One-pot 'on-solvent' multicomponent protocol for the synthesis of medicinally relevant 4H-pyrano[3,2-c]quinoline scaffold

Article abstract of DOI:10.1002/hlca.201500026

'One-pot' AcONa-catalyzed transformation of salicylaldehydes, malononitrile and 4-hydroxy-1-methylquinolin-2(1H)-one in the presence of a minimal quantity of EtOH results in fast (3 min) and efficient formation of unknown 2-amino-4-(2-hydroxyaryl)-6-methyl-5-oxo-5,6-dihydro-4H-pyrano[3,2-c]quinoline-3-carbonitriles in 85-98% yields, which are potential pharmaceutical agents for treating disorders responsive to the induction of apoptosis, antiproliferation, or vascular disruption. This efficient 'on-solvent' approach to the 4H-pyrano[3,2-c]quinoline scaffold represents a novel synthetic concept for multicomponent reaction (MCR) strategy and allows to combine the synthetic virtues of conventional MCR with ecological benefits and convenience of facile 'on-solvent' procedure.

Full text of DOI:10.1002/hlca.201500026

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One-Pot ꢀOn-solventꢁ Multicomponent Protocol for the Synthesis of
Medicinally Relevant 4H-Pyrano[3,2-c]quinoline Scaffold
by Anatoly N. Vereshchagina), Michail N. Elinson*a), Ruslan F. Nasybullina), Fedor V. Ryzhkova),
Sergey I. Bobrovskya), Ivan S. Bushmarinovb), and Mikhail P. Egorova)
a) N. D. Zelinsky Institute of Organic Chemistry, Leninsky prospect 47, RU-119991 Moscow
(phone: þ 7-499-137-38-42; fax: þ 7-499-135-53-28; e-mail: elinson@ioc.ac.ru)
b) A. N. Nesmeyanov Institute of Organoelement Compounds, Vavilova Str. 28, RU-119991 Moscow
ꢀOne-potꢁ AcONa-catalyzed transformation of salicylaldehydes, malononitrile and 4-hydroxy-1-
methylquinolin-2(1H)-one in the presence of a minimal quantity of EtOH results in fast (3 min) and
efficient formation of unknown 2-amino-4-(2-hydroxyaryl)-6-methyl-5-oxo-5,6-dihydro-4H-pyrano[3,2-
c]quinoline-3-carbonitriles in 85 – 98% yields, which are potential pharmaceutical agents for treating
disorders responsive to the induction of apoptosis, antiproliferation, or vascular disruption. This efficient
ꢀon-solventꢁ approach to the 4H-pyrano[3,2-c]quinoline scaffold represents a novel synthetic concept for
multicomponent reaction (MCR) strategy and allows to combine the synthetic virtues of conventional
MCR with ecological benefits and convenience of facile ꢀon-solventꢁ procedure.
Introduction. – The discovery of novel synthetic methodologies to facilitate the
preparation of compound libraries is a pivotal focal point of research activity in the
field of modern medicinal and combinatorial chemistry [1]. One approach to address
this challenge involves the development of multicomponent reactions (MCR), in which
three or more reactants are combined in a single reaction flask (one-pot process) to
generate a product incorporating most of the atoms contained in the starting materials
[2]. The multicomponent reaction (MCR) strategy has sufficient advantages over
conventional linear-type synthesis due to its flexible, convergent, and atom efficient
nature [2]. The rapid assembly of molecular diversity utilizing MCRs has received a
great deal of attention in the search for novel lead structures, especially for the design
and construction of elaborate small-molecule heterocyclic frameworks possessing
enhanced ꢀdrug-likeꢁ properties [3]. These reactions can be performed under mild
conditions, provide good yields, have superior atom economies, entail low costs, have
wide scopes, and provide high bond-forming efficiencies [4]. In addition, some of such
reactions are popular, because they can be carried out in environmentally benign
solvents, such as H2O [5].
Recently the term ꢀon-waterꢁ reactions was specially introduced [6]. ꢀOn-waterꢁ
reactions are a group of organic reactions that take place as an emulsion in H2O and
that exhibit an unusual reaction rate acceleration compared to the same reaction in an
organic solvent or compared to the corresponding solvent-free reaction. This effect has
been known for many years, but in 2005, researchers in the group of Sharpless
presented a systematic study of this phenomenon [6a].
ꢂ 2015 Verlag Helvetica Chimica Acta AG, Zürich

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Scheme 1. Multicomponent Solvent-Free or ꢀOn-waterꢁ Transformations of Salicylaldehydes 1, Malono-
nitrile, and Nucleophiles into 2-Amino-3-cyano-4H-chromene Scaffold 2
In our previous articles, we have accomplished several one-pot multicomponent
solvent-free or ꢀon-waterꢁ processes between salicylaldehydes 1, malononitrile, and
nucleophiles resulting in 2-amino-4H-chromene scaffold 2 formation according to
Scheme 1 [7].
The effect of H2O or alcohol additivities on the yield of 2-amino-4H-chromene was
studied for the multicomponent transformation of salicylaldehyde, malononitrile, and
alkylcyanoacetate into alkyl (2-amino-3-cyano-4H-chromene-4-yl)cyanoacetates 2b
[7b]. The best yields of 2b were achieved, when the reaction was carried out as
emulsion in a MeOH/H2O mixture in the presence of AcONa at ambient temperature.
It was the first example of an ꢀon-solventꢁ process in our studies.
Among different types of chromene systems, 2-amino-4H-chromenes are of
particular utility, since they belong to privileged medicinal scaffolds, and are used for
the treatment of viral hepatitis [8a], Alzheimerꢁs disease [8b], cardiovascular disorders,
epilepsy, inflammatory bowel syndrome [8c], hypertension, and atherosclerosis [8d].
Increasing interest to 2-amino-4H-chromene derivatives bearing a nitrile group is
connected with their application in the treatment of human inflammatory diseases such
as carcinoma [9a], arthritis [9b], leukemia [9c], and in cancer therapy [10].
Results and Discussion. – In the present study, we report our results on the
multicomponent ꢀon-solventꢁ transformation of salicylaldehydes 1, malononitrile, and
4-hydroxy-1-methylquinolin-2(1H)-one as nucleophile.
Surprisingly, the solvent-free AcONa catalyzed reaction of salicylaldehyde 1a,
malononitrile, and 4-hydroxy-1-methylquinolin-2(1H)-one at ambient conditions in
mortar with grinding resulted in formation of 2-amino-5,6-dihydro-4-(2-hydroxyphen-
yl)-6-methyl-5-oxo-4H-pyrano[3,2-c]quinoline-3-carbonitrile 3a in 19% yield instead
of the expected chromene compound 2f (Scheme 2; Table 1, Entry 1).
In this case, a new type of the multicomponent process (nonchromene-type) was
realized, where the salicylaldehyde reacts as an aromatic aldehyde, and is not involved
in the formation of a chromene system. Recently, we have accomplished a one-pot
electrocatalytic multicomponent approach to functionalized pyrano[3,2-c]quinoline

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Scheme 2. Multicomponent Transformation of Salicylaldehyde 1a, Malononitrile, and 4-Hydroxy-1-
methylquinolin-2(1H)-one on Solvent-Free and Electrocatalytical Conditions
Table 1. Multicomponent Transformation of Salicylaldehyde 1a, Malononitrile, and 4-Hydroxy-1-
methylquinolin-2(1H)-onea)
Entry
Base [mol-%]
Additive [ml]
Conditions
Time [min]
Yield of 3a [%]
1
2
3
4
5
6
7
8
9
AcONa, 10
AcONa, 10
KF, 10
AcONa, 10
AcONa, 10
AcONa, 10
AcONa, 10
AcONa, 10
AcONa, 10
–
grinding, r.t.
grinding, r.t.
grinding, r.t.
grinding, r.t.
stirring, 788
stirring, 788
stirring, 788
stirring, 648
stirring, 808
10
10
10
10
10
3
3
10
10
19b)
35b)
29b)
45b)
93c)
95c)
63c)
87c)
79c)
H2O, 2
H2O, 2
EtOH, 2
EtOH, 2
EtOH, 2
EtOH þ H2O, 1 þ 1
MeOH, 2
PrOH, 2
a) Emulsion of salicylaldehyde (1a, 5 mmol, 0.61 g), malononitrile (5 mmol, 0.33 g), 4-hydroxy-1-
b
methylquinolin-2(1H)-one (5 mmol, 0.875 g), and AcONa (0.5 mmol, 40 mg). ) NMR data (tBuOH as
standard). c) Yield of isolated product.
scaffold from benzaldehydes, malononitrile, and 4-hydroxy-1-methylquinolin-2(1H)-
one [11]. But when we used this electrocatalytic procedure (Scheme 2), pyrano[3,2-
c]quinoline 3a was obtained in only 42% yield (NMR data), together with a side
product 2a in 25% (NMR data).

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The 4H-pyrano[3,2-c]quinoline scaffold is of particular interest due to the fact that
this scaffold was found in many natural alkaloids [12] with anti-inflammatory [13] and
cancer cell growth-inhibitory activity [14]. Recently, the 4H-pyrano[3,2-c]quinoline
scaffold was found to display low nanomolar antiproliferative activity to induce
apoptosis in human cancer cell lines and to be microtubule-targeting agent [15], and a
new method for the synthesis of 4H-pyrano[3,2-c]pyridine scaffold from benzalde-
hydes (but not from salicylaldehydes), malononitrile, and 4-hydroxy-1-methylquinolin-
2(1H)-one in the presence of nanozeolite clinoptilolite in H2O under reflux was
suggested [16].
On the next stage, to optimize the general procedure, ꢀon-waterꢁ and ꢀon-solventꢁ
conditions, AcONa-initiated multicomponent transformation of salicylaldehyde 1a,
malononitrile, and 4-hydroxy-1-methylquinolin-2(1H)-one into 4H-pyrano[3,2-c]qui-
noline 3a was studied (Table 1, Scheme 3).
ꢀOn-waterꢁ reaction of salicylaldehyde 1a, malononitrile, and 4-hydroxy-1-methyl-
quinolin-2(1H)-one in the presence of AcONa or KF affords 3a in 35% and 29%,
respectively (Table 1, Entries 2 and 3). ꢀOn-ethanolꢁ (Entry 4) the yield increased up to
45%. Increasing the temperature up to 788 (Entry 5) further increases the yield up to
93%. The best yield (95%) of 3a was achieved when the reaction was carried out as
emulsion in EtOH in the presence of AcONa as catalyst at 788 for 3 min (Entry 6),
which is comparable with the timing of the processes under microwave irradiation.
Under the optimum conditions thus found (10 mol-% of AcONa, 788, reaction time
3 min, small additives of EtOH (2 ml, 1.6 g, total weight of organic compounds is more
than 1.8 g), needed to emulsify the mixture, 2-amino-5,6-dihydro-4-(2-hydroxyphenyl)-
6-methyl-5-oxo-4H-pyrano[3,2-c]quinoline-3-carbonitriles 3a – 3g were obtained in
excellent 88 – 98% yields (Table 2).
Thus, to confirm the structure 3 for our compounds, X-ray powder diffraction
(XRD) has been accomplished for compounds 3c and 3e. Results are presented in
Fig. 1 and in the Exper. Part.
Scheme 3. Multicomponent Transformation of Salicylaldehydes 1a – 1g, Malononitrile, and 4-Hydroxy-1-
methylquinolin-2(1H)-one into Pyrano[3,2-c]quinolines 3a – 3g

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Table 2. Multicomponent Transformation of Salicylaldehydes 1a – 1g, Malononitrile and 4-Hydroxy-1-
methylquinolin-2(1H)-one ꢀOn-ethanolꢁ into Pyrano[3,2-c]quinolines 3a – 3ga)
Entry
Salicylaldehyde
R1
R2
Product
Yield [%]b)
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
1g
H
H
Me
Br
NO2
Cl
H
MeO
H
H
H
3a
3b
3c
3d
3e
3f
3g
95
95
88
88
98
95
92
Cl
MeO
Br
a) Emulsion of salicylaldehyde (1, 5 mmol), malononitrile (5 mmol, 0.33 g), 4-hydroxy-1-methyl-
quinolin-2(1H)-one (5 mmol, 0.875 g), and AcONa (0.5 mmol, 40 mg) in 2 ml of EtOH was vigorously
stirring in 5 ml flask for 3 min. b) Yield of isolated product.
Figure. Molecular structures of 3c and 3e in crystal. Atoms are represented by spheres indicating their
isotropic thermal displacements (rj50%).
The mechanism of the multicomponent assembling of benzaldehydes, malononi-
trile, and 4-hydroxy-1-methylquinolin-2(1H)-one into pyrano[3,2-c]quinolines 3 is
known [11]. The initiation step of the catalytic cycle begins with the deprotonation of
malononitrile by the action of AcONa, which leads to the anion of malononitrile
(Scheme 4). Then, Knoevenagel condensation of salicylaldehyde 1 with the malononi-
trile anion takes place in the solution, with the elimination of OHÀ and formation of the
corresponding (2-hydroxybenzylidene)malononitrile 4 [16]. The subsequent OHÀ
promoted Michael addition of 4-hydroxy-1-methylquinolin-2(1H)-one to the Knoeve-
nagel adduct 4 leads to the anion A, as a key intermediate. Its tautomerization to the
anion B followed by intramolecular cyclization leads to the corresponding 4H-
pyrano[3,2-c]quinoline 3 with regeneration of the anion of malononitrile at the last
step, which continues the catalytic chain process by the interaction with the next
molecule of salicylaldehyde 1.

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Scheme 4. Mechanism of Transformation of Salicylaldehydes 1, Malononitrile, and 4-Hydroxy-1-
methylquinolin-2(1H)-one into Substituted Pyrano[3,2-c]quinolines 3
However, if the anion A is transformed into anion C, then the reaction would
proceed via the ꢀchromene type pathwayꢁ (Scheme 5).
The pathway of the reaction strongly depends on the conditions of the process.
There are processes known, where, depending on the conditions, is formed either
chromene or the nonchromene product. Some examples of such reactions are given in
Table 3.
As it shown from Table 3, the catalyst is crucial for the reaction pathway. So, InCl3
promotes the formation of an anion like C, followed by intramolecular cyclization leads
to chromene-type structure 2. Other catalysts realize the nonchromene-type process via
formation of anion like B leading to structure 3.
Conclusions. – In conclusion, the simple technique can produce, under ꢀon-solventꢁ
conditions, a very fast (3 min) and selective multicomponent transformation of
salicylaldehydes, malononitrile, and 4-hydroxy-1-methylquinolin-2(1H)-one into sub-
stituted 4H-pyrano[3,2-c]quinolines – the promising compounds for different biomed-
ical applications, in 88 – 98% yields. This process is realized via the ꢀnonchromene-typeꢁ

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Scheme 5. Chromene- and Nonchromene-Type Pathways
pathway. The developed multicomponent procedure requires simple and reasonable
starting materials. It is easily carried out, and the reaction products are crystallized
from the mixture. Earlier, the multicomponent transformation salicylaldehydes,
malononitrile, and 4-hydroxy-1-methylquinolin-2(1H)-one into substituted pyrano
[3,2-c]pyridones [16] was known.
Experimental Part
General. All starting materials were obtained from commercial sources and used without further
purification. M.p.: Gallenkamp melting point apparatus; uncorrected. IR Spectra: Bruker ALPHA-T FT-
1
IR spectrometer, in KBr pellets. H- and 13C-NMR spectra: Bruker AM-300 (300 and 75 MHz, resp.)
instrument, at ambient temp. in (D6)DMSO solns.; chemical shifts are given in d relative to Me4Si. HR-

Helvetica Chimica Acta – Vol. 98 (2015)
1111

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ESI-MS: Bruker micrOTOF II instrument; external or internal calibration was done with an Electrospray
Calibrant Solution (Fluka).
The powder patterns of 3c and 3e were measured on Bruker D8 Advance Vario diffractometer with
LynxEye detector and Ge(111) monochromator, l(CuKa1) ¼ 1.54060 Š, q/2q scan from 5.48 to 908 for 3c
and from 68 to 908 for 3e, stepsize 0.0091698. The measurement was performed in the transmission mode;
the compounds were deposited between two Mylar films. The indexing was performed using TOPAS 4.2
software [22]. The model for the solution and refinement was prepared basing on a PBE/L2 [23]
calculation of 3c and 3e using PRIRODA software [24]. The structure was solved with the FOX program
[25] using the Parallel Tempering method and refined with TOPAS 4.2. Rietveld refinement and structure
verification were performed using breakable restraints, a modification of ꢀMorseꢁ restraint model [26].
General Procedure. A suspension of salicylaldehyde 1 (5 mmol), malononitrile (5 mmol, 0.33 g), 4-
hydroxy-1-methylquinolin-2(1H)-one (5 mmol, 0.875 g), and AcONa (0.5 mmol, 0.04 g) in EtOH (2 ml)
was heated in a 5 ml flask at 788 for 3 min. After the reaction was finished, the solid was filtered, washed
with cold EtOH (2 ml) and dried to isolate pure product 3.
2-Amino-5,6-dihydro-4-(2-hydroxyphenyl)-6-methyl-5-oxo-4H-pyrano[3,2-c]quinoline-3-carboni-
trile (3a). Yield 1.64 g (95%). Yellowish solid. M.p. 227 – 2288. IR (KBr): 3453, 3295, 3182, 2195, 1675,
1610, 1581, 1384, 1265, 1155. 1H-NMR: 3.54 (s, Me); 4.73 (s, CH); 6.67 – 6.72 (m, 2 arom. H); 6.97 – 7.03
(m, 2 arom. H); 7.10 (s, NH2); 7.36 – 7.41 (m, 1 arom. H); 7.56 (d, J ¼ 8.5, 1 arom. H); 7.67 – 7.72 (m, 1
arom. H); 8.02 (d, J ¼ 7.9, 1 arom. H); 9.42 (s, OH). 13C-NMR: 29.3; 32.8; 56.8; 108.5; 112.9; 114.9; 115.9;
118.9; 120.1; 122.0; 122.1; 127.7; 129.5; 129.9; 131.4; 138.4; 150.6; 155.1; 159.4; 160.2. MS: 345 (86, Mþ),
301 (51), 262 (44), 252 (81), 175 (69), 170 (84), 143 (100), 115 (47), 104 (47), 77 (61). HR-ESI-MS:
368.1001 ([M þ Na]þ, C20H15N3NaOþ3 ; calc. 368.1006).
2-Amino-5,6-dihydro-4-(2-hydroxy-3-methoxyphenyl)-6-methyl-5-oxo-4H-pyrano[3,2-c]quinoline-
3-carbonitrile (3b). Yield 1.71 g (95%). Yellowish solid. M.p: 247 – 2488. IR (KBr): 3354, 3202, 2197, 1677,
1579, 1461, 1388, 1250, 1156, 1072. 1H-NMR: 3.55 (s, Me); 3.75 (s, MeO); 4.81 (s, CH); 6.58 – 6.69 (m, 2
arom. H); 6.79 (d, J ¼ 7.6, 1 arom. H); 7.09 (s, NH2); 7.40 – 7.43 (m, 1 arom. H); 7.58 (d, J ¼ 8.4, 1 arom. H);
7.68 – 7.73 (m, 1 arom. H); 8.04 (d, J ¼ 7.9, 1 arom. H); 8.65 (s, OH). 13C-NMR: 29.3; 32.3; 55.6; 56.9;
108.6; 110.1; 112.9; 114.9; 118.5; 120.0; 121.2; 122.1 (2C); 130.3; 131.4; 138.4; 144.2; 147.7; 150.6; 159.3;
160.2. MS: 375 (40, Mþ), 331 (19), 292 (43), 252 (73), 200 (100), 175 (85), 146 (45), 132 (34), 104 (41), 77
(43). HR-ESI-MS: 398.1105 ([M þ Na]þ, C21H17N3NaO4þ ; calc. 398.1111).
2-Amino-5,6-dihydro-4-(2-hydroxy-5-methylphenyl)-6-methyl-5-oxo-4H-pyrano[3,2-c]quinoline-3-
carbonitrile (3c). Yield 1.58 g (88%). White solid. M.p.: 236 – 2378. IR (KBr): 3323, 3187, 2200, 1677,
1
1619, 1583, 1493, 1416, 1386, 1154. H-NMR: 2.13 (s, Me); 3.55 (s, Me); 4.70 (s, CH); 6.60 (d, J ¼ 7.7, 1
arom. H); 6.79 – 6.82 (m, 2 arom. H); 7.09 (s, NH2); 7.36 – 7.41 (m, 1 arom. H); 7.56 (d, J ¼ 8.5, 1 arom. H);
7.67 – 7.72 (m, 1 arom. H); 8.03 (d, J ¼ 7.8, 1 arom. H); 9.17 (s, OH). 13C-NMR: 20.2; 29.3; 32.3; 56.9;
108.5; 112.9; 114.9; 115.9; 120.1; 122.1; 122.2; 127.2; 128.2; 129.6; 129.8; 131.4; 138.4; 150.6; 152.9; 159.4;
160.3. MS: 359 (85, Mþ), 344 (25), 327 (18), 315 (44), 276 (66), 252 (100), 184 (73), 157 (39), 104 (35), 77
(58). HR-ESI-MS: 382.1158 ([M þ Na]þ, C21H17N3NaO3þ calc. 382.1162).
Crystal data for 3c. C21H17N3O3 (M ¼ 359.38): triclinic, space group P-1 (no. 2), a ¼ 7.54595(10) Š,
b ¼ 9.56242(17) Š, c ¼ 13.8764(4) Š, a ¼ 93.0131(16)8, b ¼ 91.5017(19)8, g ¼ 116.9651(11)8, V¼
889.79(3) Š3, Z ¼ 2, T¼ 298 K, m(CuKa1) ¼ 0.748 mmÀ1, Dcalc ¼ 1.341 g/mm3, the refinement converged
to RP/RP’/RWP/RWP’/RBragg values of 2.920/9.013/4.175/9.342/0.965 with Rexp/Rexp’ values of 0.872/1.951, c2 ¼
4.789.
Crystallographic data reported for 3c have been deposited with Cambridge Crystallographic Data
Centre as supplementary publication. Copies of the data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html with the reference number CCDC-1028971.
2-Amino-4-(5-bromo-2-hydroxyphenyl)-5,6-dihydro-6-methyl-5-oxo-4H-pyrano[3,2-c]quinoline-3-
carbonitrile (3d). Yield 1.87 g (88%). White solid. M.p.: 240 – 2418. IR (KBr): 3322, 3188, 2207, 1674,
1616, 1582, 1474, 1415, 1385, 1155. 1H-NMR: 3.54 (s, Me); 4.68 (s, CH); 6.67 (d, J ¼ 8.4, 1 arom. H); 7.12 –
7.18 (m, 2 arom. H þ NH2); 7.36 – 7.41 (m, 1 arom. H); 7.56 (d, J ¼ 8.4, 1 arom. H); 7.67 – 7.72 (m, 1 arom.
H); 8.01 (d, J ¼ 7.8, 1 arom. H); 9.74 (s, OH). 13C-NMR: 29.2; 33.3; 56.0; 107.5; 109.8; 112.7; 114.9; 118.0;
119.9; 122.1 (2C); 130.3; 131.5; 131.9; 132.3; 138.5; 150.7; 154.7; 159.5; 160.0. MS: 425 (47, Mþ), 423 (53,

Helvetica Chimica Acta – Vol. 98 (2015)
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Mþ), 379 (17), 344 (39), 327 (20), 252 (100), 221 (30), 175 (58), 114 (37), 77 (40). HR-ESI-MS: 448.0078
([M þ Na]þ, C20H14BrN3NaOþ3 ; calc. 448.0091).
2-Amino-5,6-dihydro-4-(2-hydroxy-5-nitrophenyl)-6-methyl-5-oxo-4H-pyrano[3,2-c]quinoline-3-
carbonitrile (3e). Yield 1.92 g (98%). Yellowish solid. M.p.: 212 – 2148. IR (KBr): 3475, 3334, 2192, 1677,
1569, 1382, 1336, 1291, 1263, 1160. 1H-NMR: 3.54 (s, Me); 4.84 (s, CH); 6.89 (d, J ¼ 8.8, 1 arom. H); 7.24
(s, NH2); 7.39 – 7.44 (m, 1 arom. H); 7.59 (d, J ¼ 8.0, 1 arom. H); 7.70 – 7.75 (m, 1 arom. H); 7.93 – 8.05 (m, 3
arom. H); 11.20 (br. s, OH). 13C-NMR: 29.2; 33.4; 55.5; 107.1; 112.6; 115.0; 116.1; 119.8; 122.1; 122.2;
124.4; 125.5; 130.7; 131.6; 138.6; 139.3; 150.9; 159.5; 159.9; 162.0. MS: 390 (4, Mþ), 373 (16), 307 (5), 252
(14), 215 (99), 175 (100), 146 (71), 132 (50), 114 (74), 77 (46). HR-ESI-MS: 413.0848 ([M þ Na]þ,
C20H14N4NaOþ5 ; calc. 413.0856).
Crystal data for 3e. C20H14N4O5 (M ¼ 390.35): triclinic, space group P-1 (no. 2), a ¼ 12.0576(2) Š,
b ¼ 11.6734(3) Š, c ¼ 13.7110(3) Š, a ¼ 100.9920(15)8, b ¼ 96.3944(13)8, g ¼ 104.6145(14)8, V ¼
1807.15(7) Š3, Z ¼ 4 (Z’ ¼ 2), T¼ 298 K, m(CuKa1) ¼ 0.890 mmÀ1, Dcalc ¼ 1.435 g/mm3, the refinement
converged to RP/RP’/RWP/RWP’/RBragg values of 2.092/11.414/3.017/11.634/1.420 with Rexp/Rexp’ values of
0.520/2.004, c2 ¼ 5.804.
Crystallographic data reported for 3e have been deposited with Cambridge Crystallographic Data
Centre as supplementary publication. Copies of the data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html with the reference number CCDC-1028972.
2-Amino-4-(3,5-dichloro-2-hydroxyphenyl)-5,6-dihydro-6-methyl-5-oxo-4H-pyrano[3,2-c]quino-
line-3-carbonitrile (3f). Yield 1.97 g (95%). White solid. M.p.: 254 – 2568. IR (KBr): 3355, 3203, 2212,
1679, 1578, 1459, 1386, 1320, 1232, 1153. 1H-NMR: 3.57 (s, Me); 4.85 (s, CH); 7.05 (s, 1 arom. H); 7.33 (s,
NH2); 7.35 – 7.44 (m, 2 arom. H); 7.60 (d, J ¼ 8.4, 1 arom. H); 7.69 – 7.75 (m, 1 arom. H); 8.03 (d, J ¼ 7.8, 1
arom. H); 9.95 (br. s, OH). 13C-NMR: 29.5; 33.3; 55.7; 107.4; 112.8; 115.1; 119.6; 122.2; 122.3; 122.4;
123.1; 127.5; 128.0; 131.8; 134.5; 138.4; 150.0; 150.9; 159.5; 160.4. MS: 415 (19, Mþ), 413 (30, Mþ), 378
(13), 330 (16), 252 (100), 238 (54), 211 (46), 175 (61), 146 (27), 104 (21). HR-ESI-MS: 436.0211 ([M þ
Na]þ, C20H13Cl2N3NaOþ3 ; calc. 436.0226).
2-Amino-4-(5-bromo-2-hydroxy-3-methoxyphenyl)-5,6-dihydro-6-methyl-5-oxo-4H-pyrano[3,2-
c]quinoline-3-carbonitrile (3g). Yield 2.09 g (92%). White solid. M.p.: 263 – 2648. IR (KBr): 3328, 3197,
2203, 1676, 1617, 1586, 1384, 1306, 1248, 1155. 1H-NMR: 3.54 (s, Me); 3.75 (s, MeO); 4.75 (s, CH); 6.72 (s,
1 arom. H); 6.95 (s, 1 arom. H); 7.16 (s, NH2); 7.36 – 7.41 (m, 1 arom. H); 7.57 (d, J ¼ 8.4, 1 arom. H); 7.68 –
7.73 (m, 1 arom. H); 8.02 (d, J ¼ 7.9, 1 arom. H); 8.95 (s, OH). 13C-NMR: 29.3; 32.8; 56.1; 107.8; 109.5;
112.8; 113.2; 115.0; 119.9; 121.2; 122.2 (2C); 123.6; 131.5; 132.0; 138.5; 143.9; 148.8; 150.7; 159.3; 160.1.
MS: 455 (13, Mþ), 453 (12, Mþ), 372 (16), 278 (91), 252 (97), 175 (100), 146 (45), 132 (34), 104 (33), 77
(28). HR-ESI-MS: 478.0188 ([M þ Na]þ, C21H16BrN3NaO4þ ; calc. 478.0197).
The authors gratefully acknowledge the financial support of the Presidential Scholarship Program
for the State Support of young Russian scientists – PhD (project No. MK-899.2014.3). A. S. G. and I. S. B.
thank the Russian Science Foundation (grant number RSCF 14-13-00884) for financial support of their
work.
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Received January 30, 2015