Synthesis of pyrano[3,4-c]chromene skeleton via CuI-mediated domino Knoevenagel hetero-Diels-Alder reaction

Article abstract of DOI:10.1002/jhet.447

(Chemical Equation Presented) A new strategy involving domino Knoevenagel hetero-Diels-Alder reaction is described for the preparation of pyrano[3,4-c]chromenes scaffold. Reaction of O-propargylated salicylaldehyde with benzoylacetonitrile or Meldrum's ac

Full text of DOI:10.1002/jhet.447

1200
Synthesis of Pyrano[3,4-c]chromene Skeleton via CuI-Mediated
Domino Knoevenagel Hetero-Diels-Alder Reaction
Vol 47
Marjan Mollazadeh,a Malihe Javan Khoshkholgh,a Saeed Balalaie,a*
Frank Rominger,b and Hamid Reza Bijanzadehc
aDepartment of Chemistry, K.N. Toosi University of Technology, Tehran, Iran
bOrganisch-Chemisches Institut der Universitaet Heidelberg, Im Neuenheimer Feld 270,
69120 Heidelberg, Germany
cDepartment of Chemistry, Tarbiat Modares University, Tehran, Iran
*E-mail: balalaie@yahoo.com or balalaie@kntu.ac.ir
Received November 19, 2009
DOI 10.1002/jhet.447
Published online 28 July 2010 in Wiley Online Library (wileyonlinelibrary.com).
A new strategy involving domino Knoevenagel hetero-Diels-Alder reaction is described for the prepa-
ration of pyrano[3,4-c]chromenes scaffold. Reaction of O-propargylated salicylaldehyde with benzoyla-
cetonitrile or Meldrum’s acid in the presence of CuI and diammonium hydrogen phosphate affords
pyrano[3,4-c]chromenes with good yields and high bond-forming efficiency.
J. Heterocyclic Chem., 57, 1200 (2010).
INTRODUCTION
chromene family are effective photoaffinity reagents for
the cytochrome P450 superfamily of enzymes and prob-
ably other proteins as well [5]. Because of the unique
properties of pyranochromene skeletons, the develop-
ments of synthetic methods that enable facile access to
these useful entities are desirable.
The hetero-Diels-Alder reaction is one of the most
powerful methods for the preparation of heterocyclic
compounds and it has wide applications in the synthesis
of biologically active compounds and natural products
[1]. Among these reactions, domino Knoevenagel het-
ero-Diels-Alder reactions provide efficient and rapid
means for the construction of polyheterocyclic com-
pounds [2], especially pyran moieties. 2H-pyran deriva-
tives are present in many natural products with different
biological activities [3]. A family of xanthone natural
products with potent antiviral activity has been isolated
from plants, and it is a potent inhibitor of human immu-
nodeficiency virus-1 reverse transcriptase [4]. Some 2H-
In most reported reactions, in domino Knoevenagel
hetero-Diels-Alder reactions, alkenes were used as a
dienophile. The use of alkynes was limited due to their
less reactivity when compared with alkenes. The activa-
tion of alkynes toward a variety of organic transforma-
tions is an exciting field in organic synthesis. In the
recent years, the most important strategy for this aim
usually consists of applying transition metal catalysts
[6]. The activation of alkynes using various metals has
C
V
2010 HeteroCorporation

September 2010
Synthesis of Pyrano[3,4-c]chromene Skeleton via CuI-Mediated
Domino Knoevenagel Hetero-Diels-Alder Reaction
1201
Scheme 1. Synthesis of pyrano[3,4-c]chromene in the presence of CuI.
as the base. The yields and reaction times are summar-
ized in Table 1.
According to the obtained results, methanol was
selected as the best solvent and the optimized molar ra-
tio of CuI was 40%.
Under the optimal reaction conditions, pyrano[2,3-
c]chromenes 3a–g were prepared in 61–75% yields (Ta-
ble 2). The best result was obtained using aldehyde 1d
(entry 4) that contained a nitro group. It seems that the
electron-withdrawing substituent increase the yields of
this transformation, as opposed to decreased yield
obtained with electron-donating substituent (entry 3).
Structures of the products were confirmed by their
been extensively investigated and described in the litera-
ture [7]. Selection of the proper Lewis acid to achieve
this purpose is more important. Among the metal cata-
lysts, coinage metals including copper, silver, and gold
play an essential role in this field [8]. Therefore, devel-
opment of new synthetic strategy based on coinage met-
als is very attractive.
1
spectroscopic data. In H NMR of compounds 3a–g, the
AOCH2 group resonates at d ¼ 4.60 and 4.72 ppm as a
doublet with J ¼ 11.5–11.8 Hz. The ACH proton
appears at d ¼ 4.79–4.93 ppm as a singlet, and the ole-
finic proton ¼¼CH resonates at d ¼ 7.12–7.22 ppm as a
singlet. The corresponding signal of the AOCH2 and the
shielded olefinic ¼¼CACN carbons in 13C NMR appear
at 65.0–66.4 and 83.8–85.7 ppm, respectively.
During the past decade, copper (Cu) (I)-catalyzed cy-
clization of alkynes has represented a convenient tool
for the preparation of heterocycles [8]. Copper (I) iodide
(CuI), which has been applied in the synthetic and me-
dicinal chemistry, has received much attention due to
several advantages over the other coinage metals;
including the low cost, insensitivity to air, simple exper-
imental procedure, and no toxicity. Therefore, discovery
of novel Cu (I)-catalyzed reaction of alkynes is of great
interest [9].
This reaction involves two steps: (a) the Knoevenagel
condensation between benzoylacetonitrile 2 and the
propargylated salicylaldehydes 1a–g. DAHP acts as a
mild base for Knoevenagel condensation and formation
of 1-oxa-1,3-butadiene that could react as a heterodiene
to form the intermediate. (b) hetero-Diels-Alder reaction
of olefinic intermediate in the presence of CuI to afford
compounds 3a–g. Although the mechanism for this
transformation is not clear, it seems that CuI could
active the unactivated triple bond to act as a dienophile
in hetero-Diels-Alder reaction (Scheme 2).
RESULTS AND DISCUSSION
Following our research work to introduce domino
Knoevenagel hetero-Diels-Alder reaction using unacti-
vated alkynes with CuI [10] and to enlarge the scope of
this synthetic methodology, herein, we report a domino
Knoevenagel hetero-Diels-Alder reaction using O-prop-
argylated salicyclaldehyde derivatives 1(a–g) and ben-
zoylacetonitrile 2 as unactivated terminal alkynes and an
active methylene compound, respectively, in the pres-
ence of CuI (Scheme 1). The products are functionalized
pyrano[3,4-c]chromenes 3(a–g).
Initially, O-propargylated salicylaldehydes as the
starting material were prepared in excellent yields using
reaction of propargyl bromide and salicylaldehydes
derivatives in dimethyl formamide and in the presence
of K2CO3. To optimize the desired reaction conditions,
the reaction of compound 1a with benzoylacetonitrile 2
was used as the model system. The experimental results
are summarized in Table 1.
As a logical extension of domino Knoevenagel het-
ero-Diels-Alder reaction with unactivated alkynes, we
became interested in the synthesis of functionalized pyr-
anochromene derivatives, whose structures have been
found in vast numbers of natural products and pharma-
ceuticals. Reaction of O-propargylated salicylaldehyde
Table 1
Synthesis of pyrano[3,4-c]chromene using domino Knoevenagel
hetero-Diels-Alder reaction, the role of base type and molar ratio of
CuI on the formation of product 3a.
Lewis
acid
Time Yield
(h)a
Entry
Solvent
Base
(%)
1
2
3
4
5
5
6
7
–
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeCN
MeCN
(NH4)2HPO4
(NH4)2HPO4
(NH4)2HPO4
(NH4)2HPO4
(NH4)2HPO4
–
72
72
48
48
48
72
48
48
–
Trace
40
61
57
CuI (20%)
CuI (30%)
CuI (40%)
CuI (50%)
CuI (40%)
CuI (40%)
CuI (40%)
Heating aldehyde 1a and 2 in methanol under reflux
condition for 72 h did not lead to the desired product.
So, CuI was used as the Lewis acid. The reaction was
done using different ratios of CuI in the presence of dia-
mmonium hydrogen phosphate (DAHP) or triethylamine
–
50
(NH4)2HPO4
Et3N
28
a Completion of the reaction.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Table 2
CuI-mediated domino hetero-Diels-Alder reaction of aldehydes 1a–g with 2a.
Entry
1
Aldehyde
Product
Time (h)
48
Yield (%)b
61
2
3
4
32
24
20
65
61
75
5
12
70
6
16
67
7
12
67
a All of the reaction were performed with propargylated aldehydes 1a–g (1 mmol), benzoylacetonitrile 2 (1.2 mmol), (NH4)2HPO4 (20 mol %), and
CuI (40 mol %) in methanol at reflux.
b Isolated yield.

September 2010
Synthesis of Pyrano[3,4-c]chromene Skeleton via CuI-Mediated
Domino Knoevenagel Hetero-Diels-Alder Reaction
1203
Scheme 2. Plausible mechanism for the synthesis of pyrano[3,4-c]chromene skeleton via domino Knoevenagel hetero-Diels-Alder reaction using
CuI.
Scheme 3. Synthesis of pyrano[3,4-c]chromenes 8 in the presence of CuI and Meldrum’s acid.
Table 3
Synthesis of pyrano[3,4-c]chromene using domino Knoevenagel hetero-Diels-Alder reaction, the role of solvent, base type,
and molar ratio of CuI on the formation of product 8a.
Entry
Lewis acid
Solvent
Base
Time (h)
Yield (%)
1
2
–
MeCN
MeCN
MeCN
MeCN
MeCN
MeOH
EtOH
(NH4)2HPO4
(NH4)2HPO4
(NH4)2HPO4
(NH4)2HPO4
(NH4)2HPO4
(NH4)2HPO4
(NH4)2HPO4
(NH4)2HPO4
–
120
120
72
72
72
80
96
96
72
48
72
–
40
CuI (20%)
CuI (30%)
CuI (40%)
CuI (50%)
CuI (40%)
CuI (40%)
CuI (40%)
CuI (40%)
CuI (40%)
CuI (40%)
3
4
45
68
5
6
60
50
7
8
Trace
Trace
–
H2O
9
MeCN
MeCN
MeCN
13
14
Et3N
K2CO3
33
38
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1204
M. Mollazadeh, M. J. Khoshkholgh, S. Balalaie, F. Rominger, and H. R. Bijanzadeh
Vol 47
Scheme 4. Plausible mechanism for the synthesis of pyrano[3,4-c]chromene skeleton via activation of p-triple bond using CuI.
with Meldrum’s acid 7 in the presence of CuI should
afford the desired pyranochromenes 8 (Scheme 3).
Reaction of O-propargylated salicylaldehyde 1a with
Meldrum’s acid 7 was selected as a model, and the reac-
tion was done in the presence of different ratios of CuI
and also diammonium hydrogen phosphate as a base.
The details were summarized in Table 3. In this reac-
tion, the best yield was obtained using 40% CuI. The
presence of CuI is necessary for the progress of reaction
and without CuI, the Knoevenagel product were
obtained as the sole product.
contain the carboxylic acid functional group and the
product 8d is the sole product of reaction. Existence of
a catalyst such as CuI is necessary to activate the triple
bond through complexation. CuI could coordinate the
triple bond and the activated triple bond is ready to pro-
ceed hetero-Diels-Alder reaction to form pyrano[3,4-
c]chromene. Reactions were done under Argon condi-
tions to prevent the oxidation of Cu (I) to Cu (II).
On the basis of established Meldrum’s acid chemistry,
it is reasonable to assume that the formation of aryliden
Meldrum’s acid apparently results from initial addition
of Meldrum’s acid with O-propargylated salicylaldehyde
to obtain in situ dieneone 8 (Scheme 4). This intermedi-
ate under the reflux conditions and hetero-Diels-Alder
reaction converted to pyran skeleton.
The presence of the pyran skeleton is supported by
1
the spectroscopic data. In the H NMR of compound 8a,
the AOCH2 group shows two separated doublet with
J ¼ 12 Hz and also a carboxylic acid peak at d ¼ 12.75
ppm. The high J value is related to the torsion angle
that is 174.6ꢀ. The structure of compound 8a was con-
firmed using X-ray structure data. The product 8a could
form a dimmer via intermolecular hydrogen bonding
between two carboxylic acid groups (Figs. 1 and 2).
Under the optimal reaction conditions, the best result
was obtained using aldehyde 1d (entry 4) that contained
a nitro group (Table 4). In entry 4, the desired product
could be decarboxylated and the final product does not
Figure 1. X-ray structure of compound 8a.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2010
Synthesis of Pyrano[3,4-c]chromene Skeleton via CuI-Mediated
Domino Knoevenagel Hetero-Diels-Alder Reaction
1205
Figure 2. Intermolecular hydrogen bonding in compound 8a.
(NH4)2HPO4 (28 mg, 0.2 equiv.) in methanol (25 mL) was
refluxed. The progress of reaction was monitored by thin layer
chromatography (Petroleum ether: EtOAc 3:1). After comple-
tion of the reaction, the mixture of reaction was filtered and
the solvent was evaporated under reduced pressure. The
obtained oil was crystalizated in diethyl ether.
CONCLUSIONS
In conclusion, we have described an efficient
approach with a high bond-forming efficiency for the
synthesis of pyrano[3,4-c]chromene skeleton via domino
Knoevenagel hetero-Diels-Alder reaction started from
simple and inexpensive materials. Reaction of O-propar-
gylated salicylaldehyde with active methylene com-
pounds such as benzoylacetonitrile and Meldrum’s acid
leads to functionalized pyranochromenes. In this reac-
tion, CuI (40%) was used as Lewis acid for the activa-
tion of unactivated alkynes and DAHP (20%) as the
base. The products have nitrile and carboxylic acid
functional groups that could be used for further
conversion.
2-Phenyl-5H,10bH-pyrano[3,4-c]chromene-1-carbonitri le
(3a). This compound was obtained as a white solid; yield
61%; mp (Dec) 200.3ꢀC; ir (potassium bromide): 2203, 1710,
1
1615, 1578 cmꢁ1; H NMR (500 MHz, DMSO-d6): d 4.60 (d,
J ¼ 11.5 Hz, 1H, AOCH2), 4.72 (d, J ¼ 11.5 Hz, 1H,
AOCH2), 4.79 (s, 1H, ACH), 6.85 (d, J ¼ 7.9 Hz, 1H, HAr),
7.01 (t, J ¼ 7.5 Hz, 1H, HAr), 7.15 (s, 1H, ¼¼CH), 7.22 (t, J ¼
7.5 Hz, 1H, HAr), 7.53–7.61 (m, 3H, HAr), 7.69 (d, J ¼ 7.9
Hz, 1H, HAr), 7.75 ppm (d, J ¼ 7.2 Hz, 2H, HAr); 13C NMR
(125 MHz, DMSO-d6): d 31.8, 66.0, 85.7, 110.3, 118.3, 120.7,
121.8, 125.7, 127.0, 129.0, 129.3, 129.5, 132.2, 132.3, 137.8,
155.1, 163.6 ppm; HR ms (70 eV, electron impact): m/z [M]þꢂ
Calcd. for C19H13NO2: 287.0946; Found: 287.0959.
EXPERIMENTAL
9-Bromo-2-phenyl-5H,10bH-pyrano[3,4-c]chromene-1-car-
bonitrile (3b). This compound was obtained as a white solid;
yield 65%; mp 197–198ꢀC; IR (potassium bromide): 2204,
Commercially available materials were used without further
purification. Melting points were determined with Electrother-
mal 9100 apparatus and were uncorrected. IR spectra were
obtained on an ABB FTIR (FTLA 2000) spectrometer. 1H
1707, 1614, 1577 cmꢁ1 1H NMR (300 MHz, DMSO-d6): d
;
4.58 (d, J ¼ 11.6 Hz, 1H, AOCH2), 4.73 (d, J ¼ 11.6 Hz, 1H,
AOCH2), 4.80 (s, 1H, ACH), 6.81 (d, J ¼ 8.7 Hz, 1H, HAr),
7.16 (s, 1H, ¼¼CH), 7.36 (dd, J ¼ 8.7, 2.1 Hz, 1H, HAr), 7.49–
7.60 (m, 3H, HAr), 7.74 (d, J ¼ 7.2 Hz, 2H, HAr), 7.80 ppm
(d, J ¼ 2.1 Hz, 1H, HAr); 13C NMR (75 MHz, DMSO-d6): d
30.6, 65.3, 84.3, 108.4, 112.0, 119.7, 126.8, 128.2, 128.6,
128.8, 131.1, 131.2, 131.5, 137.4, 153.6, 163.0 ppm; HR ms
(70 eV, electron impact): m/z [M]þꢂ Calcd. for C19H12NO2
79Br: 365.0052; Found: 365.0039. [M þ 2]þꢂ Calcd. for
C19H12NO2 81Br: 367.0031; Found: 367.0026.
NMR and 13C NMR were run on
a Bruker DRX-300
AVANCE at 500 and 300 MHz for 1H NMR and 125 and
75 MHz for 13C NMR. CDCl3 and DMSO-d6 were used as
solvents. High resolution mass spectra were recorded on JEOL
JMS-700 (HR-EI) spectrometer and Mass spectra were
obtained using
instrument.
a GC-MS Hewlett Packard (EI, 70 eV)
General procedure for the synthesis of pyranochromenes
3a–g derivatives via hetero-Diels-Alder reactions. A solution
of O-propargylated salicylaldehydes 1a–g (1 mmol), benzoyla-
cetonitrile (174 mg, 1.2 mmol), CuI (0.4 equiv., 76 mg), and
9-Methyl-2-phenyl-5H,10bH-pyrano[3,4-c]chromene-1-car-
bonitrile (3c). This compound was obtained as a white solid,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1206
M. Mollazadeh, M. J. Khoshkholgh, S. Balalaie, F. Rominger, and H. R. Bijanzadeh
Vol 47
Table 4
One-pot synthesis of pyrano[3,4-c]chromene via domino Knoevenagel hetero-Diels-Alder reaction.
Entry
1
Aldehyde
Product
Time (h)
72
Yield (%)b
68
2
48
65
3
4
5
48
63
81
61
48
72
yield 61%; mp 169–171ꢀC; IR (potassium bromide): 2205,
1708, 1620, 1600 cmꢁ1 1H NMR (300 MHz, DMSO-d6): d
ppm; HR ms (70 eV, electron impact): m/z [M]þꢂ Calcd. for
C20H15NO2: 301.1103; Found: 301.1067.
;
2.25 (s, 3H, Me), 4.54 (d, J ¼ 11.6 Hz, 1H, AOCH2), 4.66 (d,
J ¼ 11.6 Hz, 1H, AOCH2), 4.71 (s, 1H, ACH), 6.72 (d, J ¼
8.2 Hz, 1H, HAr), 7.00 (d, J ¼ 8.2 Hz, 1H, HAr), 7.12 (s, 1H,
¼¼CH), 7.46 (s, 1H, HAr), 7.50–7.60 (m, 3H, HAr), 7.74 ppm
(dd, J ¼ 7.7, 1.5 Hz, 2H, HAr); 13C NMR (75 MHz, DMSO-
d6): d 20.4, 30.9, 65.0, 84.9, 109.6, 117.2, 119.9, 124.4, 126.4,
128.1, 128.6, 128.9, 129.5, 131.3, 131.4, 136.8, 152.0, 162.7
9-Nitro-2-phenyl-5H,10bH-pyrano[3,4-c]chromene-1-car-
bonitrile (3d). This compound was obtained as a white solid,
yield 75%; mp 185.5–187.5ꢀC; IR (potassium bromide): 2209,
1708, 1616, 1580, 1514, 1343 cmꢁ1 1H NMR (300 MHz,
;
DMSO-d6): d 4.76 (d, J ¼ 11.7 Hz, 1H, AOCH2), 4.89 (d, J
¼ 11.7 Hz, 1H, AOCH2), 4.93 (s, 1H, ACH), 7.05 (d, J ¼ 9.1
Hz, 1H, HAr), 7.22 (s, 1H, ¼¼CH), 7.51–7.61 (m, 3H, HAr),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2010
Synthesis of Pyrano[3,4-c]chromene Skeleton via CuI-Mediated
Domino Knoevenagel Hetero-Diels-Alder Reaction
1207
7.75 (d, J ¼ 6.6 Hz, 2H, HAr), 8.10 (dd, J ¼ 9.1, 2.0 Hz, 1H,
HAr), 8.63 ppm (d, J ¼ 2.0 Hz, 1H, HAr); 13C NMR (75 MHz,
DMSO-d6): d 30.7, 66.3, 83.8, 107.2, 118.5, 119.7, 122.3,
124.5, 125.4, 128.1,128.7, 131.0, 131.7, 137.8, 140.6, 159.9,
162.9 ppm; HR ms (70 eV, electron impact): m/z [M]þꢂ Calcd.
for C19H12N2O4: 332.0797; Found: 332.0769.
7-Bromo-9-chloro-2-phenyl-5H,10bH-pyrano[3,4-c]chromene-
1-carbonitrile (3e). This compound was obtained as a white
solid, yield 70%; mp 195–196ꢀC; IR (potassium bromide):
2205, 1710, 1613, 1450 cmꢁ1 1H NMR (300 MHz, DMSO-
;
d6): d 4.71 (d, J ¼ 11.8 Hz, 1H, AOCH2), 4.86 (s, 1H, ACH),
4.89 (d, J ¼ 11.8 Hz, 1H, AOCH2), 7.20 (s, 1H, ¼¼CH), 7.51–
7.59 (m, 3H, HAr), 7.67 (s, 2H, HAr), 7.76 ppm (d, J ¼ 6.79
Hz, 2H, HAr); 13C NMR (75 MHz, DMSO-d6): d 31.0, 66.4,
83.9, 107.7, 111.6, 119.6, 124.6, 125.3, 127.7, 128.2, 128.6,
131.0, 131.6, 137.7, 149.8, 163.1 ppm; HR ms (70 eV, elec-
tron impact): m/z [M]þꢂ Calcd. for C19H11NO279Br35Cl:
3414, 1761, 1692 cmꢁ1 1H NMR (300 MHz, DMSO-d6): d
;
3.43 (d, J ¼ 12.9 Hz, 1H, ACHCOOH), 4.34–4.38 (m, 2H,
AOCH2, ACH), 4.65 (d, J ¼ 12.0 Hz, 1H, AOCH2), 6.87 (d,
J ¼ 7.7 Hz, 1H, HAr), 6.92 (t, J ¼ 7.4 Hz, 1H, HAr), 7.05 (s,
1H, ¼¼CH), 7.16 (t, J ¼ 7.4 Hz, 1H, HAr), 7.24 (d, J ¼ 7.7
Hz, 1H, HAr), 12.50 ppm (brs, 1H, ACOOH); 13C NMR (125
MHz, DMSO-d6): d 32.1, 53.2, 65.0, 115.0, 118.5, 122.3,
123.8, 129.1, 129.4, 137.7, 155.6, 166.9, 170.2 ppm; ms (70
eV, electron impact): m/z 246 (Mþ), 245 (Mþ ꢁ H), 201 (Mþ
ꢁ COOH), 173 (Mþ ꢁ C2HO3).
Colorless crystal (polyhedron), dimensions 0.37 ꢃ 0.22 ꢃ
0.13 mm3, crystal system monoclinic, space group P21/n, Z ¼ 4,
˚
˚
˚
3
a ¼ 8.9193(12) A, b ¼ 12.4115(16) A, c ¼ 9.9814(13) A, a ¼
ꢀ
˚
90 , b ¼ 97.889(3) deg, c ¼ 90 deg, V ¼ 1094.5(2) A , q ¼
1.494 g/cm3, T ¼ 200(2) K, Hmax ¼ 28.31ꢀ, radiation Mo Ka, k
ꢀ
˚
¼ 0.71073 A, 0.3 omega scans with CCD area detector, cover-
ing a whole sphere in reciprocal space, 11,243 reflections meas-
ured, 2724 unique [R(int) ¼ 0.0243], 2510 observed [I > 2r(I)],
intensities were corrected for Lorentz and polarization effects,
an empirical absorption correction was applied using SADABS1
based on the Laue symmetry of the reciprocal space, mu ¼ 0.12
mmꢁ1, Tmin ¼ 0.96, Tmax ¼ 0.99, structure solved by direct
methods and refined against F2 with a Full-matrix least-squares
algorithm using the SHELXTL-PLUS (6.10) software package
[11], 171 parameters refined, hydrogen atoms were treated using
appropriate riding models, except of H3 and H16 at the carboxyl
group, which were refined isotropically, goodness of fit 1.13 for
observed reflections, final residual values R1(F) ¼ 0.061,
wR(F2) ¼ 0.158 for observed reflections, residual electron den-
398.9662; Found: 398.9637. [M
þ
2]þꢂ Calcd. for
C19H11NO279Br37Cl: 400.9641; Found: 400.9629. [M þ 4]þꢂ
Calcd. for C19H11NO281Br37Cl: 402.9612; Found: 402.9644.
7,9-Dibromo-2-phenyl-5H,10bH-pyrano[3,4-c]chromene-1-
carbonitrile (3f). This compound was obtained as a white
solid, yield 67%; mp 202.4–203.5ꢀC; IR (potassium bromide):
2204, 1709, 1613, 1599 cmꢁ1 1H NMR (300 MHz, DMSO-
;
d6): d 4.71 (d, J ¼ 11.8 Hz, 1H, AOCH2), 4.87 (s, 1H, ACH),
4.89 (d, J ¼ 11.8 Hz, 1H, AOCH2), 7.20 (s, 1H, ¼¼CH), 7.50–
7.61 (m, 3H, HAr), 7.74–7.80 ppm (m, 3H, HAr); 13C NMR
(75 MHz, DMSO-d6): d 30.9, 66.4, 83.9, 107.7, 111.9, 112.0,
119.6, 128.2, 128.6, 131.0, 131.6, 133.6, 137.7, 150.2, 163.1
ppm; HR ms (70 eV, electron impact): m/z [M]þꢂ Calcd. for
C19H11NO279Br2: 442.9157; Found: 442.9195. [M þ 2]þꢂ
Calcd. for C19H11NO279Br81Br: 444.9136; Found: 444.9091.
[M þ 4]þꢂ Calcd. for C19H11NO281Br2: 446.9115; Found:
446.9069.
sity ꢁ0.58 to 0.75 eAꢁ3. CCDC 742487 contains the supplemen-
˚
tary crystallographic data for this article. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
9-Bromo-2-oxo-1,10b-dihydro-2H,5H-pyrano[3,4-c]chromene-
1-carboxylic acid (8b). This compound was obtained as a white
solid, yield 65%; mp (ꢀC) 230ꢀC; IR (potassium bromide):
3447, 1768, 1680 cmꢁ1; 1H NMR (300 MHz, DMSO-d6): d 3.47
(d, J ¼ 13.0 Hz, 1H, ACHCOOH), 4.34–4.40 (m, 2H, AOCH2,
ACH), 4.69 (d, J ¼ 12.1 Hz, 1H, AOCH2), 6.87 (d, J ¼ 8.6 Hz,
1H, HAr), 7.07 (s, 1H, HAr), 7.32–7.38 (m, 2H, ¼¼CH, HAr),
12.65 ppm (brs, 1H, ACOOH); 13C NMR (75 MHz, DMSO-d6):
d 31.1, 52.0, 64.2, 112.7, 113.1, 119.7, 125.3, 130.8, 130.9,
137.1, 154.1, 165.6, 169.0 ppm; ms (70 eV, electron impact): m/
z 326 (Mþ þ2), 324 (Mþ), 281 ([C13H9O581Br – COOH]þ), 279
([C13H9O579Br – COOH]þ), 253 ([C13H9O581Br – C2HO3]þ),
251 ([C13H9O579Br – C2HO3]þ).
9-Methyl-2-oxo-1,10b-dihydro-2H,5H-pyrano[3,4-c]chromene-
1-carboxylic acid (8c). This compound was obtained as a white
solid; yield 63%; mp (ꢀC) 235ꢀC; IR (potassium bromide):
3416, 1764, 1690 cmꢁ1 1H NMR (300 MHz, DMSO-d6): d
;
2.14 (s,3H, Me), 3.39 (d, J ¼ 12.7 Hz, 1H, ACHCOOH),
4.27–4.30 (m, 2H, AOCH2, ACH), 4.59 (d, J ¼ 12.0 Hz, 1H,
AOCH2), 6.74 (d, J ¼ 7.5 Hz, 1H, HAr), 6.93–7.04 (m, 3H,
HAr, ¼¼CH), 12.55 ppm (brs, 1H, ACOOH); ms (70 eV, elec-
tron impact): m/z 260 (Mþ), 215 (Mþ ꢁ COOH). Because of
the low solubility of this compound in DMSO-d6, we were not
successful to have 13C NMR.
7,9-Dichloro-2-phenyl-5H,10bH-pyrano[3,4-c]chromene-1-
carbonitrile (3g). This compound was obtained as a white
solid, yield 67%; mp 193–195ꢀC; ir (potassium bromide):
;
2205, 1710, 1611, 1600 cmꢁ1 1H NMR (300 MHz, DMSO-
d6): d 4.72 (d, J ¼ 11.6 Hz, 1H, H-5), 4.85 (s, 1H, ACH),
4.90 (d, J ¼ 11.6 Hz, 1H, AOCH2), 7.20 (s, 1H, ¼¼CH), 7.50–
7.61 (m, 4H, HAr), 7.64–7.65 (m, 1H, HAr), 7.76 ppm (dd, J ¼
7.3, 1.6 Hz, 2H, HAr); 13C NMR (75 MHz, DMSO-d6): d 31.0,
66.3, 83.8, 107.6, 119.6, 122.2, 124.19, 124.2, 124.7, 127.9,
128.2, 128.3, 128.6, 131.0, 131.6, 137.7, 148.9, 163.1 ppm;
HR ms (70 eV, electron impact): m/z [M]þꢂ Calcd. for
C19H11NO235Cl2: 355.0166; Found: 355.0198. [Mþ2]þꢂ Calcd.
for C19H11NO235Cl37Cl: 357.0138; Found: 357.0185. [M þ
4]þꢂ Calcd. for C19H11NO237Cl2: 359.0108; Found: 359.0138.
General procedure for the synthesis of pyranochromenes
8 derivatives via hetero-Diels-Alder reactions. A solution of
O-propargylated salicylaldehydes (1 mmol), Meldrum’s acid
(172 mg, 1.2 mmol), CuI (0.4 equiv., 76 mg), and
(NH4)2HPO4 (28 mg, 0.2 equiv.) in acetonitrile (25 mL) was
refluxed. The progress of reaction was monitored by TLC (Pe-
troleum ether:EtOAc 4:1). After completion of the reaction,
the mixture of reaction was filtered and the solvent was evapo-
rated under reduced pressure. Further purification was done
using crystallization in acetonitrile.
9-Nitro-2-oxo-1,10b-dihydro-2H,5H-pyrano[3,4-c]chromene
(8d). This compound was obtained as a white solid; yield
81%; mp 242–243ꢀC; IR (potassium bromide): 3407, 1782,
2-Oxo-1,10b-dihydro-2H,5H-pyrano[3,4-c]chromene-1-car-
boxylic acid (8a). This compound was obtained as a white
solid, yield 72%; mp (Dec) 250ꢀC; ir (potassium bromide):
1
1680 cmꢁ1; H NMR (300 MHz, DMSO-d6): d 2.49–2.62 (m,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1208
M. Mollazadeh, M. J. Khoshkholgh, S. Balalaie, F. Rominger, and H. R. Bijanzadeh
Vol 47
Zhu, J.; Bienayme, H., Eds.; Wiley: Weinheim, 2005; p 121; (c) Tie-
tze, L. F.; Rackelmann, N. Pure Appl Chem 2004, 76, 1967; (d) Shan-
mugasundaram, M.; Manikandan, S.; Raghunathan, R. Tetrahedron
2002, 58, 997.
1H, ACH), 3.32–3.43 (m, 1H, ACH2), 4.16 (dd, J ¼ 13.3, 4.4
Hz, 1H, ACH2), 4.56 (d, J ¼ 12.3 Hz, 1H, AOCH2), 4.84 (d,
J ¼ 12.3 Hz, 1H, AOCH2), 7.07 (d, J ¼ 8.5 Hz, 2H, HAr
,
¼¼CH), 8.03 (dd, J ¼ 8.5, 2.3 Hz, 1H, HAr), 8.33 (d, J ¼ 2.3
Hz, 1H, HAr); 13C NMR (75 MHz, DMSO-d6): d 28.4, 34.4,
64.2, 111.9, 118.0, 123.6, 124.7, 124.8, 138.1, 141.2, 159.2,
167.0 ppm; ms (70 eV, electron impact): m/z 247 (Mþ), 230
(Mþ ꢁ OH), 219 (Mþ ꢁ CO).
[3] (a) Tietze, L. F.; Harfiel, U.; Hu¨bsch, T.; Voß, E.; Wich-
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Ed Engl 1983, 22, 828; (c) Tietze, L. F.; Voß, E.; Harms, K.; Shel-
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erocycl Chem 1990, 27, 47.
7-Methoxy-2-oxo-1,10b-dihydro-2H,5H-pyrano[3,4-c]chro-
mene-1-carboxylic acid (8h). This compound was obtained as
a white solid; yield 61%; mp (ꢀC) 240ꢀC; IR (potassium bro-
[4] Fox, M. F.; Lennon, I. C.; Meek, G. Tetrahedron Lett 2002,
43, 2899.
[5] Gartner, C. A.; Wen, B.; Wan, J.; Becker, R.; Jones, G.;
Gygi, S. P.; Nelson, S. D. Biochemistry 2005, 44, 1846.
[6] (a) Li, Z.; Brouwer, C.; He, C. Chem Rev 2008, 108, 3239;
(b) Tietze, L. F.; Lotz, F. Eur J Org Chem 2006, 4676; (c) Yoshida,
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5800; (d) Wender, P. A.; Paxton, T. J.; Williams, T. J. J Am Chem
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Miwa, Y.; Minami, H.; Yanada, K.; Ishikura, M.; Takemoto, Y. J Org
Chem 2008, 73, 5135.
mide): 3447, 1768, 1680 cmꢁ1 1H NMR (300 MHz, DMSO-
;
d6): d 3.41 (d, J ¼ 12.6 Hz, 1H, ACHCOOH), 3.72 (s, 3H,
OMe), 4.28–4.36 (m, 2H, AOCH2, ACH), 4.68(d, J ¼ 12.0
Hz, 1H, AOCH2), 6.79–6.90 (m, 3H, HAr), 7.05 (s, 1H,
¼¼CH), 12.60 ppm (brs, 1H, ACOOH); 13C NMR (75 MHz,
DMSO-d6): d 30.4, 51.5, 54.7, 63.2, 109.8, 113.3, 118.9,
120.0, 122.6, 135.9, 143.6, 147.9, 165.2, 168.4 ppm; ms (70
eV, electron impact): m/z 276 (Mþ), 275 (Mþ ꢁ H), 231 (Mþ
ꢁ COOH), 203 (Mþ ꢁ C2HO3).
[7] Kirsch, S. F. Synthesis 2008, 3183 and references cited
therein.
[8] (a) Patil, N.; Yamamoto, Y. J Org Chem 2004, 69, 5139;
(b) Bock, V. D.; Hiemstra, H.; van, J.; Maarseveen, H. Eur J Org
Chem 2006, 51; (c) Miura, M.; Enna, M.; Okuro, K.; Nomura, M. J
Org Chem 1995, 60, 4999; (d) Liu, F.; Ma, D. J Org Chem 2007, 72,
4844; (e) Ezquerra, J.; Pedregal, C.; Lamas, C. J Org Chem 1996, 61,
5804; (f) Cheng, G.; Hu, Y. J Org Chem 2008, 73, 4732.
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Acknowledgments. The authors thank the Kimiaexir Company
for financial support. They are grateful to the Alexander von
Humboldt foundation (AvH) for the research fellowship and
equipment donation. They are also thankful to Dr. J. H. Gross for
his assistance in Mass spectrometry analysis.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet