General non-catalytic approach to spiroacenaphthylene heterocycles: Multicomponent assembling of acenaphthenequinone, cyclic CH-acids and malononitrile

Article abstract of DOI:10.1016/j.tet.2012.05.005

The new type of non-catalytic cascade reaction was found: the direct multicomponent reaction of acenaphthenequinone, cyclic CH-acids, and malononitrile to form spiroacenaphthylene heterocycles. The direct heating in water acenaphthenequinone, cyclic CH-ac

Full text of DOI:10.1016/j.tet.2012.05.005

Tetrahedron 68 (2012) 5833e5837
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
General non-catalytic approach to spiroacenaphthylene heterocycles:
multicomponent assembling of acenaphthenequinone, cyclic CH-acids
and malononitrile
,
a
a
a
Michail N. Elinson a , Alexey I. Ilovaisky , Valentina M. Merkulova , Pavel A. Belyakov ,
*
Fructuoso Barba b, Belen Batanero b
a N.D. Zelinsky Institute of Organic Chemistry, Leninsky Prospect 47, 119991 Moscow, Russia
,
*
b
ꢀ
ꢀ
Department of Organic Chemistry, University of Alcala, 28871 Alcala de Henares, Madrid, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
The new type of non-catalytic cascade reaction was found: the direct multicomponent reaction of ace-
naphthenequinone, cyclic CH-acids, and malononitrile to form spiroacenaphthylene heterocycles. The
direct heating in water acenaphthenequinone, cyclic CH-acids, and malononitrile at 80 ꢀC results in the
formation of spiroacenaphthylene heterocycles in 90e95% yields. Thus, a new simple and efficient green
‘one-pot’ method to synthesize substituted spiroacenaphthylene frameworks was found directly from
simple starting compounds. The application of this convenient green multicomponent method is also
beneficial from the viewpoint of diversity-oriented large-scale processes.
Received 8 February 2012
Received in revised form 9 April 2012
Accepted 1 May 2012
Available online 9 May 2012
Keywords:
Multicomponent reaction
Thermal initiation
Acenaphthenequinone
Cyclic CH-acid
Ó 2012 Elsevier Ltd. All rights reserved.
Malononitrile
Spiroacenaphthylenes
1. Introduction
spirochromenes have played an ever increasing role in the syn-
thetic approaches to promising compounds in the field of medicinal
The discovery of new synthetic methodologies that facilitate the
preparation of organic compounds is a focal point of research ac-
tivity in the field of modern organic, bioorganic, and medicinal
chemistry.1 One approach to address this challenge involves the
development of multicomponent reactions (MCRs), in which three
or more reactants are combined together in a single reaction flask
to generate a product incorporating most of the atoms contained in
the starting materials.2
chemistry.6
Recently we suggested an electrocatalytic process as a facile and
convenient way to create diversely substituted medicinally privi-
leged 2-amino-4H-chromene scaffold directly from salicylalde-
hydes and two different CH-acids.7 But an electrocatalytic
procedure in the case of multicomponent reaction of acenaph-
thenequinone, cyclic CH-acids, and malononitrile was not
successful.
In recent years the concept of ‘privileged medicinal structures or
scaffolds’3 has emerged as one of the guiding principles of drug
discovery process. These privileged scaffolds commonly consist of
rigid hetero ring systems, among them spiro-chromene, -pyran,
-pyrimidine, and -pyrazole cycles with well-defined orientations
for target recognition.4
The chromene moiety often appears as an important structural
component in both biologically active and natural compounds.5
Moreover, in recent years functionalized chromenes and
Ammonium chloride (20 mol %) was found as catalyst for the
multicomponent
reaction
of
acenaphthenequinone, 1,3-
cyclohexanedione or dimedone, and malononitrile for the forma-
tion of spiroacenaphthylenechromenes in 75e90% yields (4 ex-
amples).8 Triethylamine (200 mol %) recently has been used to
catalyze general multicomponent reaction of acenaph-
thenequinone, containing carbonyl group CH-acids and malono-
nitrile with the formation of spiroacenaphthylenes in 40e85%.9
This general method needs a long reaction time (1) heating in
boiling ethanol for 4e8 h and (2) then crystallization at 4 ꢀC
overnight; moreover a large excess of catalyst (Et3N, 200 mol %)
was used and only moderate yields of spiroacenaphthylenes were
achieved.
* Corresponding authors. Tel.: þ7 499 137 38 42; fax: þ7 499 135 53 28 (M.N.E);
tel.: þ34 91 885 25 17; fax: þ34 91 885 46 86 (B.B.); e-mail addresses: elinson@
ioc.ac.ru (M.N. Elinson), belen.batanero@uah.es (B. Batanero).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.05.005

5834
M.N. Elinson et al. / Tetrahedron 68 (2012) 5833e5837
Thus, the two known procedures for the synthesis of spi-
cyclic CH-acids 2aeg and malononitrile were transformed into
corresponding substituted spiroacenaphthylenes 3aeg in 90e95%
yields (Table 2). Only in the case of N,N0-dimethylbarbituric acid 2h
the solvent (water) was changed to n-propanol to achieve a better
yield of spiroacenaphthylene 3h (93%, entry 8, Table 2); in water
only 78% yield of 3h was obtained.
Among spiroacenaphthylenes 3aeh, four compounds 3a,b,d,e
were reported earlier.8,9 But in our case the melting points of 3a,b
are at least on 20e35 ꢀC higher than reported earlier.
roacenaphthylenes are catalytic8,9 (and use large amount of cata-
lyst: 20e200%). Both of them have their merits, but the essence of
facile and convenient non-catalytic MCR methodology for the
synthesis of spiroacenaphthylenes should yet to be developed.
Thus, we were prompted to design a convenient and facile non-
catalytic methodology for the efficient synthesis of functionalized
spiroacenaphthylenes in water as a ‘green’ solvent.
Two special experiments were carried out to check the mech-
anism of the new non-catalytic multicomponent reaction. The re-
action of acenaphthenequinone 1 with malononitrile in water at
80 ꢀC resulted in the formation of the Knoevenagel condensation
product, namely (2-oxoacenaphthylen-1(2H)-ylidene)malononi-
trile 4 in 98% yield in 15 min.
2. Results and discussion
In the present study we report our results on the non-catalytic
transformation of acenaphthenequinone 1, cyclic CH-acids 2aeh,
and malononitrile into spiroacenaphthylene derivatives 3aeh
(Scheme 1, Tables 1 and 2).
From acenaphthenequinone 1 and dimedone 2a under the same
conditions only the aldol addition product, namely 2-(1-hydroxy-2-
oxo-1,2-dihydroacenaphthylen-1-yl)-5,5-dimethylcyclohexane-
1,3-dione 5 was obtained in 81% yield.
Taking into consideration all this data, the following mechanism
is proposed for the direct non-catalytic chain cascade trans-
formation of acenaphthenequinone 1, cyclic CH-acids 2, and
malononitrile into spiroacenaphthylenes 3 (Scheme 2, example for
cyclic acid 2a is shown). The initiation step of this non-catalytic
chain process begins with the dissociation of a molecule of malo-
nonitrile, which is increased by the heating and leads to the for-
mation of malononitrile anion (Scheme 2).
The subsequent reaction between the malononitrile anion and
acenaphthenequinone 1 takes place with the formation of the
Knoevenagel adduct 4 (Scheme 3).
The Michael addition of cyclic CH-acid 2a to the Knoevenagel
adduct 4 followed by intramolecular cyclization leads to the cor-
responding spiroacenaphthylene 3a (Scheme 3).
O
O
O
CN
CN
CN
+
+
ROH / H2O
O
NH2
O
3a-h
2a-h
1
OH
OH
O
O
=
O
O
O
O
O
O
O
O
a
b
c
d
N
N
N
N
O
O
O
N
N
Me
f
N
O
N
O
H
Ph
g
e
h
Scheme 1.
3. Conclusion
In conclusion, the new simple non-catalytic muticomponent
process in water as a solvent can produce an effective trans-
formation of acenaphthenequinone 1, cyclic CH-acids 2aeh, and
malononitrile into heterocyclic spiroacenaphthylene frameworks
3aeh in high 90e95% yields. This novel non-catalytic chain cascade
process offers a facile and convenient way to create substituted
medicinally relevant spiroacenaphthylene heterocyclesdthe ap-
proved basis for the generation of molecule ligands with different
biomedical properties including pronounced anticancer activities.
Compare to known MCR protocols, this non-catalytic cascade pro-
cedure represents the most efficient and ‘green’ approach to the
reliable design of heterocyclic spiroacenaphthylene frameworks.
The developed non-catalytic multicomponent procedure utilizes
simple equipment, and requires reasonable starting materials. It is
easily carried out, the reaction products were isolated by an easy
work-up procedure, and do not need any further purification steps.
Finally, this new efficient multicomponent method to synthesize
medicinally relevant spiroacenaphthylene heterocycles represents
the combination of the synthetic virtues of conventional MCR
strategy with ecological benefits and convenience of non-catalytic
chain ‘green’ processes in water. Therefore, this novel type of
MCR brings us a step closer to the notion of ‘ideal synthesis’.10
Table 1
Non-catalytic transformation of acenaphthenequinone 1, dimedone 2a and malo-
nonitrile into spiro[acenaphthylene-1,40-chromene] 3aa
Entry
Solvent
Temperature, ꢀC
Time, min
Yield of 3ab (%)
1
2
3
4
5
6
7
MeOH
MeOH
EtOH
PrOH
H2Oc
20
55
78
80
80
80
80
15
15
15
15
15
10
5
15
83
92
93
95
89
83
H2Oc
H2Oc
a
Compound 1 (5 mmol), 2a (5 mmol), malononitrile (5 mmol), solvent 10 mL.
Yield of isolated 3a.
Solvent 3 mL.
b
c
The electrocatalytic reaction of acenaphthenequinone, dime-
done, and malononitrile in methanol in the presence of sodium
bromide as electrolyte at room temperature resulted in the for-
mation of spiroacenaphthylene 3a in 37% yield in 15 min when
0.1 F/mol of electricity was passed through the cell. The analogous
process in methanol without electrolysis and in the absence of any
catalyst resulted in spiroacenaphthylene 3a formation in 15% yield
(Table 1, entry 1). In methanol at 55 ꢀC spiroacenaphthylene 3a was
obtained in 83% yield (Table 1, entry 2). The highest yields of 3a
under non-catalytic conditions were achieved with using EtOH, n-
PrOH, and H2O as solvents at 78e80 ꢀC (92e95%). A decreased re-
action time (10 min) led to a lower yield (85%) of spiroacenaph-
thylene 3a (Table 1, entry 6). Under the optimal non-catalytic
conditions [i.e., water as solvent, 80 ꢀC and 15 min reaction time]
the non-catalytic transformation of acenaphthenequinone 1, with
4. Experimental section
4.1. General remarks
All melting points were measured with a Gallenkamp melting
point apparatus and are uncorrected. 1H and 13C NMR spectra were
recorded with a Bruker Avance II-300 spectrometer at ambient

M.N. Elinson et al. / Tetrahedron 68 (2012) 5833e5837
5835
Table 2
Non-catalytic transformation of acenaphthenequinone 1, cyclic CH-acids 2aeh, and malononitrile into spiroacenaphthylenes 3aeha
Entry
Cyclic CH-acid 2
Product 3
Yield of 3b (%)
O
O
O
1
95
93
90
CN
O
2a
O
NH2
3a
O
O
O
2
CN
NH2
2b
O
3b
O
OH
O
O
3
O
CN
O
O
2c
O
NH2
3c
O
O
OH
4
5
6
7
92
91
93
O
CN
2d
O
O
O
NH2
3d
O
N
N
N
O
O
O
N
H
CN
2e
N
N
O
NH2
3e
H
O
N
CN
N
Me
2f
N
O
NH2
Me
3f
O
95
N
CN
N
Ph
2g
N
O
NH2
Ph
3g
(continued on next page)

5836
M.N. Elinson et al. / Tetrahedron 68 (2012) 5833e5837
Table 2 (continued )
Entry
Cyclic CH-acid 2
Product 3
Yield of 3b (%)
O
N
O
O
8c
93
N
CN
O
N
O
2h
O
N
O
NH2
a
Compound 1 (5 mmol), 2 (5 mmol), malononitrile (5 mmol), H2O (3 mL), 80 ꢀC, 15 min.
Yield of isolated product.
Solventdn-PrOH (3 mL), 97 ꢀC, 30 min.
b
c
80 ꢀC for 15 min. Then the reaction mixture was cooled and filtered to
isolate the solid product 3, which was washed with ethanol (2ꢁ5 mL),
and dried under reduced pressure. For 3h, the mixture of acenaph-
thenequinone 1 (5 mmol), 2h (5 mmol), and malononitrile (5 mmol)
was boiled in n-propanol (3 mL); the product was isolated as above.
Heating
-
+
CH2(CN)2
CH(CN)2
+ H
Scheme 2.
temperature. Chemical shifts values are relative to Me4Si. IR spectra
were registered with a SPECORD M82 spectrometer in KBr pellets.
Mass-spectra (EI¼70 eV) were obtained directly with a Finningan
MAT INCOS 50 spectrometer. HRMS mass-spectra (ESI) were mea-
sured on a Bruker micrOTOF II instrument; external or internal
calibration was done with Electrospray Calibrant Solution (Fluka).
All chemicals were purchased from commercial sources.
4.3.1. 20-Amino-70,70-dimethyl-2,50-dioxo-50,60,70,80-tetrahydro-2H-
spiro[acenaphthylene-1,40-chromene]-30-carbonitrile (3a). Light yel-
low solid. Yield 1.76 g (95%); mp 288e290 ꢀC (lit. mp9 268e270 ꢀC);
1H NMR (300 MHz, DMSO-d6)
d 1.02 (s, 3H, CH3), 1.04 (s, 3H, CH3),
2.02e2.17 (m, 2H, CH2), 2.62 (s, 2H, CH2), 7.30 (s, 2H, NH2), 7.39 (d, J
7.0 Hz, 1H, Ar), 7.65 (t, J 7.3 Hz, 1H, Ar), 7.82 (t, J 7.7 Hz, 1H, Ar),
7.88e7.98 (m, 2H, Ar), 8.26 (d, J 8.1 Hz, 1H, Ar) ppm; 13C NMR
(75 MHz, DMSO-d6)
d 27.2, 27.4, 32.0, 39.9, 49.7, 51.0, 58.1, 112.0,
4.2. Electrolysis procedure
117.4, 119.8, 121.4, 124.5, 128.4, 128.9, 129.8, 131.4, 132.2, 140.5,
143.2, 158.8, 164.5, 195.3, 203.5 ppm.
A solution of acenaphthenequinone 1 (5 mmol), dimedone 2a
(5 mmol), malononitrile (0.33 g, 5 mmol), and sodium bromide
(0.05 g, 0.5 mmol) in ethanol (20 mL) was electrolyzed in an un-
divided cell equipped with a magnetic stirrer, a graphite anode and
an iron cathode at 20 ꢀC under a constant current density of 10 mA/
cm2 (I¼50 mA, electrodes square 5 cm2) until the catalytic quantity
of 0.1 F/mol of electricity was passed (time 15 min). After the
electrolysis was finished, the reaction mixture was concentrated in
vacuo to one fifth of its initial volume (ca. 4 mL); the solid product
was then filtered out, twice washed with ethanol/water solution
(9:1, 5 mL), and dried under reduced pressure.
4.3.2. 20-Amino-2,50-dioxo-50,60,70,80-tetrahydro-2H-spiro[acenaph-
thylene-1,40-chromene]-30-carbonitrile (3b). Yellow solid. Yield
1.59 g (93%); mp 281e282 ꢀC (lit. mp8 245e247 ꢀC); 1H NMR
(300 MHz, DMSO-d6)
d 1.85e2.01 (m, 2H, CH2), 2.06e2.25 (m, 2H,
CH2), 2.62e2.80 (m, 2H, CH2), 7.29 (s, 2H, NH2),7.41 (d, J 7.0 Hz, 1H,
Ar), 7.65 (t, J 7.3 Hz, 1H, Ar), 7.82 (t, J 7.7 Hz, 1H, Ar), 7.89e7.98 (m,
2H, Ar), 8.26 (d, J 8.1 Hz, 1H, Ar) ppm; 13C NMR (75 MHz, DMSO-d6)
19.8, 26.7, 36.0, 51.0, 58.1,113.1,117.5,119.9,121.3,124.5,128.4,128.8,
129.7, 131.4, 132.2, 140.4, 143.3, 158.6, 166.4, 195.3, 203.5 ppm.
4.3.3. 20-Amino-70-methyl-2,50-dioxo-2H,50H-spiro[acenaphthylene-
4.3. General non-catalytic multicomponent procedure
1,40-pyrano-[4,3-b]pyran]-30-carbonitrile (3c). Creamy solid. Yield
1.60 g (90%); mp >300 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d 2.23 (s, 3H,
CH3), 6.41 (s,1H, CH), 7.52 (s, 2H, NH2), 7.53 (d, J 7.0 Hz,1H, Ar), 7.69 (t,
A mixture of acenaphthenequinone 1 (5 mmol), cyclic CH-acid 2
(5 mmol), malononitrile (5 mmol), and water (3 mL) was stirred at
O
CN
O
O
O
O
O
O
2a
-
NC
CH(CN)2
CN
-
-
R1
R1
CN
B
O
1
4
O
O
O
O
O
O
CN
CN
NH2
CN
R1
R1
CN
R1
R1
R1
R1
-
-
O
O
O
N
3a
Scheme 3.

M.N. Elinson et al. / Tetrahedron 68 (2012) 5833e5837
5837
J 7.7 Hz,1H, Ar), 7.85 (t, J 7.7 Hz,1H, Ar), 7.95e8.04 (m, 2H, Ar), 8.32 (d,
J 8.1 Hz, 1H, Ar) ppm; 13C NMR (75 MHz, DMSO-d6)
19.3, 50.9, 57.6,
98.0, 99.2, 117.2, 120.7, 121.9, 125.0, 128.6, 128.9, 129.8, 131.4, 132.0,
carbonitrile (3h). Yellow solid. Yield 1.79 g (93%); mp 203e205 ꢀC;
1H NMR (300 MHz, DMSO-d6)
2.92 (s, 3H, CH3), 3.43 (s, 3H, CH3),
d
d
7.54 (d, J 7.0 Hz, 1H, Ar), 7.63 (s, 2H, NH2), 7.68 (t, J 7.3 Hz, 1H, Ar),
7.84 (t, J 7.3 Hz, 1H, Ar), 7.92e8.03 (m, 2H, Ar), 8.29 (d, J 8.1 Hz, 1H,
141.1, 141.9, 158.6, 159.9, 160.6, 163.9, 203.4 ppm; IR (KBr):
n
¼3473,
3342, 2186,1737,1703,1668,1632,1573,1361,1343 cmꢂ1; MS (EI): m/
z (%)¼356 (12) [M]þ, 312 (16), 285 (100), 230 (82), 202 (35), 175 (30),
156 (22), 43 (88). Anal. Calcd (%) for C21H12N2O4: C 70.78, H 3.39, N
7.86. Found (%): C 70.52, H 3.23, N 7.67.
Ar) ppm; 13C NMR (75 MHz, DMSO-d6)
d
27.6, 29.5, 51.4, 58.3, 88.2,
117.0, 120.6, 121.6, 124.8, 128.5, 128.9, 129.8, 131.8, 131.9, 140.9,
142.5, 149.7, 152.3, 158.2, 160.0, 203.6 ppm; IR (KBr):
n
¼3452, 3399,
3340, 2197, 1722, 1687, 1652, 1598, 1493 cmꢂ1; MS (EI): m/z (%)¼386
(5) [M]þ, 357 (7), 342 (10), 314 (5), 230 (100), 202 (35), 156 (65), 42
(90). Anal. Calcd (%) for C21H14N4O4: C 65.28, H 3.65, N 14.50. Found
(%): C 65.01, H 3.58, N 14.32.
4.3.4. 20-Amino-2,50-dioxo-2H,50H-spiro[acenaphthylene-1,40-pyrano
[3,2-c]chromene]-30-carbonitrile (3d). Creamy solid. Yield 1.81 g
(92%); mp >300 ꢀC (lit. mp9 >300 ꢀC); 1H NMR (300 MHz, DMSO-
d6)
5H, Ar, NH2), 7.88 (t, J 7.7 Hz, 1H, Ar), 7.93e8.11 (m, 3H, Ar), 8.34 (d, J
8.1 Hz, 1H, Ar) ppm; 13C NMR (75 MHz, DMSO-d6)
51.6, 57.7, 102.3,
112.5, 116.7, 117.1, 121.0, 122.1, 122.7, 125.0, 125.1, 128.6, 129.0, 129.8,
131.3, 132.2, 133.6, 141.2, 141.7, 152.1, 155.4, 158.5, 158.9, 203.1 ppm.
d
7.47 (d, J 8.4 Hz, 1H, Ar), 7.55 (t, J 7.7 Hz, 1H, Ar), 7.60e7.82 (m,
4.3.9. (2-Oxoacenaphthylen-1(2H)-ylidene)malononitrile
(4). A
mixture of acenaphthenequinone (5 mmol), malononitrile
1
d
(5 mmol), and water (3 mL) was stirred at 80 ꢀC for 15 min. Then the
reaction mixture was cooled, the precipitate was filtered, washed
with ethanol (5 mL) and dried under reduced pressure to afford the
product 4 as orange solid. Yield 1.13 g (98%); mp 245e246 ꢀC (lit.
4.3.5. 60-Amino-30-methyl-2-oxo-10H,2H-spiro[acenaphthylene-1,40-
pyrano[2,3-c]pyrazole]-50-carbonitrile (3e). Yellow solid. Yield 1.49 g
(91%); mp >300 ꢀC (lit. mp9 298e299 ꢀC); 1H NMR (300 MHz, DMSO-
mp11 244e246 ꢀC); 1H NMR (300 MHz, DMSO-d6)
2H), 8.17 (d, J 7.0 Hz, 1H), 8.34e8.49 (m, 3H) ppm.
d 7.90e8.04 (m,
d6)
d
1.06 (s, 3H, CH3), 7.30 (s, 2H, NH2), 7.46 (d, J 7.0 Hz, 1H, Ar), 7.76 (t,
4.3.10. 2-(1-Hydroxy-2-oxo-1,2-dihydroacenaphthylen-1-yl)-5,5-
dimethylcyclohexane-1,3-dione (5). A mixture of acenaph-
thenequinone 1 (5 mmol), dimedone 2a (5 mmol), and water (3 mL)
was stirred at 80 ꢀC for 15 min. Then the reaction mixture was
cooled, the precipitate was filtered, washed with ethanol (2ꢁ5 mL)
and dried under reduced pressure to afford the product 5 as light
yellow solid. Yield 1.30 g (81%); mp 226e228 ꢀC; 1H NMR
J 7.3 Hz,1H, Ar), 7.90 (t, J 7.3 Hz,1H, Ar), 7.99e8.11 (m, 2H, Ar), 8.39 (d, J
8.1 Hz, 1H, Ar), 12.26 (s, 1H, NH) ppm; 13C NMR (75 MHz, DMSO-d6)
d
9.0, 51.7, 56.0, 96.3, 118.8, 121.2, 122.5, 124.9, 128.9, 129.4, 129.9,
130.6, 132.6, 134.7, 140.9, 141.1, 155.3, 162.5, 203.9 ppm.
4.3.6. 60-Amino-10,30-dimethyl-2-oxo-10H,2H-spiro[acenaphthylene-
1,40-pyrano[2,3-c]pyrazole]-50-carbonitrile (3f). Yellow solid. Yield
(300 MHz, DMSO-d6)
2CH2), 6.05 (s, 1H, OH), 7.40e8.25 (m, 6H, Ar),10.70e12.30 (br s, 1H,
OH) ppm; 13C NMR (75 MHz, DMSO-d6)
27.7 (2C), 32.7, 50.7 (br)
(2C), 85.5 (br), 120.1, 120.6, 121.2, 124.1, 126.5, 128.1, 128.4, 128.5,
d 0.78e1.25 (m, 6H, 2CH3), 1.85e2.45 (m, 4H,
1.59 g (93%); mp 228 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d 0.95 (s, 3H,
CH3), 3.66 (s, 3H, CH3), 7.42e7.56 (m, 3H, Ar, NH2), 7.76 (t, J 7.3 Hz,
1H, Ar), 7.91 (t, J 7.3 Hz, 1H, Ar), 8.01e8.12 (m, 2H, Ar), 8.40 (d, J
d
8.1 Hz, 1H, Ar) ppm; 13C NMR (75 MHz, DMSO-d6)
d
11.7, 33.6, 52.3,
130.3, 132.3, 142.7, 187.6, 192.5 (br) (2C) ppm; IR (KBr):
n¼3292,
56.9, 94.8, 118.3, 121.4, 122.5, 125.1, 129.0, 129.4, 130.0, 130.6, 132.7,
3049, 2959, 1739, 1602, 1356, 1245, 782 cmꢂ1; HRMS (ESI) calcd for
C20H18NaO4 345.1097, found 345.1090.
140.6, 141.0, 141.2, 145.2, 161.2, 203.7 ppm; IR (KBr):
n
¼3388, 3304,
3216, 2196, 1724, 1648, 1560, 1392 cmꢂ1; MS (EI): m/z (%)¼342 (15)
[M]þ, 313 (32), 276 (23), 244 (60), 230 (73), 202 (42), 176 (54), 112
(35), 66 (43), 41 (100). Anal. Calcd (%) for C20H14N4O2: C 70.17, H
4.12, N 16.37. Found (%): C 69.95, H 4.03, N 16.18.
References and notes
1. Nefzi, A.; Ostresh, J. M.; Houghten, R. A. Chem. Rev. 1997, 97, 449e472.
2. Mironov, M. A. QSAR Comb. Sci. 2006, 25, 423e431.
4.3.7. 60-Amino-30-methyl-2-oxo-10-phenyl-10H,2H-spiro[acenaph-
3. The term ‘privileged scaffolds or structures’ was originally introduced by
Merck researchers in their work on benzodiazepins Evans, B. E.; Rittle, K. E.;
Bock, M. G.; DiPardo, R. M.; Freidinger, R. M.; Whitter, W. L.; Lundell, G. F.;
Veber, D. F.; Anderson, P. S.; Chang, R. S. L.; Lotti, V. J.; Cerino, D. J.; Chen, T. B.;
Kling, P. J.; Kunkel, K. A.; Springer, J. P.; Hirshfield, J. J. Med. Chem. 1988, 31,
2235e2246.
thylene-1,40-pyrano-[2,3-c]pyrazole]-50-carbonitrile
(3g). Yellow
solid. Yield 1.92 g (95%); mp 193e196 ꢀC; 1H NMR (300 MHz, DMSO-
d6) 1.07 (s, 3H, CH3), 7.36 (t, J 7.0 Hz, 1H, Ar), 7.47e7.56 (m, 2H, Ar),
d
7.60 (d, J 7.0 Hz, 1H, Ar), 7.65 (s, 2H, NH2), 7.74e7.88 (m, 3H, Ar), 7.94
(t, J 7.7 Hz, 1H, Ar), 8.03e8.16 (m, 2H, Ar), 8.43 (d, J 8.1 Hz, 1H, Ar)
4. Poupaert, J.; Carato, P.; Colacillo, E. Curr. Med. Chem. 2005, 12, 877e885.
5. For examples, of natural compounds containing the chromene fragment, seeThe
FlavonoidsdAdvances in Research; Harborne, J. B., Ed.; Chapman & Hall: London,
1988.
ppm; 13C NMR (75 MHz, DMSO-d6)
d 11.9, 52.1, 56.9, 97.1,118.0,120.2
(2C), 121.7, 122.7, 125.3, 126.6, 129.0, 129.4 (2C), 129.5, 130.0, 130.5,
132.8, 137.2, 140.4, 141.1, 143.8, 144.9, 161.0, 203.4 ppm; IR (KBr):
€
€
6. Skommer, J.; Wlodkowic, D.; Matto, M.; Eray, M.; Pelkonen, J. Leuk. Res. 2006,
30, 322e331.
¼3357, 3299, 3189, 2201, 1717, 1648, 1599, 1523, 1383 cmꢂ1; MS
7. Elinson, M. N.; Dorofeev, A. S.; Miloserdov, F. M.; Ilovaisky, A. I.; Feducovich, S.
K.; Belyakov, P. A.; Nikishin, G. I. Adv. Synth. Catal. 2008, 350, 591e601.
8. Dabiri, M.; Bahramnejad, M.; Baghbanzadeh, M. Tetrahedron 2009, 65,
9443e9447.
9. Saeedi, M.; Heravi, M. M.; Beheshtiha, Y. S.; Oskooie, H. A. Tetrahedron 2010, 66,
5345e5348.
n
(EI): m/z (%)¼404 (3) [M]þ, 375 (5), 338 (12), 309 (14), 230 (100), 202
(45), 174 (85), 91 (62), 77 (86). Anal. Calcd (%) for C25H16N4O2: C
74.25, H 3.99, N 13.85. Found (%): C 74.01, H 3.75, N 13.62.
10. Wender, P. A.; Handy, S. T.; Wright, D. L. Chem. Ind. (London, U. K.) 1977,
765e769.
11. Dandia, A.; Jain, A. K.; Bhati, D. S. Tetrahedron Lett. 2011, 52, 5333e5337.
4.3.8. 70-Amino-10,30-dimethyl-2,20,40-trioxo-10,20,30,40-tetrahydro-
2H-spiro[acenaphthylene-1,50-pyrano[2,3-d]pyrimidine]-60-