀC (decomp.); 1H
(236e238 ꢀC (decomp.)28); 1H NMR (CDCl3)
d
ppm: 3.34 (s, 1H),
NMR (CDCl3)
d
ppm: 3.73 (s, 1H), 7.87e7.99 (m, 2H), 8.10e8.19 (m,
3.51 (s, 3H), 3.69 (s, 3H), 8.69 (s, 1H); 13C NMR (CDCl3)
d
ppm: 29.2,
2H); 13C NMR (CDCl3)
d
ppm: 78.2, 85.9, 114.8, 129.4, 129.8, 131.8,
29.6, 79.1, 81.7, 127.3, 134.3, 146.8, 150.3, 150.6, 159.0; IR, cmꢁ1
:
132.6, 134.0, 138.9, 140.4, 142.0; IR, cmꢁ1: 2107 (С≡C), 2234 (С≡N);
1653, 1724 (C¼O), 2108 (С≡C); MS m/z: 216 ([Mþ], 100), 159 (14),
131 (34), 104 (39), 77 (25), 56 (15), 28 (17), 18 (19), 15 (17). Anal.
calcd for C10H8N4O2: C, 55.55; H, 3.73; N, 25.91. Found: C, 55.41; H,
3.99; N, 25.84.
MS m/z: 179 ([Mþ], 100), 127 (60), 76 (35), 50 (22). Anal. calcd for
C
11H5N3: C, 73.74; H, 2.81; N, 23.45. Found: C, 73.47; H, 2.94; N,
23.66.
4.4.4. 2-(Phenylethynyl)-3-((trimethylsilyl)ethynyl)quinoxaline
4.4.11. 6,8-Dimethyl-3-((trimethylsilyl)ethynyl)pyrimido[4,5-c]
pyridazine-5,7(6H,8H)-dione
Rf 0.6, 87%. Brown solid with mp 123e125 ꢀC; 1H NMR (CDCl3)
d
ppm: 0.34 (s, 9H), 7.38e7.42 (m, 3H), 7.70 (dd, J ¼ 7.5, 1.6 Hz, 2H),
Rf 0.2, 70%. Off-white solid with mp 123e124 ꢀC (120e121 ꢀC29);
7.73e7.76 (m, 2H), 8.04e8.06 (m, 2H); 13C NMR (CDCl3)
1H NMR (CDCl3)
d ppm: 0.27 (s, 9H), 3.45 (s, 3H), 3.85 (s, 3H), 8.11 (s,
d
ppm: ꢁ0.3, 86.7, 95.7, 101.1, 102.5, 121.7, 128.5, 128.9, 129.0, 129.8,
1H); 13C NMR (CDCl3)
d
ppm: ꢁ0.47, 28.9, 30.0, 99.5, 101.0, 112.4,
130.9, 131.1, 132.4, 140.3, 140.4140.6, 140.8; IR, cmꢁ1: 2104, 2221
(С≡C); MS m/z: 254 ([MþHꢁSiMe3]þ, 100), 253 ([MꢁSiMe3]þ, 26),
204 (10), 176 (10), 127 (81), 100 (190), 77 (12), 74 (20). Anal. calcd
for C21H18N2Si: C, 77.26; H, 5.56; N, 8.58; Si, 8.60. Found: C, 77.01; H,
5.80; N, 8.87.
128.0, 144.4, 149.5, 150.2, 159.8; IR, cmꢁ1: 1674, 1730 (C¼O), 2184
(C≡C); MS m/z: 288 ([Mþ], 49), 273 (100). Anal. calcd for
C13H16N4O2Si: C, 54.14; H, 5.59; N,19.43; Si, 9.74. Found: C, 54.28; H,
5.47; N, 19.55.
4.4.12. 3-Ethynyl-6,8-dimethylpyrimido[4,5-c]pyridazine-
5,7(6H,8H)-dione (5)
4.4.5. 2-Ethynyl-3-(phenylethynyl)quinoxaline (1e)
Rf 0.7, 87%. Brown solid with mp 119e121 ꢀC; 1H NMR (CDCl3)
Rf 0.2, 85%. Off-white solid, with mp 201e203 ꢀC; 1H NMR
d
ppm: 3.65 (s, 1H), 7.41e7.47 (m, 3H), 7.72 (dd, J ¼ 7.8, 1.5 Hz, 2H),
(CDCl3)
NMR (CDCl3)
d C
ppm: 3.45 (s, 1H), 3.48 (s, 3H), 3.89 (s, 3H), 8.18 (s, 1H); 13
7.76e7.82 (m, 2H), 8.07e8.10 (m, 2H); 13C NMR (CDCl3)
d
ppm: 80.5,
d ppm: 28.9, 30.1, 79.0, 82.2, 112.5, 128.2, 143.7, 149.7,
83.2, 86.4, 96.1, 121.6, 128.6, 128.9, 129.1, 129.9, 131.0, 131.4, 132.4,
139.8, 140.3, 140.8(0), 140.8(3); IR, cmꢁ1: 2103, 2218 (С≡C); MS m/z:
254 ([Mþ], 100), 253 (24), 203 (55), 127 (62), 100 (14), 76 (61). Anal.
calcd for C18H10N2: C, 85.02; H, 3.96; N, 11.02. Found: C, 85.13; H,
4.09; N, 11.11.
150.2, 159.7; IR, cmꢁ1: 1661, 1711 (C¼O), 2108 (С≡C); MS m/z: 216
([Mþ], 100), 159 (14), 131 (19), 104 (31), 88 (29), 81 (27), 62 (12), 56
(14), 53 (16), 15 (22). Anal. calcd for C10H8N4O2: C, 55.55; H, 3.73; N,
25.91. Found: C, 55.32; H, 4.01; N, 25.78.
4.5. General procedure for the synthesis of 6-hetaryl-5-phenyl-2,3-
dihydropyrazolo[1,2-a]pyrazol-1(5H)-ones 7
4.4.6. 2,3-Diethynylquinoxaline (1f)
Rf 0.6, 78%. Tan solid, decomp. > 170 ꢀC (mp 175e176 ꢀC
(decomp.)25); 1H NMR (CDCl3)
d
ppm: 3.61 (s, 1H), 7.81 (dd, J ¼ 6.4,
Method A. To a stirred for 5 min mixture of 2-arylidene-5-
oxopyrazolidin-2-ium-1-ide 6 (0.3 mmol), CuI (3 mg, 0.015 mmol)
and CHCl3 (2 mL), a solution of the corresponding ethynyl hetarene
1e5 (0.3 mmol) and Cy2NMe (29 mg, 0.032 mL, 0.15 mmol) in CHCl3
(2 mL) was added dropwise. The reaction mixture was heated un-
der reflux for 22 h and evaporated to dryness. The residue was
mixed with silica gel and purified by flash column chromatography
on silica gel (3 ꢂ 40 cm) with CH2Cl2 e Et2O (1:1, v/v) as the eluent.
The first colorless fraction gave unreacted starting alkyne. The next
3.4 Hz, 1H), 8.08 (dd, J ¼ 6.4, 3.4 Hz, 1H); 13C NMR (CDCl3)
d ppm:
80.0, 83.5, 129.0, 131.5, 139.7, 140.6; IR, cmꢁ1: 2129 (С≡C); HRMS
(ESI): found 179.0609 [MþH]þ, calcd for C12H6N2 179.0604 [MþH]þ.
4.4.7. 2-Ethynyl-3-(phenylethynyl)pyrazine (2)
Rf 0.6, 85%. Off-white solid, with mp 73e75 ꢀC; 1H NMR (CDCl3)
d
ppm: 3.57 (s, 1H), 7.32e7.43 (m, 3H), 7.59e7.63 (m, 2H), 8.43 (d,
J ¼ 2.4 Hz, 2H), 8.49 (d, J ¼ 2.4 Hz, 2H); 13C NMR (CDCl3)
d ppm:
Please cite this article in press as: Nelina-Nemtseva JI, et al., 1,3-Dipolar cycloaddition of azomethine imines to ethynyl hetarenes: A synthetic
route to 2,3-dihydropyrazolo[1,2-a]pyrazol-1(5H)-one based heterobiaryls, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.01.046

J.I. Nelina-Nemtseva et al. / Tetrahedron xxx (2018) 1e9
7
yellow fraction gave 6-hetaryl-5-phenyl-2,3-dihydropyrazolo[1,2-
a]pyrazol-1(5H)-one 7. Starting compounds and yields are indi-
cated in Table 2. Rf and other characteristics of the products 7 are
indicated below.
Method B. A solution of 2-benzylidene-5-oxopyrazolidin-2-ium-
1-ide 6a (35 mg, 0.2 mmol), ethynyl hetarene 1a or 1d (0.3 mmol)
in p-xylene (1 mL) was stirred at 130 ꢀC for 7 h. The reaction
mixture was evaporated to dryness. Isolation of the product 7 was
carried out similarly to the above method A.
139.5, 140.5, 147.0, 151.7, 163.8; IR, cmꢁ1: 1703 (С ¼ O); UVevis, lmax
(lg ε), nm: 283 (4.34), 335 sh (4.10), 391 (4.49), end absorption up to
480 nm; MS m/z: 342 ([Mþ], 19), 313 (100), 299 (32), 287 (11), 271
(21), 257 (11), 211 (27), 143 (14), 102 (162), 77 (16), 55 (37), 14 (13).
Anal. calcd for C21H18N4O: C, 73.67; H, 5.30; N, 16.36. Found: C,
73.54; H, 5.42; N, 16.17.
4.5.5. 3-(5-Oxo-1-phenyl-1,5,6,7-tetrahydropyrazolo[1,2-a]
pyrazol-2-yl)quinoxaline-2-carbonitrile (7f)
Rf 0.7. Orange solid, with mp 212e214 ꢀC (i-PrOH); 1H NMR
4.5.1. 5-Phenyl-6-(quinoxalin-2-yl)-2,3-dihydropyrazolo[1,2-a]
pyrazol-1(5H)-one (7a)
(CDCl3) d ppm: 2.84e3.09 (m, 2H), 3.17e3.27 (m, 1H), 3.50 (ddd,
J ¼ 8.0, 7.8, 4.3 Hz, 1H), 5.85 (d, J ¼ 1.4 Hz, 1H), 7.25e7.39 (m, 3H),
Rf 0.4. Yellow solid, with mp 208e211 ꢀC (i-PrOH); 1H NMR
7.52e7.58 (m, 2H), 7.72e7.88 (m, 3H), 8.03 (dd, J ¼ 7.5, 1.2 Hz, 1H),
(CDCl3)
d
ppm: 2.76e3.00 (m, 2H), 3.15 (pseudoquartet, J ¼ 8.6 Hz,
8.25 (d, J ¼ 0.9 Hz, 1H); 13C NMR (CDCl3)
d ppm: 35.9, 51.3, 74.7,
1H), 3.39 (ddd, J ¼ 8.1, 8.1, 4.8 Hz, 1H), 5.64 (d, 1H), 7.26e7.35 (m,
3H), 7.44e7.48 (m, 2H), 7.56e7.67 (m, 2H), 7.78e7.83 (m, 2H),
116.6, 122.4, 124.4, 126.6, 128.3, 128.5, 128.7, 128.8, 129.5, 130.8,
133.4, 138.1, 139.3, 142.0, 147.3, 164.2; IR, cmꢁ1: 1701 (С ¼ O), 2232
(C≡N); UVevis, lmax (lg ε), nm: 259 (4.53), 309 sh (3.96), 382 (4.12),
end absorption up to 525 nm; MS m/z: 353 ([Mþ], 62), 324 (29), 310
(25), 298 (21), 283 (22), 276 (100), 269 (13), 256 (12), 222 (18), 140
(11), 115 (10), 102 (17), 77 (13), 55 (40), 42 (11), 28 (11). Anal. calcd
for C21H15N5O: C, 71.38; H, 4.28; N, 19.82. Found: C, 71.43; H, 4.03;
N, 20.04.
7.89e7.95 (m, 1H), 8.68 (s, 1H); 13C NMR (CDCl3)
d ppm: 36.0, 51.1,
73.6, 121.8, 125.5, 128.5, 128.6(8), 128.7(1), 129.0, 129.1, 129.2, 130.2,
137.8, 140.7, 142.2, 142.7, 147.0, 163.7; IR, cmꢁ1: 1693 (С ¼ O);
UVevis, lmax (lg ε), nm: 269 sh (4.37), 340 sh (3.95), 396 (4.11), end
absorption up to 484 nm; MS m/z: 328 ([Mþ], 39), 300 (38), 299
(100), 285 (31), 271 (24), 258 (21), 251 (60), 243 (20), 231 (14), 197
(58), 155 (16), 140 (12), 129 (45), 115 (28), 102 (50), 89 (12), 76 (40),
55 (79), 51 (21), 42 (30), 28 (22). Anal. calcd for C20H16N4O: C, 73.15;
H, 4.91; N, 17.06. Found: C, 73.22; H, 4.79; N, 17.23.
4.5.6. 5-Phenyl-6-(3-(phenylethynyl)quinoxalin-2-yl)-2,3-
dihydropyrazolo[1,2-a]pyrazol-1(5H)-one (7g)
Rf 0.8. Yellow solid, with mp 245e246 ꢀC (i-PrOH); 1H NMR
4.5.2. 5-(4-Nitrophenyl)-6-(quinoxalin-2-yl)-2,3-dihydropyrazolo
[1,2-a]pyrazol-1(5H)-one (7b)
(CDCl3)
d
ppm: 2.77e3.01 (m, 2H), 3.17 (pseudoquartet, J ¼ 8.6 Hz,
1H), 3.41 (ddd, J ¼ 8.1, 8.1, 4.9 Hz, 1H), 5.83 (d, J ¼ 1.3 Hz, 1H),
7.17e7.32 (m, 3H), 7.43e7.51 (m, 5H), 7.55e7.63 (m, 2H), 7.69e7.77
(m, 3H), 7.90e7.98 (m, 1H), 8.42 (d, J ¼ 0.9 Hz, 1H); 13C NMR (CDCl3)
Rf 0.2. Yellow solid, with mp 164e166 ꢀC (i-PrOH); 1H NMR
(CDCl3)
d
ppm: 2.80 (ddd, J ¼ 16.0, 7.0, 2.2 Hz, 1H), 2.96e3.10 (m,
1H), 3.15e3.26 (m, 1H), 3.59 (td, J ¼ 8.2, 2.0 Hz, 1H), 5.73 (d,
d ppm: 36.0, 51.2, 74.8, 88.1, 96.0, 121.2, 123.7, 124.7, 128.1, 128.4,
J ¼ 1.5 Hz, 1H), 7.58e7.68 (m, 2H), 7.71e7.78 (m, 4H), 7.93e7.97 (m,
128.6 (2С), 128.7, 128.8, 129.8, 130.1, 130.6, 132.3, 136.7, 138.6, 139.7,
140.3,147.3,164.1; IR, cmꢁ1: 1702 (С ¼ O), 2204 (C≡C); UVevis, lmax
(lg ε), nm: 269 (4.52), 296 (4.49), 407 (4.20), end absorption up to
515 nm; MS m/z: 428 ([Mþ], 42), 373 (11), 351 (20), 343 (35), 297
(27), 140 (11), 127 (26), 115 (14), 102 (32), 77 (51), 55 (100), 51 (18),
42 (16), 28 (40), 16 (27), 14 (58). Anal. calcd for C28H20N4O: C, 78.49;
H, 4.70; N, 13.08. Found: C, 78.37; H, 4.82; N, 13.21.
1H), 8.14e8.18 (m, 2H), 8.85 (s, 1H); 13C NMR (CDCl3)
d ppm: 35.7,
52.5, 73.9, 122.1, 123.5, 124.4, 128.7, 129.2, 129.5, 129.7, 130.5, 140.6,
141.7, 142.7, 146.5, 146.8, 147.7, 164.4; IR, cmꢁ1: 1705 (С ¼ O);
UVevis, lmax (lg ε), nm: 277 sh (4.38), 335 sh (3.94), 392 (4.33), end
absorption up to 483 nm; MS m/z: 373 ([Mþ], 31), 344 (100), 330
(34), 318 (11), 316 (14), 298 (11), 257 (11), 251 (42), 242 (16), 197
(41), 129 (13), 102 (15), 55 (27), 28 (15). Anal. calcd for C20H15N5O3:
C, 64.34; H, 4.05; N, 18.76. Found: C, 64.19; H, 4.20; N, 18.93.
4.5.7. 6-(3-Ethynylquinoxalin-2-yl)-5-phenyl-2,3-dihydropyrazolo
[1,2-a]pyrazol-1(5H)-one (7h)
4.5.3. 5-(4-Methoxyphenyl)-6-(quinoxalin-2-yl)-2,3-
dihydropyrazolo[1,2-a]pyrazol-1(5H)-one (7c)
Rf 0.7 (Et2O
e hexane, 3:1, v/v). Yellow solid, with mp
123e125 ꢀC (i-PrOH); 1H NMR (CDCl3)
d
ppm: 2.86 (ddd, J ¼ 16.3,
Rf 0.4. Yellow solid, with mp 172e174 ꢀC (i-PrOH); 1H NMR
7.6, 4.4 Hz, 1H), 2.93e3.04 (m, 1H), 3.17 (pseudoquartet, J ¼ 8.6 Hz,
1H), 3.43 (ddd, J ¼ 8.1, 8.1, 4.5 Hz, 1H), 3.73 (s, 1H), 5.81 (s, 1H),
7.22e7.25 (m, 1H), 7.29e7.33 (m, 2H), 7.51 (d, J ¼ 7.2 Hz, 2H),
7.61e7.66 (m, 2H), 7.74e7.76 (m, 1H), 7.93e7.96 (m, 1H), 8.38 (s,
(CDCl3)
d
ppm: 2.76e2.96 (m, 2H), 3.11 (pseudoquartet, J ¼ 8.4 Hz,
1H), 3.29e3.37 (m, 1H), 3.74 (s, 3H), 5.60 (s, 1H), 6.84 (d, J ¼ 8.4 Hz,
2H), 7.36 (d, J ¼ 8.4 Hz, 2H), 7.57e7.66 (m, 2H), 7.77 (s, 1H),
7.81e7.84 (m, 1H), 7.91e7.94 (m, 1H), 8.65 (s, 1H); 13C NMR (CDCl3)
1H); 13C NMR (CDCl3)
d ppm: 36.0, 51.1, 74.6, 82.0, 84.2, 123.7, 124.5,
d
ppm: 36.1, 50.6, 55.3, 72.7, 114.2, 121.7, 125.8, 129.0 (2C), 129.2,
128.0, 128.3, 128.5, 128.6(8), 128.7(1), 129.9, 131.0, 135.4, 138.6,
139.4, 140.6, 147.3, 164.0; IR, cmꢁ1: 1706 (С ¼ O), 2105 (C≡C);
UVevis, lmax (lg ε), nm: 254 (4.51), 262 (4.50), 364 (3.97), 404
(4.01), end absorption up to 480 nm; MS (ESI) m/z: found 353.1397
[MþH]þ, calcd for C22H17N4O 353.1397 [MþH]þ.
129.4, 129.8, 130.2, 140.7, 142.2, 142.7, 147.0, 159.8, 163.5; IR, cmꢁ1
:
1714 (С ¼ O); UVevis, lmax (lg ε), nm: 288 (4.05), 335 sh (3.82), 397
(4.23), end absorption up to 499 nm; MS m/z: 358 ([Mþ], 49), 329
(100), 315 (30), 303 (22), 288 (20), 274 (10), 259 (17), 251 (35), 231
(18), 229 (14), 197 (38), 129 (26), 102 (26), 76 (14), 55 (48), 42 (11),
28 (26), 15 (16). Anal. calcd for C21H18N4O2: C, 70.38; H, 5.06; N,
15.63. Found: C, 70.52; H, 4.89; N, 15.35.
4.5.8. 1,3-Dimethyl-6-(5-oxo-1-phenyl-1,5,6,7-tetrahydropyrazolo
[1,2-a]pyrazol-2-yl)pteridine-2,4(1H,3H)-dione (7i)
Rf 0.2. Yellow solid, with mp 239e242 ꢀC (i-PrOH); 1H NMR
4.5.4. 6-(3-Methylquinoxalin-2-yl)-5-phenyl-2,3-dihydropyrazolo
[1,2-a]pyrazol-1(5H)-one (7d)
(CDCl3)
d
ppm: 2.74e2.99 (m, 2H), 3.13 (pseudoquartet, J ¼ 8.8 Hz,
1H), 3.39 (ddd, J ¼ 8.1, 8.1, 4.2 Hz, 1H), 3.48 (s, 3H), 3.59 (s, 3H), 5.55
(br s, 1H), 7.28e7.37 (m, 3H), 7.45e7.48 (m, 2H), 7.71 (br s, 1H), 8.25
Rf 0.4. Yellow solid, with mp 155e157 ꢀC (n-heptane); 1H NMR
(CDCl3)
d
ppm: 2.75e2.86 (m, 4H), 2.92e3.02 (m, 1H), 3.09e3.19
(s, 1H); 13C NMR (CDCl3)
d ppm: 29.0, 29.4, 35.6, 51.2, 73.5, 121.4,
(m, 1H), 3.44 (ddd, J ¼ 8.1, 8.1, 4.0 Hz, 1H), 5.82 (d, J ¼ 1.5 Hz, 1H),
123.3, 126.9, 128.7, 128.8, 128.9, 137.2, 143.5, 144.1, 145.9, 150.4,
159.5, 163.6; IR, cmꢁ1: 1668, 1677, 1714 (С ¼ O); UVevis, lmax (lg ε),
nm: 351 (4.25), 407 (4.08), end absorption up to 541 nm; MS m/z:
390 ([Mþ], 57), 361 (63), 347 (33), 334 (24), 320 (17), 313 (81), 306
7.13e7.28 (m, 3H), 7.43e7.50 (m, 3H), 7.52e7.62 (m, 2H), 7.72e7.78
(m, 1H), 7.83e7.90 (m, 1H); 13C NMR (CDCl3)
d
ppm: 25.0, 36.0, 51.6,
75.6,122.0,126.4,128.0,128.1, 128.3,128.5,128.6,129.1, 129.5,138.9,
Please cite this article in press as: Nelina-Nemtseva JI, et al., 1,3-Dipolar cycloaddition of azomethine imines to ethynyl hetarenes: A synthetic
route to 2,3-dihydropyrazolo[1,2-a]pyrazol-1(5H)-one based heterobiaryls, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.01.046

8
J.I. Nelina-Nemtseva et al. / Tetrahedron xxx (2018) 1e9
(c) Ternansky RJ, Draheim SE, Pike AJ, Counter FT, Eudaly JA, Kasher JS. J Med
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287e302;
(22), 259 (82), 206 (10), 193 (11), 179 (13), 140 (20), 91 (12), 77 (24),
55 (100), 42 (16), 28 (21). Anal. calcd for C20H18N6O3: C, 61.53; H,
4.65; N, 21.53. Found: C, 61.34; H, 4.56; N, 21.80.
(e) Hanessian S, McNaughton-Smith G, Lombart HG, Lubell WD. Tetrahedron.
1997;53:12789e12854;
(f) Marchand-Brynaert J, Ghosez L. In: Lukacs G, Ohno M, eds. Recent Progress in
the Chemical Synthesis of Antibiotics. Berlin: Springer; 1990:727e794;
(g) Fischer R, Bretschneider T, Gesing ERF, et al. PCT Int. Appl. WO 2005016873
Chem Abstr. 2005;142, 261530;
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(i) Hatayama S, Hayashi K, Honma M, Takahashi I. Jpn Kokai Tokkyo Koho JP
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4.5.9. 6,8-Dimethyl-3-(5-oxo-1-phenyl-1,5,6,7-tetrahydropyrazolo
[1,2-a]pyrazol-2-yl)pyrimido[4,5-c]pyridazine-5,7(6H,8H)-dione
(7j)
Rf 0.3. Yellow solid, with mp 226e228 ꢀC (i-PrOH); 1H NMR
(CDCl3)
d
ppm: 2.75e2.96 (m, 2H), 3.13 (pseudoquartet, J ¼ 8.4 Hz,
1H), 3.27e3.35 (m, 1H), 3.42 (s, 3H), 3.79 (s, 3H), 5.61 (br s, 1H),
7.28e7.41 (m, 5H), 7.71 (br s, 1H), 7.81 (s, 1H); 13C NMR (CDCl3)
(j) Bhandari A, Boros EE, Cowan DJ, et al. PCT Int Appl WO 2003076440 Chem
Abstr. 2003;139, 261291;
d
ppm: 28.8, 29.9, 36.0, 50.6, 73.3, 113.0, 121.2, 121.4, 123.4, 128.6,
128.9, 129.0, 136.8, 149.3, 150.2, 151.8, 160.2, 163.5; IR, cmꢁ1: 1670,
1698, 1719 (С ¼ O); UVevis, lmax (lg ε), nm: 359 (4.29), end ab-
sorption up to 514 nm; MS m/z: 390 ([Mþ], 96), 361 (76), 320 (18),
313 (57), 306 (16), 292 (11), 259 (50), 206 (13),192 (17),177 (11),166
(10), 164 (11), 152 (14), 139 (12), 115 (11), 91 (16), 77 (19), 55 (100),
15 (17). Anal. calcd for C20H18N6O3: C, 61.53; H, 4.65; N, 21.53.
Found: C, 61.41; H, 4.39; N, 21.47.
(k) Kosower EM, Hershkowitz E. Isr Patent ISXXAQ IL 94658; Chem Abstr
1994;122:214077.
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1013e1018;
4.5.10. 5-Phenyl-6-(3-(phenylethynyl)pyrazin-2-yl)-2,3-
dihydropyrazolo[1,2-a]pyrazol-1(5H)-one (7k)
Rf 0.8. Yellow solid, with mp 161e163 ꢀC (i-PrOH); 1H NMR
(CDCl3) d ppm: 2.80e3.01 (m, 2H), 3.12e3.22 (m,1H), 3.32e3.40 (m,
1H), 5.75 (d, J ¼ 1.3 Hz, 1H), 7.27e7.44 (m, 5H), 7.47e7.51 (m, 3H),
(h) Golebiewski WM, Gucma M. J Heterocycl Chem. 2008;45:1687e1693;
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7.71e7.75 (m, 2H), 8.25 (d, J ¼ 2.4 Hz, 1H), 8.28 (d, J ¼ 2.4 Hz, 1H),
(j) Kissane M, Maguire AR. Chem Soc Rev. 2010;39:845e883;
(k) Najera C, Sansano JM, Yus M. J Braz Chem Soc. 2010;21:377e412;
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(o) Belskaya NP, Bakulev VA, Fan Z. Chem Heterocycl Comp. 2016;52:627e636;
8.33 (d, J ¼ 1.3 Hz, 1H); 13C NMR (CDCl3)
d ppm: 36.0, 50.8, 74.2,
87.3, 97.1, 121.4, 123.1, 124.0, 128.2, 128.5 (2C), 128.8, 129.9, 132.1,
136.1, 138.1, 140.7, 141.9, 148.7, 163.8; IR, cmꢁ1: 1685 (С ¼ O), 2207
(C≡C); UVevis, lmax (lg ε), nm: 283 (4.33), 366 (4.18); MS (ESI) m/z:
found 379.1569 [MþH]þ, calcd for C24H18N4O 379.1559 [MþH]þ.
€
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2819e2851.
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4.5.11. 2-(5-Oxo-1-phenyl-1,5,6,7-tetrahydropyrazolo[1,2-a]
pyrazol-2-yl)nicotinonitrile (7l)
Rf 0.4. Yellow solid, with mp 185e187 ꢀC (i-PrOH); 1H NMR
(CDCl3)
d
ppm: 2.78e3.08 (m, 2H), 3.17 (pseudoquartet, J ¼ 8.6 Hz,
(c) Jungheim LN, Sigmund SK. J Org Chem. 1987;52:4007e4013;
1H), 3.42 (ddd, J ¼ 8.0, 8.0, 4.4 Hz, 1H), 5.77 (s, 1H), 7.11 (dd, J ¼ 7.9,
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4.8 Hz, 1H), 7.27e7.38 (m, 3H), 7.34e7.46 (m, 2H), 7.87 (d, J ¼ 7.9 Hz,
1H), 7.99 (s, 1H), 8.55 (d, J ¼ 4.8 Hz, 1H); 13C NMR (CDCl3)
d ppm:
(e) Chuang TH, Sharpless KB. Helv Chim Acta. 2000;83:1734e1743;
(f) Turk C, Svete J, Stanovnik B, et al. Helv Chim Acta. 2001;84:146e156;
35.9, 51.3, 74.5, 105.6, 117.4, 120.4, 123.7, 124.4, 128.3, 128.5, 128.7,
138.2, 141.2, 152.2, 153.9, 163.9; IR, cmꢁ1: 1708 (С ¼ O), 2220 (C≡N);
UVevis, lmax (lg ε), nm: 368 (4.04), end absorption up to 474 nm;
MS (ESI) m/z: found 303.1251 [MþH]þ, calcd for C18H14N4O
303.1240 [MþH]þ.
́
ꢁ
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Acknowledgements
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́
2010;157:359e363;
(f) Yoshimura K, Oishi T, Yamaguchi K, Mizuno N. Chem Eur J. 2011;17:
We gratefully acknowledge Southern Federal University (grant
No VnGr 07/2017-18) for financial support of this research. We also
thank Drs. Anna V. Tkachuk and Oleg N. Burov (Scientific and
Educational Laboratory of Resonance Spectroscopy, Department of
Natural and High Molecular Compounds Chemistry, Southern
Federal University) for NMR measurements.
3827e3831;
́
(g) Imaizumi T, Yamashita Y, Kobayashi S.
J Am Chem Soc. 2012;134:
20049e20052;
(h) Yamashita Y, Kobayashi S. Chem Eur J. 2013;19:9420e9427;
(i) Arai T, Ogino Y. Molecules. 2012;17:6170e6178;
(j) Arai T, Ogino Y, Sato T. Chem Commun. 2013;49:7776e7778;
(k) Shao C, Zhang Q, Cheng G, Cheng C, Wang X, Hu Y. Eur J Org Chem.
2013;2013:6443e6448;
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(l) Mirnik J, Pusavec Kirar E, Ricko S, et al. Tetrahedron. 2017;73:3329e3337.
7. Hori M, Sakakura A, Ishihara K. J Am Chem Soc. 2014;136:13198e13201.
8. Luo N, Zheng Z, Yu Z. Org Lett. 2011;13:3384e3387.
9. Yang ZW, Wang JF, Peng LJ, You XL, Cui HL. Tetrahedron Lett. 2016;57:
5219e5222.
Appendix ASupplementary data
Supplementary data associated with this article can be found in
the online version, at https://doi.org/10.1016/j.tet.2018.01.046.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
10. Winterton SE, Ready JM. Org Lett. 2016;18:2608e2611.
11. (a) Meldal M, Tomøe CW. Chem Rev. 2008;108:2952e3015;
(b) Kouznetsov VV, Vargas-Mendez LY, Zubkov FI. Mini Rev Org Chem. 2016;13:
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Please cite this article in press as: Nelina-Nemtseva JI, et al., 1,3-Dipolar cycloaddition of azomethine imines to ethynyl hetarenes: A synthetic
route to 2,3-dihydropyrazolo[1,2-a]pyrazol-1(5H)-one based heterobiaryls, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.01.046