Synthesis and characterization of 2H-pyrano[3,2-c]coumarin derivatives and their photochromic and redox properties

Article abstract of DOI:10.1016/j.tet.2007.07.041

A series of 2H-pyrano[3,2-c]chromen-5-one derivatives were synthesized and characterized. Their photochromic and redox properties were investigated by the UV-vis absorption spectroscopy. While compounds with one or two phenyl groups incorporated at the 2-

Full text of DOI:10.1016/j.tet.2007.07.041

Tetrahedron 63 (2007) 10025–10033
Synthesis and characterization of 2H-pyrano[3,2-c]coumarin
derivatives and their photochromic and redox properties
*
Chin-Neng Huang, Pei-Yu Kuo, Chi-Hui Lin and Ding-Yah Yang
Department of Chemistry and Center for Nanoscience and Technology, Tunghai University,
181 Taichung-Kang Rd. Sec.3, Taichung 407, Taiwan
Received 2 May 2007; revised 5 July 2007; accepted 13 July 2007
Available online 19 July 2007
Abstract—A series of 2H-pyrano[3,2-c]chromen-5-one derivatives were synthesized and characterized. Their photochromic and redox
properties were investigated by the UV–vis absorption spectroscopy. While compounds with one or two phenyl groups incorporated at the
2-position were present in both ring-opened (5a and 10a) and ring-closed (6a and 11a) forms, the incorporation of an N,N-dimethylamino
group on either side of the aromatic ring resulted in formation of the ring-opened (5b and 10b) forms only. The ring-closed forms 13
and 18 with a methyl substituent at the 3-position of the pyran moiety failed to exhibit photochromic behavior. Compound 23 with an
N,N-dimethylamino group on the aromatic ring displayed increasing shoulder absorption in the visible region and a distinct change of color
upon UV irradiation. The non-fluorescent 10b instantly changed from dark red to colorless, when treated with sodium borohydride. The
reduced 28 was blue fluorescent with a quantum yield of 0.46 and could be returned to its original color via DDQ oxidation.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
annelation at the 7,8-positions, and the conjugative substitu-
tion at the 8,9- and 9,10-position of 2H-pyrano[3,2-c]-
chromen-5-ones on their photochemical properties were
investigated. Moreover, the redox switch property of some
ring-opened compounds was also explored.
Photochromism1 refers to a reversible phototransformation
of a chemical species between two forms having different
absorption spectra. Compounds with photochromic proper-
ties may have a wide range of applications in the area of
photonic materials. Flindersine, a pyrano[3,2-c]quinoline
derivative, was proven to possess photochromic properties
half a century ago due to the presence of a light-sensitive
pyran functionality.2 The corresponding coumarin derivative
1 (Scheme 1) exhibited similar photochemical behavior.3
While much effort has been made to improve the photo-
chromic properties of chromenes,4 diarylethenes,5 and spiro-
pyrans6 for practical applications, little attention has been
paid to the photochromism of pyrano[3,2-c]quinoline and
pyrano[3,2-c]coumarin derivatives. One possible explana-
tion is that the ring-closed and ring-opened forms of these
molecules do not differ substantially in their absorption
spectra, which is a prerequisite for practical applications.
For instance, the negligent color variance prior to and after
the irradiation of flindersine hampers its potential to serve
as materials used in photochromic ophthalmic lenses.7 In
this paper, we describe the synthesis of various substituted
pyrano[3,2-c]coumarins in an aim to find molecules with
the desired photochromic property, which is that the photo-
generated forms exhibit broad absorption in the visible
region. The effects of the conjugative substitution at the
2-position, the bulky substituents at the 3-position, the benzo
O
O
UV
visible light
N
H
O
N
H
O
flindersine
1
O
1
3
2
O
10
7
UV
4
9
visible light
O
O
5
8
O
6
O
2
3
Scheme 1. Photochromism of flindersine and a coumarin derivative 2.
2. Results and discussion
The incorporation of aromatic substituents at the 2-position
of 2H-pyrano[3,2-c]chromen-5-one represents a simple
way to cause the photogenerated forms 1 and 3 to exhibit
broad absorption in the visible region. Although several
2-phenyl-substituted 2H-pyrano[3,2-c]chromen-5-ones have
been previously prepared, whether they existed in either
Keywords: Coumarin; Flindersine; Photochromism; Redox switch.
* Corresponding author. Tel.: +886 4 2359 7613; fax: +886 4 2359 0426;
e-mail: yang@thu.edu.tw
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.07.041

10026
C.-N. Huang et al. / Tetrahedron 63 (2007) 10025–10033
R
O
H
H
OH
O
O
O
O
O
OH
O
OH
O
R
4
+
+
i
O
O
R
O
O
O
5a: R=H, 4%
5b: R=N(CH3)2, 82%
6a: R=H, 8%
7a: 53%
O
H
OH
O
O
O
9
+
i
R
O
O
R
O
R
O
O
11a: R = H, 16%
10a: R = H, 64%
10b:
8a: R = H
8b: R=N(CH3)2
R=N(CH3)2, 84%
Scheme 2. Reagents and conditions: (i) ethylenediammonium diacetate (cat.), CH2Cl2/MeOH, rt, 3 h.
the ring-opened or the ring-closed forms remains uncertain.8
We repeated the synthesis according to the literature proce-
dure, as shown in Scheme 2. The results demonstrated that
the condensation products were present in both ring-opened
and ring-closed forms when one or two phenyl groups were
incorporated at the 2-position of 2H-pyrano[3,2-c]chromen-
5-ones. Based on proton NMR integrations, the ratios of
ring-opened forms (5a and 10a) to ring-closed forms (6a
and 11a) are 1 to 2 and 4 to 1, respectively. Incorporation
of an N,N-dimethylamino group on either side of the
aromatic ring, however, resulted in the formation of ring-
opened forms 5b and 10b only, presumably due to the
enhancement of the mesomeric effects by the substituents.
In an effort to switch the products to the ring-closed pyran
forms for photochromic studies, a methyl group at the
3-position of 2H-pyrano[3,2-c]chromen-5-one was intro-
duced to destabilize the ring-opened form by increasing
the steric hindrance between the methyl group and the
phenyl group. Compounds 13 and 18 were prepared by
reacting 4-hydroxycoumarin with 12 and 17, respectively,
as shown in Scheme 3. Scheme 4 describes the preparation
of 17.9 The results indicated that both 13 and 18 existed in
the ring-closed forms only, suggesting that the methyl group
at the 3-position can indeed switch their presence to the
ring-closed form. Unfortunately, the irradiation of 13 and
18 with UV light (354 nm) revealed no photochromic behav-
ior. Since the desired photochromic properties had not been
obtained by 2- and 3-position substitutions, the effects of
substitution at the 8- and 9-position of the coumarin moiety
were considered. Scheme 5 shows the synthesis of 9-N,N-di-
methylamino-substituted 22, which began with the nitration
O
H
OH
O
O
O
12
i
O
O
13, 95%
N
O
H
OH
N
O
17
O
O
i
O
O
18, 93%
Scheme 3. Reagents and conditions: (i) ethylenediammonium diacetate
(cat.), MeOH, rt, 3 h.
O
O
O
1. Zn, I2 (cat.), THF, rt, 1 h
EtO
Br
+
EtO
2. p-TsOH, toluene
Dean-Stark trap, 2 h, 72%
N
N
14
15
DIBALH, ether
0 °C, 1 h, 87%
O
Dess-Martin
HO
H
CH2Cl2, rt, 1 h, 83%
N
N
17
16
Scheme 4. Preparation of compound 17.

C.-N. Huang et al. / Tetrahedron 63 (2007) 10025–10033
10027
OH
3-methyl-2-butenal
O2N
O
O
OH
O
O2N
NaNO3, H2SO4
0 °C, 1 h, 70%
ethylenediammonium diacetate
CH2Cl2/MeOH, rt, 3 h, 90%
O
O
O
O
19
20
Zn, NH4Cl
ClCH2CH2Cl
70 °C, 12 h, 82%
O
O
O
O
CH3I, K2CO3
N
H2N
CH3CN, rt, 3 h, 60%
O
O
22
21
Scheme 5. Preparation of compound 22.
of 4-hydroxycoumarin to give the 9-nitro-substituted 19, fol-
lowed by coupling with 3-methyl-2-butenal to yield 20. The
nitro group was reduced by treating 20 with zinc and ammo-
nium chloride to afford the 9-amino-substituted 21. Final
methylation of the amino group with excess methyl iodide
using potassium carbonate as a base in acetonitrile furnished
the target 22. Scheme 6 presents the preparation of 8-N,N-di-
methylamino-substituted 23 and corresponding 3-bromo-
and 3-nitro-substituted derivatives 24 and 25 from 8b.10
The annelation of 7-N,N-dimethylamino-4-hydroxycou-
marin with 3-methyl-2-butenal afforded 23 in a favorable
yield. A routine bromination and nitration of 23 with bro-
mine and sodium nitrate gave compounds 24 and 25, respec-
tively. The irradiation results demonstrated that neither 24
nor 25 was sensitive to light, indicating that the incorpora-
tion of a substituent at the 3-position is detrimental to its
photochromism. Although compounds 20–22 exhibited pho-
tochromic property, none had a distinct change in color. The
only compound that exhibited photochromic behavior with
a noticeable color change was compound 23. It turned
from colorless to yellow within seconds upon UV irradiation
(Fig. 1). The resulting ring-opened 26 can cyclize back to 23
Br
OH
O
O
O
O
3-methyl-2-butenal
ethylenediammonium diacetate
CH2Cl2/MeOH, rt, 3 h, 93%
Br2, FeBr3
CH2Cl2, rt
4 h, 89%
N
O
O
N
O
N
O
8b
23
24
NaNO3, H2SO4
0 °C, 1 h, 84%
NO2
O
N
O
O
25
Scheme 6. Preparation of compounds 23–25.
O
OH
O
NaBH4
MeOH
hv (354 nm) light
visible light
N
O
O
N
O
O
N
O
O
27
23
26
Figure 1. The photochromic switch of 23 and the color difference prior to and after photoirradiation (l¼354 nm).

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C.-N. Huang et al. / Tetrahedron 63 (2007) 10025–10033
Figure 2. Time course of the UV–vis absorption spectra of 23 (3.68ꢁ10ꢀ5 M) in CH2Cl2 under continuous irradiation using 354 nm light at 25 ꢂC.
With respect to the redox property of the ring-opened mole-
cules, compound 10b instantly changed from dark red to
colorless, when treated with sodium borohydride in metha-
nol at room temperature. Figure 4 depicts the redox switch
between 10b and 28, and the corresponding colors in the
oxidized (dark red) and the reduced (colorless) forms.
Figure 5 presents the UV–vis absorption spectra of 10b
prior to and after reduction. It displays two long-wavelength
broad bands at 410 (3¼30,791 Mꢀ1 cmꢀ1) and 490 nm (3¼
28,938 Mꢀ1 cmꢀ1) before reduction, which is associated
with the increased p-delocalization of the chromophore. A
different spectrum was obtained when 10b was reduced to
28. The reduction of 10b to 28 caused the complete disap-
pearance of long-wavelength absorbance by the disruption
of the conjugation, and the appearance of a single intense
band at 340 nm (3¼33,812 Mꢀ1 cmꢀ1), which resembles
Figure 3. X-ray crystal structure of compound 23.
the absorption behavior of 8b. Additionally, the reduced
28 can swiftly revert to its original color via 2,3-dichloro-
5,6-dicyanobenzoquinone (DDQ) oxidation. The reversible
redox switch process was repeated 10 times without signif-
icant changes in the UV spectra. While 10b emitted no fluo-
rescence at room temperature, the corresponding reduced 28
was blue fluorescent in methanol with a quantum yield of
0.46. Figure 6 displays the excitation and emission spectra
of 28. The reversible redox process between 10b and 28
can be regarded as a molecular switching system, in which
the absorption and emission characteristics are controlled
by the redox state of the 4-hydroxycoumarin moiety. This
within seconds under visible light. Figure 2 displays the time
course of the UV–vis absorption spectra of 23 in CH2Cl2
under continuous irradiation (354 nm) with four clear
isosbestic points (242, 273, 368, and 419 nm). The structure
of compound 23 was unambiguously verified by X-ray crys-
tallography (Fig. 3). The structure of photogenerated 26 was
indirectly confirmed by reducing it in situ with sodium boro-
hydride in methanol to give compound 27 (Fig. 1), which
was stable enough to be further characterized.
OH
O
NaBH4 /MeOH
DDQ/CH2Cl2
N
O
O
N
O
O
28
10b
dark red
colorless
Figure 4. The redox switch between 10b and 28 and the corresponding colors in the oxidized (left) and the reduced form (right).

C.-N. Huang et al. / Tetrahedron 63 (2007) 10025–10033
10029
Figure 5. UV–vis spectra of 10b (3.8ꢁ10ꢀ5 M in MeOH) prior to and after reduction.
Mass spectra were recorded on JOEL JMS-SX/SX 102A
spectrometer. Infrared spectra were obtained using a
1725XFT-IR spectrophotometer. Absorption spectra were
acquired using an HP8453 spectrophotometer. Single-
crystal structures were determined by a Bruker AXS
1
SMART-1000 X-ray single-crystal diffractometer. H and
13C NMR spectra were recorded at 300 and 75 MHz on a
Varian VXR300 spectrometer. Chemical shifts were re-
ported in parts per million on the d scale relative to an inter-
nal standard (tetramethylsilane, or appropriate solvent
1
peaks) with coupling constants given in hertz. H NMR
multiplicity data are denoted by s (singlet), d (doublet),
t (triplet), q (quartet), and m (multiplet). Analytical thin-
layer chromatography (TLC) was carried out on Merck silica
gel 60G-254 plates (25 mm) and developed with the solvents
mentioned. Flash chromatography was performed in col-
umns of various diameters with Merck silica gel (230–400
mesh ASTM 9385 kieselgel 60H). Solvents, unless other-
wise specified, were of reagent grade and distilled once prior
to use.
Figure 6. The excitation (339 nm) and emission (383 nm) spectra of 28
(6.54ꢁ10ꢀ6 M) in CH2Cl2 at room temperature.
redox switch system is quite unique because the redox reac-
tion occurs at the fluorophore rather than the fluorescent
quencher, as in most reported donor–acceptor systems.11
4.2. UV and fluorescence measurements
Absorption spectra were acquired using an HP8453 spectro-
photometer with a 1 cm path length quartz cell and emission
spectra were obtained on a Hitachi F-4500 fluorospectrometer.
3. Conclusions
This study synthesized and characterized a series of 2H-pyr-
ano[3,2-c]chromen-5-one derivatives. The incorporation of
either phenyl groups at the 2-position or a methyl substituent
at the 3-position of 2H-pyrano[3,2-c]chromen-5-one elimi-
nated their photochromic behavior. Compound 23 with an
N,N-dimethylamino group substituted at the 8-position on
the benzene ring exhibited a distinct change of color within
seconds upon UV irradiation, and can potentially be used
as a material in photochromic ophthalmic lenses. Moreover,
the reversible redox conversion between 10b and 28 has the
potential to function as an active fluorescence redox switch.
4.3. Calculation of fluorescence quantum yield
Anthracene (Ff¼0.27, lmax¼345 nm in hexane) was used as
an external standard for the measurement of fluorescence
quantum yield of 28. Fluorescence quantum yield was mea-
sured by comparing the integrated area under the fluo-
rescence curve for compound 28 and anthracene at equal
absorbance at the same excitation wavelength and was cor-
rected for the refractive index of the solvent.
4.4. General procedure for the preparation of
compounds 5a,b, 6a, 7a, 10a,b, 11a, 13, 18, 20, and 23
4. Experimental
4.1. General
To a solution of 4-hydroxycoumarin (1.00 g, 6.16 mmol)
in a mixture of methylene chloride (20 mL) and me-
thanol (10 mL) were added appropriate substituted
cinnamaldehyde (6.16 mmol) and a catalytic amount of
Melting points were determined on a Mel-Temp melting
point apparatus in open capillaries and are uncorrected.

10030
C.-N. Huang et al. / Tetrahedron 63 (2007) 10025–10033
ethylenediammonium diacetate (0.01 g, 0.06 mmol). After
the mixture was stirred at room temperature for 3 h, water
(20 mL) was added and the product was extracted twice
with methylene chloride. The combined organic extracts
were dried over MgSO4, filtered, and concentrated. The re-
sulting crude product was purified by column chromato-
graphy (2:8 EtOAc/hexanes) to give the pure product.
7.49–7.25 (m, 10H), 6.57 (dd, J¼9.0, 2.4 Hz, 1H), 6.32 (d,
J¼2.4 Hz, 1H), 3.10 (s, 6H). 13C NMR (CDCl3, 75 MHz)
d 178.3, 164.3, 161.6, 157.1, 155.8, 155.0, 154.1, 140.9,
137.8, 131.2, 130.5, 129.7, 128.5, 124.8, 108.8, 97.4, 40.1.
Minor isomer: 1H NMR (CDCl3, 300 MHz) d 8.91 (d,
J¼12.3 Hz, 1H), 8.16 (d, J¼12.3 Hz, 1H), 7.87 (d, J¼
9.0 Hz, 1H), 7.49–7.25 (m, 10H), 6.35 (dd, J¼9.0, 2.4 Hz,
1H), 6.30 (d, J¼2.4 Hz, 1H), 3.10 (s, 6H). 13C NMR
(CDCl3, 75 MHz) d 179.3, 164.0, 161.0, 156.4, 155.6,
155.0, 154.0, 140.9, 137.6, 131.2, 129.7, 128.9, 128.4,
125.3, 108.9, 97.4, 40.1. HRMS (EI) m/z calcd for
C26H21NO3 395.1521, found 395.1526 (M+). IR n (KBr)
4.4.1. 3-(3-Phenylprop-2-enylidene)-2H-benzopyran-
2,4(3H)-dione (5a). Orange solid. Yield 4%. Rf¼
0.40 (30% EtOAc/hexanes). Mp 184–185 ꢂC (lit.12 183–
1
185 ꢂC). H NMR (DMSO-d6, 300 MHz) d 8.69 (dd, J¼
15.3, 12.0 Hz, 1H), 8.38 (m, 2H), 7.75–7.30 (m, 9H).
1725, 1643, 1609, 1441, 1203, 1114 cmꢀ1
.
4.4.2. 2-Phenyl-2H,5H-pyran[3,2-c]chromen-5-one (6a).
Orange solid. Yield 8%. Rf¼0.40 (30% EtOAc/hexanes).
4.4.8. 3-Methyl-2-phenyl-2H-pyrano[3,2-c]chromen-5-
one (13). Yellow solid. Yield 95%. Rf¼0.40 (20% EtOAc/
1
1
Mp 184–185 ꢂC (lit.12 183–185 ꢂC). H NMR (DMSO-d6,
hexanes). Mp 143–144 ꢂC. H NMR (CDCl3, 300 MHz)
300 MHz) d 7.75–7.30 (m, 9H), 6.61 (dd, J¼9.9, 1.5 Hz,
1H), 6.39 (dd, J¼3.6, 1.5 Hz, 1H), 5.95 (dd, J¼9.9,
3.6 Hz, 1H). Compounds 5a and 6a cannot be separated
from column chromatography.
d 7.67 (dd, J¼7.2, 1.5 Hz, 1H), 7.48–7.25 (m, 6H), 7.18
(td, J¼7.2, 1.2 Hz, 1H), 6.60 (q, J¼1.5 Hz, 1H), 5.94 (s,
1H), 1.75 (d, J¼1.5 Hz, 3H). 13C NMR (CDCl3, 75 MHz)
d 160.6, 156.4, 152.6, 137.6, 131.5, 129.3, 128.8, 127.6,
123.7, 122.4, 116.3, 115.0, 113.7, 100.7, 82.6, 19.6.
HRMS (EI) m/z calcd for C19H14O3 290.0943, found
4.4.3. (E)-3,3-(3-Phenylprop-2-enylidene)bis[4-hydroxy-
2H-benzopyran-2-one] (7a). White solid. Yield 53%.
Rf¼0.43 (40% EtOAc/hexanes). Mp 221–222 ꢂC (lit.12
290.0940 (M+). IR n (KBr) 1707, 1661, 1540, 1187 cmꢀ1
.
1
220–224 ꢂC). H NMR (DMSO-d6, 300 MHz) d 7.92 (d,
4.4.9. 2-(4-N,N-Dimethylaminophenyl)-2-methyl-2H-
pyrano[3,2-c]chromen-5-one (18). Yellow solid. Yield
J¼7.8 Hz, 2H), 7.56 (t, J¼7.8 Hz, 2H), 7.36–7.16 (m, 9H),
6.76 (dd, J¼15.9, 8.7 Hz, 1H), 6.26 (d, J¼15.9 Hz, 1H),
5.73 (d, J¼8.7 Hz, 1H).
1
93%. Rf¼0.30 (30% EtOAc/hexanes). Mp 218–219 ꢂC. H
NMR (CDCl3, 300 MHz) d 7.73 (dd, J¼8.1, 1.5 Hz, 1H),
7.45 (td, J¼8.4, 1.5 Hz, 1H), 7.38 (d, J¼9.0 Hz, 1H), 7.25
(dd, J¼8.1, 0.9 Hz, 1H), 7.19 (td, J¼8.4, 0.9 Hz, 1H), 6.68
(d, J¼9.0 Hz, 1H), 6.53 (d, J¼1.5 Hz, 1H), 2.94 (s, 6H),
1.95 (s, 3H), 1.79 (d, J¼1.5 Hz, 3H). 13C NMR (CDCl3,
75 MHz) d 161.8, 158.0, 155.0, 153.0, 138.3, 129.1, 128.8,
127.7, 125.9, 123.4, 114.3, 108.7, 103.9, 97.7, 96.6, 82.5,
40.1, 19.6. HRMS (EI) m/z calcd for C22H21NO3
347.1521, found 347.1520 (M+). IR n (KBr) 1718, 1645,
4.4.4. (E,E)-3-[3-(4-N,N-Dimethylaminophenyl)prop-2-
enylidene]-2H-1-benzopyran-2,4(3H)-dione (5b). Purple
solid. Yield 82%. Rf¼0.46 (40% EtOAc/hexanes). Mp
1
180–181 ꢂC (lit.13 180–182 ꢂC). Major isomer: H NMR
(CDCl3, 300 MHz) d 8.78 (dd, J¼15.0, 12.6 Hz, 1H), 8.35
(d, J¼12.9 Hz, 1H), 8.11 (dd, J¼7.8, 1.5 Hz, 1H), 7.62–
7.55 (m, 4H), 7.28–7.21 (m, 2H), 6.70 (dd, J¼9.3, 1.5 Hz,
2H), 3.13 (s, 6H). Minor isomer: 1H NMR (CDCl3,
300 MHz) d 8.45 (d, J¼5.1 Hz, 1H), 8.43 (dd, J¼18.6,
12.6 Hz, 1H), 8.08 (dd, J¼5.7, 1.8 Hz, 1H), 7.67 (d,
J¼9.0 Hz, 4H), 7.28–7.21 (m, 2H), 6.70 (dd, J¼9.0,
1.8 Hz, 2H), 3.13 (s, 6H).
1478, 1126, 1167 cmꢀ1
.
4.4.10. 2,2-Dimethyl-9-nitro-2H-pyrano[3,2-c]chromen-
5-one (20). Yellow solid. Yield 90%. Rf¼0.30 (20%
EtOAc/hexanes). Mp 181–182 ꢂC. 1H NMR (CDCl3,
300 MHz) d 8.68 (d, J¼2.7 Hz, 1H), 8.38 (dd, J¼9.0,
2.7 Hz, 1H), 7.43 (d, J¼9.0 Hz, 1H), 6.52 (d, J¼9.9 Hz,
1H), 5.64 (d, J¼9.9 Hz, 1H), 1.61 (s, 6H). 13C NMR
(CDCl3, 75 MHz) d 159.3, 157.2, 156.2, 143.8, 127.7,
126.5, 119.0, 117.8, 115.9, 115.8, 101.3, 81.7, 28.6.
HRMS (EI) m/z calcd for C14H11NO5 273.0638, found
273.0637 (M+). IR n (KBr) 3082, 1725, 1641, 1486,
4.4.5. 3-(3,3-Diphenylallylidene)chromen-2,4-dione
(10a). Yellow solid. Yield 64%. Rf¼0.35 (20% EtOAc/
hexanes). Major isomer: 1H NMR (CDCl3, 300 MHz)
d 8.53 (d, J¼12.6 Hz, 1H), 8.39 (d, J¼12.6 Hz, 1H), 8.04
(dd, J¼7.8, 1.5 Hz, 1H), 7.63–7.20 (m, 13H). Minor isomer:
1H NMR (CDCl3, 300 MHz) d 8.84 (d, J¼12.3 Hz, 1H), 8.29
(d, J¼12.3 Hz, 1H), 8.10 (dd, J¼7.8, 1.5 Hz, 1H), 7.63–7.20
(m, 13H).
1219 cmꢀ1
.
4.4.11. 8-N,N-Dimethylamino-2,2-dimethyl-2H-pyr-
ano[3,2-c]chromen-5-one (23). Yellow solid. Yield 93%.
4.4.6. 2,2-Diphenyl-2H-pyrano[3,2-c]chromen-5-one
(11a). Yellow solid. Yield 16%. Rf¼0.35 (20% EtOAc/hex-
anes). 1H NMR (CDCl3, 300 MHz) d 7.92 (dd, J¼8.4,
1.8 Hz, 1H), 7.63–7.20 (m, 13H), 6.86 (d, J¼9.9 Hz, 1H),
6.05 (d, J¼9.9 Hz, 1H).
1
Rf¼0.40 (30% EtOAc/hexanes). Mp 148–149 ꢂC. H NMR
(CDCl3, 300 MHz) d 7.60 (d, J¼9.0 Hz, 1H), 6.61 (dd,
J¼9.0, 2.7 Hz, 1H), 6.52 (d, J¼9.9 Hz, 1H), 6.48 (d,
J¼2.7 Hz, 1H), 5.40 (d, J¼9.9 Hz, 1H), 3.05 (s, 6H), 1.51
(s, 6H). 13C NMR (CDCl3, 75 MHz) d 161.7, 160.0, 155.2,
153.1, 123.6, 123.5, 117.2, 108.7, 104.1, 97.6, 95.9, 79.8,
40.0, 28.4. HRMS (EI) m/z calcd for C16H17NO3
271.1208, found 271.1208 (M+). IR n (KBr) 2925, 1706,
1612, 1417, 1197 cmꢀ1. Crystallographic data (excluding
structural factors) of this compound have been deposited at
4.4.7. 7-N,N-Dimethylamino-3-(3,3-diphenylallylidene)-
3H-chromen-2,4-dione (10b). Orange solid. Yield 84%.
Rf¼0.35 (25% EtOAc/hexanes). Mp 221–222 ꢂC. Major iso-
1
mer: H NMR (CDCl3, 300 MHz) d 8.48 (d, J¼12.6 Hz,
1H), 8.33 (d, J¼12.6 Hz, 1H), 7.92 (d, J¼9.0 Hz, 1H),

C.-N. Huang et al. / Tetrahedron 63 (2007) 10025–10033
10031
the Cambridge Crystallographic Data Center as supplemen-
tary publication number CCDC-622320. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_
request/cif or by emailing data_request@ccdc.cam.ac.uk
or by contacting The Cambridge Crystallographic Data
Center, 12 Union Road, Cambridge CB2 1EZ, UK; fax:
+44 1223 336033.
300 MHz) d 7.29 (dd, J¼6.6, 2.1 Hz, 2H), 6.71 (dd, J¼6.6,
2.1 Hz, 2H), 5.27 (d, J¼0.9 Hz, 1H), 4.96 (d, J¼0.9 Hz,
1H), 3.65, 3.53 (ABdq, J¼10.8, 6.3 Hz, 2H), 2.96–2.91
(m, 1H), 2.95 (s, 6H), 1.17 (d, J¼6.9 Hz, 3H). 13C NMR
(CDCl3, 75 MHz) d 150.4, 149.9, 129.8, 127.1, 112.1,
109.5, 66.6, 40.4, 40.1, 16.8. HRMS (EI) m/z calcd for
C13H19NO 205.1467, found 205.1460 (M+). IR n (KBr)
3420, 1611, 1522 cmꢀ1
.
4.5. 3,3-Diphenyl-2-propenal (9)
4.8. 3-(4-N,N-Dimethylaminophenyl)-2-methyl-
2-butenal (17)
To a solution of benzophenone (2.0 g, 11.0 mmol) and TiCl4
(4.8 mL, 43.9 mmol) in methylene chloride (100 mL) was
added dropwise a solution of triethylamine (6.1 mL,
43.9 mmol) at 0 ꢂC. The resulting mixture was stirred for
12 h at room temperature. An aqueous NH4Cl solution
was then added to quench the reaction. The product was
extracted twice with methylene chloride. The combined
extracts were dried over MgSO4, filtered, and concentrated
in vacuo. The crude product was purified by column chroma-
tography to give a yellow liquid with an 86% Yield. Rf¼0.50
To a solution of 16 (1.0 g, 6.16 mmol) in methylene chloride
(20 mL) was added Dess–Martin reagent (5 mL, 15% in
methylene chloride) at 0 ꢂC. The mixture was stirred for
1 h and water was then added to quench the reaction. The
product was extracted twice with methylene chloride. The
combined extracts were dried over MgSO4, filtered, and con-
centrated. The resulting crude product was purified by col-
umn chromatography (2:8 EtOAc/hexanes) to give
a yellow liquid with an 83% yield. Rf¼0.50 (15% EtOAc/
hexanes). 1H NMR (CDCl3, 300 MHz) d 9.50 (s, 1H), 7.13
(dd, J¼6.6, 2.1 Hz, 2H), 6.71 (dd, J¼6.6, 2.1 Hz, 2H),
2.99 (s, 6H), 2.27 (q, J¼1.2 Hz, 3H), 1.91 (q, J¼1.2 Hz,
3H). 13C NMR (CDCl3, 75 MHz) d 188.2, 149.5, 138.0,
134.6, 129.8, 129.3, 122.4, 40.2, 13.5, 10.6. HRMS (EI)
m/z calcd for C13H17NO 203.1310, found 203.1316 (M+).
1
(15% EtOAc/hexanes). Mp 46–47 ꢂC (lit.14 46–47 ꢂC). H
NMR (CDCl3, 300 MHz) d 9.53 (d, J¼8.1 Hz, 1H), 7.47–
7.30 (m, 10H), 6.60 (d, J¼8.1 Hz, 1H).
4.6. Ethyl 3-(4-N,N-dimethylaminophenyl)-2-methyl-
crotonate (15)
To a solution of 4-dimethylaminoacetophenone (1.00 g,
8.32 mmol) and ethyl 2-bromoacetate (1.81 g, 9.99 mmol)
in benzene (30 mL) were added activated zinc (0.82 g,
12.48 mmol) and a catalytic amount of iodine. The mixture
was stirred at 80 ꢂC for 8 h, and the solvent was concentrated
in vacuo. To this mixture in toluene (50 mL) was added a
catalytic amount of p-toluenesulfonic acid. The mixture was
then refluxed in a Dean-Stark trap. After completion of the
reaction within 2 h, it was cooled down to room temperature
and the solvent was concentrated in vacuo. The resulting
residue was poured into water, and the product was then
extracted twice with methylene chloride. The combined
organic extracts were dried over MgSO4, filtered, and
concentrated. The resulting crude product was purified by
column chromatography (1:9 EtOAc/hexanes) to give a yel-
low liquid with a 72% yield. Rf¼0.45 (20% EtOAc/hexanes).
1H NMR (CDCl3, 300 MHz) d 7.31 (dd, J¼6.6, 2.1 Hz, 2H),
6.68 (dd, J¼6.6, 2.1 Hz, 2H), 5.30 (s, 1H), 5.06 (s, 1H), 4.11
(q, J¼7.2 Hz, 2H), 3.66 (q, J¼6.9 Hz, 1H), 2.95 (s, 6H), 1.38
(d, J¼0.9 Hz, 3H), 1.18 (t, J¼7.2 Hz, 3H). 13C NMR
(CDCl3, 75 MHz) d 170.3, 149.4, 145.6, 131.1, 128.4,
127.8, 123.7, 111.8, 60.1, 40.4, 21.6, 17.5. HRMS (EI) m/z
calcd for C15H21NO2 247.1572, found 247.1569 (M+). IR
IR n (KBr) 1683, 1623, 1450 cmꢀ1
.
4.9. 4-Hydroxy-6-nitro-2H-chromen-2-one (19)
To a solution of NaNO3 (0.52 g, 6.17 mmol) in an ice-cooled
sulfuric acid (20 mL) was added 4-hydroxycoumarin
(1.00 g, 6.17 mmol). After stirred at 0 ꢂC for 1 h, the mixture
was poured into an ice-cooled water to precipitate the prod-
uct. Upon filtration, the crude product was recrystallized
from EtOAc/hexanes (7:3) to give a white solid with a
70% yield. Rf¼0.4 (70% EtOAc/hexanes). Mp 253–254 ꢂC
(lit.12 253–254 ꢂC). 1H NMR (CDCl3, 300 MHz) d 8.29 (d,
J¼0.9 Hz, 1H), 8.28 (d, J¼8.7 Hz, 1H), 7.42 (dd, J¼8.7,
0.9 Hz, 1H), 5.55 (s, 1H).
4.10. 9-Amino-2,2-dimethyl-2H-pyrano[3,2-c]chromen-
5-one (21)
To a solution of 20 (1.00 g, 3.66 mmol) were added sequen-
tially activated zinc (0.48 g, 7.32 mmol), NH4Cl (0.59 g,
10.98 mmol, in 100 mL of 1,2-dichloroethane), and acetic
acid (three drops). The mixture was refluxed for 3 h and
then cooled to room temperature. The product was extracted
twice with methylene chloride. The combined organic ex-
tracts were dried over MgSO4, filtered, and concentrated.
The resulting crude product was purified by column chroma-
tography (3:7 EtOAc/hexanes) to give a yellow solid with an
82% yield. Rf¼0.30 (30% EtOAc/hexanes). Mp 136–
n (KBr) 1734, 1610, 1523, 1189 cmꢀ1
.
4.7. 2-Methyl-3-(4-N,N-dimethylaminophenyl)-3-buten-
1-ol (16)
1
To a solution of 15 (1.0 g, 8.32 mmol) in dry ether (20 mL)
was added DIBALH (5 mL, 20% in hexane) at 0 ꢂC. The
mixture was stirred for 1 h and the product extracted twice
with methylene chloride. The extract was dried over
MgSO4, filtered, and concentrated. The resulting crude prod-
uct was purified by column chromatography (2:8 EtOAc/
hexanes) to give a yellow liquid with an 87% yield.
Rf¼0.30 (20% EtOAc/hexanes). 1H NMR (CDCl3,
137 ꢂC. H NMR (CDCl3, 300 MHz) d 7.08 (d, J¼9.0 Hz,
1H), 7.02 (d, J¼2.4 Hz, 1H), 6.89 (dd, J¼9.9, 2.4 Hz, 1H),
6.52 (d, J¼9.9 Hz, 1H), 5.50 (d, J¼9.0 Hz, 1H), 3.80 (br s,
2H), 1.52 (s, 6H). 13C NMR (CDCl3, 75 MHz) d 161.2,
158.6, 146.3, 142.9, 125.8, 120.0, 117.2, 116.7, 115.8,
106.2, 100.1, 80.2, 28.4. HRMS (EI) m/z calcd for
C14H13NO3 243.0895, found 243.0896 (M+). IR n (KBr)
3353, 1678, 1570, 1456, 1205 cmꢀ1
.

10032
C.-N. Huang et al. / Tetrahedron 63 (2007) 10025–10033
4.11. 9-N,N-Dimethylamino-2,2-dimethyl-2H-
pyrano[3,2-c]chromen-5-one (22)
temperature. The resulting mixture was irradiated in a photo-
reactor under a 354 nm light for 2 h. The solvent was then
concentrated in vacuo and water (40 mL) was added. The
product was extracted with methylene chloride. The organic
extracts were dried over MgSO4, filtered, and concentrated.
The crude product was purified by column chromatography
(2:8 EtOAc/hexanes) to give a white solid 27 with a 10%
yield (compound 23 was recovered in a 78% yield). Rf¼
0.40 (30% EtOAc/hexanes). Mp 99–100 ꢂC. 1H NMR
(CDCl3, 300 MHz) d 7.56 (d, J¼9.0 Hz, 1H), 6.61 (dd, J¼
9.0, 2.4 Hz, 1H), 6.48 (d, J¼2.4 Hz, 1H), 5.44 (tq, J¼7.5,
1.5 Hz, 1H), 3.38 (d, J¼7.5 Hz, 2H), 3.04 (s, 6H), 1.85 (s,
3H), 1.83 (d, J¼1.5 Hz, 3H). 13C NMR (CDCl3, 75 MHz)
d 164.4, 162.1, 154.5, 152.9, 138.2, 123.3, 121.0, 108.7,
104.7, 98.0, 97.6, 40.2, 25.8, 23.7, 18.1. HRMS (EI) m/zcalcd
for C16H19NO3 273.1365, found 273.1362 (M+). IR n (KBr)
To a solution of 21 (1.00 g, 4.11 mmol) in dry acetonitrile
(30 mL) were added K2CO3 (0.88 g, 6.62 mmol) and excess
CH3I. After the mixture was stirred at room temperature for
24 h, water was added to quench the reaction. The product
was extracted twice with methylene chloride. The combined
organic extracts were dried over MgSO4, filtered, and
concentrated. The resulting crude product was purified by
column chromatography (2:8 EtOAc/hexanes) to give a yel-
low solid with a 60% yield. Rf¼0.35 (20% EtOAc/hexanes).
1
Mp 153–154 ꢂC. H NMR (CDCl3, 300 MHz) d 7.20 (dd,
J¼8.7, 0.9 Hz, 1H), 6.98 (d, J¼8.7 Hz, 1H), 6.96 (d,
J¼0.9 Hz, 1H), 6.55 (d, J¼9.9 Hz, 1H), 5.51 (d, J¼9.9 Hz,
1H), 2.99 (s, 6H), 1.55 (s, 6H). 13C NMR (CDCl3,
75 MHz) d 160.1, 158.2, 127.9, 127.3, 126.4, 125.8, 123.7,
116.6, 116.2, 114.3, 100.1, 80.8, 39.2, 22.5. HRMS (EI)
m/z calcd for C16H17NO3 271.1208, found 271.1203 (M+).
2923, 1700, 1616, 1528, 1380, 1232, 1120 cmꢀ1
.
4.15. Procedure for the reduction of 10b
and oxidation of 28
IR n (KBr) 1702, 1615, 1152, 1195, 1110 cmꢀ1
.
4.12. 3-Bromo-2,2-dimethyl-2H-pyrano[3,2-c]chromen-
5-one (24)
To a solutionof10b(500 mg, 1.26 mmol) in methanol(20 mL)
was added sodium borohydride (57.4 mg, 1.52 mmol). The
mixture was stirred at room temperature for 5 min and water
was then added. The reduced product was extracted twice
with methylene chloride. The combined organic extracts
were dried over MgSO4, filtered, and concentrated to give
a white solid 28, quantitatively. Rf¼0.25 (30% EtOAc/
To a solution of 23 (1.00 g, 3.69 mmol) in methylene chloride
were added FeBr3 (1.09 g, 3.69 mmol) and bromine (0.71 g,
4.42 mmol). After the mixturewas stirred atroom temperature
for 4 h, water was added to quench the reaction. The product
was extracted twice with methylene chloride. The combined
organic extracts were dried over MgSO4, filtered, and concen-
trated. The resulting crude product was purified by column
chromatography (2:8 EtOAc/hexanes) to give a yellow solid
with an 89% yield. Rf¼0.35 (20% EtOAc/hexanes). Mp
138–139 ꢂC. 1H NMR (CDCl3, 300 MHz) d 7.57 (d,
J¼9.0 Hz, 1H), 6.88 (s, 1H), 6.61 (d, J¼9.0, 2.7 Hz, 1H),
6.46 (d, J¼2.7 Hz, 1H), 3.06 (s, 6H), 1.65 (s, 6H). 13C NMR
(CDCl3, 75 MHz) d 160.5, 158.9, 155.3, 153.4, 123.5, 120.6,
116.8, 108.9, 103.4, 97.7, 96.8, 83.3, 40.1, 27.0. HRMS (EI)
m/z calcd for C16H16BrNO3 349.0314, found 349.0316 (M+).
1
hexanes). H NMR (DMSO-d6, 300 MHz) d 7.55 (d, J¼
8.7 Hz, 1H), 7.39–7.05 (m, 10H), 6.48 (dd, J¼9.0, 2.4 Hz,
1H), 6.24 (d, J¼2.4 Hz, 1H), 6.05 (t, J¼6.9 Hz, 1H), 3.11
(d, J¼6.9 Hz, 2H), 2.90 (s, 6H). 13C NMR (DMSO-d6,
75 MHz) d 164.8, 155.0, 151.6, 143.5, 140.2, 137.7, 132.6,
130.2, 128.0, 126.8, 126.5, 126.3, 125.2, 107.0, 97.4, 40.3,
24.9. HRMS (EI) m/z calcd for C26H23NO3 397.1678, found
397.1682 (M+). IR n (KBr) 1725, 1643, 1609, 1441, 1203,
1114 cmꢀ1. To a solution of 28 (500 mg, 1.25 mmol) in
methylene chloride (30 mL) was added DDQ (286 mg,
1.25 mmol) at room temperature. The oxidation was moni-
tored by TLC and completed within 3 min.
IR n (KBr) 1709, 1521, 1121, 671 cmꢀ1
.
4.13. 2,2-Dimethyl-3-nitro-2H-pyrano[3,2-c]chromen-
5-one (25)
Acknowledgements
To a solution of NaNO3 (0.32 g, 3.69 mmol) in an ice-cooled
sulfuric acid (20 mL) was added 23 (1.00 g, 3.69 mmol).
After stirred at 0 ꢂC for 1 h, the mixture was poured into
an ice-cooled water to precipitate the product. Upon filtra-
tion, the product was further recrystallized from EtOAc/
hexanes (7:3) to give a red solid with an 84% yield.
The authors would like to thank the National Science Coun-
cil of Republic of China, Taiwan for financially supporting
this research under Contract No. NSC 94-2113-M-029-001.
References and notes
1
Rf¼0.30 (30% EtOAc/hexanes). Mp 233–234 ꢂC. H NMR
(CDCl3, 300 MHz) d 8.05 (s, 1H), 7.61 (d, J¼9.0 Hz, 1H),
6.64 (dd, J¼9.0, 2.4 Hz, 1H), 6.45 (d, J¼2.4 Hz, 1H), 3.13
(s, 6H), 1.87 (s, 6H). 13C NMR (CDCl3, 75 MHz) d 161.8,
158.0, 155.0, 152.9, 128.8, 127.7, 114.3, 108.7, 103.9, 97.7,
96.6, 82.5, 40.1, 19.6. HRMS (EI) m/z calcd for C16H16N2O5
316.1059, found 316.1051 (M+). IR n (KBr) 3077, 1661,
€
1. Bouas-Laurent, H.; Durr, H. Pure Appl. Chem. 2001, 73, 639–
665.
2. Becker, R. S.; Michl, J. J. Am. Chem. Soc. 1966, 88, 5931–
5933.
3. Ahluwalia, V. K.; Arora, K. K.; Mukherjee, I. Heterocycles
1984, 22, 223–227.
4. Berkovic, G.; Krongauz, V.; Weiss, V. Chem. Rev. 2000, 100,
1741–1753.
5. Peters, A.; Vitols, C.; McDonald, R.; Branda, N. R. Org. Lett.
2003, 5, 1183–1186.
1606, 1489, 1188 cmꢀ1
.
4.14. 4-Hydroxy-7,7-N,N-dimethylamino-3-(3-methyl-2-
butenyl)coumarin (27)
To a solutionof23 (300 mg, 1.10 mmol)in methanol(15 mL)
was added sodium borohydride (83 mg, 2.20 mmol) at room
6. Fischer, E.; Hirshberg, Y. J. Chem. Soc. 1952, 4522–4524.
7. Davis, R.; Tamaoki, N. Org. Lett. 2005, 7, 1461–1464.

C.-N. Huang et al. / Tetrahedron 63 (2007) 10025–10033
10033
8. Cravotto, G.; Nano, G. M.; Tagliapietra, S. Synthesis 2001, 1,
49–51.
11. Illos, R. A.; Shamir, D.; Shimon, L. J.; Zibermann, I. W.;
Bittner, S. Tetrahedron Lett. 2006, 31, 5543–5546.
9. (a) Ross, N. A.; Bartsch, R. A. J. Org. Chem. 2003, 68, 360–
366; (b) Kano, S.; Yuasa, Y.; Yokomatsu, T.; Asami, K.;
Shibuya, S. J. Chem. Soc., Chem. Commun. 1986, 1717–1718.
10. Chen, Y. S.; Kuo, P. Y.; Shie, T. L.; Yang, D. Y. Tetrahedron
2006, 62, 9410–9416.
12. Appendino, G.; Cravotto, G.; Tagliapietra, S.; Nano, G. M.;
Palmisano, G. Helv. Chim. Acta 1990, 73, 1865–1878.
13. Cravotto, G.; Nano, G. M.; Palmisano, G.; Tagliapietra, S.
Synthesis 2003, 8, 1286–1291.
14. Bharathi, P.; Periasamy, M. Org. Lett. 1999, 1, 857–859.