N-Propargylation and Copper(I)-Catalyzed Azide-Alkyne Cycloaddition as a Convenient Strategy for Directed Post-Synthetic Modification of 4-Oxo-1,4-Dihydrocinnoline Derivatives

Article abstract of DOI:10.1007/s10593-020-02750-0

[Figure not available: see fulltext.] 4-Oxo-1,4-dihydrocinnoline derivatives as promising inhibitors of protein tyrosine phosphatase 1В were subjected to post-synthetic modification via a sequence of propargylation and copper(I)-catalyzed azide-alkyne cycloaddition reactions. The propargylation of 4-oxo- 1,4-dihydrocinnolines with propargyl bromide in the presence of various bases proceeded regioselectively at the cinnolinone N-1 atom. In the cycloaddition reaction of N-propargylcinnolinones and benzyl azide, the highest catalytic activity of copper(I) N-heterocyclic carbene complex [(IMes)Cu(Br,I)] was observed, compared to [(IMes)CuCl], [(IPr)Cu(Cl,Br,I)], and CuI.

Full text of DOI:10.1007/s10593-020-02750-0

DOI 10.1007/s10593-020-02750-0
Chemistry of Heterocyclic Compounds 2020, 56(7), 915–922
N-Propargylation and copper(I)-catalyzed azide-alkyne cycloaddition
as a convenient strategy for directed post-synthetic modification of
4-oxo-1,4-dihydrocinnoline derivatives
Vladimir N. Mikhaylov1, Artem O. Pavlov1, Yaroslav V. Ogorodnov1,
Dar'ya V. Spiridonova1, Viktor N. Sorokoumov1, Irina A. Balova1*
1 Saint Petersburg State University,
7/9 University Embankment, Saint Petersburg 199034, Russia; е-mail: i.balova@spbu.ru
Submitted May 8, 2020
Accepted May 14, 2020
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2020, 56(7), 915–922
4-Oxo-1,4-dihydrocinnoline derivatives as promising inhibitors of protein tyrosine phosphatase 1В were subjected to post-synthetic
modification via a sequence of propargylation and copper(I)-catalyzed azide-alkyne cycloaddition reactions. The propargylation of 4-oxo-
1,4-dihydrocinnolines with propargyl bromide in the presence of various bases proceeded regioselectively at the cinnolinone N-1 atom. In
the cycloaddition reaction of N-propargylcinnolinones and benzyl azide, the highest catalytic activity of copper(I) N-heterocyclic carbene
complex [(IMes)Cu(Br,I)] was observed, compared to [(IMes)CuCl], [(IPr)Cu(Cl,Br,I)], and CuI.
Keywords: copper(I) N-heterocyclic carbene complexes, anionic effect, copper(I)-catalyzed azide-alkyne cycloaddition, cross coupling,
protein tyrosine phosphatase 1В inhibitors, von Richter cyclization.
Diseases caused by changes in the activity of insulin and
leptin signaling pathways in the central and peripheral
nervous systems have great social impact, since they are
often associated with loss of physical function and
impaired health-related quality of life. One of the principal
factors leading to insulin and leptin resistance is the
increase in enzymatic activity of protein tyrosine
phosphatase 1В (PTP1B)1–4 which dephosphorylates
insulin and leptin receptors, as well as the associated
insulin receptor substrates (IRS proteins), blocking the
transmission of insulin and leptin signals into the cell.
inhibitory ability, which sharply decreased after methy-
lation of the ОН group. We have recently demonstrated the
high inhibitory activity of a structural analog of the
quinolone-type inhibitors 2 upon treatment of rat models of
obesity and metabolic syndrome.6
High biological activity and specificity of cinnolinone
derivatives 2 (Fig. 1) allow to consider them as lead
compounds in the development of PTP1B inhibitors. It is
still important to develop an effective strategy for directed
A study of bidentate PTP1B ligands derived from 4-oxa-
1,4-dihydroquinoline-3-carboxylic acid derivatives 15
(Fig. 1) showed that a hydrophilic substituent at the С-3
atom is required in the quinolone ring together with a
hydrophobic substituent at the С-6 atom. The presence of a
hydroxy group in the hydroxymethyl substituent at the С-3
atom of ethyl 3-(hydroxymethyl)-4-oxo-1,4-dihydrocinno-
line-6-carboxylic acid (2) (Fig. 1) affected the desired
Figure 1. Pharmacophoric structures on the basis of 4-quinolone
derivatives 1 and 1,4-dihydrocinnoline derivatives 2, exhibiting
inhibitory activity against PTP1B.
0009-3122/20/56(7)-0915©2020 Springer Science+Business Media, LLC
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Chemistry of Heterocyclic Compounds 2020, 56(7), 915–922
Scheme 1
modification of such compounds for further optimization of
their biological activity and for designing molecular probes
enabling the visualization of metabolic processes.
The copper(I)-catalyzed azide-alkyne cycloaddition
reaction (CuAAC) is often used in the synthesis of various
biologically active compounds,7–9 for example, PTP1B
inhibitors10,11 and biological imaging agents.12–14
In the present work, we propose a simple and effective
approach for post-synthetic modification of 4-oxo-1,4-di-
hydrocinnoline derivatives, which includes a propargyla-
tion reaction at the cinnolinone N-1 atom, followed by
CuAAC reactions of the obtained propargyl derivatives. In
order to identify the most effective catalyst for the second
6-bromo-4-chloro-3-hydroxymethylcinnoline (6) according
1
to H NMR data. Such a difference can be associated with
the weaker electron-withdrawing properties of the
substituent at the C-6 position of cinnolinone, which likely
reduced the rate of hydrolysis of the intermediate 6-bromo-
4-chloro-3-hydroxymethylcinnoline (6). An additional
treatment of this mixture with 50% H2SO4 led to its
complete conversion into the target product 7b in 87%
yield. Remarkably, in the case of homolog 5c, the
formation of the target product 7a occurred without an
impurity of the respective 4-chlorocinnoline. The facile
hydrolysis of the intermediate 4-chlorocinnoline in this
case was likely associated with the possibility of
intramolecular nucleophilic substitution reaction occurring
in the first step, which involved the hydroxyethyl group at
the С-3 position. The obtained cyclic ester underwent fast
hydrolysis with the formation of product 7a, in agreement
with the previously obtained experimental data.25,26
According to the analysis of 1H NMR spectra, the
characteristic shifts of NH protons in compounds 2 and
7a,b were observed at 13.58 ppm (compound 2), 13.39 and
13.50 ppm (compounds 7а and 7b, respectively), which
corresponded to the cinnolinone tautomer.
step,
a series of copper(I) N-heterocyclic carbene
complexes were prepared and studied: [(IMes)CuХ],
[(IPr)CuХ] (Х = Cl, Br, I), CuI was also tested.
4-Oxo-1,4-dihydrocinnolines containing a hydroxyalkyl
group at position 3 and a CO2Et or Br substituent at
position 6 were chosen for the study. The selection of
substituents at position 6 was based on their hydrophobic
nature, as well as the potential for subsequent
functionalization via amidation, transesterification,15 and
palladium-catalyzed cross-coupling16 reactions.
Substituted alkynes are convenient substrates for the
synthesis of a wide range of heterocyclic compounds.17–19
In particular, ortho-ethynylated aniline derivatives undergo
intramolecular cyclization with the formation of cinnolines
under the von Richter cyclization conditions,20–22 while
starting unsymmetrical alkynes can be obtained by using
the Sonogashira–Hagihara reaction.23 For the synthesis of
the target compounds, we chose the following reaction
sequence: a Sonogashira–Hagihara coupling of acetylenic
alcohol with aryl iodides, followed by cyclization of the
obtained ortho-ethynylated derivatives, providing the
corresponding cinnolinones.
The first transformation of substrates 3a,b and 4a,b led
to the formation of compounds 5a–c in good yields (76–
82%), which under the previously described von Richter
cyclization conditions24 provided cinnolinone derivatives 2
and 7а,b (Scheme 1). In the case of compound 5а, the
cyclization proceeded selectively, with the formation of
cinnolinone 2 in a high yield. However, when aniline
derivative 5b containing a bromine substituent at the para
position was introduced into reaction under the same
conditions, a product mixture was obtained, which
contained 56% of the target product 7b and 44% of
At the next stage of our study, the propargylation
reactions of substrates 2 and 7a,b were studied in the
presence of K2СO3 or NaH (Table 1). The reactions were
performed in aprotic solvents: Me2CO, THF, and DMF.
Depending on the reaction conditions, the product yields
were 55–86%. It was found that the propargylation reactions
proceeded regioselectively at the cinnolinone ring N-1
atom and did not affect the ОН group of the substituent at
the С-3 position. The most effective reaction conditions
were a combination of NaH and DMF (Table 1). According
1
to H NMR data, the obtained compounds 8a–c did not
exhibit NH proton signals, while the signals of OH protons
appeared at 3.28 ppm for compound 8a (t, J = 6.4 Hz,
CDCl3), at 5.10 ppm for compound 8b (t, J = 5.9 Hz,
DMSO-d6), and at 4.62 ppm for compound 8c (t, J = 5.5 Hz,
DMSO-d6). Additionally, NOESY spectrum of compound
8c showed cross peaks of CH2CCH methylene protons at
5.31 ppm and the protons bonded to the cinnolinone ring
С-8 atom at 7.76 ppm (d, J = 9.2 Hz). The analysis of
compound 8b by IR spectroscopy confirmed the successful
N-functionalization of cinnolinone. The characteristic absorp-
tion bands due to the stretching vibrations of С≡С and С–H
bonds appeared at 2121 and 3246 cm–1, respectively.
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Chemistry of Heterocyclic Compounds 2020, 56(7), 915–922
Table 1. The yields of compounds 8a–c depending on
mixture with [(IMes)2Cu]CuI2. The ratio of these
complexes varied depending on the order of reagent
mixing: after the addition of NaI solution to a suspension
of [(IMes)CuCl], the part of homoleptic [(IMes)2Cu]CuI2
complex in the mixture reached 15%, while the opposite
order of mixing led to its increase up to 36%. This
observation presumably indicates the critical influence of
the iodide concentration on the course of the reaction. Both
forms of the obtained complexes were easily resolved in
1H NMR spectra by the characteristic chemical shifts of the
methyl protons in the 2,4,6-trimethylphenyl substituents:
2.12 (o-Me) and 2.35 ppm (p-Me) for the [(IMes)CuI]
complex, 1.69 (o-Me) and 2.44 ppm (p-Me) for the
[(IMes)2Cu]CuI2 complex (Fig. 2).
Washing the mixture of complexes with MeOH reduced
the fraction of [(IMes)2Cu]CuI2 complex due to its superior
solubility. There were no X-ray structural analysis data for
[(IMes)CuI] complex available in the Cambridge
Crystallographic Data Center (CCDC) database, unlike in
the case of [(IMes)Cu(Cl/Br)] complex.33,34 For the purpose
of growing monocrystals, the crystallization was performed
in different solvent systems: pentane–CH2Cl2, pentane–
CHCl3, MeOH–H2O. In all of the cases, according to the
X-ray structural analysis results, only the homoleptic form
of [(IMes)2Cu]CuI2 complex was found (Fig. 3). No
suitable crystals of the heteroleptic form [(IMes)CuI] could
be obtained. It was concluded that the solution likely
contained an equilibrium mixture of the heteroleptic and
homoleptic forms. This equilibrium presumably shifted
toward the formation of the homoleptic [(IMes)2Cu]CuI2
complex during the crystallization procedure (Scheme 2).
A similar equilibrium in solution was studied earlier in the
case of silver(I) halide N-heterocyclic carbene complexes,
including the [(IMes)AgCl] complex.35
the propargylation conditions of cinnolinones 2, 7a,b
Base
Compound
Solvent
Yield, %
(amount, equiv)
K2CO3 (3)
Me2CO
DMF
Me2CO
DMF
DMF
THF
55
86
61
62
75
62
79
8а
8а
8b
8b
8b
8b
8c
NaH (1.05)
K2CO3 (3)*
K2CO3 (3)*
NaH (1.05)
NaH (1.05)
NaH (1.05)
DMF
* The amount of propargyl bromide was 4 equiv.
The copper(I) carbene complexes employed as catalysts
in the azide-alkyne cycloaddition reaction27 do not usually
require the use of an additional external base.28 1,3-Bis(2,6-
diisopropylphenyl)-imidazol-2-ylidene (IPr) and 1,3-bis-
(2,4,6-trimethylphenyl)imidazol-2-ylidene (IMes) are the
most common ligands used in the catalytic systems for
CuAAC due to the high catalytic activity and synthetic
availability of the corresponding complexes. It has been
previously shown that the reactivity of N-heterocyclic
carbene complexes of copper(I) halides under the
CuAAC conditions may depend on the nature of the halide
anion.29 That motivated us to study the catalytic activity of
the complete series of [(NHC)CuX] complexes, where
NHC = IPr, IMes, while Х = Cl, Br, I.
The possibilities of the functionalization of the N-
propargylated cinnolinones synthesized were initially
explored using compound 8a as a substrate in a CuAAC
reaction with benzyl azide as a model compound in CHCl3
medium at room temperature (Table 2).
Under the given conditions, the complexes of
[(IPr)CuX] series (X = Cl, Br, I) did not exhibit catalytic
The synthesis of imidazolium salts IPr·HCl and
IMes·HCl was performed according to a previously described
procedure.30 The preparation of a series of [(IPr)CuX]
complexes (X = Cl, Br, I) was achieved starting from
the corresponding IPr·HCl salt in aqueous ammonia
medium, using CuX(I) as a source of copper(I).31 The
application of these reaction conditions for synthesizing the
[(IMes)CuX] complexes (X = Cl, Br, I) was successful
only in the presence of CuBr, and the heteroleptic
[(IMes)CuBr] complex was isolated in 49% yield.
When CuCl or CuI were used, a mixture of heteroleptic
[(IMes)CuX] complex (X = Cl, I) and its homoleptic form
1
[(IMes)2Cu]+Y– was formed, as confirmed by H and 13C
NMR data. For this reason, the heteroleptic [(IMes)CuCl]
complex was obtained via an alternative procedure32 by a
reaction of IMes·HCl with 0.55 equiv of Cu2O in CH2Cl2
medium. Under these conditions, Cu2O is a base and a Сu(I)
source at the same time. The [(IMes)CuCl] complex was
obtained by this method in 96% yield. For the synthesis of
[(IMes)CuI] complex, we proposed another approach
involving the treatment of [(IMes)CuCl] with 2 equiv of
NaI in Me2CO under argon atmosphere. The main product
[(IMes)CuI] was formed under these conditions in a
Figure 2. The characteristic chemical shifts of methyl proton
signals in 1H NMR spectrum acquired for a mixture of
[(IMes)CuI] and [(IMes)2Cu]CuI2 complexes.
917

Chemistry of Heterocyclic Compounds 2020, 56(7), 915–922
Table 2. Conversion of compounds 8a–c and the yields of
compounds 9a–c depending on the CuAAC reaction conditions
Conversion of compounds
Com-
8a–c according to 1Н NMR
[(NHC)CuX]
Solvent
pound
spectrum, %
Figure 3. The molecular structure of [(IMes)2Cu]CuI2 complex with
atoms represented by thermal vibration ellipsoids of 50%
probability.
[(IPr)CuX]*
[(IMes)CuCl]
[(IMes)CuBr]
[(IMes)CuI]
CuI
[(IMes)CuI]*4
[(IMes)CuI]
[(IMes)CuI]
[(IMes)CuI]
[(IMes)CuI]
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CHCl3
CHCl3
THF
Trace
9a
9a
10
75
82 (75**)
0
9a
Scheme 2
9a
9a
9b***
9c***
9c***
9c***
9c***
62 (55**)
50
87
Me2CO
MeCN
92
99 (94**)
* X = Cl, Br, I.
** Isolated product 9a–c yield.
*** The reaction was performed at 40°C.
*4 [(IMes)CuI] (4 mol %) was used.
to compound 8a. We achieved a complete conversion of
the starting compound 8b to product 9b using MeCN as a
solvent (Table 2).
It has been proposed that the most probable
intermediates in
a CuAAC reaction with terminal
acetylenes are binuclear copper(I) clusters containing
acetylenide and azide ligands oriented at each other
through a metal center.36–38 A recent study29 of the reaction
between phenylacetylene and benzyl azide, catalyzed by
[(NHC)CuX] (NHC = 1-benzyl-3-methylimidazolin-2-yl-
idene, X = I, Br, Cl, BF4, PF6) and [(NHC)2CuBr]
complexes, showed that the strongly basic ligand was
capable of deprotonating phenylacetylene, leading to the
formation of copper phenylacetylenide I with a coordinated
halide anion in the form of PhC≡CCuX– (Fig. 4) in ionic
pair with the corresponding imidazolium cation (NHC·H+).
A computational study at the level of DFT was used to
propose a mechanism for the preparation of triazole VI
activity (Table 2). On the other hand, [(IMes)CuX]
complexes (X = Cl, Br, I) containing a less sterically
hindered ligand showed higher activity under the same
reaction conditions. It should be noted that the catalytic
activity of [(IMes)CuX] complex depended on the nature of
the anion and increased in the order of Cl– < Br– ≈ I–,
leading to an increase in the conversion of the starting
compound 8a to product 9а from 10% (for X = Cl–) to 82%
(for X = I–) (Table 2).
It should be also noted that CuI in the absence of ligands
and a base under the given conditions did not exhibit any
catalytic activity (Table 2). Compounds 8b,с showed lower
reactivity in a CuAAC reaction, therefore the reactions
were performed at 40°С. When using the [(IMes)CuI]
complex, the starting compounds 8b,c formed the reaction
products 9b,c with conversion 62% and 50% yields,
respectively (Table 2), while product 9b was isolated in
55% yield. It is likely that the low reactivity of [(IMes)CuI]
complex could be attributed to diffusion limitations due to
the lower solubility of compounds 8b,c in CHCl3 compared
involving
a
sequence of bimetallic intermediates
II→III→IV→V–, with protonation of intermediate V
during the last step and regeneration of the catalyst
[(NHC)CuX] (Fig. 4).29
At the same time, a study by Titov and coworkers
showed the possibility of performing the CuAAC reaction
using a trinuclear copper(I) pyrazolate complex via
the activation of acetylene group in the presence of Cu(I)
species, involving the formation of the corresponding
π-complex without generation of copper(I) acetylenide.39
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Chemistry of Heterocyclic Compounds 2020, 56(7), 915–922
–N
spectrometer in KBr pellets. 1H NMR and 13C spectra were
acquired on a Bruker Avance III 400 instrument (400 and
101 MHz, respectively) in DMSO-d6 and CDCl3. The
residual proton signals of solvents (DMSO-d6: 2.50 ppm;
CDCl3: 7.26 ppm) were used as internal standards for
1H NMR spectra and deuterated solvent signals (DMSO-d6:
39.5 ppm; CDCl3: 77.2 ppm) were used as internal
standards for 13C NMR spectra. High-resolution mass
spectra were recorded in positive ion mode over the m/z
range of 50–1200, using a maXis mass spectrometer with
electrospray ionization (ESI-QTOF). The capillary voltage
of the ion source was set at 4500 V (ESI+). The nebulizer gas
pressure was 0.4 bar and the drying gas flow was 4.0 l/min.
The samples were dissolved in МеОН or MeCN. A sodium
formate solution was used for mass calibration. The
reaction progress was controlled by TLC on Macherey-
Nagel plates coated with layer of SIL G/UV254 silica gel
(0.2 mm). Preparative column chromatography was per-
formed using silica gel from Macherey-Nagel, with 40–63 µm
particle size. In order to exclude the possible influence of
catalyst traces remaining on glassware, all reactions
intended for the study of catalytic activity were performed
in fresh vials, while magnetic stir bars were treated prior to
use in a mixture of concd HCl with H2O2 for 1 h at 70°С.44
Commercially available reagents and solvents were
purchased from Sigma-Aldrich, Carl Roth, and abcr GmbH.
Compounds 3а,45 3b,46 [(IPr)CuX] (X = Cl, Br, I),31
[(IMes)CuBr],31 and [(IMes)CuCl]32 were synthesized
according to the published procedures. The observed
1H NMR features of the synthesized compounds matched
the literature precedents. All solvents were dried prior to
use according to standard procedures.
Preparation of propargylanilines 5a–с (General
method – a modified literature procedure47). A solution of
the appropriate aryl iodide 3а,b (9 mmol) in a mixture of
Et3N (15 ml) and MeCN (15 ml) was cooled to 0°С,
degassed by bubbling of argon and treated by adding
PdCl2(PPh3)2 (0.130 g, 0.18 mmol) and CuI (0.034 g,
0.18 mmol), followed by stirring for 5 min. The reaction
mixture was then treated by dropwise addition of the
appropriate alkyne 4а,b (10.65 mmol). The obtained
mixture was stirred at 50°С for 12 h. The reaction mixture
was diluted with ЕtОАс, and the organic layer was washed
with saturated aqueous NH4Cl solution, saturated aqueous
NaCl solution, and with H2O. The organic layer was
separated, dried over anhydrous Na2SO4, and evaporated at
reduced pressure. The obtained residue was purified by the
column chromatography, using a 7:1 mixture of CH2Cl2–
Me2CO as eluent.
N+
Ph
Ph
Ph
R
X
N
Cu
Cu
X
Cu
Cu
X
X
Cu
X
N
NHC
NHC
I
II
III
Ph
Ph
N
Ph
NHC
N
N
N
N
Cu X
Cu
X
N
N
R
N
R
Cu
X
R
NHC
Cu
X
VI
IV
V
Figure 4. The possible intermediate structures in a CuAAC
reaction in the presence of [(NHC)CuX] complex as catalyst.29
According to the Dewar–Chatt–Duncanson model,
copper(I) compounds can form relatively stable
π-complexes with a triple bond,40 featuring two three-
center molecular orbitals. The overlap of unoccupied
orbital of Cu(I) and the π-molecular orbital of C≡C bond in
these complexes results in an electron donor-acceptor
interaction. Some contribution to the bonding is also made
by the π-back donation from the occupied d-orbitals of the
metal center to the π*-molecular orbital of the C≡C bond.
However, the specific activation of acetylene group
through Cu(I) in such π-complexes is primarily mediated
by electron donor-acceptor interaction41 and can point to
the critical role of Lewis acidity in such activation of the
considered Cu(I) complexes. The transfer of π-molecular
orbital electrons of C≡C bond to the sp3-hybrid orbital of
Cu(I) center results in decreased electron density on the
carbon atoms of C≡C bond, conferring this functional
group the properties of a mild electrophile.42
Apparently, the studied copper(I) N-heterocyclic
carbene complexes can substantially contribute to the
activation of C≡C bond via π-coordination with free
terminal alkynes, as well as with the intermediate Cu
acetylenide. Furthermore, the catalytic activity difference
in the studied series of [(IMes)CuX] complexes (X = Cl,
Br, I) may be associated with the different degrees of C≡C
bond activation, depending on the acidity of the complex,
which changes depending on the anion. At the same time,
the possible presence of an equilibrium (Scheme 2) pointed
to the tendency of [(IMes)CuI] complex to the formation
of homoleptic form [(IMes)2Cu]CuI2 in solution, which
likely contributed to the observed catalytic activity. This
assumption was supported by the observed high activity
of homoleptic copper(I) N-heterocyclic complexes
[(NHC)2CuY] (Y = PF6, BF4) in the CuAAC reaction.43
Thus, the proposed approach to post-synthetic
modification of 4-oxo-1,4-dihydrocinnoline derivatives by
using the [(IMes)CuI] complex in CuAAC reaction can be
recommended for the development of a compound library
suitable for molecular structure optimization in the search
for biologically active agents.
Ethyl 4-amino-3-(3-hydroxyprop-1-yn-1-yl)benzoate
(5а).48 Yield 1.55 g (76%), brown powder. 1H NMR
spectrum (CDCl3), δ, ppm: 7.99 (1H, d, J = 1.9, Н-2); 7.81
(1H, dd, J = 8.5, J = 2.0, H-6); 6.66 (1H, d, J = 8.6, Н-5);
4.62 (2H, s, СН2ОН(NH2)); 4.55 (2H, s, NH2(СН2ОН));
4.31 (2H, q, J = 7.1, СO2CH2CH3); 1.89 (1H, s, OH); 1.36
(3H, t, J = 7.1, СO2CH2CH3).
3-(2-Amino-5-bromophenyl)prop-2-yn-1-ol (5b).47
Experimental
IR spectrum (4000–200 cm–1) of compound 8b with
Yield 1.62 g (82%), brown powder. H NMR spectrum
1
1 cm–1 resolution was recorded on a Shimadzu IR Prestige-21
(CDCl3), δ, ppm: 7.37 (1H, d, J = 2.3, H-6); 7.20 (1H, dd,
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Chemistry of Heterocyclic Compounds 2020, 56(7), 915–922
J = 8.6, J = 2.3, H-4); 6.57 (1H, d, J = 8.6 , H-3); 4.53 (2H,
(5 ml). The product was air-dried. Yield 1.77 g (87%),
1
s, CH2); 3.28 (3H, br. s, NH2, OH). 13C NMR spectrum
(CDCl3), δ, ppm: 147.2; 134.5; 132.8; 116.0; 109.2; 109.1;
93.9; 81.2; 51.7.
beige powder. H NMR spectrum (DMSO-d6), δ, ppm:
13.50 (1H, s, NH); 8.12 (1H, d, J = 2.2, Н-5); 7.88 (1H, dd,
J = 9.0, J = 2.3, Н-7); 7.56 (1H, d, J = 9.0, Н-8); 4.51 (2H,
s, CH2). 13C NMR spectrum (DMSO-d6), δ, ppm: 168.3;
149.6; 140.1; 136.4; 126.1; 123.2; 119.2; 117.1; 58.7.
Found, m/z: 276.9591 [M+Na]+. C9H7BrN2NaO2.
Calculated, m/z: 276.9583.
4-(2-Amino-5-bromophenyl)but-3-yn-1-ol (5c). Yield
1
1.68 g (78%), brown powder. H NMR spectrum (CDCl3),
δ, ppm: 7.35 (1H, d, J = 2.3, Н-6); 7.17 (1H, dd, J = 8.6,
J = 2.3, Н-4); 6.58 (1H, d, J = 8.6, Н-3); 3.82 (2H, t,
J = 6.2, CH2CH2OH); 3.46 (3H, br. s, NH2, OH); 2.73 (2H,
t, J = 6.2, CH2CH2OH). 13C NMR spectrum (CDCl3),
δ, ppm: 147.0; 134.3; 132.1; 115.7; 110.3; 109.0; 93.4; 77.8;
61.2; 24.1. Found, m/z: 240.0021 [M+H]+. C10H11BrNO.
Calculated, m/z: 240.0019.
Preparation of N-propargylcinnolinones 8а–с
(General method). A solution of the appropriate 4-oxo-1,4-
dihydrocinnoline 2, 7а,b (2 mmol) in DMF (4 ml) was
stirred and treated by the addition of NaH (60% dispersion
in mineral oil) (84 mg, 2.1 mmol), then after 10 min,
propargyl bromide (400 mg, 3.3 mmol, 1.65 equiv) was
added dropwise. The reaction mixture was heated on oil
bath to 40°С and stirred at that temperature for 12 h. The
mixture was then poured into Н2О (150 ml), the obtained
precipitate was filtered off. The product was air-dried and
washed with pentane (3×3 ml). The isolated product was
dried at reduced pressure.
Preparation of 4-oxo-1,4-dihydrocinnolines 2, 7а,b
(General method). A suspension of propargylaniline 5а–c
(8 mmol) in 2 М НСl (15 ml) was treated by portionwise
addition of NaNO2 (0.82 g, 12 mmol) at 0–5°С. The
reaction mixture was stirred for 15 min at 0–5°С, then
further stirred for 2 h at room temperature. The obtained
precipitate was filtered off and washed consistently with
Н2О (2×5 ml), МеОН (5 ml), and Еt2О (5 ml).
Ethyl 3-(hydroxymethyl)-4-oxo-1-(prop-2-yn-1-yl)-
1,4-dihydrocinnoline-6-carboxylate (8а). Yield 0.492 g
Ethyl 3-(hydroxymethyl)-4-oxo-1,4-dihydrocinnoline-
6-carboxylate (2) was obtained from propargylaniline 5а.
1
(86%), beige powder. H NMR spectrum (CDCl3), δ, ppm:
1
Yield 1.83 g (92%), white powder. H NMR spectrum
9.00 (1H, d, J = 1.9, Н-5); 8.41 (1H, dd, J = 9.1, J = 2.0,
Н-7); 7.63 (1H, d, J = 9.1, Н-8); 5.17 (2H, d, J = 2.5,
CH2C≡CH); 4.81 (2H, d, J = 6.5, CH2OH); 4.43 (2H, q,
J = 7.1, СO2CH2CH3); 3.28 (1H, t, J = 6.4, OH); 2.52 (1H,
t, J = 2.5, ≡CH); 1.43 (3H, t, J = 7.1, СO2CH2CH3).
13C NMR spectrum (CDCl3), δ, ppm: 171.1; 165.3; 149.5;
142.6; 134.5; 128.5; 127.1; 123.1; 115.6; 76.3; 75.7; 61.8;
61.7; 46.6; 14.5. Found, m/z: 309.0848 [M+Na]+.
C15H14N2NaO4. Calculated, m/z: 309.0846.
(DMSO-d6), δ, ppm: 13.58 (1H, s, NH); 8.60 (1H, d, J = 1.8,
Н-5); 8.22 (1H, dd, J = 8.9, J = 1.9, Н-7); 7.66 (1H, d,
J = 8.8, Н-8); 4.99 (1H, br. s, ОН); 4.53 (2H, s, CH2); 4.35
(2H, q, J = 7.1, СO2CH2CH3); 1.35 (3H, t, J = 7.1,
СO2CH2CH3). 13C NMR spectrum (DMSO-d6), δ, ppm:
169.6; 164.8; 150.4; 143.3; 132.9; 126.5; 125.2; 121.0;
117.1; 61.1; 58.5; 14.2. Found, m/z: 271.0692 [M+Na]+.
C12H12N2NaO4. Calculated, m/z: 271.0689.
6-Bromo-3-(2-hydroxyethyl)cinnolin-4(1H)-one (7а)
was obtained from propargylaniline 5с. The product was
additionally purified according to the following procedure:
the obtained precipitate was dissolved in aqueous 0.3 M
NaOH solution (50 ml), the obtained suspension was
filtered through a thin layer of Celite, the filtrate was
neutralized with aqueous 2 M HCl solution to pH 7. The
obtained precipitate was filtered off and washed
consistently with Н2О (2×5 ml), МеОН (5 ml), and Еt2О
(5 ml). The product was air-dried. Yield 1.79 g (83%), light-
6-Bromo-3-(hydroxymethyl)-1-(prop-2-yn-1-yl)cinnolin-
4(1H)-one (8b). Yield 0.439 g (75%), beige powder.
IR spectrum, ν, cm–1: 2121 (C≡C), 3246 (C(sp)–H), 3431
(OH). 1H NMR spectrum (DMSO-d6), δ, ppm: 8.22 (1H, d,
J = 2.3, Н-5); 8.06 (1H, dd, J = 9.2, J = 2.4, Н-7); 7.80
(1H, d, J = 9.2, Н-8); 5.34 (2H, d, J = 2.3, CH2C≡CH);
5.10 (1H, t, J = 5.9, OH); 4.51 (2H, d, J = 5.9, CH2); 3.57
(1H, t, J = 2.3, ≡CH). 13C NMR spectrum (DMSO-d6),
δ, ppm: 168.0; 149.3; 139.0; 136.7; 126.9; 124.4; 119.1;
117.8; 77.9; 77.5; 58.4; 45.9. Found, m/z: 314.9731
[M+Na]+. C12H9BrN2NaO2. Calculated, m/z: 314.9740.
6-Bromo-3-(hydroxyethyl)-1-(prop-2-yn-1-yl)cinnolin-
4(1H)-one (8c). Yield 0.483 g (79%), beige powder.
1H NMR spectrum (DMSO-d6), δ, ppm: 8.19 (1H, d,
J = 2.2, Н-5); 8.01 (1H, dd, J = 9.2, J = 2.3, Н-7); 7.76
(1H, d, J = 9.2, Н-8); 5.31 (2H, d, J = 2.4, CH2C≡CH);
4.62 (1H, t, J = 5.5, OH); 3.72 (2H, dd, J = 12.1, J = 6.6,
CH2CH2OH); 3.54 (1H, t, J = 2.4, ≡CH); 2.85 (2H, t,
1
brown powder. H NMR spectrum (DMSO-d6), δ, ppm:
13.39 (1H, s, NH); 8.09 (1H, d, J = 2.2, Н-5); 7.85 (1H, dd,
J = 9.0, J = 2.3, Н-7); 7.51 (1H, d, J = 9.0, Н-8); 3.71 (2H,
t, J = 6.9, CH2CH2ОН); 2.86 (2H, t, J = 6.9, CH2CH2ОН).
13C NMR spectrum (DMSO-d6), δ, ppm: 168.6; 148.9;
139.9; 136.6; 126.1; 122.3; 119.0; 116.7; 58.7; 33.8.
Found, m/z: 290.9751 [M+Na]+. C10H9BrN2NaO2.
Calculated, m/z: 290.9740.
6-Bromo-3-(hydroxymethyl)cinnolin-4(1H)-4-one (7b)
was obtained from propargylaniline 5b. The precipitate
formed during the reaction was treated with aqueous 15%
H2SO4 solution (15 ml) at 60°С for 12 h, then dissolved in
aqueous 0.3 M NaOH solution (50 ml), the obtained
suspension was filtered through a thin layer of Celite, the
filtrate was neutralized with aqueous 2 M HCl solution to
pH 7. The obtained precipitate was filtered off and washed
consistently with Н2О (2×5 ml), МеОН (5 ml), and Еt2О
1
J = 6.8, CH2CH2OH). H NMR spectrum (CDCl3), δ, ppm:
8.46 (1H, d, J = 2.3, Н-5); 7.83 (1H, dd, J = 9.1, J = 2.3,
Н-7); 7.47 (1H, d, J = 9.2, Н-5); 5.12 (2H, d, J = 2.5,
CH2C≡CH); 3.99 (2H, dd, J = 10.8, J = 5.4, CH2CH2OH);
3.07 (2H, t, J = 5.6, CH2CH2OH); 2.52 (1H, t, J = 2.5,
≡CH). 13C NMR spectrum (DMSO-d6), δ, ppm: 168.5;
148.8; 138.9; 136.5; 127.0; 123.6; 118.9; 117.5; 77.7; 77.6;
58.5; 45.8; 33.7. Found, m/z: 328.9899 [M+Na]+.
C13H11BrN2NaO2. Calculated, m/z: 328.9897.
920

Chemistry of Heterocyclic Compounds 2020, 56(7), 915–922
Preparation of triazole derivatives 9а–с in СuААC
CH2Cl2 (5 ml), filtered, and the filtrate was evaporated at
reduced pressure. The obtained residue was treated with
pentane, resulting in a precipitate. The precipitate was
separated by decantation and dried at reduced pressure. Yield
160 mg (81%), white powder representing a mixture of
[(IMes)CuI] and [(IMes)2Cu]CuI2. Spectral characteristics are
reaction (General method). A vial was charged with the
appropriate N-propargylcinnolinone 8а–с (0.2 mmol), the
appropriate [(NHC)CuX] complex (2 mol %), benzyl azide
(30 mg, 0.22 mmol), and 2 ml of the selected solvent
(CDCl3, CHCl3, THF, Me2CO). The reaction mixture was
stirred for 18 h at room temperature or with heating to 40°С.
1
reported for the major component [(IMes)CuI]. H NMR
1
In order to determine the product yield from H NMR
spectrum (CDCl3), δ, ppm: 7.05 (2H, s, H imidazole); 7.00
(4H, s, H Ar); 2.35 (6H, s, 4-CH3); 2.12 (12H, s, 2,6-CH3). 13C
NMR spectrum (CDCl3), δ, ppm: 139.5; 135.1; 134.7; 129.5;
122.3; 21.2; 17.9; the carbene carbon atom was not observed.
X-ray structural analysis of the [(IMes)2Cu]CuI2
complex was performed on a SuperNova (Oxford
Diffraction) monocrystal diffractometer with an Atlas two-
dimensional CCD detector, microfocus CuKα radiation
source (wavelength 1.54184 Å), and a Cryostream crystal
thermostat system (Oxford Cryosystems) set at 100 K. The
primary processing of experimental data was performed
with the CrysAlisPro software suite (Agilent Techno-
logies). A correction for absorption was introduced using
the SCALE3 ABSPACK algorithm, integrated in the
CrysAlisPro software suite. The crystal structures were
solved and refined with the Olex2 program49 within the
SHELX software suite.50 The crystal had a rhombic
syngony, space group Aea2, unit cell parameters: a 16.669(1),
b 16.508(1), c 15.339(1) Å. The structure was refined by
35447 reflections, including 4005 independent reflections,
to R1 0.024. The complete crystallographic dataset for
[(IMes)2Cu]CuI2 complex was deposited at the Cambridge
Crystallographic Data Center (deposit CCDC 2001172).
spectral data, an aliquot of the reaction mixture (0.65 ml) was
evaporated at reduced pressure and the residue was dissolved
in DMSO-d6. The results are presented in Table 2. In order to
determine the isolated product yield, the reaction mixture
after evaporation was purified by column chromatography,
using a 3:1 mixture of CH2Cl2–Me2CO as eluent.
Ethyl 1-[(1-benzyl-1Н-1,2,3-triazol-4-yl)methyl]-3-(hydroxy-
methyl)-4-oxo-1,4-dihydrocinnoline-6-carboxylate (9а).
1
Yield 0.069 g (75%), beige powder. H NMR spectrum
(CDCl3), δ, ppm: 8.95 (1H, d, J = 1.9, H Ar); 8.34 (1H, dd,
J = 9.1, J = 2.0, H Ar); 7.91 (1H, d, J = 9.1, H Ar); 7.47
(1H, s, H triazole); 7.42–7.32 (3H, m, H Ar); 7.29–7.17
(2H, m, H Ar); 5.68 (2H, s, CH2); 5.47 (2H, s, CH2); 4.79
(2H, d, J = 6.2, CH2); 4.41 (2H, q, J = 7.1, СO2CH2CH3);
3.38 (1H, t,
J
=
6.4, OH); 1.41 (3H, t,
J = 7.1, СO2CH2CH3). 13C NMR spectrum (CDCl3), δ, ppm:
171.1; 165.3; 149.3; 143.0; 142.4; 134.5; 134.1; 129.4
(2C); 129.2; 128.3 (3C); 127.0; 123.0; 122.8; 116.1; 62.1;
61.7; 54.6; 52.0; 14.4. Found, m/z: 420.1668 [M+H]+.
C22H22N5O4. Calculated, m/z: 420.1666.
1-[(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl]-6-bromo-
3-(hydroxymethyl)cinnolin-4(1H)-one (9b). Yield 0.051 g
(55%), beige powder. 1H NMR spectrum (DMSO-d6),
δ, ppm: 8.21 (1H, s, Н Ar); 8.19 (1H, d, J = 1.9, H Ar);
7.98–7.90 (2H, m, H Ar, Н triazole); 7.46–7.14 (5H, m,
H Ar); 5.75 (2H, s, CH2); 5.55 (2H, s, CH2); 5.07 (1H, t,
J = 5.7, OH); 4.51 (2H, d, J = 5.7, CH2OH). 13C NMR
spectrum (CDCl3), δ, ppm: 168.0; 149.2; 142.1; 139.6;
136.5; 135.9; 128.7 (2C); 128.2; 127.9 (2C); 126.7; 124.4;
123.9; 119.5; 117.6; 58.5; 52.9; 51.1. Found, m/z: 448.0385
[M+Na]+. C19H16BrN5NaO2. Calculated, m/z: 448.0380.
1-[(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl]-6-bromo-
3-(2-hydroxyethyl)cinnolin-4(1H)-one (9с). Yield 0.093 g
(94%), beige powder. 1H NMR spectrum (DMSO-d6),
δ, ppm: 8.20 (1H, s, Н Ar); 8.16 (1H, d, J = 1.9, H Ar);
7.97–7.82 (2H, m, H Ar, Н triazole); 7.45–7.20 (5H, m,
Н Ar); 5.72 (2H, s, CH2); 5.55 (2H, s, CH2); 4.62 (1H, t,
J = 5.7, OH); 3.73 (2H, dd, J = 12.7, J = 6.7, CH2CH2OH);
2.87 (2H, t, J = 6.9, CH2CH2OH). 13C NMR spectrum
(DMSO-d6), δ, ppm: 168.3; 148.6; 142.1; 139.4; 136.3;
135.9; 128.7 (2C); 128.1; 127.9 (2C); 126.8; 123.9; 123.6; 119.2;
117.2; 58.6; 52.8; 50.8; 33.7. Found, m/z: 462.0541
[M+Na]+. C20H18BrN5NaO2. Calculated, m/z: 462.0537.
Preparation of the heteroleptic complex [(IMes)CuI].
A solution of NaI (60 mg, 0.4 mmol) in Me2CO (4 ml)
was vigorously stirred while adding a suspension of
[(IMes)CuCl] complex (80 mg, 0.2 mmol) in Me2CO (2 ml).
The mixture was stirred at room temperature under argon
atmosphere for 1 h (Me2CO was degassed prior to use).
Then Me2CO was removed by evaporation at reduced
pressure, the residue was treated by adding anhydrous
1
Supplementary information file containing Н and 13С
NMR spectra of compounds 2, 5b,c, 7a,b, 8a–c, 9a–c,
[(IMes)CuI]], as well as IR spectrum of compound 8b, is
available at the journal website at http://link.springer.com/
journal/10593.
This work received financial support from the Russian
Science Foundation (grant 19-73-00228).
The characterization of compounds was performed by
using the instruments at the ''Magnetic Resonance Research
Center'', ''Chemical Analysis and Materials Research Center'',
and ''Research Center for X-ray Diffraction Studies''
Resource centers of the Saint Petersburg State University.
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