Fast Efficient and General PASE Approach to Medicinally Relevant 4H,5H-Pyrano-[4,3-b]pyran-5-one and 4,6-Dihydro-5H-pyrano-[3,2-c]pyridine-5-one Scaffolds

Article abstract of DOI:10.1002/hlca.201600150

The general ‘on-solvent’ PASE approach was found to be medicinally relevant for 4H,5H-pyrano[4,3-b]pyran-5-one and 4,6-dihydro-5H-pyrano[3,2-c]pyridine-5-one scaffolds. Ammonium acetate-catalyzed multicomponent reaction of aldehydes and two different C–H

Full text of DOI:10.1002/hlca.201600150

724
Helv. Chim. Acta 2016, 99, 724 – 731
FULL PAPER
Fast Efficient and General PASE Approach to Medicinally Relevant 4H,5H-Pyrano-
4,3-b]pyran-5-one and 4,6-Dihydro-5H-pyrano-[3,2-c]pyridine-5-one Scaffolds
[
by Michail N. Elinson*, Fedor V. Ryzhkov, Ruslan F. Nasybullin, Anatoly N. Vereshchagin, and Mikhail P. Egorov
N. D. Zelinsky Institute of Organic Chemistry, Leninsky Prospect 47, 119991 Moscow, Russia (phone: +7-499-137-3842;
e-mail: elinson@ioc.ac.ru)
The general ‘on-solvent’ PASE approach was found to be medicinally relevant for 4H,5H-pyrano[4,3-b]pyran-5-one and
,6-dihydro-5H-pyrano[3,2-c]pyridine-5-one scaffolds. Ammonium acetate-catalyzed multicomponent reaction of aldehydes
4
and two different C–H acids in the presence of small amounts of EtOH results in fast (3 – 15 min) and efficient formation of
scaffolds, promising for many diverse oriented medical applications.
Keywords: Multicomponent reactions, Malononitrile, 4-Hydroxy-6-methyl-2H-pyran-2-one, 4-Hydroxy-1-methylquinolin-2(1H)-
one, Coumarin.
discovery design. Hence, the synthesis of new types of
medicinally privileged scaffolds is an important step in
Introduction
The development of ecofriendly green approaches for the drug discovery process.
chemical synthesis and the elimination of volatile organic
solvents in the synthesis of organic compounds is one of
the most demanding goal in organic chemistry. Solvent-
free method has more advantages, such as high efficiency,
selectivity, and operational simplicity, than the classic
method of synthesis on solvent method [1][2]. But ‘sol-
vent-assisted’ or so-called ‘on-solvent’ method [3][4] when
compared with solvent-less mechanochemical process has
much more application due to its advantages like more
flexibility, high rate, selectivity, and reduced reaction time
Fused pyran scaffold produces an immense variety of
pharmacological and biological properties; thence well-
known pyran derivatives attract attention as an important
class of heterocycles (Fig. 1).
Many of fused pyrans are nonpeptide human immun-
odeficiency virus (HIV) protease inhibitors [11] or com-
pounds which exhibit antiviral, antileishmanial [12],
stimulant [13], and anticonvulsant [14] properties. Among
natural compounds, pyranes occur as supellapyrone, the
female sex pheromone of the brownbanded cockroach
[15]. UCPH 101 and UCPH-102F are selective EAAT1
inhibitors [16] (Fig. 1).
[5].
However, not only the solvent reducing, but also
reducing the number of stages makes process far less
harmful [6]. Often it is connected with multicomponent antianaphylactic [18], spasmolytics, antitumoral [19], and
Pyran annulated scaffolds are used as anticancer [17],
processes [7], when at least three different substrates
assemble a new compound.
anti-HIV agents [20]. Moreover, warfarin is well-known
anticoagulant [21], which affects the interconversion of
vitamin K (Fig. 1).
Pyridone structural motif is a part of many natural
and synthetic molecules, which exhibit diverse biological
The more bonds were constructed, the more simplified
is the whole process by reducing intermediate steps, sav-
ing time, and improving many other practical aspects. In
this way multicomponent processes overlap with PASE
strategy [8], which claims pot and step economy, and also
introduces atom economy, that means the number of
atoms of all reagents which should constitute the final
compound [9].
activities. Diazaquinomycin
A shows antitumor and
antibiotic properties [22], and it is known as nonnucle-
oside HIV reverse transcriptase inhibitor L-697,661 [23].
Phosphodiesterase inhibitor milrinone [24] is used in the
treatment of heart failure (Fig. 2). Fusaricide is active as
an anticancer agent [25].
The design of functional organic and hybrid molecular
systems has shown outstanding recent growth and is a
high priority in the development of new technologies and
Catalytic methods have been reported for the synthe-
sis of 4H,5H-pyrano[4,3-b]pyran-5-one derivatives. These
novel functional materials [10]. In this connection, the procedures, in which aldehydes were condensed with
concept of ‘privileged medicinal structures or scaffolds’
has emerged as one of the guiding principles of drug
CH (CN)
and 4-hydroxy-6-methylpyran-2-one using
ultrasound irradiation [26][27] or in the presence of
2
2
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Helv. Chim. Acta 2016, 99, 724 – 731
725
Fig. 1. Biologically active pyranes.
Fig. 2. Biologically active pyridones.
various catalysts, such as piperidine [28], KF/Al O [29], 4a increased to 57% (Table 1, Entry 3). AcONH4 was
2
3
MgO [30], DBU [31], DCDBTSD [32], or ionic liquids
33], suffer from long reaction times, high temperature,
found as an optimal catalyst (AcONH , 10 mol-%), which
4
[
produced 4H,5H-pyrano[4,3-b]pyran 4a in 64% yield
(Table 1, Entry 4). Increasing the reaction time led to the
increase in the yield of 4a to 79% (Table 1, Entry 5).
expensive catalysts or complicated preparation of cata-
lysts, and insufficient yields. Moreover, some of these
methods used successive two-step procedure.
Earlier we have found that small additives of H O or
2
Only few methods have been reported for the synthe-
sis of pyridone annulated structures. These methods uti-
lize nanozeolite clinoptilolite in H O [34], Me N [35], [3] or ‘on-solvent’ [4] reactions). Both kinetic and thermo-
alcohols could improve multicomponent processes, which
were initiated by grinding [39 – 41] (so-called ‘on-water’
2
3
piperidine [36], or DMF [37] in EtOH, but suffer from
complicated tedious preparation of catalyst, or long reac-
tion time and insufficient yields.
dynamic outcomes have established that the H-bonding
ability of the surface H O molecules plays a critical role
2
in the ‘on-water’ organic reaction mechanism [42].
The next ‘on-water’ reaction in a mortar was carried
merits, but ecofriendly general PASE-multicomponent out with addition of 2 ml of H O with 10 mol-%
Although all the above-mentioned methods have its
2
method for synthesis of medicinally relevant 4H,5H-pyr- AcONH4 as a catalyst (Table 1, Entry 6). However, in
ano[4,3-b]pyran-5-ones and 4,6-dihydro-5H-pyrano[3,2-c]- this case, 4a was obtained in 65% yield, and in 81% yield
pyridine-5-ones has yet to be developed.
with addition of EtOH (2 ml, Table 1, Entry 7).
The thermal activation, which ensured success earlier
[
39][43], led to 4H,5H-pyrano[4,3-b]pyran 4a in 87% yield
Results and Discussion
in only 3 min (Table 1, Entry 8). In this case, the mortar
was replaced by a flask, and the reaction was carried out
at 78 °C using a magnetic stirring bar.
In this investigation, we were prompted to design eco-
friendly PASE approach for the synthesis of relevant
4H,5H-pyrano[4,3-b]pyran-5-ones and 4,6-dihydro-5H-pyr-
ano[3,2-c]pyridine-5-ones. Based on the success in sol-
vent-free noncatalytic process [38], this investigation was
started with solvent-free multicomponent transformation
without any catalyst by grinding PhCHO (1a), CH (CN)
Scheme 1. Multicomponent transformation of PhCHO (1a), CH
2a), and 4-hydroxy-6-methyl-2H-pyran-2-one (3a) into 2-amino-7-
methyl-5-oxo-4-phenyl-4H,5H-pyrano[4,3-b]pyran-3-carbonitrile (4a).
2 2
(CN)
(
2
2
(2a), and 4-hydroxy-6-methyl-2H-pyran-2-one (3a) in a
mortar with a pestle within 15 min (Scheme 1). In this
case, 4H,5H-pyrano[4,3-b]pyran 4a was obtained in 38%
yield (Table 1, Entry 1).
Using NaOH, the yield of 4a increased to 45%
Table 1, Entry 2). Replacing NaOH by KF, the yield of
(
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Helv. Chim. Acta 2016, 99, 724 – 731
Table 1. Assembling of benzaldehyde 1a, malononitrile 2a, C–H acid 3a into pyrano[4,3-b]pyran-5-one 4a )
a
a
Entry )
b
Yield [%] )
Additive [ml]
Catalyst [mol-%]
Time [min]
Temperature [°C]
1
2
3
4
5
6
Neat
Neat
Neat
Neat
Neat
Without
NaOH, 10
KF, 10
15
15
15
15
30
15
15
3
25
25
25
25
25
25
25
78
78
38
45
57
64
79
65
81
AcONH
AcONH
AcONH
AcONH
AcONH
AcONH
4
4
4
4
4
4
, 10
, 10
, 10
, 10
, 10
, 10
2
H O, 2
7
EtOH, 2
EtOH, 3
EtOH, 3
c
d
8
9
)
87 )
d
95 )
e
)
3
a
b
1a (3 mmol), 2a (3 mmol), 3a (3 mmol), and catalyst were grinded with a pestle in a mortar neat or with an additive. ) According to
)
NMR data. ) 1a (3 mmol), 2a (3 mmol), 3a (3 mmol), AcONH
c
d
4
(0.3 mmol), and 3 ml of EtOH were stirred at 78 °C. ) Yield of isolated
e
compounds. ) 1a (3.3 mmol), 2a (3.3 mmol), 3a (3 mmol), AcONH (0.3 mmol), and 3 ml of EtOH were stirred at 78 °C.
4
Scheme 2. General PASE approach to synthesis of 4H,5H-pyrano[4,3-b]pyran-5-one and 4,6-dihydro-5H-pyrano[3,2-c]pyridine-5-one
compounds 4a – 4s from aldehydes 1a – 1l, C–H acids 2a and 2b, and C–H acids 3a – 3c.
The next reaction was performed with excess of Based on above results and the data on mechanisms
PhCHO (1.1 equiv.) and excess of CH (CN) (1.1. equiv.) of the multicomponent transformation of CO compounds
2
2
with 3a (1 equiv.), AcONH4 (0.1. equiv.), and 3 ml of
and C–H acids into heterocyclic systems [38][39][44], the
EtOH (3 min reaction time at 78 °C). These conditions following mechanism for the assembling of aldehydes
led to formation of 4a in excellent 95% yield (Table 1, 1a – 1l, C–H acids 2a and 2b, and heterocyclic C–H acids
Entry 9).
3a – 3c into substituted 4H,5H-pyrano[4,3-b]pyranes or
Under these optimal conditions (10 mol-% excess 4,6-dihydro-5H-pyrano[3,2-c]pyridine-5-ones 4a – 4s was
of aldehyde and CH (CN) , AcONH4 10 mol-%, proposed (Scheme 3). Catalytic cycle starts with deproto-
2
2
EtOH 3 ml, 78 °C), the reactions of aldehydes
a – 1l, C–H acids 2a and 2b, and heterocyclic C–H which leads to the anion A formation (Scheme 3). Then
acids 3a – 3c resulted in formation of substituted the Knoevenagel condensation of the anion A with alde-
H,5H-pyrano[4,3-b]pyranes and 4,6-dihydro-5H-pyr- hyde 1 leads to the Knoevenagel adduct 5 with elimina-
ano[3,2-c]pyridine-5-ones 4a – 4s in 88 – 97% yields tion of OH anion. The subsequent OH-promoted the
nation of a molecule of C–H acid 2, induced by AcONH4,
1
4
(
Scheme 2, Table 2).
Michael addition of heterocyclic C–H acids 3 to an
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727
Table 2. General PASE approach to synthesis of 4H,5H-pyrano[4,3-b]pyran-5-one and 4,6-dihydro-5H-pyrano[3,2-c]pyridine-5-one compounds
a
4a – 4s from aldehydes 1a – 1l, C–H acids 2a and 2b, and C–H acids 3a – 3c ). See the structures, see Scheme 2
a
Entry )
b
Yield [%] )
Carbonyl compound
C–H acid 2
C–H acid 3
Time [min]
Compound 4
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1g
1i
2a
2a
2a
2a
2a
2a
2a
2a
2b
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3b
3b
3b
3b
3b
3c
3c
3c
3c
3
3
4a
4b
4c
4d
4e
4f
95
91
92
90
91
92
90
91
90
93
97
94
92
90
88
92
94
92
93
8
3
3
5
1k
1l
10
10
15
3
4g
4h
4i
1a
1a
1b
1e
1h
1j
1
1
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
8
9
4j
6
4k
4l
3
3
4m
4n
4o
4p
4q
4r
6
1l
15
3
1a
1b
1d
1f
3
3
3
4s
a
)
4
Aldehydes 1a – 1l (3.3 mmol), C–H acids 2a and 2b (3.3 mmol), C–H acids 3a – 3c (3 mmol), AcONH (0.3 mmol), and 3 ml of EtOH
b
were stirred at 78 °C for appropriate time. ) Yield of isolated products.
Scheme 3. Assembling of aldehydes 1a – 1l, C–H acids 2a and 2b, and C–H acid 3a – 3c into 4H,5H-pyrano[4,3-b]pyran-5-ones or 4,6-dihydro-
5H-pyrano[3,2c]pyridine-5-ones 4a – 4s.
AcONH4
O
R
1
a-l
Z
2
a-b
CN
R
OH
-
O
Z
Z
-
NC
X
O
O
CN
R
OH-
3
a-c
X
A
Z
O
R
O
O
R
NH2
Z
X
4
a-s
'
ON-SOLVENT'
NC
-
Z
NH
MULTICOMPONENT
PROCESS
H O
2
5
O
-
X
O
O
R
O
Z
O
R
O
R
X
Z
-
Z
N-
X
X
O- CN
CN
OH
C
B
electron-deficient Knoevenagel adduct 5 results in the sub- 4H,5H-pyrano[4,3-b]pyran-5-one or 4,6-dihydro-5H-pyr-
sequent anions B and C formation. Further cyclization of ano[3,2-c]pyridine-5-one 4 formation with the regenera-
anion C and protonation with the participation of the tion of anion A as the beginning of the next catalytic
next molecule of C–H acid 2 leads to the corresponding cycle.
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Helv. Chim. Acta 2016, 99, 724 – 731
2-Amino-7-methyl-4-(4-methylphenyl)-5-oxo-4H,5H-pyr-
ano[4,3-b]pyran-3-carbonitrile (4b). Yield 0.80 g (91%).
White solid. M.p. 228 – 230 °C ([12]: 228 – 230 °C). H-
Conclusions
1
In conclusion, under simple and highly efficient PASE
‘
(
on-solvent’
3 – 15 min) and selective transformation of aldehydes Me); 4.24 (s, CH); 6.25 (s, CH); 7.05 – 7.12 (m, 4 arom.
and two different C–H acids; among them heterocyclic C– H); 7.16 (s, NH ).
H acids are transformed into substituted 4H,5H-pyrano 2-Amino-4-(4-methoxyphenyl)-7-methyl-5-oxo-4H,5H-pyr-
4,3-b]pyran-5-ones and 4,6-dihydro-5H-pyrano[3,2-c]pyri- ano[4,3-b]pyran-3-carbonitrile (4c). White solid. Yield
conditions,
AcONH4
produces
fast NMR (300 MHz, (D )DMSO): 2.20 (s, Me); 2.25 (s,
6
2
[
1
dine-5-ones, which are privileged scaffolds, promising for 0.86 g (92%). M.p. 221 – 223 °C ([28]: 205 – 207 °C); H-
many diverse oriented medical applications with anti-
HIV, antiviral, antileishmanial, and anticancer activities.
This new general and fast approach allows to combine
NMR (300 MHz, (D )DMSO): 2.21 (s, Me); 3.72 (s,
6
MeO); 4.22 (s, CH); 6.24 (s, CH); 6.86 (d, J = 8.3, 2 arom.
H); 7.09 (d, J = 8.3, 2 arom. H); 7.13 (s, NH2).
the synthetic virtues of conventional multicomponent 2-Amino-4-(4-chlorophenyl)-7-methyl-5-oxo-4H,5H-pyr-
reactions with ecological benefits and the convenience of ano[4,3-b]pyran-3-carbonitrile (4d). White solid. Yield
on-solvent’ processes. This method leads to excellent 0.85 g (90%). M.p. 228 – 230 °C ([26]: 228 – 230 °C);
‘
1
yields, utilizes simple equipment and it is easy to carry
H-NMR (300 MHz, (D )DMSO): 2.22 (s, Me); 4.31 (s,
6
out. The final compounds obtained by this method needs CH); 6.27 (s, CH); 7.21 – 7.23 (m, 2 arom. H, NH );
2
no further purification, thereby this method reduces the 7.35 – 7.38 (d, J = 8.4, 2 arom. H).
waste generation.
2-Amino-4-(3-bromophenyl)-7-methyl-5-oxo-4H,5H-pyr-
ano[4,3-b]pyran-3-carbonitrile (4e). White solid. Yield
The authors gratefully acknowledge the financial support
of the Russian Science Foundation (Grant no. 14-50-
0.98 g (91%). M.p. 218 – 220 °C ([26]: 217 – 219 °C);
H-NMR (300 MHz, (D )DMSO): 2.22 (s, Me); 4.33 (s,
1
6
0
0126).
CH); 6.27 (s, CH); 7.20 – 7.44 (m, 4 arom. H, NH ).
2
2
[
-Amino-7-methyl-5-oxo-4-(pyridin-3-yl)-4H,5H-pyrano-
4,3-b]pyran-3-carbonitrile (4f). Beige solid. Yield 0.78 g
(
92%). M.p. 221 – 223 °C. IR (KBr): 3409, 3129, 2886,
Experimental Part
1
192, 1704, 1668, 1646, 1621, 1379, 1258. H-NMR
2
(
(
(
(
300 MHz, (D )DMSO): 2.23 (s, Me); 4.39 (s, CH); 6.30
6
General Remarks
s, CH); 7.30 (s, NH ); 7.33 – 7.37 (m, 1 arom. H); 7.62
2
All melting points were measured using a Gallenkamp
13
melting point apparatus and are uncorrected. H and C-
13
d, J = 7.6, 1 arom. H); 8.46 (m, 2 arom. H). C-NMR
75 MHz, (D )DMSO): 19.3; 34.0; 56.9; 98.0; 99.7; 119.1;
1
6
NMR spectra were recorded with a Bruker AM-300 at
ambient temp. in (D )DMSO solns. Chemical shift values
are given in d scale relative to Me Si. IR spectra were
1
23.7; 135.2; 138.9; 148.2; 149.0; 158.2; 158.4; 161.3; 163.2.
6
2-Amino-7-methyl-5-oxo-4-propyl-4H,5H-pyrano[4,3-b]-
pyran-3-carbonitrile (4g). White solid. Yield 0.75 g (90%).
4
registered with a Bruker ALPHA-T FT-IR spectrometer
in KBr pellets. HR-ESI-MS was measured on a Bruker
microTOF II instrument; external or internal calibration
was done with Electrospray Calibrant Solution (Fluka).
All chemicals used in this study were commercially
available.
M.p. 185 – 187 °C. IR (KBr): 3362, 3198, 2952, 2197,
1
1
710, 1678, 1621, 1397, 1149, 1037. H-NMR (300 MHz,
(
D )DMSO): 0.86 (t, J = 7.1, Me); 1.07 – 1.30 (m, CH );
6
2
1
2
.42 – 1.51 (m, 1 H of CH ); 1.60 – 1.72 (m, 1 H of CH );
2 2
.23 (s, Me); 3.27 – 3.33 (m, CH); 6.17 (s, CH); 7.07 (s,
13
NH2). C-NMR (75 MHz, (D )DMSO): 13.8; 17.4; 19.2;
6
3
1
0.0; 35.8; 55.3; 97.9; 100.6; 119.7; 159.0; 159.3; 161.7;
+
þ
62.4. HR-ESI-MS: 247.1079 ([M + H] , C13H15N2O ;
General ‘On-Solvent’ Procedure
3
calc. 247.1077).
-Amino-4-butyl-7-methyl-5-oxo-4H,5H-pyrano[4,3-b]pyran-
3-carbonitrile (4h). White solid. Yield 0.71 g (91%). M.p.
Aldehyde 1a – 1l (3.3 mmol), C–H acid 2a or 2b
2
(3.3 mmol), C–H acid 3a – 3c (3 mmol), AcONH4
(0.023 g, 0.3 mmol), and EtOH 3 ml were stirred with
1
1
0
82 – 184 °C. IR (KBr): 3366, 3200, 2195, 1708, 1622, 1397,
magnetic stirring bar 3 – 15 min. The time of the reac-
tion was determined by TLC. The solid was filtered out
1
266, 1147, 1041, 560. H-NMR (300 MHz, (D )DMSO):
6
.80 (t, J = 7.0, Me); 1.02 – 1.22 (m, 2 CH ); 1.41 – 1.49 (m,
2
after cooling, washed with 5 ml of H O, and dried
2
1 H of CH ); 1.61 – 1.69 (m, 1 H of CH ); 2.19 (s, Me);
2 2
under reduced pressure to isolate pure compounds
13
3
.24 – 3.33 (m, CH); 6.13 (s, CH); 7.03 (s, NH2). C-NMR
4
2
a – 4s.
-Amino-7-methyl-5-oxo-4-phenyl-4H,5H-pyrano[4,3-b]-
(75 MHz, (D )DMSO): 13.6; 19.2; 22.0; 26.2; 30.0; 33.0;
6
5
5.2; 97.8; 100.5; 119.6; 159.0; 159.3; 161.7; 162.4. HR-ESI-
+
pyran-3-carbonitrile (4a). Yield 0.80 g (95%). White solid.
1
þ
MS: 261.1236 ([M + H] , C14H17N2O ; calc. 261.1233).
3
M.p. 231 – 233 °C ([12]: 231 – 233 °C).
H-NMR
300 MHz, (D )DMSO): 2.22 (s, Me); 4.28 (s, CH); 6.27
Methyl 2-Amino-7-methyl-5-oxo-4-phenyl-4H,5H-pyrano-
[4,3-b]pyran-3-carboxylate (4i). White solid. Yield 0.85 g
(
6
(
s, CH); 7.17 (s, NH ); 7.20 – 7.24 (m, 3 arom. H);
1
2
(90%). M.p. 200 – 202 °C ([28]: 197 – 199 °C). H-NMR
7
.29 – 7.33 (m, 2 arom. H).
(300 MHz, (D )DMSO): 2.20 (s, Me); 3.55 (s, MeO); 4.54
6
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Helv. Chim. Acta 2016, 99, 724 – 731
729
(
s, CH); 6.28 (s, CH); 7.10 – 7.25 (m, 5 arom. H); 7.70 (s, 3409, 3313, 2967, 2185, 1673, 1597, 1505, 1462, 1378,
1
1257. H-NMR (300 MHz, (D )DMSO): 2.25 (s, Me);
NH2).
-amino-5-oxo-4-phenyl-4H,5H-pyrano[3,2-c]chromene-3-
carbonitrile (4j). White solid. Yield 0.88 g (93%). M.p.
6
2
3.54 (s, Me); 4.49 (s, CH); 7.05 – 7.12 (m, 4 arom. H);
7.24 (s, NH ); 7.38 – 7.43 (m, 1 arom. H); 7.58 (d,
2
1
2
(
61 – 263 °C ([27]: 260 – 261 °C). H-NMR (300 MHz,
J = 8.5, 1 arom. H); 7.69 – 7.74 (m, 1 arom. H); 8.04 (d,
1
3
D )DMSO): 4.45 (s, CH); 7.21 – 7.51 (m, 7 arom. H,
J = 7.9, 1 arom. H). C-NMR (75 MHz, (D )DMSO):
6
6
NH ); 7.71 (t, J = 7.5, 1 arom. H); 7.91 (d, J = 7.6, 1
arom. H).
20.5; 29.2; 36.9; 58.1; 109.1; 112.6; 114.8; 119.7; 122.0;
122.1; 127.3 (2C); 128.8 (2C); 131.4; 135.7; 138.8; 141.3;
2
+
2
-Amino-4-(4-methylphenyl)-5-oxo-4H,5H-pyrano[3,2-c]-
chromene-3-carbonitrile (4k). White solid. Yield 0.96 g
149.9; 158.8; 159.7. HR-ESI-MS: 366.1213 ([M + H] ,
þ
C21H17N3NaO ; calc. 366.1218).
2-Amino-4-(4-chlorophenyl)-6-methyl-5-oxo-5,6-dihydro-
2
1
(
97%). M.p. 253 – 254 °C ([32]: 253 – 254 °C). H-NMR
(
300 MHz, (D )DMSO): 2.27 (s, Me); 4.41 (s, CH); 4H-pyrano[3,2-c]quinoline-3-carbonitrile (4r). White solid.
6
7
2
.10 – 7.16 (m, 4 arom. H); 7.37 (s, NH ); 7.44 – 7.52 (m, Yield 1.00 g (92%). M.p. 280 – 282 °C ([34]: 280 –
2
1
arom. H); 7.71 (t, J = 9.0, 1 arom. H); 7.90 (d, J = 7.3, 1
282 °C). H-NMR (300 MHz, (D )DMSO): 3.54 (s, Me);
6
arom. H).
-Amino-4-(2-chlorophenyl)-5-oxo-4H,5H-pyrano[3,2-c]-
chromene-3-carbonitrile (4l). White solid. Yield 0.99 g
4.55 (s, CH); 7.24 – 7.26 (m, 2 arom. H); 7.33 – 7.42 (m, 3
2
arom. NH ); 7.57 (d, J = 8.4, 1 arom. H); 7.69 – 7.74 (m,
2
1 arom. H); 8.03 (d, J = 7.9, 1 arom. H).
2-Amino-4-(4-bromophenyl)-6-methyl-5-oxo-5,6-dihydro-
4H-pyrano[3,2-c]quinoline-3-carbonitrile (4s). Beige solid.
1
(
(
94%). M.p. 257 – 259 °C ([32]: 257 – 259 °C). H-NMR
300 MHz, (D )DMSO): 4.98 (s, CH); 7.24 – 7.52 (m, 6
6
arom. H, NH ); 7.71 (t, J = 7.6, 1 arom. H); 7.92 (d, Yield 1.14 g (93%). M.p. 285 – 286 °C ([37]: 275 –
2
1
J = 7.6, 1 arom. H).
-Amino-4-(4-nitrophenyl)-5-oxo-4H,5H-pyrano[3,2-c]chro-
277 °C). H-NMR (300 MHz, (D )DMSO): 3.53 (s, Me);
6
2
4.52 (s, CH); 7.19 (d, J = 7.8, 2 arom. H); 7.31 (s, NH2);
mene-3-carbonitrile (4m). White solid. Yield 1.00 g (92%). 7.37 – 7.42 (m, 1 arom. H); 7.47 (d, J = 7.8, 2 arom. H);
1
M.p. 261 – 263 °C ([32]: 260 – 262 °C).
H-NMR 7.56 (d, J = 8.5, 1 arom. H); 7.68 – 7.73 (m, 1 arom. H);
(
300 MHz, (D )DMSO): 4.67 (s, CH); 7.45 – 7.61 (m, 4 8.02 (d, J = 7.8, 1 arom. H).
6
arom. H, NH ); 7.72 (t, J = 8.2, 1 arom. H); 7.91 (d,
2
J = 7.6, 1 arom. H); 8.17 (d, J = 8.2, 2 arom. H).
REFERENCES
2
-Amino-4-(furan-2-yl)-5-oxo-4H,5H-pyrano[3,2-c]chro-
mene-3-carbonitrile (4n). Yellowish solid. Yield 0.83 g
[
1] P. A. Wender, ‘Toward the ideal synthesis and molecular func-
tion through synthesis-informed design’, Nat. Prod. Rep. 2014,
1
(
90%). M.p. 258 – 260 °C ([27]: 255 – 256 °C). H-
3
1, 433 – 440.
NMR (300 MHz, (D )DMSO): 4.62 (s, CH); 6.27 – 6.28
6
[2] K. Tanaka, G. Kaupp, ‘Solvent-free Organic Synthesis’, Wiley,
2009.
(
(
m, 1 H of fur); 6.36 – 6.38 (m, 1 H of fur); 7.45 – 7.52
[
3] S. Narayan, J. Muldoon, M. G. Finn, V. V. Fokin, H. C. Kolb,
K. B. Sharpless, ‘“On water”: Unique reactivity of organic com-
pounds in aqueous suspension’, Angew. Chem., Int. Ed. 2005,
m, 2 arom. H, NH , 1 H of fur); 7.71 (t, J = 7.7, 1
2
arom. H); 7.87 (d, J = 7.7, 1 arom. H).
-Amino-4-butyl-5-oxo-4H,5H-pyrano[3,2-c]chromene-3-
carbonitrile (4o). White solid. Yield 0.78 g (88%). M.p.
2
4
4, 3275 – 3279.
[
4] M. N. Elinson, F. V. Ryzhkov, R. F. Nasybullin, T. A. Zaimovs-
kaya, M. P. Egorov, ‘Sodium acetate catalyzed multicomponent
approach to medicinally privileged 2-amino-4H-chromene scaf-
fold from salicylaldehydes, malononitrile and cyanoacetates’,
Mendeleev Commun. 2014, 24, 170 – 172.
2
1
08 – 210 °C. IR (KBr): 3393, 3291, 3188, 2926, 2192,
714, 1672, 1395, 1046, 755. H-NMR (300 MHz, (D6)
1
DMSO): 0.80 (t, J = 7.0, Me); 1.11 – 1.24 (m, 2 CH );
2
1
.51 – 1.59 (m, 1 H of CH ); 1.68 – 1.75 (m, 1 H of
2
[
[
5] G. A. Bowmaker, ‘Solvent-assisted mechanochemistry’, Chem.
Commun. 2013, 49, 334 – 348.
6] Y. Hayashi, ‘Pot economy and one-pot synthesis’, Chem. Sci.
2016, 7, 866 – 880.
CH ); 3.35 – 3.42 (m, CH); 7.27 (s, NH ); 7.40 – 7.45
2
2
(
m, 2 arom. H); 7.67 (t, J = 7.8, 1 arom. H); 7.79 (d,
1
3
J = 7.8, 1 arom. H). C-NMR (75 MHz, (D )DMSO):
6
1
1
3.8; 22.1; 26.4; 30.8; 33.4; 55.2; 104.2; 112.9; 116.4;
19.6; 122.0; 124.4; 132.6; 152.0; 154.0; 159.4; 159.8. HR-
[7] L. F. Tietze, G. Brasche, K. Gericke, ‘Domino Reactions in
Organic Synthesis’, Wiley, 2006.
+
+
[8] P. A. Clarke, S. Santos, W. H. C. Martin, ‘Combining pot, atom
and step economy (PASE) in organic synthesis. Synthesis of
tetrahydropyran-4-ones’, Green Chem. 2007, 9, 438 – 440.
ESI-MS: 297.1236 ([M + H] , C H N O ; calc.
1
7
16
2
2
97.1233).
-Amino-6-methyl-5-oxo-4-phenyl-5,6-dihydro-4H-pyrano-
3,2-c]quinoline-3-carbonitrile (4p). White solid. Yield
2
[
[
9] B. M. Trost, ‘Atom Economy – A Challenge for Organic Syn-
thesis: Homogeneous Catalysis Leads the Way’, Angew. Chem.,
Int. Ed. 1995, 34, 259 – 281.
1
0.91 g (92%). M.p. 257 – 259 °C ([34]: 255 – 258 °C). H-
NMR (300 MHz, (D )DMSO): 3.53 (s, Me); 4.52 (s, CH);
[
10] V. P. Ananikov, E. A. Khokhlova, M. P. Egorov, A. M.
Sakharov, S. G. Zlotin, A. V. Kucherov, L. M. Kustov, M. L.
Gening, N. E. Nifantiev, ‘Organic and hybrid molecular sys-
tems’, Mendeleev Commun. 2015, 25, 75 – 82.
11] S. Wang, G. W. A. Milne, X. Yan, I. J. Posey, M. C. Nicklaus,
L. Graham, W. G. Rice, ‘Discovery of Novel, Non-Peptide
HIV-1 Protease Inhibitors by Pharmacophore Searching’, J.
Med. Chem. 1996, 39, 2047 – 2054.
6
7
.17 – 7.30 (m, 5 arom. H, NH ); 7.39 (t, J = 7.8, 1 arom.
2
H); 7.56 (d, J = 7.8, 1 arom. H); 7.70 (t, J = 7.8,1 arom.
H); 8.02 (d, J = 7.8, 1 arom. H).
2
4
[
-Amino-6-methyl-4-(4-methylphenyl)-5-oxo-5,6-dihydro-
H-pyrano[3,2-c]quinoline-3-carbonitrile (4q). White
solid. Yield 0.97 g (94%). M.p. 281 – 282 °C. IR (KBr):
©
2016 Wiley-VHCA AG, Z u€ rich
www.helv.wiley.com

7
30
Helv. Chim. Acta 2016, 99, 724 – 731
pyran and 3,4-dihydropyrano[c]chromene derivatives using a
[
12] X. Fan, D. Feng, Y. Qu, X. Zhang, J. Wang, P. M. Loiseau, G.
Andrei, R. Snoeck, E. D. Clercq, ‘Practical and efficient synthe-
sis of pyrano[3,2-c]pyridone, pyrano[4,3-b]pyran and their
hybrids with nucleoside as potential antiviral and antileishma-
nial agents’, Bioorg. Med. Chem. Lett. 2010, 20, 809 – 813.
n
3 4 2
Fe O @SiO -imid-PMA magnetic nanocatalyst under ultrasonic
irradiation or reflux conditions’, RSC Adv. 2015, 5,
26625 – 26633.
[28] E. V. Stoyanov, I. C. Ivanov, D. Heber, ‘General Method for
the Preparation of Substituted 2-Amino-4H,5H-pyrano[4,3-b]-
pyran-5-ones and 2-Amino-4H-pyrano[3,2-c]pyridine-5-ones’,
Molecules 2000, 5, 19.
[
[
[
13] J. Zamocka, E. Misikova, J. Durinda, ‘Preparation, structure
elucidation and activity of some [(5-hydroxy- or 5-methoxy-4-
oxo-4H-pyran-2-yl)methyl]-2-alkoxycarbanilates’, Pharmazie 1991,
4
6, 610.
[29] X.-S. Wang, J.-X. Zhou, Z.-S. Zeng, Y.-L. Li, D.-Q. Shi, S.-J.
Tu, ‘One-pot synthesis of pyrano[3,2-c]pyran derivatives cat-
€
14] M. D. Aytemir, U. Cßalißs, M. Ozalp, ‘Synthesis and Evaluation
of Anticonvulsant and Antimicrobial Activities of 3-Hydroxy-6-
methyl-2-substituted 4H-Pyran-4-one Derivatives’, Arch. Pharm.
2 3
alyzed by KF/Al O ’, Arkivoc 2006, xi, 107 – 113.
[30] M. Seifi, H. Sheibani, ‘High Surface Area MgO as a Highly
Effective Heterogeneous Base Catalyst for Three-Component
Synthesis of Tetrahydrobenzopyran and 3,4-Dihydropyrano[c]-
chromene Derivatives in Aqueous Media’, Catal. Lett. 2008,
126, 275 – 279.
[31] J. M. Khurana, B. Nand, P. Saluja, ‘DBU: a highly efficient cat-
alyst for one-pot synthesis of substituted 3,4-dihydropyrano[3,2-
c]chromenes, dihydropyrano[4,3-b]pyranes, 2-amino-4H-benzo-
[h]chromenes and 2-amino-4H benzo[g]chromenes in aqueous
medium’, Tetrahedron 2010, 66, 5637 – 5641.
[32] A. Khazaei, M. A. Zolfigol, F. Karimitabar, I. Nikokar, A. R.
Moosavi-Zare, ‘N,2-Dibromo-6-chloro-3,4-dihydro-2H-benzo-[e]
[1,2,4]thiadiazine-7-sulfonamide 1,1-dioxide: an efficient and
homogeneous catalyst for one-pot synthesis of 4H-pyran,
pyranopyrazole and pyrazolo[1,2-b]phthalazine derivatives under
aqueous media’, RSC Adv. 2015, 5, 71402 – 71412.
[33] A. Shaabani, S. Samadi, Z. Badri, A. Rahmati, ‘Ionic liquid
promoted efficient and rapid one-pot synthesis of pyran annu-
lated heterocyclic systems’, Catal. Lett. 2005, 104, 39 – 43.
[34] S. M. Baghbanian, N. Rezaei, H. Tashakkorian, ‘Nanozeolite
clinoptilolite as a highly efficient heterogeneous catalyst for the
synthesis of various 2-amino-4H-chromene derivatives in aque-
ous media’, Green Chem. 2013, 15, 3446 – 3458.
[35] I. V. Magedov, M. Manpadi, M. A. Ogasawara, A. S. Dhawan,
S. Rogelj, S. Van slambrouck, W. F. A. Steelant, N. M. Evdoki-
mov, P. Y. Uglinskii, E. M. Elias, E. J. Knee, P. Tongwa, M. Y.
Antipin, A. Kornienko, ‘Structural Simplification of Bioactive
Natural Products with Multicomponent Synthesis. 2. Antiprolif-
erative and Antitubulin Activities of Pyrano[3,2-c]pyridones
and Pyrano[3,2-c]quinolones’, J. Med. Chem. 2008, 51,
2561 – 2570.
[36] A. G. A. Elagamey, S. Z. Sawllim, F. M. A. El-Taweel, M. H.
Elnagdi, ‘Nitriles in heterocyclic synthesis: novel syntheses of
benzo[b]pyrans, naphtho[1,2-b]pyrans, naphtho[2,1-b]pyrans,
pyrano[3,2-h]quinolines and pyrano[3,2-c]quinolines’, Collect.
Czech. Chem. Commun. 1988, 53, 1534 – 1538.
[37] F. M. el-Taweel, D. A. Ibrahim, M. A. Hanna, ‘Synthesis of
some new quinoline derivatives: new routes to synthesize poly-
substituted 2(1H)-quinolone derivatives’, Boll. Chim. Farm.
2001, 140, 287 – 296.
[38] M. N. Elinson, A. N. Vereshchagin, R. F. Nasybullin, S. I.
Bobrovsky, A. I. Ilovaisky, V. M. Merkulova, I. S. Bushmari-
nov, M. P. Egorov, ‘General approach to a spiro indole-3,1’-
naphthalene tetracyclic system: stereoselective pseudo four-
component reaction of isatins and cyclic ketones with
two molecules of malononitrile’, RSC Adv. 2015, 5,
50421 – 50424.
2
004, 337, 281 – 288.
15] K. Mori, N. P. Argade, ‘Pheromone synthesis, CLXIII. Synthe-
sis of (9Z,25S,26R,43Z)-25,26-Epoxy-9,43-henpentacontadiene
and its Antipode, Components of the Nymph Recognition Pher-
omone Produced by Nymphs of the Cockroach Nauphoeta
cinerea’, Liebigs Ann. Chem. 1994, 695 – 700.
[
16] T. H. V. Huynh, B. Abrahamsen, K. K. Madsen, A. Gonzalez-
Franquesa, A. A. Jensen, L. Bunch, ‘Design, synthesis and
pharmacological characterization of coumarin-based fluorescent
analogs of excitatory amino acid transporter subtype 1 selective
inhibitors, UCPH-101 and UCPH-102’, Bioorg. Med. Chem.
2
012, 20, 6831 – 6839.
[
17] J. Y.-C. Wu, W.-F. Fong, J.-X. Zhang, C.-H. Leung, H.-L.
Kwong, M.-S. Yang, D. Li, H.-Y. Cheung, ‘Reversal of mul-
tidrug resistance in cancer cells by pyranocoumarins isolated
from Radix Peucedani’, Eur. J. Pharmacol. 2003, 473, 9 – 17.
18] L. Bonsignore, G. Loy, D. Secci, A. Calignano, ‘Synthesis and
pharmacological activity of 2-oxo-(2H)1-benzopyran-3-carbox-
amide derivatives’, Eur. J. Med. Chem. 1993, 28, 517 – 520.
19] F. W. Perrella, S.-F. Chen, D. L. Behrens, R. F. Kaltenbach III,
S. P. Seitz, ‘Phospholipase C Inhibitors: A New Class of Cyto-
toxic Agents’, J. Med. Chem. 1994, 37, 2232 – 2237.
20] A. D. Patil, A. J. Freyer, D. S. Eggleston, R. C. Haltiwanger,
M. F. Bean, P. B. Taylor, M. J. Caranfa, A. L. Breen, H. R.
Bartus, R. K. Johnson, R. P. Hertzberg, J. W. Westley, ‘The
Inophyllums, Novel Inhibitors of HIV-1 Reverse Transcriptase
Isolated from the Malaysian Tree, Calophyllum inophyllum
Linn’, J. Med. Chem. 1993, 36, 4131 – 4138.
[
[
[
[
[
[
21] J. Hirsh, V. Fuster, J. Ansell, J. L. Halperin, ‘American Heart
Association/American College of Cardiology Foundation guide
to warfarin therapy’, J. Am. Coll. Cardiol. 2003, 41,
1633 – 1652.
22] G. R. Pettit, J. Du, R. K. Pettit, L. A. Richert, F. Hogan, V.
Mukku, M. S. Hoard, ‘Antineoplastic agents. 554. The Mani-
toba bacterium Streptomyces sp’, J. Nat. Prod. 2006, 69,
804 – 806.
23] M. S. Saag, E. A. Emini, O. L. Laskin, J. Douglas, W. I. Lapi-
dus, W. A. Schleif, R. J. Whitley, C. Hildebrand, V. W. Byrnes,
J. C. Kappes, K. W. Anderson, F. E. Massari, G. M. Shaw, ‘A
Short-Term Clinical Evaluation of L-697,661, a Non-Nucleoside
Inhibitor of HIV-1 Reverse-Transcriptase’, N. Engl. J. Med.
1993, 329, 1065 – 1072.
[24] G. R. Hasegawa, ‘Milrinone, a new agent for the treatment of
congestive heart failure’, Clin. Pharm. 1986, 5, 201 – 205.
[
25] K. D. McBrien, Q. Gao, S. Huang, S. E. Klohr, R. R. Wang, D.
M. Pirnik, K. M. Neddermann, I. Bursuker, K. F. Kadow, J. E.
Leet, ‘Fusaricide, a New Cytotoxic N-Hydroxypyridone from
Fusarium sp’, J. Nat. Prod. 1996, 59, 1151 – 1153.
[39] M. N. Elinson, A. I. Ilovaisky, V. M. Merkulova, T. A. Zai-
movskaya, G. I. Nikishin, ‘Non-Catalytic Thermal Multicompo-
nent Assembling of Isatin, Cyclic CH-Acids and Malononitrile:
An Efficient Approach to Spirooxindole Scaffold’, Mendeleev
Commun. 2012, 22, 143 – 144.
[26] N. G. Khaligh, S. B. A. Hamid, ‘4-(Succinimido)-1-butane sul-
fonic acid as a Br o€ nsted acid catalyst for the synthesis of pyrano
[
4,3-b]pyran derivatives using thermal and ultrasonic irradia-
tion’, Chin. J. Catal. 2015, 36, 728 – 733.
27] M. Esmaeilpour, J. Javidi, F. Dehghani, F. Nowroozi Dodeji, ‘A
green one-pot three-component synthesis of tetrahydrobenzo[b]-
[40] D. V. Demchuk, M. N. Elinson, G. I. Nikishin, ‘On water Kno-
evenagel condensation of isatins with malononitrile’, Mendeleev
Commun. 2011, 21, 224 – 225.
[
www.helv.wiley.com
© 2016 Wiley-VHCA AG, Z u€ rich

Helv. Chim. Acta 2016, 99, 724 – 731
731
[41] A. N. Vereshchagin, M. N. Elinson, R. F. Nasybullin, F. V.
Ryzhkov, S. I. Bobrovsky, I. S. Bushmarinov, M. P. Egorov,
salicylaldehydes, dimedone, and barbituric acids’, Monatsh.
Chem. 2015, 146, 1689 – 1694.
‘
One-Pot ‘On-solvent’ Multicomponent Protocol for the Synthe-
[44] M. N. Elinson, V. M. Merkulova, A. I. Ilovaisky, D. V. Dem-
chuk, P. A. Belyakov, G. I. Nikishin, ‘Electrochemically
induced multicomponent assembling of isatins, 4-hydroxyquino-
lin-2(1H)-one and malononitrile: a convenient and efficient way
to functionalized spirocyclic [indole-3,4’-pyrano[3,2-c]quinoline]
scaffold’, Mol. Diversity 2009, 14, 833 – 839.
sis of Medicinally Relevant 4H-Pyrano[3,2-c]quinoline Scaffold’,
Helv. Chim. Acta 2015, 98, 1104 – 1114.
42] A. Manna, A. Kumar, ‘Why Does Water Accelerate Organic
Reactions under Heterogeneous Condition?’, J. Phys. Chem. A
[
2
013, 117, 2446 – 2454.
[
43] M. N. Elinson, R. F. Nasybullin, O. O. Sokolova, T. A. Zai-
movskaya, M. P. Egorov, ‘Non-catalytic multicomponent rapid
and efficient approach to 10-(2,4,6-trioxohexahydropyrimidin-5-
Received May 26, 2016
Accepted June 15, 2016
yl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-xanthen-1-ones
from
©
2016 Wiley-VHCA AG, Z u€ rich
www.helv.wiley.com