Substituted 3-E-styryl-2H-chromenes and 3-E-styryl-2 H-thiochromenes: Synthesis, photophysical studies, anticancer activity, and exploration to tricyclic benzopyran skeleton

Article abstract of DOI:10.1021/jo5011125

A series of densely substituted 2H-chromenes and 2H-thiochromenes were synthesized in good yield through cyanuric chloride-dimethylformamide mediated cleavage of different spiro-4-hydroxychroman-3,1′-cyclopropanes and similar thiochroman analogues. This p

Full text of DOI:10.1021/jo5011125

Article
pubs.acs.org/joc
Substituted 3-E-Styryl‑2H‑chromenes and 3-E-
Styryl‑2H‑thiochromenes: Synthesis, Photophysical Studies,
Anticancer Activity, and Exploration to Tricyclic Benzopyran Skeleton
Rimi Roy,† Soumyadipta Rakshit,‡ Tanmoy Bhowmik,§ Sagar Khan,† Avishek Ghatak,† and Sanjay Bhar*,†
†Department of Chemistry, Organic Chemistry Section, Jadavpur University, Kolkata 700 032, India
‡Department of Chemistry, Physical Chemistry Section, Jadavpur University, Kolkata 700 032, India
§Laboratory of Toxinology & Experimental Pharmacodynamics, Department of Physiology, University College of Science, University
of Calcutta, Kolkata 700 009, India
S
* Supporting Information
ABSTRACT: A series of densely substituted 2H-chromenes and 2H-thiochromenes were synthesized in good yield through
cyanuric chloride-dimethylformamide mediated cleavage of different spiro-4-hydroxychroman-3,1′-cyclopropanes and similar
thiochroman analogues. This protocol involves operationally very simple, facile and cost-effective reactions using easily accessible
reagents under mild reaction condition with tolerance of a variety of sensitive moieties. Results of steady state and time-resolved
absorption and emission spectroscopy highlighted the potential of these compounds as fluorescence probes and designated the
suitability for subcellular bioimaging. The prepared 2H-chromenes demonstrated profound cytotoxic activity against MCF-7 cell
line. DFT calculations were done on a representative compound where the results indicated promising reactivity of the title
compounds as electron-donating dienes. As a continuation, some of these compounds underwent [4 + 2] Diels−Alder
cycloaddition with electron-deficient dienophiles in the absence of any activator or catalyst, which provided an easy access to an
array of hitherto unreported molecular frameworks related to bioactive cannabinoid skeletons. These newly constructed Diels−
Alder adducts also bear substantial antiproliferative properties.
protocols toward the synthesis of multifunctionalized 2H-1-
benzopyran derivatives have been developed in the recent past,
which include transition metal-catalyzed7 and organocatalytic
reactions.8 However, many of the reported methods employ
exotic and expensive metal catalysts, entail costly and
complicated starting materials, suffer from severe drawbacks
such as poor product yield, harsh reaction condition, use of
stoichiometric amount of reagents and limited applicability to
specific substitution pattern. Over the past decade, cyanuric
chloride (2,4,6-trichloro-1,3,5-triazine or TCT) has emerged as
a convenient solid reagent for a number of important organic
transformations and been utilized as a mild chlorinating agent9
for the conversion of alcohols to alkyl chloride, as a coupling
agent10 during the synthesis of hydroxamic acids from
carboxylic acids, as a catalyst11 for Pictet−Spengler reaction
with electron-releasing aldehydes and as an activator12 of
DMSO during structure dependent conversion of various
INTRODUCTION
■
Substituted 2H-chromenes (2H-1-benzopyran derivatives), 2H-
thiochromenes and their analogues constitute a significant
family of scaffolds found in a myriad of physiologically active
naturally occurring and artificial molecules.1 Because of a rich
array of functionalities these motifs are acknowledged as
expedient building blocks in a wide range of bioactive
heterocyclic compounds having anticancer, anti-HIV, anti-
inflammatory, antioxidant, antitubercular, antiviral, antitumor,
antibacterial/antimicrobial, antidiabetic, anticoagulant, antiana-
phylatic, diuretic, fungicidal, sex-pheromone and many other
activities.2 Because of their intense photophysical behavior,3
these compounds have also been applied in diverse fields
including laser dyes, organic light emitting devices (OLEDs),
optical brighteners, organic scintillators, triplet sensitizer,
fluorescence probes and exhibit outstanding photochromic
properties.4 They play a pivotal role as a regulator of numerous
biopolymers.5 Therefore, construction of these important
molecular skeletons has elicited a great deal of interest in the
field of organic synthesis and chemical biology.6 Different
Received: May 20, 2014
Published: July 7, 2014
© 2014 American Chemical Society
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alcohols to methylene acetal or methyl thioether or methyl
enethioether. Continuing on this theme, we report herein
highly selective, convenient, and cost-effective synthesis of a
variety of substituted 2H-chromenes from easily accessible and
inexpensive starting materials utilizing TCT in combination
with DMF (TCT-DMF) as the potent reagent.
was isolated by fractional crystallization, whereas the homo-
allylic chloride 3m could not be purified from the mother liquor
despite several attempts. Therefore, it is evident that a
substituent at p-position with +R effect preferentially promotes
the formation of the diene in comparison to the substituent at
the same location with only +I effect. For the substrate 1n,
where an electron-donating substituent (OMe) was placed at
the m-position of the aromatic ring connected to the carbinyl
carbon, the homoallylic chloride 3n was obtained as the sole
product with high yield (95%, entry 14 in Table 1). When the
aromatic ring at carbinol carbon carried an electron-with-
drawing substituent (Cl) in 1o, homoallylic chloride 3o was
formed exclusively (yield 94%, entry 15 in Table 1).
Homoallylic chlorides have been a subject of consistent interest
due to their appearance as a key structural element in a large
number of natural and unnatural products,15 found an extensive
use as pharmaceutically active substrates,16 as well as functional
molecules in a variety of organic conversions.17 As shown in
Table 1, the present protocol was compatible with acid-labile
functional groups like benzyl (entry 7, Table 1) and
methylenedioxy (entries 3, 6, 11, Table 1) and they were
well tolerated during the process. Differently substituted 2H-
chromenes synthesized by this protocol bear the promise of
having important functional attributes.
RESULTS AND DISCUSSION
■
At the outset, chroman-4-ones and 1-thiochroman-4-ones were
treated with aryl aldehydes bearing a variety of substituents in
the presence of alcoholic HCl13 under refluxing condition to
afford the corresponding E-3-arylidene derivatives in good
yield. Cyclopropanation of the resulting chromanochalcones
with dimethylsulfoxonium methylide, generated in situ by phase
transfer catalyst (nBu4N+Br−) mediated deprotonation of
trimethylsulfoxonium iodide under alkaline condition14 fol-
lowed by reduction with methanolic sodium borohydride at
room temperature furnished differently substituted spiro-4-
hydroxychroman-3,1′-cyclopropanes 1 as inseparable 1:1
diastereomeric mixtures, which were used as the substrates.
Compounds 1a−1o reacted with TCT-DMF9 in anhydrous
condition (Scheme 1). The results are summarized in Table 1.
Scheme 1. Synthesis of 3-Substituted 2H-chromenes with
A plausible mechanistic proposition for this reaction is
outlined in Figure 2. The substrates 1 initially react with TCT-
DMF adduct9 to generate 4 and the byproduct of TCT as 5.
The cleavage of cyclopropane ring in 4 leads to release of angle
strain and the carbocationic intermediate 6 is produced as an
intimate ion pair. Attainment of extended conjugation with the
aromatic moiety seems to facilitate this process. Substituents at
the p-position of the aryl moiety (G2) with electron-donating
mesomeric effect render additional stabilization to the
carbocationic intermediates through canonical 6′. Facile
deprotonation from the acidic −CH2− moiety in 6 with mildly
basic compound 5 leads to the formation of 2 with extended
conjugation. In 1n (where the electron-releasing substituent is
at m-position) and 1o (where an electron-withdrawing
substituent is located at the p-position), the homoallylic
chlorides 3n and 3o were obtained as the exclusive products
through internal capture of Cl− by 6.
TCT-DMF Adduct
As evident in Table 1, spiro-4-hydroxychroman-3,1′-cyclo-
propanes with cyclopropyl moiety bearing aromatic ring with
mesomerically electron-releasing group at p-position (1a−1h)
furnished substituted 3-E-styryl-2H-chromenes (2a−2h) ex-
clusively on treatment with TCT-DMF adduct in anhydrous
dichloromethane under stirring condition in good yield (80−
92%, entries 1−8 in Table 1). Similar trend was also observed
for the thiochroman analogues (1i−1k) where the correspond-
ing substituted 3-E-styryl-2H-thiochromenes (2i−2k) were
obtained (yield 84−88%, entries 9−11 in Table 1). Likewise
2H-thiochromene 2l was acquired from 1l with OMe
substituent at the o-position (yield 91%, entry 12 in Table 1).
The structures of all the products were assigned from 1H NMR,
13C NMR and HRMS analyses (see Supporting Information).
In all the products 2, the exocyclic double bond had E-
configuration, which was confirmed by the 3J values (16.1−16.5
Hz) between the exocyclic olefinic protons. X-ray crystallo-
graphic study of the compound 2i corroborated further with
the E-configuration of both the olefinic linkages along with s-
trans conformation of the conjugated diene framework (Figure
1). To the best of our knowledge, all these compounds 2 did
not have any literature precedence until date.
Photophysical Studies. Of late, 2H-chromenes have
attracted considerable attention due to their wide range of
photophysical activities.3 Therefore, we have measured the
UV−vis absorption, steady state and time-resolved fluorescence
to investigate the optical behavior of these 2H-chromenes
containing various substituents at different positions. The
fluorescence studies of all the compounds were performed in
1,4-dioxane (a polar aprotic solvent) at 1 × 10−4
M
concentration. The results are listed in Table 2. From the
UV spectroscopic studies, it was observed that the longest
absorption maxima of these derivatives (2a−2l) appeared
between 359 and 373 nm and they were attributed mainly to π
→ π* transition. There is no detectable change in absorption
maxima (359−365 nm) irrespective of the locations of the
substituents like OMe and Me in either chromene or styryl
aromatic ring. Apparently, the thiochromene analogues (2i−2l)
displayed broad absorption bands with peaks in the 361 and
373 nm interval, due to the presence of electron-releasing sulfur
in the heterocyclic ring. The fluorescence spectra were recorded
using the right-angle configuration, by exciting the compounds
at their wavelengths of maximum longest absorption. The
compounds (2a−2c) exhibited longer emission at 421−426 nm
In this connection it was interesting to note that the spiro-4-
hydroxychroman-3,1′-cyclopropane 1m substituted with the
Me group at the p-position of the aromatic ring at the carbinol
center produced a mixture of the diene 2m and the
corresponding homoallylic chloride 3m in a ratio of 1:2
under identical condition (entry 13 Table 1). The diene 2m
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Table 1. Reaction of 1 with TCT-DMF for the Synthesis of 3-Substituted 2H-Chromenes
a
b
Yield of the isolated pure product characterized spectroscopically. 1:2 mixture of diene 2m and homoallylic chloride 3m was obtained, out of
which the diene 2m was isolated by crystallization.
because of mildly electron-donating Me substituent in the
chromene moiety. Among the 2H-chromenes (2d−2h), the
compound 2h with a thiophene ring showed emission at 429
nm. Likewise, the emissions for the 2H-thiochromenes (2i−2l)
were found in a range from 430 to 445 nm. It was quite
noticeable that in polar aprotic solvent the fluorescence
quantum yields (Φ) of 2H-chromenes (2a−2h) were relatively
higher than those of thiochromenes (2i−2l). Fluorescence
lifetime measurements revealed biexponential decays for all the
compounds (2a−2l) when excited near their absorption
maximum (359−373 nm) in dioxane (Figure 3). For the
chromenes (2a−2l) it is assumed that the biexponential decay
in dioxane may be attributed to two different local environ-
ments due to solvent reorganization and collisional deactivation
with the solvent. Lifetime values range from 0.30 to 0.54 ns
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Table 2. Photophysical Parameters of 3-Substituted 2H-
Chromenes 2 in 1,4-Dioxane
a
max
λabs
λem
(nm)
ε
b
c
compound
(nm)
(M−1 cm−1
)
Δυ (cm−1
)
Φ
2a
2b
2c
2d
2e
2f
363
364
364
359
361
363
364
365
361
373
369
361
426
421
425
414
417
417
413
429
430
434
431
445
3461.9
4489.6
3152.2
3544.6
3343.3
3452.2
3659.2
4090.9
3440.8
3651.6
2736.3
158 730.16
175 438.59
163 934.42
181 818.18
178 571.43
185 185.18
204 081.63
156 250.00
144 927.53
163 934.42
161 290.32
0.37
0.46
0.44
0.30
0.31
0.35
0.27
0.31
0.09
0.12
0.11
0.10
Figure 1. ORTEP drawing of compound 2i18
2g
2h
2i
(Table 3). Quantum yield and lifetime values established their
potential application as new fluorescence probes.
2j
Cell Imaging. To evaluate the practical utility of the
compounds as fluorescent probes for in vivo cellular imaging,
MCF-7 breast cancer cells were used as a model to envisage its
cell uptake and imaging. We selected compounds 2b and 2f
with sufficiently higher fluorescence quantum yields and
another representative thiochromene 2i with relatively lower
fluorescence quantum yield for comparison. As shown in Figure
4, intense intracellular blue fluorescence was observed
throughout the cell cytosol after being incubated with the
probes 2b, 2f and 2i (10 μM) for 30 min. The intense
fluorescence might be originated mainly because the probes
internalize in the MCF-7 cell cytoplasm and the distribution of
the probes in the nucleus is significantly lower (the cell nuclei
appear as dark black spots in the fluorescence images). The
results clearly demonstrate that the probes 2b, 2f and 2i are
capable of penetrating the cell membrane and can specifically
label cytosol. This prominent feature should render the
prepared 2H-chromenes as useful biological tools to examine
subtle subcellular biochemical processes.
2k
2l
2925.4
b
119 047.62
a
c
Molar extinction coefficient ( × 10−4). Stoke’s shift. Fluorescence
quantum yield.
Among these psychotropic compounds (−)-Δ9-tetrahydrocan-
nabinol (Δ9-THC) is the most eminent because it is the key
psychoactive constituent of marijuana and consists of a tricyclic
6a,7,8,10a-tetrahydro-6H-benzo[c]chromene core structure.19
A survey of the literature reveal that Δ9-THC and other
cannabinoids provide pharmacochemical benefits for cancer
and AIDS patients by acting as appetite stimulants, mitigating
nausea and vomiting during chemotherapy.20 Besides, it has
also been applied to alleviate neuropathic pain, to treat
spasticity in multiple sclerosis21 and found to aid glaucoma
patients by reducing ophthalmic pressure. Other naturally
existing privileged structured cannabinoids are the Δ8-isomer,
cannabinol. The identification of two distinct cannabinoid
receptors CB122 and CB223 and their selective binding of THC
analogues have led to a resurgence of interest to provide
efficient synthetic routes. Because of their intriguing bioactivity
it is worthwhile to generate a collection of natural product-like
small molecular probes with diverse benzopyran-embedded
core skeletons. However, there are only a few synthetic routes
reported in the literature.24
Construction of Tricyclic Benzopyran Skeletons. To
explore the synthetic utility of the prepared dienes 2, attempts
were made to use them in [4 + 2] cycloaddition with various
dienophiles in order to achieve a molecular framework related
to cannabinoids. Classical cannabinoids belong to a well-known
group of approximately 70 terpenophenolic secondary
metabolites found in Indian hemp (Cannabis sativa var. indica).
Figure 2. Proposed mechanistic explanation of the substituent effect.
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Figure 3. Absorption, emission spectra and fluorescence decay curve of 2a−2l in dioxane.
Table 3. Fluorescence Lifetimes (τ) of 3-Substituted 2H-
Chromenes 2 in 1,4-Dioxane
a
a
b
b
compound
a1
a2
τ1 (ns)
τ2 (ns)
τavg (ns)
χ2
2a
2b
2c
2d
2e
2f
0.98
0.93
0.97
0.90
0.92
0.97
0.80
0.92
0.90
0.98
0.94
0.92
0.02
0.07
0.03
0.10
0.08
0.03
0.20
0.08
0.10
0.02
0.06
0.01
0.36
0.36
0.43
0.22
0.35
0.29
0.20
0.36
0.33
0.32
0.34
0.33
2.14
2.86
2.03
1.71
3.18
1.47
0.72
1.08
2.11
2.71
1.52
1.36
0.39
0.54
0.49
0.37
0.33
0.33
0.30
0.42
0.51
0.37
0.41
0.45
1.02
1.01
1.02
1.01
1.02
1.01
1.03
1.01
1.04
1.01
1.01
1.04
2g
2h
2i
2j
2k
2l
a
b
The corresponding pre-exponential coefficients. The short (τ1) and
long (τ2) lived decay times.
Theoretical Calculation. Diels−Alder reaction is one of
the most fundamental reactions to form carbocyclic and
heterocyclic frameworks and represents an efficient tool for
the stereocontrolled access to a plethora of organic
compounds.25 Quantum calculations have been performed by
density functional theory (DFT) method using the Gaussian 09
program to find out the feasibility of [4 + 2] cycloaddition
Figure 4. Confocal fluorescence images of living MCF-7 cells with 2b,
2f and 2i (10 μM).
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Figure 5. DFT-computed (B3LYP functional, 6-31G(d,p) basis set) HOMO and LUMO pictures of 2a, 7a and 8a.
reaction of the dienes 2 with dienophiles 7. For this purpose,
the diene 2a and the dienophile tetracyanoethylene (7a) were
chosen as the representative examples (Figure 5). The ground
states of chromenes and cannabinoids were optimized using the
restricted correlation function B3LYP with 6-31G(d,p) basis
set. As discussed before, the dienes 2 exist exclusively in s-trans
conformation, but in order to participate in [4 + 2]
cycloaddition they must assume s-cis conformation. Therefore,
HOMO and LUMO energies of 2 in both s-trans and s-cis
conformations as well as of 7a were calculated and listed in
Table 4. From Figure 5, it is evident that the HOMO energy is
[4 + 2] Cycloaddition of 2H-Chromenes and 2H-
Thiochromenes with Dienophiles. Inspired by the afore-
mentioned theoretical studies, we have exploited Diels−Alder
cycloaddition reaction for the synthesis of a series of
compounds containing benzopyran embedded moiety analo-
gous to classical cannabinoids starting from the synthesized 2H-
chromenes 2 as model precursors. Indeed, the compounds 2
underwent facile intermolecular [4 + 2] cycloaddition with
electron-deficient dienophiles, for example, tetracyanoethylene
(7a), maleic anhydride (7b) and N-phenylmaleimide (7c), in
1,4-dioxane at 80−100 °C without any metal or metal−organic
framework as catalyst (Scheme 2) to produce compounds 8
containing potentially bioactive tricyclic benzopyran core.
Results of the cycloaddition reaction are reported in Table 5.
Table 4. HOMO and LUMO Energies for the 3-Substituted
a
2H-Chromene Derivatives 2
s-trans HOMO/LUMO s-cis HOMO/LUMO
b
c
Scheme 2. Diels−Alder Reaction of 3-Substituted 2H-
Chromenes 2 with Various Dienophiles 7
diene 2
(eV)
(eV)
ΔE1
ΔE2
2a
2d
2e
2f
−5.116/−1.580
−5.197/−1.616
−5.242/−1.667
−5.126/−1.719
−5.044/−1.605
−4.965/−1.655
−4.967/−1.644
−5.002/−1.685
−4.830/−1.716
−4.892/−1.575
0.021
0.019
0.016
0.156
0.094
8.132
8.143
8.102
8.071
8.212
2g
a
Tetracyanoethylene (7a): HOMO −9.787 eV, LUMO −4.986 eV.
b
c
DieneHOMO(s-cis)-dienophileLUMO
cis).
.
DienophileHOMO-dieneLUMO(s-
Cycloaddition reaction of 2d with 7a afforded 8b in 94%
yield. The structure of 8b was deciphered easily with 1H NMR
analysis, where the peaks due to olefinic protons C6−H and
C7−H (at δ 6.73 and δ 6.39) of 2d disappeared, indicating that
the Diels−Alder reaction occurred on the electron rich C13−
C5−C6−C7 diene system. The 1H NMR spectrum of 8b
displayed signals for methine protons (i.e., C7−H and C13−H)
at δ 4.74 and δ 4.66 respectively, along with the singlet of
olefinic proton C6−H at δ 6.25 clearly demonstrating formation
of an annulated scaffold resembling cannabinoid. To widen the
scope of reaction, dienes 2 were allowed to react with other
dienophiles (7b, 7c), and in all cases good yields of the product
were obtained. However, at lower temperature, a substantial
decrease in the conversion was noted. Hence, a good number of
increased with decrease in LUMO energy when the
conformation of 2a is changed from s-trans to s-cis. It was
also found that the energy gap between the LUMO of
dienophile (7a) and the HOMO of diene (2a) is smaller than
that between the LUMO of diene (2a) and the HOMO of
dienophile (7a) in s-cis conformer. Moreover, the energy of
HOMO-diene in s-cis conformation is slightly higher than that
of LUMO-dienophile and the energy difference is quite small
(ΔE = 0.021). Hence, it was concluded that the Diels−Alder
reaction would smoothly proceed by the normal electron-
demand pathway. As the frontier orbitals are of comparable
energies, no catalyst might be essential.
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compounds were synthesized through the aforesaid inves-
tigation with a tricyclic benzopyran core related to
cannabinoids.
Table 5. Synthesis of Cannabinoid Derivatives 8 by Diels−
Alder Reaction of 2H-Chromenes 2 with Various
Dienophiles 7
Pharmacology. The significant cytotoxic activity showed
by several members of benzopyran family prompted us to
investigate in vitro antiproliferative activity of compounds 2 and
8 against MCF-7 (human breast adenocarcinoma) cell line
employing the standard MTT (3-(4,5-dimethylthiazol-2-yl)-
2,5-diphenyltetrazolium bromide) reduction assay26 and
compared with the standard drug Doxorubicin. To this end,
MCF-7 line was treated for different time intervals 24, 48 and
72 h with various concentrations (20−80 μM/mL) of some of
the selected compounds 2 and 8. The calculated IC50 values
suggested that these compounds inhibited the growth of the
above-mentioned leukemic cell compared with the control cell
in a time- and concentration-dependent manner. The results of
the cell viability assay are presented in Table 6. As it could be
a
Table 6. Inhibition of Cell Viability (IC50, μM/mL) of 3-
Substituted 2H-Chromenes 2 and Cannabinoid Derivatives 8
against MCF-7 Cell Line in Comparison with Standard Drug
Doxorubicin
entry
compound
IC50 (24 h)
IC50 (48 h)
IC50 (72 h)
1
2d
52.79
65.95
30.54
45.15
68.14
54.29
29.20
43.71
43.19
45.52
25.80
51.32
55.43
22.91
43.69
63.97
54.21
28.94
40.06
34.79
36.21
21.86
51.04
51.16
21.30
43.11
57.73
54.18
28.78
39.33
33.33
33.26
19.67
1.8
2
2e
3
2f
4
2g
5
2h
6
2j
7
2k
8
8d
9
8g
10
11
12
8h
8l
b
b
doxorubicin
ND
ND
a
The IC50 value corresponded to the compound concentration causing
50% mortality in carcinoma after 24, 48 and 72 h incubation,
respectively. The data is a mean value of three independent
b
experiments. Not determined.
noticed that the compounds 2f, 2k and 8l carrying
methylenedioxy functionality on aromatic ring had the distinct
tendency to escalate in vitro antitumor efficacy and exhibited
slightly better cytotoxicity against MCF-7 (entries 3, 7, 11 in
Table 6), while the others unveiled moderate cytotoxic activity.
Figure 6 shows the inhibition of cell proliferation for MCF 7
cells incubated with 2f, 2k, 8h and 8l at different concentrations
for 24, 48 and 72 h. The results clearly revealed that the
synthesized 3-substituted 2H-chromenes and the cannabinoid
analogues derived from them came out as excellent scaffolds for
further biomolecular study in the arena of cancer chemo-
therapy.
CONCLUSION
■
During this investigation we have found that variably
substituted spiro-4-hydroxychroman-3,1′-cyclopropanes and
the thiochroman analogues underwent facile reaction with
TCT-DMF adduct to afford novel 3-E-styryl-2H-chromenes
and 3-E-styryl-2H-thiochromenes respectively with good to
excellent yield, which serve as the useful precursors for the
synthesis of widely substituted tricyclic benzopyran skeletons.
Furthermore, the photophysical properties manifested by the
a
Yield of the isolated and purified product characterized spectroscopi-
cally.
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Figure 6. Inhibition of cell proliferation by compounds 2f, 2k, 8h and 8l on MCF-7 cell line.
as reference. The concentration of the standard was adjusted to give
the same absorbance, which is around 0.1 as the sample at the
excitation wavelength. Fluorescence decay measurements were
performed using time correlated single photon counting method and
using a nanosecond diode laser at 370 nm as light source. The decays
were analyzed using IBH DAS-6 decay analysis software. All the
experiments were performed at ambient temperature (298 K) with air-
equilibrated solutions. The IR spectra were recorded as thin films with
KBr and reported in wavenumbers (cm−1). The conversion of starting
materials was monitored by thin layer chromatography (TLC) using
silica gel (60−120 mesh) coated glass slides and precoated Al plates,
which were analyzed with iodine. Melting points were determined with
a commercially available melting point apparatus. All reactions
involving moisture-sensitive reactants were executed with oven-dried
glassware.
General Procedure for the Synthesis of 3-Substituted 2H-
Chromene Derivatives. To a round-bottomed flask containing
cyanuric chloride (277 mg, 1.5 mmol), anhydrous N,N-dimethylfor-
mamide (0.4 mL, 5.2 mmol) was added in drops at 5−10 °C under
stirring condition. After 20 min of stirring at that temperature, a white
curdy precipitate was obtained (if the precipitate turned pale yellow,
then it failed to react further and was discarded). To this mixture a
solution of the suitable spiro-4-hydroxychroman-3,1′-cyclopropanes
(1, 1 mmol) in dry dichloromethane (2 mL) was added dropwise with
stirring under cold condition. After complete addition of the substrate
1, the reaction mixture was allowed to attain the ambient temperature,
and the stirring was continued for the stipulated period of time (as
mentioned in Table 1) until the completion of the reaction (progress
of the reaction was monitored with TLC). After the reaction was
complete, the resulted mixture was diluted with ether (30 mL), and
the precipitate was filtered off. The organic layer was then washed with
10% Na2CO3 solution followed by water and dried over anhydrous
Na2SO4. Evaporation of the solvent followed by purification gave the
product 2 in good yields.
chromenes revealed that they were very suitable for in vivo
high-resolution microscope imaging. So they can provide
remarkable tools to investigate subtle biochemical processes
in the cell environment. Finally, cytotoxicity tests (in vitro)
indicated that the 2H-chromenes and the cannabinoid
derivatives are cytotoxic against MCF-7 cell line, which would
widen the structural diversity of these anticancer targets and
confirm the perspectives of further investigations in this area.
Simple execution, easy accessibility of the substrates, good
yields, and immense synthetic potential of the products along
with important photophysical properties make this protocol
highly attractive and utilitarian. We believe that these structural
motifs would further augment the engineering of more
compounds tailored to specific applications because of the
significance and prevalence of these functionalities.
EXPERIMENTAL SECTION
■
General Methods. All reagents were used without further
purification as received from commercial suppliers unless otherwise
noted. All solvents were dried and distilled prior to use according to
the standard protocols. The 1H NMR spectra were recorded on a 300
or 400 MHz spectrometer, in CDCl3 or DMSO-d6 solutions and
resonances (δ) are given in parts per million (ppm) relative to the
singlets at δ 0.0 and δ 7.26 for tetramethylsilane and chloroform,
respectively. The following abbreviations were used to designate
chemical shift multiplicities: s = singlet, d = doublet, t = triplet, dd =
doublet of doublets, m = multiplet, br = broad, integration, and all
coupling constants (J) are absolute values given in hertz (Hz). 13C
NMR spectra were recorded at 75 MHz with complete proton
decoupling. Chemical shifts are reported in ppm relative to the central
line of the heptalet at 77.0 ppm for CDCl3, 39.5 ppm for DMSO-d6.
High resolution mass spectra (HRMS) were acquired using an
electron spray ionization time-of-flight (ESI-TOF) mass spectrometer
in positive mode in acetonitrile or methanol solvent. The molecular
fragments are quoted as the relation between mass and charge (m/z).
UV−vis and fluorescence spectroscopy measurements were carried out
using matched quartz cells with a slit width of 2.5 mm. The
fluorescence quantum yields (Φ) were estimated by comparison of the
integrated area of the corrected emission spectra of samples with a
reference. Specifically, using quinine sulfate (Φ = 0.54, 0.1 N H2SO4)
3-(4-Methoxystyryl)-6-methyl-2H-chromene (2a). Light yellow
solid (255.2 mg, 92%): mp 170−172 °C; 1H NMR (300 MHz,
CDCl3) δ 7.38 (d, J = 8.6 Hz, 2H), 6.91−6.71 (m, 6H), 6.43 (s, 1H),
6.37 (s, 1H), 5.04 (s, 2H), 3.83 (s, 3H), 2.26 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 159.4, 151.4, 131.1, 130.7, 129.7, 129.3, 127.6, 127.4,
127.1, 124.7, 123.0, 122.8, 115.1, 114.2, 65.6, 55.3, 20.5; HRMS (ESI-
TOF, m/z) calcd for C19H18NaO2 [M + Na+] 301.1205, found
301.1204.
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3-(3,4-Dimethoxystyryl)-6-methyl-2H-chromene (2b). Yellow
solid (261.7 mg, 85%): mp 130−131 °C; 1H NMR (300 MHz,
CDCl3) δ 6.99−6.71 (m, 7H), 6.45 (s, 1H), 6.38 (d, J = 16.4 Hz, 1H),
5.04 (s, 2H), 3.93 (s, 3H), 3.90 (s, 3H), 2.26 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 151.4, 149.1, 149.0, 130.9, 130.6, 130.0, 129.3, 127.6,
127.1, 124.8, 123.2, 122.7, 119.8, 115.1, 111.2, 108.5, 65.5, 55.9, 55.8,
20.5; HRMS (ESI-TOF, m/z) calcd for C20H21O3 [M + H+] 309.1485,
found 309.1486.
5-((1E)-2-(2H-Thiochromen-3-yl)vinyl)benzo[d][1,3]dioxole (2k).
Orange yellow solid (250.0 mg, 85%): mp 100−101 °C; H NMR
(300 MHz, CDCl3) δ 7.26−6.54 (m, 10H), 5.97 (s, 2H), 3.70 (s, 2H);
13C NMR (75 MHz, CDCl3) δ 148.2, 147.5, 133.1, 131.7, 131.5, 131.3,
128.6, 128.5, 128.3, 127.9, 127.7, 126.7, 125.6, 121.7, 108.5, 105.4,
101.2, 24.9; HRMS (ESI-TOF, m/z) calcd for C18H14KO2S [M + K+]
333.0352, found 333.0352.
1
3-(2-Methoxystyryl)-2H-thiochromene (2l). Yellow solid (255.0
1
3-((E)-2-(Benzo[d][1,3]dioxol-6-yl)vinyl)-6-methyl-2H-chromene
mg, 91%): mp 111−113 °C; H NMR (300 MHz, CDCl3) δ 7.59−
1
6.90 (m, 10H), 6.59 (s, 1H), 3.89 (s, 3H), 3.79 (s, 2H); 13C NMR (75
MHz, CDCl3) δ 156.6, 133.1, 132.3, 131.4, 129.7, 128.8(2), 128.4,
127.6, 126.6, 126.1, 125.9, 125.5, 123.2, 120.7, 110.8, 55.4, 24.9;
HRMS (ESI-TOF, m/z) calcd for C18H16KOS [M + K+] 319.0559,
found 319.0558.
(2c). Light yellow solid (233.6 mg, 80%): mp 157−158 °C; H NMR
(300 MHz, CDCl3) δ 6.99 (s, 1H), 6.91−6.66 (m, 6H), 6.43 (s, 1H),
6.35 (d, J = 16.4 Hz, 1H), 5.97 (s, 2H), 5.02 (s, 2H), 2.26 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 151.4, 148.2, 147.4, 131.5, 130.7, 129.4,
127.4, 127.2, 125.0, 123.4, 122.7, 121.5, 115.1, 108.4, 105.2, 101.1,
65.5, 29.7, 20.5; HRMS (ESI-TOF, m/z) calcd for C19H17O3 [M +
H+] 293.1172, found 293.1171.
3-(4-Methylstyryl)-2H-chromene (2m). Pale yellow solid (80.0 mg,
1
32%): mp 118−120 °C; H NMR (300 MHz, CDCl3) δ 7.38 (d, J =
3-(4-Methoxystyryl)-2H-chromene (2d). Light yellow solid (237.1
mg, 90%): mp 134−136 °C; 1H NMR (300 MHz, CDCl3) δ 7.38 (d, J
= 8.7 Hz, 2H), 7.12−6.81 (m, 6H), 6.73 (d, J = 16.5 Hz, 1H), 6.46 (s,
1H), 6.39 (d, J = 16.5 Hz, 1H), 5.07 (s, 2H), 3.82 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 159.5, 153.6, 130.9, 129.7, 128.8, 127.7, 127.5,
126.7, 124.6, 122.9, 122.8, 121.5, 115.4, 114.2, 65.6, 55.3; HRMS (ESI-
TOF, m/z) calcd for C18H17O2 [M + H+] 265.1223, found 265.1222.
3-(3,4-Dimethoxystyryl)-2H-chromene (2e). Yellow solid (253.0
8.0 Hz, 2H), 7.21−7.06 (m, 4H), 6.95−6.83 (m, 3H), 6.52 (s, 1H),
6.46 (d, J = 16.5 Hz, 1H), 5.12 (s, 2H), 2.40 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 153.7, 137.9, 134.2, 130.9, 129.5, 129.0, 128.0, 126.9,
126.4, 125.7, 123.4, 122.9, 121.5, 115.5, 65.7, 21.3; HRMS (ESI-TOF,
m/z) calcd for C18H17O [M + H+] 249.1280, found 249.1279.
3-(2-Chloro-2-(3-methoxyphenyl)ethyl)-2H-chromene (3n). Light
1
yellow semisolid (285.7 mg, 95%): H NMR (300 MHz, CDCl3) δ
7.31 (t, J = 8.3 Hz, 1H), 7.12−6.87 (m, 6H), 6.82 (d, J = 8.0 Hz, 1H),
6.28 (s, 1H), 5.00 (t, J = 7.7 Hz, 1H), 4.68 (distorted AB quartet, J =
14.4 Hz, 1H), 4.57 (distorted AB quartet, J = 14.4 Hz, 1H), 3.83 (s,
3H), 2.99−2.83 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 159.7, 152.9,
142.4, 130.2, 129.7, 128.7, 126.3, 122.7, 122.4, 121.3, 119.1, 115.3,
113.9, 112.6, 67.9, 61.0, 55.2, 44.1. Elemental analysis calculated (%)
for C18H17ClO2: C 71.88, H 5.70, Cl 11.78, O 10.64. Found: C 71.92,
H 5.75.
1
mg, 86%): mp 111−113 °C; H NMR (300 MHz, CDCl3) δ 7.13−
6.82 (m, 7H), 6.74 (d, J = 16.4 Hz, 1H), 6.49 (s, 1H), 6.39 (d, J = 16.4
Hz, 1H), 5.08 (s, 2H), 3.94 (s, 3H), 3.90 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 153.6, 149.2, 130.9, 130.1, 128.9, 127.8, 126.8, 124.8, 123.1,
122.9, 121.5, 119.9, 115.4, 111.3, 108.7, 65.7, 56.0, 55.9; HRMS (ESI-
TOF, m/z) calcd for C19H18NaO3 [M + Na+] 317.1154, found
317.1153.
3-((E)-2-(Benzo[d][1,3]dioxol-6-yl)vinyl)-2H-chromene (2f). Yel-
3-(2-Chloro-2-(4-chlorophenyl)ethyl)-2H-chromene (3o). Light
1
1
low solid (250.4 mg, 90%): mp 128−130 °C; H NMR (300 MHz,
yellow semisolid (286.9 mg, 94%): H NMR (300 MHz, CDCl3) δ
CDCl3) δ 7.12−6.76 (m, 7H), 6.68 (d, J = 16.2 Hz, 1H), 6.46 (s, 1H),
6.34 (d, J = 16.5 Hz, 1H), 5.96 (s, 2H), 5.05 (s, 2H); 13C NMR (75
MHz, DMSO-d6) δ 153.2, 147.9, 147.2, 131.4, 131.3, 128.8, 128.3,
126.8, 124.6, 122.8, 122.5, 121.8, 121.5, 115.2, 108.5, 105.2, 101.2,
65.0; HRMS (ESI-TOF, m/z) calcd for C18H14NaO3 [M + Na+]
301.0841, found 301.0840.
7.34 (s, 4H), 7.08 (t, J = 7.7 Hz, 1H), 6.94−6.75 (m, 3H), 6.22 (s,
1H), 4.96 (t, J = 7.6 Hz, 1H), 4.64 (distorted AB quartet, J = 14.4 Hz,
1H), 4.54 (distorted AB quartet, J = 14.4 Hz, 1H), 2.96−2.78 (m,
2H); 13C NMR (75 MHz, CDCl3) δ 152.9, 139.4, 134.4, 129.8, 129.0,
128.9, 128.3, 126.4, 123.1, 122.3, 121.5, 115.4, 68.0, 60.1, 44.2.
Elemental analysis calculated (%) for C17H14Cl2O: C 66.90, H 4.62, Cl
23.24, O 5.24. Found: C 66.83, H 4.68.
General Procedure for the Synthesis of Cannabinoid
Derivatives. Compound 2 (1 mmol) and the dienophile 7 (2
mmol) were gently refluxed (at 80−100 °C) in dry dioxane (2 mL)
under anhydrous condition for the required period of time (as
mentioned in Table 5). After complete consumption of compound 2
(evident from TLC), the solution was cooled to room temperature
and was evaporated to obtain a sticky mass, which was extracted with
dichloromethane (3 × 15 mL). The combined organic extracts were
washed with water and dried over anhydrous Na2SO4 and
concentrated in vacuo. The residue was purified by column
chromatography (silica gel, hexane/EtOAc = 80/20) to afford the
product 8 in excellent yield.
8-(4-Methoxyphenyl)-2-methyl-6H-benzo[c]chromene-9,9,10,10-
(8H,10aH)-tetracarbonitrile (8a). Yellow solid (333.5 mg, 82%): mp
125−126 °C (dec); 1H NMR (300 MHz, CDCl3) δ 7.68 (s, 1H), 7.40
(d, J = 8.6 Hz, 2H), 7.17 (d, J = 8.3 Hz, 1H), 6.94 (t, J = 8.5 Hz, 3H),
6.24 (s, 1H), 4.70 (d, J = 11.9 Hz, 1H), 4.59 (s, 1H), 4.51−4.47 (m,
2H), 3.82 (s, 3H), 2.37 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.0,
154.5, 132.5, 131.8, 130.8, 128.0, 123.9, 123.6, 118.5, 115.7, 114.1,
112.8, 112.1, 109.8, 108.1, 69.8, 55.3, 47.1, 45.2, 42.5, 40.6, 20.8; IR
(KBr, cm−1) ν 3426.63, 2931.05, 1611.34, 1514.28, 1502.41, 1464.68,
1427.48, 1246.89, 1182.44, 1032.47, 1000.00, 845.60, 819.53, 737.35;
HRMS (ESI-TOF, m/z) calcd for C25H18N4NaO2 [M + Na+]
429.1328, found 429.1326.
8-(4-Methoxyphenyl)-6H-benzo[c]chromene-9,9,10,10(8H,10aH)-
tetracarbonitrile (8b). Yellow solid (370.0 mg, 94%): mp 118−120 °C
(dec); 1H NMR (300 MHz, CDCl3) δ 7.90 (d, J = 7.9 Hz, 1H), 7.41−
7.36 (m, 3H), 7.15 (t, J = 7.6 Hz, 1H), 7.07 (d, J = 8.2 Hz, 1H), 6.93
(d, J = 8.6 Hz, 2H), 6.25 (s, 1H), 4.74 (d, J = 11.8 Hz, 1H), 4.66 (s,
1H), 4.55−4.49 (m, 2H), 3.81 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
3-(4-(Benzyloxy)-3-methoxystyryl)-2H-chromene (2g). Light yel-
1
low solid (303.6 mg, 82%): mp 132−133 °C; H NMR (300 MHz,
CDCl3) δ 7.45−6.81 (m, 12H), 6.73 (d, J = 16.5 Hz, 1H), 6.48 (s,
1H), 6.37 (d, J = 16.5 Hz, 1H), 5.17 (s, 2H), 5.07 (s, 2H), 3.94 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 153.6, 149.7, 148.2, 136.9, 130.8,
130.5, 128.9, 128.5, 127.9, 127.7, 127.2, 126.7, 124.9, 123.1, 122.8,
121.5, 119.7, 115.4, 113.9, 109.2, 70.9, 65.6, 55.9; HRMS (ESI-TOF,
m/z) calcd for C25H22NaO3 [M + Na+] 393.1467, found 393.1467.
3-((E)-2-(Thiophen-2-yl)vinyl)-2H-chromene (2h). Yellow solid
1
(199.4 mg, 83%): mp 123−124 °C; H NMR (300 MHz, CDCl3) δ
7.21−6.81 (m, 7H), 6.68 (distorted AB quartet, J = 16.1 Hz, 1H), 6.59
(distorted AB quartet, J = 16.3 Hz, 1H), 6.49 (s, 1H), 5.04 (s, 2H);
13C NMR (75 MHz, CDCl3) δ 153.6, 142.6, 130.3, 129.1, 127.8, 126.9,
126.4, 126.2, 124.8, 123.7, 122.8, 121.6, 121.1, 115.5, 65.4; HRMS
(ESI-TOF, m/z) calcd for C15H13OS [M + H+] 241.0687, found
241.0688.
3-(4-Methoxystyryl)-2H-thiochromene (2i). Light yellow solid
1
(246.8 mg, 88%): mp 120−122 °C; H NMR (300 MHz, CDCl3) δ
7.40 (d, J = 6.9 Hz, 2H), 7.26−7.08 (m, 4H), 6.90 (d, J = 6.9 Hz, 2H),
6.85 (d, J = 16.1 Hz, 1H), 6.62 (d, J = 16.2 Hz, 1H), 6.55 (s, 1H), 3.83
(s, 3H), 3.72 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 159.4, 133.1,
131.9, 131.2, 129.7, 128.4, 128.2(2), 127.7, 127.5, 127.4, 126.6, 125.6,
114.2, 55.2, 24.9; HRMS (ESI-TOF, m/z) calcd for C18H17OS [M +
H+] 281.0995, found 281.0996.
3-(3,4-Dimethoxystyryl)-2H-thiochromene (2j). Light yellow semi-
solid (260.7 mg, 84%): 1H NMR (300 MHz, CDCl3) δ 7.25−6.82 (m,
8H), 6.61 (d, J = 16.5 Hz, 1H), 6.57 (s, 1H), 3.93 (s, 3H), 3.90 (s,
3H), 3.72 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 149.0(2), 133.0,
131.7, 131.1, 130.0, 128.4, 127.5, 126.6, 125.5, 119.9, 111.1, 108.5,
55.8, 55.7, 24.9; HRMS (ESI-TOF, m/z) calcd for C19H18KO2S [M +
K+] 349.0665, found 349.0666.
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161.0, 156.6, 132.5, 130.9, 130.4, 127.9, 123.9, 123.4, 122.9, 118.8,
116.0, 114.1, 112.8, 112.1, 109.8, 108.0, 69.7, 55.3, 47.0, 45.1, 42.3,
40.7; IR (KBr, cm−1) ν 3448.02, 2928.85, 1608.36, 1514.44, 1490.15,
1460.24, 1238.72, 1180.55, 1029.66, 761.61; HRMS (ESI-TOF, m/z)
calcd for C24H16N4NaO2 [M + Na+] 415.1173, found 415.1171.
8-(3,4-Dimethoxyphenyl)-6H-benzo[c]chromene-9,9,10,10-
(8H,10aH)-tetracarbonitrile (8c). Yellow solid (389.1 mg, 92%): mp
136−138 °C; 1H NMR (300 MHz, CDCl3) δ 7.88 (d, J = 7.7 Hz, 1H),
7.37 (t, J = 7.4 Hz, 1H), 7.17−6.86 (m, 5H), 6.25 (s, 1H), 4.73 (d, J =
11.6 Hz, 1H), 4.64 (s, 1H), 4.53−4.49 (m, 2H), 3.87 (s, 3H), 3.85 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 156.7, 150.5, 148.8, 130.9, 130.6,
128.0, 124.1, 124.0(2), 122.9, 118.8, 116.0, 113.8, 112.8, 112.1, 110.8,
109.8, 108.3, 69.7, 56.0, 55.8, 47.4, 45.2, 42.6, 40.6; IR (KBr, cm−1) ν
3449.01, 2933.95, 1607.30, 1516.65, 1490.27, 1462.97, 1270.54,
1238.15, 1146.40, 1023.85, 760.42; HRMS (ESI-TOF, m/z) calcd
for C25H18N4NaO3 [M + Na+] 445.1278, found 445.1277.
13C NMR (75 MHz, DMSO-d6) δ 171.0, 170.9, 158.2, 156.6, 138.1,
130.7, 129.7, 128.9, 127.7, 124.1, 123.2, 121.9, 117.3, 113.6, 67.9, 55.0,
48.4, 46.8, 34.4; IR (KBr, cm−1) ν 3421.89, 2935.54, 2839.34, 1777.81.
1614.71, 1584.66, 1519.63, 1489.80, 1460.48, 1257.22, 1179.23,
1005.06, 937.35, 758.03; HRMS (ESI-TOF, m/z) calcd for
C22H18O5K [M + K+] 401.0791, found 401.0792.
3a,4-Dihydro-4-(3,4-dimethoxyphenyl)-6H-isobenzofuro[5,4-c]-
chromene-1,3(11bH,11cH)-dione (8i). Whitish yellow solid (370.0
1
mg, 94%): mp 190−192 °C; H NMR (300 MHz, DMSO-d6) δ 7.41
(d, J = 7.4 Hz, 1H), 7.17 (t, J = 7.7 Hz, 1H), 7.02 (t, J = 7.4 Hz, 1H),
6.94−6.85 (m, 4H), 6.36 (s, 1H), 4.60 (d, J = 13.5 Hz, 1H), 4.45 (d, J
= 13.5 Hz, 1H), 4.07−3.80 (m, 4H), 3.75 (s, 6H); 13C NMR (75
MHz, DMSO-d6) δ 171.0, 170.9, 156.6, 148.4, 147.8, 138.0, 131.1,
128.9, 127.7, 124.1, 123.2, 121.9, 120.6, 117.3, 112.6, 111.5, 67.9,
55.5(2), 48.4, 46.8, 34.4; IR (KBr, cm−1) ν 3423.10, 2932.22, 2836.88,
1778.13, 1586.01, 1519.79, 1490.61, 1464.78, 1246.36, 1027.85,
1004.46, 954.35, 923.92, 764.64; HRMS (ESI-TOF, m/z) calcd for
C23H20NaO6 [M + Na+] 415.1158, found 415.1157.
8-(Benzo[d][1,3]dioxol-6-yl)-6H-benzo[c]chromene-9,9,10,10-
(8H,10aH)-tetracarbonitrile (8d). Light yellow solid (378.3 mg, 93%):
1
mp 167−168 °C (dec); H NMR (300 MHz, CDCl3) δ 7.89 (d, J =
3a,4-Dihydro-4-(3,4-dimethoxyphenyl)-2-phenylchromeno[4,3-
e]isoindole-1,3(2H,6H,11bH,11cH)-dione (8j). Yellow solid (435.0
mg, 93%): mp 98−100 °C; 1H NMR (300 MHz, DMSO-d6) δ 7.51−
6.76 (m, 12H), 6.37 (s, 1H), 4.62−4.49 (s, 1H), 3.94−3.92 (m, 2H),
3.80−3.70 (m, 8H, containing two singlets at δ 3.75 (s, 3H) and δ 3.74
(s, 3H)); 13C NMR (75 MHz, CDCl3) δ 174.7, 169.5, 157.0, 148.8,
148.2, 137.8, 134.2, 131.2, 129.1, 128.9, 128.4, 128.2, 128.0, 126.2,
126.1, 124.4, 122.9, 122.2, 120.9, 117.9, 112.1, 111.0, 68.7, 55.9, 55.8,
47.4, 45.9, 41.7, 35.7; IR (KBr, cm−1) ν 3464.64, 2935.34, 2836.59,
1715.00, 1597.70, 1517.46, 1457.14, 1380.98, 1264.95, 1235.80,
1143.86, 1024.90, 758.72, 693.41; HRMS (ESI-TOF, m/z) calcd for
C29H26NO5 [M + H+] 468.1805, found 468.1808.
7.8 Hz, 1H), 7.38 (t, J = 7.5 Hz, 1H), 7.18−6.82 (m, 5H), 6.23 (s,
1H), 6.01 (s, 2H), 4.73 (d, J = 11.9 Hz, 1H), 4.64 (s, 1H), 4.54−4.45
(m, 2H); 13C NMR (75 MHz, CDCl3) δ 156.6, 149.3, 148.0, 131.0,
130.7, 128.0, 125.6, 125.2, 123.8, 123.0, 118.9, 116.0, 112.8, 112.0,
111.0, 109.7, 108.3, 108.2, 101.9, 69.7, 47.3, 45.1, 42.6, 40.6; IR (KBr,
cm−1) ν 3424.53, 2915.90, 1608.33, 1504.97, 1489.83, 1447.32,
1256.61, 1239.18, 1103.95, 1039.21, 1003.18, 924.40, 763.70, 668.07;
HRMS (ESI-TOF, m/z) calcd for C24H14N4NaO3 [M + Na+]
429.0964, found 429.0966.
8-(4-(Benzyloxy)-3-methoxyphenyl)-6H-benzo[c]chromene-
9,9,10,10(8H,10aH)-tetracarbonitrile (8e). Greenish yellow solid
1
(444.2 mg, 89%): mp 104−106 °C; H NMR (300 MHz, CDCl3) δ
4-(Benzo[d][1,3]dioxol-6-yl)-3a,4-dihydro-2-phenylchromeno-
7.90 (d, J = 7.9 Hz, 1H), 7.43−6.88 (m, 11H), 6.24 (s, 1H), 5.14 (s,
2H), 4.73 (d, J = 11.8 Hz, 1H), 4.64 (s, 1H), 4.53−4.47 (m, 2H), 3.87
(s, 3H) ; 13C NMR (75 MHz, CDCl3) δ 156.7, 149.7, 149.3, 136.3,
130.9, 130.5, 128.6, 128.0, 127.3, 124.4, 124.0, 123.9, 122.9, 118.8,
116.0, 114.3, 113.0, 112.7, 112.1, 109.8, 108.2, 70.8, 69.7, 56.1, 47.5,
45.2, 42.6, 40.6; IR (KBr, cm−1) ν 3426.62, 2875.17, 1606.66, 1514.30,
1490.06, 1462.43, 1270.72, 1237.56, 1144.89, 1004.70, 758.73, 698.06,
668.03; HRMS (ESI-TOF, m/z) calcd for C31H22N4NaO3 [M + Na+]
521.1589, found 521.1588.
[4,3-e]isoindole-1,3(2H,6H,11bH,11cH)-dione (8k). Yellow solid
1
(424.8 mg, 94%): mp 109−110 °C; H NMR (400 MHz, CDCl3) δ
7.56−6.83 (m, 12H), 6.26 (s, 1H), 5.98 (s, 2H), 4.66 (d, J = 13.6 Hz,
1H), 4.57 (d, J = 13.6 Hz, 1H), 3.89 (brs, 1H), 3.82 (brs, 1H), 3.71 (t,
J = 8.4 Hz, 1H), 3.61 (t, J = 7.6 Hz, 1H); 13C NMR (75 MHz, CDCl3)
δ 174.7, 174.3, 169.6, 157.0, 147.8, 146.8, 138.0, 134.2, 131.2, 129.2,
128.9, 128.4, 128.2, 128.0, 126.3, 126.1, 124.1, 123.0, 122.2, 117.9,
109.2, 108.2, 101.1, 68.7, 47.5, 45.9, 41.7, 35.7; IR (KBr, cm−1) ν
3464.16, 2892.64, 1713.97, 1597.83, 1490.07, 1444.72, 1381.45,
1237.09, 1037.17, 930.87, 826.90, 758.09, 693.11; HRMS (ESI-TOF,
m/z) calcd for C28H21NNaO5 [M + Na+] 474.1317, found 474.1315.
4-(Benzo[d][1,3]dioxol-6-yl)-3a,4-dihydro-2-phenylthio-
chromeno[4,3-e]isoindole-1,3(2H,6H,11bH,11cH)-dione (8l). Yellow
solid (426.0 mg, 91%): mp 95−97 °C; 1H NMR (300 MHz, CDCl3) δ
7.50−6.78 (m, 12H), 6.25 (s, 1H), 5.93 (s, 2H), 3.90 (brs, 1H), 3.70
(brs, 2H), 3.63−3.35 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 175.0,
173.5, 169.3, 147.3, 146.3, 138.1, 136.2, 133.9, 132.7, 131.6, 131.0,
129.5, 128.9, 128.6, 128.3, 128.0, 126.2, 126.0, 123.5, 121.5, 109.1,
107.7, 100.8, 66.8, 47.4, 46.8, 40.9, 33.7; IR (KBr, cm−1) ν 3468.78,
2891.89, 1712.95, 1597.02, 1502.56, 1443.08, 1380.89, 1232.34,
1185.64, 1035.99, 931.88, 826.54, 756.23, 698.26; HRMS (ESI-TOF,
m/z) calcd for C28H21NO4S [M + H+] 468.1264, found 468.1266.
Crystallographic Data Collection and Refinement. Com-
pound 2i (30 mg) in CH2Cl2/petroleum ether (v/v = 1:2) solution
was left to evaporate. Light yellow single crystals suitable for X-ray
diffraction were obtained. A suitable single crystal was selected and
mounted in air onto thin glass fibers. Accurate unit cell parameters
were determined by a least-squares fit of 2θ values, and intensity data
were measured on a CCD diffractometer with Mo Kα radiation (λ =
0.71073 Å) at 296 K. The detector was placed at a distance 6.03 cm
from the crystal. The data were reduced in SAINTPLUS,27 and
empirical absorption correction was applied using the SADABS
package.27 The structures were solved by direct methods and refined
with full-matrix least-squares technique using the SHELXTL v.6.14
program package.28,29 All non-hydrogen atoms were refined with
anisotropic thermal parameters. The hydrogen atoms were added
theoretically and riding on the concerned atoms. Molecular structure
plots were drawn using Platon.30
3a,4-Dihydro-4-(4-methoxyphenyl)-10-methyl-6H-isobenzofuro-
[5,4-c]chromene-1,3(11bH,11cH)-dione (8f). Orange yellow solid
1
(309.5 mg, 82%): mp 206−207 °C; H NMR (300 MHz, DMSO-d6)
δ 7.26 (d, J = 8.3 Hz, 2H), 7.20 (s, 1H), 6.98−6.91 (m, 3H), 6.77 (d, J
= 8.2 Hz, 1H), 6.30 (s, 1H), 4.56 (d, J = 13.4 Hz, 1H), 4.40 (d, J =
13.3 Hz, 1H), 4.06−3.78 (m, 4H), 3.76 (s, 3H), 2.27 (s, 3H); 13C
NMR (75 MHz, DMSO-d6) δ 171.0, 170.9, 158.2, 154.5, 138.3, 130.7,
130.4, 129.6, 129.0, 128.3, 123.9, 122.8, 117.1, 113.6, 67.9, 55.0, 48.4,
46.8, 34.4, 20.5; IR (KBr, cm−1) ν 3424.40, 2920.09, 2836.30, 1778.21,
1615.33, 1518.98, 1497.87, 1461.01, 1288.10, 1252.45, 1176.07,
1037.22, 1005.68, 932.19, 835.86, 819.65, 756.68; HRMS (ESI-TOF,
m/z) calcd for C23H20NaO5 [M + Na+] 399.1208, found 399.1207.
3a,4-Dihydro-4-(3,4-dimethoxyphenyl)-10-methyl-6H-isobenzo-
furo[5,4-c]chromene-1,3(11bH,11cH)-dione (8g). Orange yellow
solid (366.4 mg, 90%): mp 169−170 °C; 1H NMR (300 MHz,
DMSO-d6) δ 7.30 (s, 1H), 6.99−6.77 (m, 5H), 6.35 (s, 1H), 4.58 (d, J
= 13.1 Hz, 1H), 4.41 (d, J = 13.2 Hz, 1H), 4.04−3.80 (m, 4H), 3.76 (s,
6H), 2.28 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 171.0, 170.8,
154.5, 148.4, 147.8, 138.2, 131.1, 130.5, 129.0, 128.3, 124.0, 122.8,
120.6, 117.1, 112.6, 111.5, 67.9, 55.5, 55.4, 48.4, 46.8, 34.4, 20.5; IR
(KBr, cm−1) ν 3424.71, 2934.70, 2837.52, 1779.24, 1733.89, 1518.04,
1500.05, 1464.63, 1243.82, 1143.40, 1024.98, 931.49, 820.50, 765.74;
HRMS (ESI-TOF, m/z) calcd for C24H22NaO6 [M + Na+] 429.1314,
found 429.1315.
3a,4-Dihydro-4-(4-methoxyphenyl)-6H-isobenzofuro[5,4-c]-
chromene-1,3(11bH,11cH)-dione (8h). Light yellow solid (315.8 mg,
87%): mp 213−215 °C; 1H NMR (300 MHz, DMSO-d6) δ 7.41 (d, J
= 7.3 Hz, 1H), 7.25 (d, J = 8.6 Hz, 2H), 7.16 (t, J = 7.5 Hz, 1H), 7.02
(t, J = 7.3 Hz, 1H), 6.93−6.86 (m, 3H), 6.32 (s, 1H), 4.60 (d, J = 13.6
Hz, 1H), 4.45 (d, J = 13.5 Hz, 1H), 4.07−3.78 (m, 4H), 3.75 (s, 3H);
6612
dx.doi.org/10.1021/jo5011125 | J. Org. Chem. 2014, 79, 6603−6614

The Journal of Organic Chemistry
Article
Trivedi, R.; Dwivedi, A.; Kumar, K. R.; Saxena, A. K.; Hajela, K. RSC
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ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra, cytotoxicity data, HOMO and
LUMO pictures, Cartesian coordinates and energies, crystallo-
graphic data and CIF file. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: sanjaybharin@yahoo.com; sanjay_bhar@chemistry.
jdvu.ac.in.
■
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
The authors express sincere gratitude to Professor S. C.
Bhattacharya, Professor S. Bhattacharya and Dr. K. K. Rajak of
Jadavpur University for extending generous instrumental and
intellectual support during the entire course of this journey.
The aforesaid investigation has enjoyed financial support from
the Council of Scientific and Industrial Research, New Delhi,
Government of India (CSIR Grant No. 01 (2383)/10/EMR-II)
and DST-PURSE-programme at Jadavpur University, which are
also gratefully acknowledged. R. R. and A. G. thank CSIR, New
Delhi, Government of India for senior research fellowship and
junior research fellowship, respectively. S. R. and S. K. thank
UGC, New Delhi, Government of India for senior research
fellowships. Thanks to Mr. J. Poddar of Jadavpur University and
Mr. N. Dutta of Indian Association for the Cultivation of
Science for necessary assistance.
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