Diastereoselective synthesis of novel spiro indanone fused pyrano[3,2-: c] chromene derivatives following hetero-Diels-Alder reaction and in vitro anticancer studies

Article abstract of DOI:10.1039/c8ra02729c

The development of concise methods for the synthesis of small functionalised spirocyclic molecules is important in the search of new bioactive molecules. To contribute this, here we represent a diastereoselective oxa-hetero-Diels-Alder reaction for the synthesis of novel spiro indanone fused pyrano[3,2-c]chromene derivatives and studied their in vitro anticancer activities. Using previously less explored cyclic ketone i.e. indane-1,3-dione and 3-vinyl-2H-chromene derivatives, we obtained novel spiro-heterocyclic frameworks at the interphase between "drug-like" molecules and natural products. Various spiro indanone fused pyrano[3,2-c]chromene derivatives were synthesized regiospecifically bearing a quaternary stereocenter in high yields (up to 85%) with excellent diastereoselectivity in toluene using 4 ? MS as additive under reflux condition at 120 °C. In vitro cytotoxic studies of these compounds against MCF-7 (breast cancer), HCT-116 (colon cancer), H-357 (oral cancer), MD-MB-231(Breast cancer) cell lines were evaluated by MTT {3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide} assay in vitro. The screening results revealed that many of the compounds are showing moderate to high levels of anticancer activities against the tested cancer cell lines and some displayed potent inhibitory activities in comparison to the commercial anticancer drug 5-fluorouracil (5-FU). Among the series, compound 3′c showed most potent cytotoxicity (15.0-27.5 μM) in three cancer cell lines (MCF-7, HCT-116 and MD-MB-231).

Full text of DOI:10.1039/c8ra02729c

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Diastereoselective synthesis of novel spiro
indanone fused pyrano[3,2-c]chromene derivatives
following hetero-Diels–Alder reaction and in vitro
anticancer studies†
Cite this: RSC Adv., 2018, 8, 16802
a
a
a
a
Pravati Panda, Sabita Nayak, * Susanta Ku. Sahoo, Seetaram Mohapatra,
b
b
b
Deepika Nayak, Rajalaxmi Pradhan and Chanakya Nath Kundu*
The development of concise methods for the synthesis of small functionalised spirocyclic molecules is
important in the search of new bioactive molecules. To contribute this, here we represent
a diastereoselective oxa-hetero-Diels–Alder reaction for the synthesis of novel spiro indanone fused
pyrano[3,2-c]chromene derivatives and studied their in vitro anticancer activities. Using previously less
explored cyclic ketone i.e. indane-1,3-dione and 3-vinyl-2H-chromene derivatives, we obtained novel
spiro-heterocyclic frameworks at the interphase between “drug-like” molecules and natural products.
Various spiro indanone fused pyrano[3,2-c]chromene derivatives were synthesized regiospecifically
bearing a quaternary stereocenter in high yields (up to 85%) with excellent diastereoselectivity in toluene
ꢀ
ꢀ
using 4 A MS as additive under reflux condition at 120 C. In vitro cytotoxic studies of these compounds
against MCF-7 (breast cancer), HCT-116 (colon cancer), H-357 (oral cancer), MD-MB-231(Breast cancer)
cell lines were evaluated by MTT {3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide} assay
in vitro. The screening results revealed that many of the compounds are showing moderate to high
levels of anticancer activities against the tested cancer cell lines and some displayed potent inhibitory
activities in comparison to the commercial anticancer drug 5-fluorouracil (5-FU). Among the series,
Received 29th March 2018
Accepted 23rd April 2018
DOI: 10.1039/c8ra02729c
0
compound 3 c showed most potent cytotoxicity (15.0–27.5 mM) in three cancer cell lines (MCF-7, HCT-
rsc.li/rsc-advances
116 and MD-MB-231).
4–8
transformation.
Organocatalyst mediated synthesis of oxa
Introduction
spirocyclic indanone scaffold was reported in the literature in
1
Chiral indane frameworks, particularly indanone subunits, 2013 by Peng et al. following Morita–Baylis–Hillman reaction.
constitute a unique group of desirable targets in organic Although good stereoselectivity was observed in product
synthesis and attracted the attention of organic chemists and formation, however the synthetic method suffers from draw-
biologists because of their broad distribution in biologically backs in reaction conditions and yields. Efficient cost effective
active natural products and pharmaceutically active synthesis methods of the oxa spirocyclic indanone backbone
compounds such as fredericamycin, colephomone-D, radde- are needed in order to expand the usefulness of this intriguing
1,2
none and yenhusomidine. Due to their synthetic utility and combination of pharmacologically interesting pyran and inda-
application in pharmaceuticals, a variety of synthetic protocols none motifs.
have been developed for the synthesis of optically pure inda-
On the other hand, the pyran ring is among one of the most
3
9
none skeleton. Of particular interest are methods for stereo- widely investigated heterocycles. It is the core unit of benzo-
selective formation of medicinally important spirocyclic pyran, chromene, avonoids, coumaroin, xanthones and
indanone frameworks, such as those that enantioselectively naphthoquinones, which exhibit diverse pharmacological
10–15
generate a quaternary stereocenter, considered a challenging activities.
The benzopyran or chromene cores are prevalent
in many natural products show fascinating therapeutic activi-
16–22
ties.
In recent years, chromeno fused pyran based hetero-
a
Department of Chemistry, Ravenshaw University, Cuttack, Odisha, India. E-mail:
cyclic natural products such as Ethuliacoumarion and its
derivatives, spiro oxindole fused pyranochromene, dihydropyr-
sabitanayak18@gmail.com
b
Cancer Biology Division, School of Biotechnology, Kalinga Institutue of Industrial
23,24
Technology, Campus-11, Patia, Bhubaneswar, Odisha-751024, India. E-mail: anochromene etc.
have attracted tremendous interest
cnkundu@kiitbiotech.ac.in
among researchers because they possess both a chromene and
pyran moiety which has potential applications in medicinal
†
Electronic supplementary information (ESI) available. See DOI:
0.1039/c8ra02729c
1
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Fig. 1 Various natural and synthetic products based on biologically active indanone and pyranochromene scaffolds.
chemistry and exhibit signicant biological activities, such as heterocycles bearing a chiral tertiary or quaternary carbon
25
anticancer, anthelmintic and molluscicidal activity (Fig. 1).
Due to the biomedical importance of chromeno fused pyran Although asymmetric HDA reactions of aldehydes as dienophile
centre in a single step from commercially available substrates.
23
and spiro-indane-1,3-dione skeletons, combination of these two have been extensively studied, ketone substrates, in contrast,
units in one molecule may benet diversity of structure and are much less reactive in HDA reactions due to electronic and
drug discovery. The hetero-Diels–Alder (HDA) reaction is argu- steric properties, and are still challenging substrates for
26
ably the most powerful way of constructing six-membered chemists.
Scheme 1 Model for synthesis of spiro indanone fused pyrano chromene.
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Scheme 2 Synthesis of 2H-chromene-3-carbaldehyde 8(a–h) and 10(a–g) and 3-vinyl-2H-chromene 2(a–h) and 2 (a–h).
As a part of our continuing efforts for the synthesis of anticancer candidates through concise construction of novel
heterocycles, to combine the interesting and remarkable bio- chiral spiro indanone fused pyrano[3,2-c]chromene exhibiting
logical activities of both indanone and chromeno fused pyran a unique prole of biological activities via hetero Diels Alder
derivatives we sought a synthesis of spiro indanone fused pyr- reaction. Furthermore, we hope this new type of spiro pyrano
ano[3,2-c]chromene skeleton. Literature survey disclosed chromene can serve as a potential anticancer agent.
number of reports describing the synthesis of spiro pyran
A novel synthetic approach for the regiospecic and dia-
26–29
derivatives using isatin backbone.
However, to the best of stereoselective synthesis of spiro indanone fused pyrano[3,2-c]
our knowledge only a very few reports are there for the synthesis chromene 3(a–h) by the reaction of indane-1,3-dione 1 and 3-
30
0
of oxa spirocyclic indanone scaffold. In this study, we present vinyl-2H-chromene 2(a–h) and 2 (a–h) in toluene via hetero
our contribution to the successful discovery of new potent Diels Alder reaction was reported (Scheme 1). It was interesting
Table 1 Optimisation for the synthesis of 3a
ꢀ
a
Entry
Solvent
Additive
Temp. ( C)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
Toluene
Toluene
Toluene
Benzene
Benzene
_
_
RT
12 h
12 h
2 h
12 h
4 h
12 h
6 h
12 h
6 h
n.r
Reux
Reux
RT
Reux
RT
Reux
RT
Reux
40%
80%
n.r
50%
n.r
40%
n.r
20%
ꢀ
4 A MS
4 A MS
4 A MS
4 A MS
4 A MS
4 A MS
4 A MS
ꢀ
ꢀ
ꢀ
ꢀ
CH
CH
3
CN
CN
3
ꢀ
DCM
DCM
ꢀ
a
ꢀ
Indane-1,3-dione 1 (1 mmol) and 3-vinyl-2H-chromene 2a (1 mmol) at reux in toluene for 3 h in the presence of 4 A MS.
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Scheme 3 Synthesis of spiro indanone fused pyrano chromene 3(a–h) and 3 (a–g).
0
that regioisomer 3(a–h) and 3 (a–g) were formed regiospeci-
Results and discussion
0
cally whereas regioisomers 4(a–h) and 4 (a–g) were not observed
might be due to the non-interaction of *C orbital of the diene Initially, 2H-chromene-3-carbaldehydes 8(a–h) and 10(a–g) were
lower orbital co-efficient) with carbonyl carbon orbital of the prepared by the reaction of salicylaldehyde 6(a–g) with cinna-
(
dienophile (Scheme 1).
maldehyde 7 or acrolein 9 following Oxa–Michael–Aldol
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Scheme 4 A plausible mechanism for the formation of compound 3a.
31,32
reaction in good yields (Scheme 2).
2H-Chromene-3- conversion was observed and the starting material remains
carbaldehyde derivatives 8(a–h) and 10(a–g) were completely unreacted (entry 2). The same reaction was again repeated using
ꢀ
ꢀ
characterised using their analytical and spectral data. For 4 A MS as additive. Gratifyingly, the addition of 4 A MS
1
example, the H NMR spectrum of 8a and 10a exhibited a singlet increased the yield of the product to 80% and decreased the
at 9.66 and 9.59 ppm due to CHO, also the characteristic olenic time of reaction to 2 h (entry 3). From this we come to the point
protons came at 7.42 and 7.26 ppm. The 2H-protons of chro- that additives have signicant inuence to the yield of the
mene aldehyde appeared as singlet at 6.35 and 5.11 ppm in 8a product. The effect of other solvents such as benzene, CH CN
3
ꢀ
and 10a which indicates the formation of chromene aldehydes. and DCM in the presence of 4 A MS were also studied to improve
Wittig reaction of 8(a–h) and 10(a–g) with methyl triphenyl the yield. No product formation was observed under room
phosphonium bromide in BuLi afforded 3-vinyl-2H-chromene temperature stirring for 12 h in all cases (entries 4, 6 and 8). Also
0
33
3
derivatives 2(a–h) and 2 (a–h) in good yield. Compounds 2(a– reuxing in various solvents such as benzene, CH CN and DCM
0
1
13
h) and 2 (a–f) were successfully characterised by H, C NMR did not give signicant inuence to the yield of the product
and IR. For example, the aldehydic proton which appears at (entries 5, 7 and 9). So we conclude that the greatest reaction
1
9
.66 ppm for compound 8a vanishes in the H NMR of efficacy and stereocontrol in the product formation was ob-
ꢀ
compound 2a. The olenic protons of compound 2a appeared tained using toluene and 4 A MS (entry 3). In all cases regio-
as double doublet at 6.52 ppm (J ¼ 11.2 Hz, 17.6 Hz, CH) and specically a single diastereoisomer was formed as major
5
.09 ppm (J ¼ 11.2 Hz, 18.8 Hz, CH ) which indicates the isomer.
2
formation of compound 2a.
Results of experiments under the optimised conditions for
Literature reports revealed that dienes can undergo hetero probing the scope of the reaction are summarized in Scheme 3.
0
Diels Alder reaction with aldehyde or ketone to form an oxa A range of 3-vinyl-2H-chromene 2(a–h) and 2 (a–h) derivatives
ꢀ
spirocyclic scaffold. Prompted by the literature ndings we were examined with indane-1,3-dione 1 in toluene using 4 A MS
ꢀ
planned to synthesize spiro indanone fused pyranochromene as additives under reux condition at 120 C for the construc-
derivatives by the reaction of indane-1,3-dione and 3-vinyl-2H- tion of spiro indanone fused pyranochromene derivatives 3(a–
0
chromene.
To optimise the reaction conditions, we screened the hetero
h) and 3 (a–g) (Scheme 3).
The results showed that, in general variation of the elec-
Diels–Alder reaction of indane-1,3-dione 1 (1 mmol) and 3-vinyl- tronic properties of the substituent at different positions of the
0
2
H-chromene 2a (1 mmol) as a model. The effect of several 3-vinyl-2H-chromene 2(a–h) and 2 (a–g) was well tolerated
solvents and additive were studied (Table 1). Using toluene as giving the spiro indanone fused pyranochromene derivatives
0
solvent at room temperature under additive free condition for 3(a–h) and 3 (a–g) with excellent yields with diastereoselectivity
1
2 h, no product formation was observed (entry 1). When the albeit with a slight low yield for 3g. Additionally, dienes
ꢀ
reaction was put under reux condition at 120 C for 12 h, 40% substituted with halogen groups took a slight longer reaction
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a
Table 2 IC50 values of compound 3(a–h) and 3 (a–g) in MCF-7, HCT-116, H-357 and MD-MB-231 cell line
Compound
name
MCF-7 (mM)
HCT-116 (mM)
H-357 (mM)
MD-MB-231 (mM)
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
5
a
b
c
d
e
f
31.5 ꢁ 2.0
52.5 ꢁ 4.0
91 ꢁ 6.2
32 ꢁ 3.2
34 ꢁ 2.2
40 ꢁ 1.0
32.5 ꢁ 3.0
48 ꢁ 2.2
65 ꢁ 7.2
41 ꢁ 2.1
20 ꢁ 1.0
41.5 ꢁ 6.0
65 ꢁ 4.8
38.5 ꢁ 2.1
50 ꢁ 8.0
40 ꢁ 6.0
35.5 ꢁ 3.0
41.5 ꢁ 3.6
41 ꢁ 3.0
36 ꢁ 1.0
40 ꢁ 4.0
50 ꢁ 8.2
38 ꢁ 2.0
35 ꢁ 1.0
43 ꢁ 1.0
40 ꢁ 4.0
27.5 ꢁ 1.0
44 ꢁ 3.0
39.5 ꢁ 1.8
50 ꢁ 8.0
54 ꢁ 8.0
42 ꢁ 1.0
64.5 ꢁ 10.0
68 ꢁ 10.0
66 ꢁ 8.0
67 ꢁ 6.0
65.5 ꢁ 2.8
54.5 ꢁ 8.0
63.5 ꢁ 6.0
69 ꢁ 6.0
76.5 ꢁ 7.0
74 ꢁ 11.3
55 ꢁ 4.0
73 ꢁ 6.3
71 ꢁ 5.8
75 ꢁ 7.4
70 ꢁ 8.1
48 ꢁ 1.0
38 ꢁ 1.0
63 ꢁ 5.6
78 ꢁ 8.0
19 ꢁ 1.0
37.5 ꢁ 2.0
36 ꢁ 1.2
33.5 ꢁ 1.8
51 ꢁ 4.0
72.5 ꢁ 6.2
52.5 ꢁ 4.0
15 ꢁ 1.0
47 ꢁ 4.0
69 ꢁ 6.0
31 ꢁ 2.0
27 ꢁ 1.0
40 ꢁ 2.0
g
h
0
a
0
0
0
0
0
0
b
c
d
e
f
g
-FU
a
The data was presented as mean ꢁ SD of 4 different experiments.
time might be due to the negative inductive effect of halogens. stereochemistry of the diene in the transition state. Here we
0
Dienes containing benzoate group 2 g also underwent the assume that the cycloadducts 3a could form via an endo-
reaction smoothly affording good yield of the product with transition state A i.e. the dienophile approaches from the
excellent diastereoselectivity. Unexpectedly, dienes containing opposite face to the Ph group giving the anti product (major
0
hydroxyl groups 2 h and nitro group when treated with indane- isomer), where Ha and Hb show no NOESY interaction, and the
1,3-dione do not provide the Diels Alder adduct. Presence of –I dienophile approaches from the same face to the Ph group i.e.
effecting group (NO , –OH) in diene might be decreasing HOMO more hindered side giving syn product i.e. 5a (minor isomer) as
2
energy level causing higher HOMO–LUMO energy gap. The represented in Scheme 4. The diastereoisomeric ratio remains
applied thermal energy is not sufficient enough to crossover the high throughout the course of the reaction.
energy gap, causing no interaction between diene and dien-
Literature report reveals that indanone based natural prod-
ophile to give the product. The structures of the products 3(a–h) ucts such as Fredericamycin and related synthetic derivatives
0
and 3 (a–g) were established on the basis of their spectral data are showing anticancer activity. Similarly pyranochromene
1
13
(
H and C NMR) as well as HRMS analysis. The regiospecic based molecules also shows potent anticancer activity. The
0
formation of the products 3(a–h) and 3 (a–g) were conrmed by synthesized spiro indanone fused pyrano[3,2-c]chromene
1
0
H NMR. For instance, the allylic –CH of newly formed pyran molecules 3(a–h) and 3 (a–g) were explored for in vitro cytotox-
2
ring in all cases comes at 2–3 ppm which indicates the forma- icity activity in various human cancer cell lines such as MCF-7
0
tion of 3(a–h) and 3 (a–g). The regiospecic product formation (breast cancer), HCT-116 (colon cancer), H-357 (oral cancer),
3
a might be obtained due to the ow of electron from oxygen MD-MB-231(breast cancer) using MTT assay as shown in Table
0
atom of the chromene ring to the olenic *C of the diene which 2. The results exhibited that compounds 3 c shows most potent
results the interaction of highest negative charge density *C of cytotoxic activity [IC50 (y percent cell death in culture) 15.0–
the diene with the lowest positive charge density carbonyl 27.5 mM] against MCF-7 (breast cancer), HCT-116 (colon
carbon of the dienophile. The stereochemistry of the major cancer), MD-MB-231 (breast cancer) cell lines. Compounds 3a,
0
isomer 3a was determined by 2D NMR (NOESY). In the NOESY 3d, 3e, 3f, 3g, 3 f (IC50: 31.5–40.1 mM) shows better activity in
spectra of compound 3a (Major) the benzylic proton and 2H- MCF7 cell line comparison to standard drug 5-FU. Compounds
0
0
chromene proton do not show interaction with each other 3a, 3b, 3c, 3d, 3e, 3h, 3 b, 3 e, (IC50: 35.5–41.5 mM) shows better
whereas in case of minor isomer both the protons shows activity in HCT-116 cell line comparison to standard drug 5-FU.
0
0
interaction from which we come to the point that the trans- Compounds 3a, 3d, 3e, 3f, 3g, 3 f, 3 g (IC50: 19.0–38.0 mM)
isomer is major where as syn- is minor. Only in two cases we are shows better activity in MD-MB-231 cell line comparison to
able to separate out the minor cis-isomer whereas in other cases standard drug 5-FU. However none of the compounds in the
we failed. Diastereoselective trans-isomer is formed as the series shows better activity in H-357 cancer cell line. SAR
0
major isomer in all cases.
showed that possibly, the ethoxy group present in 3 c could be
0
A plausible mechanism for the hetero-Diels–Alder reaction responsible for more cytotoxic activity. Though compound 3 c
of indane-1,3-dione 1 and 3-vinyl-2H-chromene 2a is shown in and 3d, both having ethoxy group but absence of phenyl group
0
Scheme 4. The stereochemistry of the product depends on the in 3 c might increase the cytotoxic activities.
endo-orientation of the dienophile as well as by the
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-Methoxy-2-phenyl-2H-chromene-3-carboxaldehyde (8b).
Conclusion
ꢀ
ꢂ1
Yellow solid (85%); mp 117–119 C. IR (KBr) (nmax/cm ): 3051,
In summary, we have developed a novel protocol for regiospe- 2908, 2811, 2720, 1657, 1631, 1573, 1378, 1255, 1210, 1093, 964,
1
cic and diastereoselective synthesis of spiro indanone fused 892, 763, 723, 691, 581, 510. H NMR (400 MHz, CDCl ): d 9.67
3
H
pyrano chromene frameworks containing indanone, pyran and (1H, s, CHO), 7.40 (1H, s, CH), 7.38–7.36 (2H, m, H–Ar), 7.28–
chromene moieties through oxa-hetero Diels–Alder approach by 7.24 (3H, m, H–Ar), 6.94–6.88 (3H, m, H–Ar), 6.44 (1H, s, CH),
1
3
the reaction of indane-1,3-dione and 3-vinyl-2H-chromene in 3.84 (3H, s, OCH3); C NMR (100 MHz, CDCl ): d 190.3, 148.6,
3
C
good to excellent yields with a wide substrate scope. Several 144.2, 141.1, 139.1, 134.1, 128.7, 128.6, 126.7, 121.7, 121.4,
+
advantages associated with this protocol such as cost effective, 120.9, 116.2, 74.3, 56.4. ESI-HRMS [M + Na] : calcd for
high yields, easy accessibility, wide substrate scope and short C H O : 289.0835, found: 289.0837. Anal. calcd for C H O :
1
7
14
3
17 14 3
reaction time. The synthesized products were evaluated for their C, 76.68; H, 5.30. Found: C, 76.69; H, 5.33.
potential anticancer activities. Most of these compounds
showed potent activities. Compound 3 c is signicantly more Yellow solid (75%); mp 121–123 C. IR (KBr) (nmax/cm ): 3051,
7-Methoxy-2-phenyl-2H-chromene-3-carboxaldehyde (8c).
0
ꢀ
ꢂ1
potent. The possible mechanism of this kind of spiro indanone 2908, 2811, 2720, 1657, 1631, 1573, 1378, 1255, 1210, 1093, 964,
1
fused pyrano[3,2-c]chromene as an anticancer agent will be 892, 763, 723, 691, 581, 510. H NMR (400 MHz, CDCl ): d 9.59
3
H
studied in future.
(1H, s, CHO), 7.40 (1H, s, CH), 7.38–7.36 (2H, m, H–Ar), 7.32–
7
.25 (5H, m, H–Ar), 6.53 (1H, dd, J ¼ 8.0 Hz, 4.0 Hz, H–Ar), 6.34
13
(1H, s, CH), 3.80 (3H, s, OCH
3
); C NMR (100 MHz, CDCl
3 C
): d
Experimental section
General methods
1
89.7, 164.5, 156.7, 141.0, 139.3, 131.0, 128.5, 126.7, 113.4,
+
108.9, 105.8, 102.0, 98.0, 74.6, 55.5. ESI-HRMS [M + Na] : calcd
for C H O : 289.0835, found: 289.0837. Anal. calcd for
C H O : C, 76.68; H, 5.30. Found: C, 76.72; H, 5.34.
1
13
1
7
14 3
H NMR spectra were recorded on 400 MHz (100 MHz for
C
1
7
14 3
3
NMR) JEOL NMR spectrometer with CDCl as solvent and tet-
ramethylsilane (TMS) as internal standard. Chemical shis
were reported in parts per million (ppm, d scale) downeld from
8
-Ethoxy-2-phenyl-2H-chromene-3-carboxaldehyde (8d). Yellow
ꢀ
ꢂ1
solid (85%); mp 98–100 C. IR (KBr) (nmax/cm ): 2974, 2807,
748, 1664, 1627, 1609, 1469, 1376, 1256, 1218, 1098, 1005, 902,
1
TMS at 0.00 ppm and referenced to the CDCl
3
at 7.26 ppm (for
1
1
13
3 H
754, 689, 642, 615, 521. H NMR (400 MHz, CDCl ): d 9.70
H NMR) or 77.0 ppm (for C NMR). Melting points are
(1H, s, CHO), 7.41 (1H, s, CH), 7.40–7.37 (2H, m, H–Ar), 7.30–
uncorrected and were determined with SMP10 digital melting
point apparatus using open capillary tubes. All reagents and
solvents used in this study were commercially available (from
Sigma-Aldrich) and were used without further purication.
7
4
.26 (3H, m, H–Ar), 6.96–6.88 (3H, m, H–Ar), 6.46 (1H, s, CH),
.08 (2H, q, J ¼ 8.0 Hz, CH
1
3
2
), 1.40 (3H, t, J ¼ 8.0 Hz, CH
3
);
C
NMR (100 MHz, CDCl ): d 190.4, 147.9, 144.7, 141.3, 139.1,
3
C
1
1
3
34.1, 128.6, 128.5, 126.6, 121.7, 121.5, 121.2, 118.1, 73.9, 65.1,
4.9. ESI-HRMS [M + Na] : calcd for C H O : 303.0992, found:
03.0985. Anal. calcd for C18H O : C, 77.12; H, 5.75. Found: C,
16 3
+
1
8
16 3
General procedure for the synthesis of 8(a–h)
Salicylaldehyde (1 mmole) and cinnamaldehyde (1.1 mmole) 77.15; H, 5.77.
were taken in a round bottom ask and 3 ml of dry DMSO was
6-Bromo-2-phenyl-2H-chromene-3-carboxaldehyde (8e). Pale
ꢀ
ꢂ1
added to it followed by pyrrolidine (0.2 mmol). Then it was yellow solid (80%); mp 137–139 C. IR (KBr) (nmax/cm ): 3058,
stirred at room temperature in argon atmosphere. The progress 2934, 2824, 2714, 1891, 1819, 1677, 1631, 1586, 1560, 1482,
of the reaction was monitored by TLC and was found to be 1411, 1384, 1307, 1203, 1158, 1132, 1067, 957, 814, 691, 626,
1
completed aer 12 h. Aer completion of reaction, 50 ml of 522. H NMR (400 MHz, CDCl ): d 9.66 (1H, s, CHO), 7.39–7.27
3
H
water was added to it and then extracted with ethyl acetate. The (8H, m, CH, H–Ar), 6.78 (1H, d, J ¼ 8.0 Hz, H–Ar), 6.34 (1H, s,
1
3
combined organic layers were washed with brine (30 mL). The CH); C NMR (100 MHz, CDCl ): d 189.9, 153.9, 139.2, 138.6,
3
C
organic layers were dried over Na
2 4
SO and concentrated in 136.2, 134.7, 131.6, 129.1, 128.8, 126.9, 121.9, 119.2, 113.8, 74.6.
+
rotavapor. The crude product was crystallised in isopropanol at ESI-HRMS [M + Na] : calcd for C H BrO : 336.9835, found:
1
6
11
2
ꢀ
0
C provided aldehyde compound in pure form. In some cases 336.9833. Anal. calcd for C H BrO : C, 60.98; H, 3.52. Found:
16 11 2
column chromatography has been done in order to purify the C, 61.01; H, 3.54.
compound. Synthesized chromene aldehydes were successfully
6-Chloro-2-phenyl-2H-chromene-3-carboxaldehyde (8f). Faint
1
13
ꢀ
ꢂ1
characterised by H, C NMR, IR and mass analysis.
-Phenyl-2H-chromene-3-carboxaldehyde (8a). Yellow solid 2934, 2824, 2714, 1891, 1819, 1677, 1631, 1586, 1560, 1482,
yellow solid (81%); mp 129–131 C. IR (KBr) (nmax/cm ): 3058,
2
ꢀ
ꢂ1
(
88%); mp 72–74 C. IR (KBr) (nmax/cm ): 3048, 2820, 2707, 1411, 1384, 1307, 1203, 1158, 1132, 1067, 957, 814, 691, 626,
670, 1570, 1457, 1216, 1102, 996, 768, 612, 520. H NMR (400 522. H NMR (400 MHz, CDCl ): d 9.67 (1H, s, CHO), 7.36
1
1
1
3 H
MHz, CDCl
3
): d
H
9.66 (1H, s, CHO), 7.42 (1H, s, CH), 7.37–7.35 (1H, s, CH), 7.34–7.22 (7H, m, H–Ar), 6.82 (1H, d, J ¼ 8.0 Hz, H–
13
(2H, m, H–Ar), 7.30–7.25 (5H, m, H–Ar), 6.96–6.87 (2H, m, H– Ar), 6.34 (1H, s, CH); C NMR (100 MHz, CDCl ): d 189.8,
3 C
1
3
Ar), 6.35 (1H, s, CH); C NMR (100 MHz, CDCl
3
): d
C
190.1, 153.3, 139.3, 138.5, 134.6, 133.1, 128.9, 128.7, 128.5, 126.8,
+
154.9, 140.8, 139.1, 133.7, 129.5, 128.7, 126.8, 121.8, 120.0, 126.7, 121.2, 118.6, 74.5. ESI-HRMS [M + Na] : calcd for
+
117.1, 74.2. ESI-HRMS [M + Na] : calcd for C H O : 259.0730, C H ClO : 293.0340, found: 293.0338. Anal. calcd for
16 12 2
16 11 2
12 2
16 11 2
found: 259.0730. Anal. calcd for C16H O : C, 81.34; H, 5.12. C H ClO : C, 70.99; H, 4.10. Found: C, 71.02; H, 4.13.
Found: C, 81.35; H, 5.15.
16808 | RSC Adv., 2018, 8, 16802–16814
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6
3 H
,8-Dichloro-2-phenyl-2H-chromene-3-carboxaldehyde (8g). 782, 723, 704, 594, 490. H NMR (400 MHz, CDCl ): d 9.60
ꢀ
ꢂ1
Golden yellow solid (82%); mp 136–138 C. IR (KBr) (nmax/cm ): (1H, s, CHO), 7.26 (1H, s, CH), 6.96 (1H, dd, J ¼ 8.0 Hz, 4.0 Hz,
3
8
(
071, 2811, 1683, 1631, 1462, 1398, 1333, 1242, 1171, 1086, 88, H–Ar), 6.91 (1H, t, J ¼ 8.0 Hz, H–Ar), 6.85 (1H, dd, J ¼ 4.0 Hz,
1
83, 723, 652, 555, 451. H NMR (400 MHz, CDCl
3
): d
H
9.73 4.8 Hz, H–Ar), 5.11 (2H, s, CH
2
), 4.12 (2H, q, J ¼ 4.0 Hz, CH
2
),
): d
1H, s, CH); C NMR (100 MHz, CDCl ): d 189.8, 149.3, 138.7, 189.9, 147.4, 145.4, 141.5, 131.7, 121.6, 121.3, 117.0, 64.7, 63.6,
1
3
1H, s, CHO), 7.35–7.27 (7H, m, H–Ar), 7.17 (1H, s, CH), 6.48 1.47 (3H, t, J ¼ 4.8 Hz, CH
3
); C NMR (100 MHz, CDCl
3
C
1
3
(
3
C
1
38.0, 135.4, 133.0, 129.1, 128.8, 127.1, 126.6, 123.3, 122.4, 74.8. 14.8. MS m/z: calcd for C12
H
12
O
3
: 204.0, found: 204.1. Anal.
: C, 70.57; H, 5.92. Found: C, 70.59; H, 5.95.
6-Bromo-2H-chromene-3-carbaldehyde (10d). Straw yellow
+
12 3
ESI-HRMS [M + Na] : calcd for C H Cl O : 326.9950, found: calcd for C12H O
1
6
10
2 2
3
26.9947. Anal. calcd for C16
C, 62.99; H, 3.28.
-Bromo-8-chloro-2-phenyl-2H-chromene-3-carboxaldehyde
2 2
H10Cl O : C, 62.97; H, 3.30. Found:
ꢀ
ꢂ1
solid (79%); mp 104–106 C. IR (KBr) (nmax/cm ): 3058, 2934,
6
2824, 2714, 1891, 1819, 1677, 1631, 1586, 1560, 1482, 1411,
ꢀ
ꢂ1
1
(
8h). Yellow solid (81%); mp 132–134 C. IR (KBr) (nmax/cm ): 1384, 1307, 1203, 1158, 1132, 1067, 957, 814, 691, 626, 522. H
3
8
(
071, 2811, 1683, 1631, 1462, 1398, 1333, 1242, 1171, 1086, 88, NMR (400 MHz, CDCl
3
): d
H
9.58(1H, s, CHO), 7.37–7.35(1H, m,
1
83, 723, 652, 555, 451. H NMR (400 MHz, CDCl ): d 9.75 H–Ar), 7.31(1H, d, J ¼ 1.6 Hz, H–Ar), 7.16(1H, s, CH), 6.75(1H, d,
3
H
1
3
1H, s, CHO), 7.53 (1H, s, CH), 7.36–7.31 (6H, m, H–Ar), 7.22 J ¼ 6.8 Hz, H–Ar), 5.02(2H, s, CH
2
); C NMR (100 MHz, CDCl
3
):
1
3
(
1H, d, J ¼ 4.0 Hz, H–Ar), 6.51 (1H, s, CH); C NMR (100 MHz,
): d
189.9, 149.3, 138.7, 138.0, 135.4, 133.0, 131.6, 129.5, 63.7. ESI-HRMS [M + H] : calcd for C10
26.9, 121.9, 119.2, 117.1, 113.8, 74.5. Anal. calcd for C16
BrClO : C, 54.97; H, 2.88. Found: C, 54.95; H, 2.89.
d 189.8, 155.2, 139.7, 135.8, 132.7, 131.7, 122.4, 118.6, 114.0,
C
+
CDCl
1
3
C
H
7
BrO
H BrO : C, 50.24; H, 2.95. Found: C,
7 2
2
: 238.9702, found:
H
10
-
239.9736. Anal. calcd for C10
50.22; H, 2.97.
2
6
-Chloro-2H-chromene-3-carbaldehyde (10e). Yellow solid
ꢀ
ꢂ1
(
82%); mp 93–95 C. IR (KBr) (nmax/cm ): 3058, 2934, 2824,
General procedure for the synthesis of 10(a–f)
To a solution of salicylaldehyde (1 mmol) in dioxane (100 ml) 1307, 1203, 1158, 1132, 1067, 957, 814, 691, 626, 522. H NMR
was added K CO (4–5 mmol) and acrolein (2 mmol). The (400 MHz, CDCl ): d
9.52(1H, s, CHO), 7.15(1H, dd, J ¼ 8.0 Hz,
reaction mixture was reuxed for 2 h. The progress of the 4.0 Hz, H–Ar), 7.10(2H, m, CH, H–Ar), 6.74(1H, d, J ¼ 8.0 Hz, H–
2
714, 1891, 1819, 1677, 1631, 1586, 1560, 1482, 1411, 1384,
1
2
3
3
H
1
3
reaction was monitored by TLC checking. Aer 2 h the reaction Ar), 4.95(2H, s, CH
completed, the reaction mixture was then poured into water 154.5, 139.6, 132.7, 132.6, 128.5, 126.7, 121.7, 118.0, 63.5. GCMS
100 ml). The solution was extracted with ethyl acetate (30 mL ꢃ m/z: calcd for C10 ClO : 194.0, found: 194.0. Anal. calcd for
). The combined organic layers were washed with brine (30
ClO : C, 61.72; H, 3.63. Found: C, 61.73; H, 3.65.
mL). Then the organic layers were dried over anhydrous Na SO 6,8-Dichloro-2H-chromene-3-carbaldehyde (10f). Yellow solid
); C NMR (100 MHz, CDCl ): d 189.6,
2
3 C
(
3
H
7
2
C
10
H
7
2
2
4
ꢀ
ꢂ1
and evaporated under vaccum. The residue was crystallised (80%); mp 127–129 C. IR (KBr) (nmax/cm ): 3077, 2857, 1683,
from CHCl /n-hexane to give 2H-chromene-3-carbaldehyde as 1631, 1553, 1456, 1339, 1210, 1152, 1093, 970, 866, 847, 717,
solid. Synthesized chromene aldehydes were successfully char- 645, 568. H NMR (400 MHz, CDCl
3
1
3
): d
H
9.55(1H, s, CHO), 7.27
1
13
acterised by H, C NMR, IR and mass analysis.
H-chromene-3-carbaldehyde (10a). Yellow solid (90%); mp CH
(1H, s, CH), 7.09 (1H, s, H–Ar), 7.03(1H, s, H–Ar), 5.06(2H, s,
1
3
2
2
); C NMR (100 MHz, CDCl
): d 189.3, 150.3, 138.6, 133.0,
3 C
ꢀ
ꢂ1
6
1
4–66 C. IR (KBr) (nmax/cm ): 3045, 2818, 2708, 2312, 1683, 132.7, 127.1, 126.6, 122.6, 122.4, 64.3. GCMS m/z: calcd for
1
631, 1462, 1398, 1242, 1171, 1086, 886, 833, 723, 652. H NMR
C
10
H
6
Cl
2
O
2
: 227.9, found: 228.0. Anal. calcd for C10
H
6
Cl
2 2
O : C,
(
400 MHz, CDCl ): d 9.59 (1H, s, CHO), 7.33–7.29 (2H, m, CH, 52.43; H, 2.64. Found: C, 52.45; H, 2.67.
3 H
H–Ar), 7.22 (1H, dd, J ¼ 8.0 Hz, 4.0 Hz, H–Ar), 6.97 (1H, td, J ¼
6-Hydroxy-2H-chromene-3-carbaldehyde (10g). Straw yellow
.0 Hz, 2.0 Hz, H–Ar), 6.88 (1H, d, J ¼ 8.0 Hz, H–Ar), 5.04 (2H, s, solid (68%); mp 170–172 C. IR (KBr) (nmax/cm ): 3206, 2954,
ꢀ
ꢂ1
8
13
2 3 C
CH ); C NMR (100 MHz, CDCl ): d 189.9, 156.1, 141.3, 133.3, 2837, 2714, 1650, 1573, 1482, 1405, 1346, 1294, 1287, 1216, 1145,
+
1
1
31.8, 129.4, 122.0, 120.5, 116.6, 63.3. ESI-HRMS [M + H] : calcd 1106, 1021, 898, 814, 717, 626, 568. H NMR (400 MHz, CDCl
for C10 : 161.0558, found: 161.0594. Anal. alcd for C10
9.58 (1H, s, CHO), 7.19 (1H, s, CH), 6.82–6.71 (3H, m, H–Ar), 4.97
C, 74.99; H, 5.03. Found: C, 75.02; H, 5.06.
-Methoxy-2H-chromene-3-carbaldehyde (10b). Yellow solid 141.2, 132.6, 121.3, 120.2, 117.4, 115.0, 63.2. GCMS m/z: calcd for
): d
3 H
H
8
O
2
8 2
H O :
1
3
(2H, s, CH ); C NMR (100 MHz, CDCl ): d 189.9, 150.3, 150.1,
2 3 C
8
ꢀ
ꢂ1
(
87%); mp 82–84 C. IR (KBr) (nmax/cm ): 2974, 2883, 2818,
C
10 8 3 8 3
H O : 176.0, found: 176.0. Anal. calcd for C10H O : C, 68.18;
2
7
733, 2364, 2325, 1663, 1560, 1475, 1339, 1216, 1093, 1002, 886, H, 4.58. Found: C, 68.19; H, 4.61.
82, 723, 704, 594, 490. H NMR (400 MHz, CDCl ): d 9.59
3 H
1
(
(
1H, s, CHO), 7.26 (1H, s, CH), 6.97–6.92 (2H, m, H–Ar), 6.86
), 3.90 (3H, s,
189.9, 148.1, 145.0, Wittig salt methyl triphenylphosphonium bromide (3 mmol)
0
General procedure for the synthesis of 2(a–h) and 2 (a–h)
1H, dd, J ¼ 8.0 Hz, 4.0 Hz, H–Ar), 5.11 (2H, s, CH
2
1
3
3 3 C
OCH ); C NMR (100 MHz, CDCl ): d
1
41.3, 131.8, 121.7, 121.3, 121.1, 115.5, 63.7, 56.2. GCMS m/z: dissolved in dry THF was taken in a round bottom ask and
ꢀ
calcd for C11
C H O : C, 69.46; H, 5.30. Found: C, 69.49; H, 5.32.
H
10
O
3
: 190.0, found: 190.2. Anal. calcd for stirred at 0 C in argon atmosphere. To it BuLi(1.6 M) (3 mmol)
was added in a drop wise manner. Aer half an hour the
-Ethoxy-2H-chromene-3-carbaldehyde (10c). Yellow solid previously prepared 2-phenyl-2H-chromene aldehyde (1 mmol)
1
1
10 3
8
ꢀ
ꢂ1
ꢀ
(
2
85%); mp 89–91 C. IR (KBr) (nmax/cm ): 2974, 2883, 2818, in dry THF was added slowly at ꢂ20 C and stirred for 1 h. The
733, 2364, 2325, 1663, 1560, 1475, 1339, 1216, 1093, 1002, 886, progress of the reaction was monitored by TLC checking. Aer
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completion of the reaction, the reaction mixture was quenched 134.7, 133.5, 131.9, 129.0, 128.7, 128.5, 127.6, 124.2, 123.0,
+
by saturated ammonium chloride and extracted with ethyl 118.2, 115.9, 113.2, 76.4. EI-HRMS [M + H] : calcd for
acetate. The organic layers were washed with brine, dried over C H BrO: 313.1885, found: 314.3597. Anal. calcd for
1
7
13
anhydrous Na SO and evaporated in vaccum. The crude C H BrO: C, 65.19; H, 4.18. Found: C, 65.17; H, 4.21.
2
4
17 13
product was puried by column chromatography to afford the
pure product. Most of the puried compounds are amorphous (66%); IR (KBr) (nmax/cm ): 3018, 2915, 1631, 1579, 1475, 1417,
6-Chloro-2-phenyl-3-vinyl-2H-chromene (2f). White solid
ꢂ1
1
solid.
1249, 1210, 1106, 1080, 989, 898, 814, 704, 626, 542. H NMR
): d 7.37–7.35 (2H, m, H–Ar), 7.32–7.28 (3H,
KBr) (nmax/cm ): 3058, 2824, 2727, 1663, 1573, 1462, 1333, m, H–Ar), 7.03–6.97 (2H, m, H–Ar), 6.66 (1H, d, J ¼ 8.4 Hz, H–
2-Phenyl-3-vinyl-2H-chromene (2a). White solid (70%); IR (400 MHz, CDCl
3
H
ꢂ1
(
1
1
314, 1152, 1093, 996, 879, 763, 691, 607, 522. H NMR (400 Ar), 6.59 (1H, s, CH), 6.50 (1H, dd, J ¼ 10.8 Hz, 16.8 Hz, CH), 6.09
13
MHz, CDCl ): d 7.40–7.38 (2H, m, H–Ar), 7.28–7.26 (3H, m, H– (1H, s, CH), 5.15 (2H, dd, J ¼ 11.2 Hz, 24.0 Hz, CH ); C NMR
3
H
2
Ar), 7.06–7.03 (2H, m, H–Ar), 6.85–6.81 (1H, t, J ¼ 8.0 Hz, H–Ar), (100 MHz, CDCl ): d 150.4, 138.0, 134.7, 133.6, 129.0, 128.7,
3
C
6
1
1
1
1
.73 (1H, d, J ¼ 8.0 Hz, H–Ar), 6.66 (1H, s, CH), 6.52 (1H, dd, J ¼ 128.5, 128.4, 127.6, 126.1, 126.0, 123.7, 123.2, 117.7, 115.9, 76.4.
1.2 Hz, 17.6 Hz, CH), 6.10 (1H, s, CH), 5.09 (2H, dd, J ¼ 11.2 Hz, EI-HRMS m/z: calcd for C17 13ClO: 268.0655, found: 268.9242.
13ClO: C, 75.98; H, 4.88. Found: C, 75.95; H,
H
1
3
8.8 Hz, CH
35.2, 132.4, 129.5, 128.5, 127.6, 126.1, 124.4, 122.3, 121.3, 4.88.
16.4, 114.9, 76.3. EI-HRMS m/z: calcd for C17 14O: 234.1045,
2 3 C
); C NMR (100 MHz, CDCl ): d 152.0, 138.6, Anal. calcd for C17H
H
6,8-Dichloro-2-phenyl-3-vinyl-2H-chromene (2g). White solid
ꢂ1
found: 234.9634. Anal. calcd for C H O: C, 87.15; H, 6.02. (65%); IR (KBr) (nmax/cm ): 3071, 2928, 1819, 1637, 1612, 1560,
1
7
14
1
Found: C, 87.12; H, 6.05.
1462, 1262, 1210, 1048, 976, 905, 873, 840, 723, 685, 658, 588. H
8
-Methoxy-2-phenyl-3-vinyl-2H-chromene (2b). White solid NMR (400 MHz, CDCl ): d 7.42–7.27 (5H, m, H–Ar), 7.09 (1H, d,
3
H
ꢂ1
(
1
68%); IR (KBr) (nmax/cm ): 2928, 1627, 1488, 1442, 1311, 1209, J ¼ 2.0 Hz, H–Ar), 6.93 (1H, d, J ¼ 2.8 Hz, H–Ar), 6.58–6.50 (2H,
1
153, 1014, 884, 819, 763, 689, 568. H NMR (400 MHz, CDCl
7.44–7.42 (2H, m, H–Ar), 7.24–7.16 (3H, m, H–Ar), 6.75–6.71 CH
1H, m, H–Ar), 6.66–6.59 (3H, m, H–Ar, CH), 6.49 (1H, dd, J ¼ 129.0, 128.8, 128.5, 127.4, 126.0, 125.0, 124.7, 122.7, 122.2,
3
): m, CH), 6.24 (1H, s, CH), 5.24 (2H, dd, J ¼ 11.2 Hz, 26.4 Hz,
13
d
H
2 3 C
); C NMR (100 MHz, CDCl ): d 146.5, 137.4, 134.6, 134.5,
(
1
1
1
1
1.2 Hz, 17.6 Hz, CH), 6.18 (1H, s, CH), 5.07 (2H, dd, J ¼ 6.4 Hz, 116.9, 76.4. Anal. calcd for C17
2
H12Cl O: C, 67.35; H, 3.99. Found:
1
3
1.2 Hz, CH ), 3.65 (3H, s, CH ); C NMR (100 MHz, CDCl ): d
C
C, 67.38; H, 3.97.
2
3
3
48.0, 140.8, 138.2, 135.0, 132.4, 128.3, 128.2, 127.3, 124.1,
23.0, 120.8, 119.0, 114.7, 112.6, 75.8, 55.9. EI-HRMS m/z: calcd liquid (69%); IR (KBr) (nmax/cm ): 3071, 2928, 1819, 1637, 1612,
8-Bromo-6-chloro-2-phenyl-3-vinyl-2H-chromene (2h). Orange
ꢂ1
16 2
for C18H O : 264.1150, found: 264.9737. Anal. calcd for 1560, 1462, 1262, 1210, 1048, 976, 905, 873, 840, 723, 685, 658,
1
C
18
H
16
O
2
: C, 81.79; H, 6.10. Found: C, 81.80; H, 6.14.
3 H
588. H NMR (400 MHz, CDCl ): d 7.42–7.40 (2H, m, H–Ar),
6
-Methoxy-2-phenyl-3-vinyl-2H-chromene (2c). White solid 7.27–7.22 (4H, m, H–Ar), 6.94 (1H, d, J ¼ 2.4 Hz, H–Ar), 6.56–
ꢂ1
(
1
d
70%); IR (KBr) (nmax/cm ): 2928, 1627, 1488, 1442, 1311, 1209, 6.49 (2H, m, CH), 6.24 (1H, s, CH), 5.21 (2H, dd, J ¼ 11.2 Hz,
1
13
3 2 3 C
153, 1014, 884, 819, 763, 689, 568. H NMR (400 MHz, CDCl ): 24.8 Hz, CH ); C NMR (100 MHz, CDCl ): d 147.5, 137.3,
7.31–7.29 (2H, m, H–Ar), 7.21–7.14 (3H, m, H–Ar), 6.59–6.50 134.5, 134.4, 131.6, 128.8, 128.4, 127.4, 126.3, 125.3, 124.9,
4H, m, H–Ar, CH), 6.45 (1H, dd, J ¼ 10.8 Hz, 17.2 Hz, CH), 5.97 122.8, 116.8, 111.0, 76.4. Anal. calcd for C H BrClO: C, 58.73;
H
(
(
1
7
12
1H, s, CH), 5.04 (2H, dd, J ¼ 10.8 Hz, 16.4 Hz, CH ), 3.65 (3H, s, H, 3.48. Found: C, 58.75; H, 3.45.
2
13
0
CH
3
); C NMR (100 MHz, CDCl
3
): d
C
154.0, 145.8, 138.4, 135.1,
3-Vinyl-2H-chromene (2 a). Orange liquid (65%); IR (nmax
/
ꢂ1
1
5
8
33.3, 128.4, 127.6, 124.4, 122.9, 116.9, 115.0, 114.8, 111.5, 76.0, cm ): 2974, 2928, 1722, 1605, 1586, 1469, 1405, 1255, 1210,
5.6. Anal. calcd for C18
1.75; H, 6.09.
1
H
16
O
2
: C, 81.79; H, 6.10. Found: C, 1086, 976, 782, 730, 658. H NMR (400 MHz, CDCl
3 H
): d 7.09–
7.05 (1H, m, H–Ar), 6.98 (1H, d, J ¼ 6.0 Hz, H–Ar), 6.86–6.78 (2H,
8
-Ethoxy-2-phenyl-3-vinyl-2H-chromene (2d). Orange liquid m, H–Ar), 6.43 (1H, dd, J ¼ 10.8 Hz, 26.8 Hz, CH), 6.35 (1H, s,
ꢂ1
(
1
67%); IR (nmax/cm ): 2928, 1627, 1488, 1442, 1311, 1209, 1153, CH), 5.14 (2H, dd, J ¼ 10.8 Hz, 20.4 Hz, CH ), 4.94 (2H, s, CH );
2
2
1
13
014, 884, 819, 763, 689, 568. H NMR (400 MHz, CDCl ): d 7.45
C NMR (100 MHz, CDCl ): d 153.7, 134.6, 130.7, 129.1, 127.0,
3 C
3
H
(
(
(
2H, d, J ¼ 8.8 Hz, H–Ar), 7.25–7.23 (3H, m, H–Ar), 6.77–6.63 123.6, 122.3, 121.3, 115.3, 113.3, 65.1. Anal. calcd for C H O:
1
1
10
3H, m, H–Ar), 6.55 (2H, dd, J ¼ 11.2 Hz, 18.0 Hz, CH), 6.19 C, 83.51; H, 6.37. Found: C, 83.53; H, 6.34.
0
1H, s, CH), 5.13–5.06 (2H, m, CH
2
), 3.95 (2H, q, J ¼ 11.2 Hz,
8-Methoxy-3-vinyl-2H-chromene (2 b). Orange liquid (68%);
1
3
ꢂ1
CH
d
2
), 1.29 (3H, t, J ¼ 6.8 Hz, CH
3
); C NMR (100 MHz, CDCl
3
): IR (nmax/cm ): 2974, 2928, 1722, 1605, 1586, 1469, 1405, 1255,
1
C
147.3, 141.5, 138.4, 135.3, 132.6, 128.3, 128.2, 127.5, 124.4, 1210, 1086, 976, 782, 730, 658. H NMR (400 MHz, CDCl
3
): d
H
123.5, 121.0, 119.4, 115.0, 114.8, 75.6, 65.0, 14.8. Anal. calcd for 6.83–6.75 (2H, m, H–Ar), 6.60–6.64 (1H, m, H–Ar), 6.58–6.36
C H O : C, 81.99; H, 6.52. Found: C, 81.97; H, 6.53.
(2H, m, CH), 5.16 (2H, dd, J ¼ 9.2 Hz, 17.8 Hz, CH ), 5.02 (2H, s,
1
9
18
2
2
1
3
6
-Bromo-2-phenyl-3-vinyl-2H-chromene (2e). White solid CH ), 3.86 (3H, s, CH ); C NMR (100 MHz, CDCl ): d 147.4,
2 3 3 C
ꢂ1
(
70%); IR (KBr) (nmax/cm ): 3018, 2915, 1631, 1579, 1475, 1417, 142.3, 134.4, 130.7, 123.4, 123.0, 121.0, 119.3, 113.6, 112.0, 65.3,
1
1249, 1210, 1106, 1080, 989, 898, 814, 704, 626, 542. H NMR 56.0. Anal. calcd for C12
H
12
O
2
: C, 76.57; H, 6.43. Found: C,
(
400 MHz, CDCl ): d 7.35–7.27 (5H, m, H–Ar), 7.19–7.13 (2H, 76.59; H, 6.40.
3
H
0
m, H–Ar), 6.61–6.58 (2H, m, H–Ar, CH), 6.49 (1H, dd, J ¼
8-Ethoxy-3-vinyl-2H-chromene (2 c). Orange liquid (70%); IR
ꢂ1
1
2
1.2 Hz, 17.6 Hz, CH), 6.09 (1H, s, CH), 5.15 (2H, dd, J ¼ 10.8 Hz, (nmax/cm ): 2974, 2928, 1722, 1605, 1586, 1469, 1405, 1255,
1
3
1
2 3 C 3 H
4.8 Hz, CH ); C NMR (100 MHz, CDCl ): d 150.9, 137.9, 1210, 1086, 976, 782, 730, 658. H NMR (400 MHz, CDCl ): d
16810 | RSC Adv., 2018, 8, 16802–16814
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0
6
.78–6.74 (2H, m, H–Ar), 6.64–6.62 (1H, m, H–Ar), 6.45–6.35 General procedure for the synthesis of 3(a–h) and 3 (a–f)
(
2H, m, CH), 5.15 (2H, dd, J ¼ 10.8 Hz, 16.4 Hz, CH ), 5.01
2
ꢀ
Ninhydrin (1 mmol) was taken in dry toluene (5 mL) to it 4 A MS
(
8
2H, s, CH ), 4.07 (2H, q, J ¼ 14.0 Hz, CH ), 1.44 (3H, t, J ¼
ꢀ
2
2
was added and stirred at 120 C for 10 min till the colour change
1
3
.8 Hz, CH ); C NMR (100 MHz, CDCl ): d 146.6, 142.7, 134.4,
3 3 C
observed. Then 3-vinyl-2H-chromene (1 mmol) was added to it.
The progress of the reaction was monitored by TLC checking.
The reaction was completed in 2–3 h. The reaction mixture was
1
30.5, 123.5, 123.1, 120.8, 119.2, 113.6, 113.4, 65.2, 64.3, 14.7.
Anal. calcd for C13
.97.
H
14
O
2
: C, 77.20; H, 6.98. Found: C, 77.19; H,
6
ꢀ
cooled, 4 A MS were ltered and the toluene was removed under
0
6
-Bromo-3-vinyl-2H-chromene (2 d). White solid (65%); IR
vaccum. The crude reaction mixture was puried by ash
column chromatography to get the pure product. Aer column
purication most of the compounds obtained as amorphous
solid.
ꢂ1
(
1
KBr) (nmax/cm ): 3018, 2915, 1631, 1579, 1475, 1417, 1249,
210, 1106, 1080, 989, 898, 814, 704, 626, 542. H NMR (400
1
MHz, CDCl ): d 7.10–7.02 (2H, m, H–Ar), 6.61 (1H, d, J ¼
3
H
9
.2 Hz, H–Ar), 6.38–6.30 (1H, m, CH), 6.22 (1H, s, CH), 5.13 (2H,
0 0 0 0 0 0 0
(
5 R,10b R)-5 -Phenyl-5 ,10b -dihydro-3 H-spiro[indene-2,2 -
1
3
dd, J ¼ 11.2 Hz, 26.0 Hz, CH
2 2
), 4.88 (2H, s, CH ); C NMR (100
pyrano[3,2-c]chromene]-1,3-dione (3a). White solid (80%); IR
KBr) (nmax/cm ): 3058, 2921, 2863, 1735, 1715, 1573, 1482,
287, 1229, 1035, 996, 892, 756, 704, 652, 594. H NMR (400
MHz, CDCl ) d 8.04–8.02 (2H, m, H–Ar), 7.93–7.90 (2H, m, H–
MHz, CDCl
3
): d
C
152.7, 134.2, 131.7, 131.5, 129.2, 124.2, 122.3,
ꢂ1
(
+
1
2
17.1, 114.4, 113.3, 65.2. EI-HRMS [M + H] : calcd for C11
H
9
BrO:
1
1
37.0926, found: 238.9675. Anal. calcd for C11 BrO: C, 55.72;
H
9
3
H, 3.83. Found: C, 55.74; H, 3.85.
Ar), 7.58 (2H, d, J ¼ 8.4 Hz, H–Ar), 7.40–7.36 (2H, m, H–Ar), 7.28–
0
6
-Chloro-3-vinyl-2H-chromene (2 e). White solid (67%); IR
7
.16 (3H, m, H–Ar), 7.00 (1H, d, J ¼ 8.4 Hz, H–Ar), 6.86–6.82 (1H,
ꢂ1
(
KBr) (nmax/cm ): 3018, 2915, 1631, 1579, 1475, 1417, 1249,
m, H–Ar), 6.27–6.25 (1H, m, CH), 5.82 (1H, s, CH), 5.52 (1H, s,
1
1
210, 1106, 1080, 989, 898, 814, 704, 626, 542. H NMR (400
MHz, CDCl ): d
7.10–6.98 (2H, m, H–Ar), 6.72 (1H, d, J ¼
.2 Hz, H–Ar), 6.48–6.39 (1H, m, CH), 6.28 (1H, s, CH), 5.27 (2H,
13
CH), 2.87–2.81 (1H, m, CH
100 MHz, CDCl ) d 197.9, 196.6, 152.8, 140.5, 140.4, 139.1,
36.6, 136.4, 132.5, 129.1, 128.5, 127.6, 127.4, 125.8, 124.3,
2 2
), 2.33–2.26 (1H, m, CH ); C NMR
3
H
(
3
9
1
1
+
1
3
dd, J ¼ 11.4 Hz, 26.2 Hz, CH
MHz, CDCl ): d 152.2, 134.3, 131.9, 128.9, 126.9, 126.2, 123.9,
22.8, 116.9, 114.4, 65.2. Anal. calcd for C11 ClO: C, 68.58; H,
.71; found: C, 68.57; H, 4.73.
2 2
), 4.98 (2H, s, CH ); C NMR (100
24.1, 121.8, 121.0, 119.8, 116.6, 79.8, 74.3, 66.1, 25.9. HRMS [M
H] calcd for C H O : 394.4187, found: 395.1326. Anal. calcd
3
C
+
2
6
18 4
1
4
H
9
for C H O : C, 79.17; H, 4.60. Found: C, 79.19; H, 4.59.
2
0
6
18 4
0
0
0
0
0
0
(
5 S,10b R)-5 -Phenyl-5 ,10b -dihydro-3 H-spiro[indene-2,2 -
pyrano[3,2-c]chromene]-1,3-dione (5a). White solid (70%); IR
KBr) (nmax/cm ): 3058, 2921, 2863, 1735, 1715, 1573, 1482,
287, 1229, 1035, 996, 892, 756, 704, 652, 594. H NMR (400
MHz, CDCl ): d 8.04–8.02 (2H, m, H–Ar), 7.95–7.91 (2H, m, H–
Ar), 7.50–7.38 (6H, m, H–Ar), 7.22–7.17 (1H, m, H–Ar), 6.94–6.89
2H, m, H–Ar), 6.07 (1H, s, CH), 5.71 (1H, s, CH), 5.28–5.25 (1H,
m, CH), 2.65–2.59 (1H, m, CH ), 2.13–2.04 (1H, m, CH );
NMR (100 MHz, CDCl ): d 198.3, 196.8, 154.1, 140.1, 136.6,
0
6
,8-Dichloro-3-vinyl-2H-chromene (2 f). White solid (70%);
ꢂ1
IR (KBr) (nmax/cm ): 3071, 2928, 1819, 1637, 1612, 1560, 1462,
ꢂ1
(
1
1
(
262, 1210, 1048, 976, 905, 873, 840, 723, 685, 658, 588. H NMR
400 MHz, CDCl ): d
2.0 Hz, H–Ar), 6.45 (1H, dd, J ¼ 11.2 Hz, 18.0 Hz, CH), 6.30
), 5.07 (2H, s,
148.0, 133.9, 132.3, 128.8,
1
1
3
H
7.14 (1H, d, J ¼ 2.0 Hz, H–Ar), 6.88 (1H, d, J
3
H
¼
(
1H, s, CH), 5.27 (2H, dd, J ¼ 10.8 Hz, 29.6 Hz, CH
2
(
1
3
CH
2
); C NMR (100 MHz, CDCl
3
): d
C
13
C
2
2
+
1
25.9, 125.0, 124.5, 121.9, 121.2, 115.4, 65.9. GCMS [M + H] :
3
C
calcd for C H Cl O: 227.0, found: 228.0. Anal. calcd for
C H Cl O: C, 58.18; H, 3.55. Found: C, 58.20; H, 3.58.
1
1
8
2
1
1
7
36.5, 129.1, 128.4, 128.3, 127.9, 127.6, 124.2, 124.1, 121.1,
1
1
8
2
19.3, 116.5, 78.4, 74.3, 68.8, 26.1. Anal. calcd for C26
9.17; H, 4.60. Found: C, 79.18; H, 4.57.
7
H
18
O
4
: C,
0
3
-Vinyl-2H-chromen-8-yl benzoate (2 g). Colour less liquid
ꢂ1
(
65%); IR (nmax/cm ): 3071, 1800, 1722, 1683, 1593, 1437, 1268,
0
0
0
0
0
0
-Methoxy-5 -phenyl-5 ,10b -dihydro-3 H-spiro[indene-2,2 -
pyrano[3,2-c]chromene]-1,3-dione (3b). White solid (82%); IR
KBr) (nmax/cm ): 2921, 2863, 1761, 1696, 1586, 1475, 1346,
255, 1210, 1086, 989, 924, 873, 710, 645. H NMR (400 MHz,
1
1
d
216, 1171, 983, 769, 685, 626, 555. H NMR (400 MHz, CDCl
8.23–8.20 (2H, m, H–Ar), 7.82–7.48 (3H, m, H–Ar), 7.28–6.82
3H, m, H–Ar), 6.46–6.38 (2H, m, CH), 5.14 (2H, dd, J ¼ 11.2 Hz,
3
):
H
ꢂ1
(
(
1
1
1
3
3
1
1
1.6 Hz, CH ), 4.94 (2H, s, CH ); C NMR (100 MHz, CDCl ): d
2 2 3 C
CDCl ): d 8.03–8.01 (2H, m, H–Ar), 7.91–7.87 (2H, m, H–Ar),
3
H
64.4, 145.6, 138.3, 134.3, 133.4, 131.3, 130.2, 129.4, 129.2,
28.4, 128.2, 124.4, 124.2, 123.1, 122.5, 121.1, 113.9, 65.3. Anal.
7
7
4
2
.58 (2H, d, J ¼ 7.6 Hz, H–Ar), 7.39–7.37 (2H, m, H–Ar), 7.28–
.23 (1H, m, H–Ar), 6.82–6.78 (3H, m, H–Ar), 6.28 (1H, d, J ¼
calcd for C18
H
14
O
3
: C, 77.68; H, 5.07. Found: C, 77.69; H, 5.09.
.8 Hz, CH), 5.93 (1H, s, CH), 5.52 (1H, s, CH), 3.92 (3H, s, CH
3
),
); C NMR (100
197.8, 196.4, 148.1, 142.2, 140.3, 140.2, 138.6,
36.5, 136.4, 132.1, 128.4, 127.6, 125.5, 124.1, 124.0, 122.4,
20.6, 119.9, 119.1, 110.7, 80.0, 74.3, 66.0, 56.0, 25.8. HRMS
0
3
-Vinyl-2H-chromen-8-ol (2 h). Yellow liquid (60%); IR
max/cm ): 3206, 1650, 1573, 1482, 1405, 1346, 1294, 1287,
216, 1145, 1106, 1021, 898, 814, 717, 626, 568. H NMR (400
13
.85–2.80 (1H, m, CH
): d
2 2
), 2.31–2.25 (1H, m, CH
ꢂ1
(
1
n
MHz, CDCl
3
C
1
1
1
3 H
MHz, CDCl ): d 6.78–6.73 (2H, m, H–Ar), 6.59–6.56 (1H, m,
H–Ar), 6.43 (1H, dd, J ¼ 10.8 Hz, 18.4 Hz, CH), 6.37 (1H, s,
calcd for C H O : 424.4447, found: 425.1440. Anal. calcd for
2
7
20 5
CH), 5.65 (1H, broad singlet, CH), 5.15 (2H, dd, J ¼ 10.8 Hz,
C
27
H
9
20 5
O : C, 76.40; H, 4.75. Found: C, 76.42; H, 4.73.
1
3
2
d
6.8 Hz, CH ), 4.97 (2H, s, CH ); C NMR (100 MHz, CDCl ):
0
0 0 0 0 0
2
2
3
-Methoxy-5 -phenyl-5 ,10b -dihydro-3 H-spiro[indene-2,2 -
C
143.7, 139.9, 134.5, 130.6, 123.5, 122.5, 121.5, 118.4, 115.4,
13.5, 65.4. Anal. calcd for C11 : C, 75.84; H, 5.79.
pyrano[3,2-c]chromene]-1,3-dione (3c). White solid (78%); IR
KBr) (nmax/cm ): 2921, 2863, 1761, 1696, 1586, 1475, 1346,
255, 1210, 1086, 989, 924, 873, 710, 645. H NMR (400 MHz,
1
H
10
O
2
ꢂ1
(
Found: C, 75.86; H, 5.77.
1
1
CDCl ): d 8.04–8.00 (2H, m, H–Ar), 7.92–7.87 (2H, m, H–Ar),
3
H
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7
(
5
.56–7.54 (2H, m, H–Ar), 7.38–7.29 (3H, m, H–Ar), 6.92–6.90 Ar), 7.56 (2H, d, J ¼ 8.0 Hz, H–Ar), 7.43–7.39 (2H, m, H–Ar), 7.32–
1H, m, H–Ar), 6.76–6.70 (2H, m, H–Ar), 6.23–6.22 (1H, m, CH), 7.25 (2H, m, H–Ar), 7.11 (1H, d, J ¼ 4.0 Hz, H–Ar), 6.37–6.31 (1H,
.76 (1H, s, CH), 5.51 (1H, s, CH), 3.62 (3H, s, CH ), 2.84–2.79 m, CH), 5.98 (1H, s, CH), 5.51 (1H, s, CH), 2.88–2.82 (1H, m,
3
1
3
13
(1H, m, CH ), 2.32–2.25 (1H, m, CH ); C NMR (100 MHz, CH ), 2.36–2.30 (1H, m, CH ); C NMR (100 MHz, CDCl ): dC
2 2 2 2 3
3 C
CDCl ): d 197.9, 196.6, 153.9, 146.8, 140.4, 140.3, 139.2, 136.6, 197.6, 196.2, 147.4, 140.3, 137.7, 136.8, 136.7, 130.7, 129.3,
1
1
36.5, 132.7, 128.4, 127.5, 125.9, 124.2, 124.1, 122.2, 119.7, 128.7, 128.1, 126.0, 125.8, 125.6, 124.5, 124.4, 124.2, 122.3,
19.5, 117.4, 115.9, 115.8, 111.2, 79.7, 74.3, 66.3, 55.6, 26.0. 121.3, 80.6, 74.3, 65.8, 25.9. HRMS [M + H] calcd for
+
HRMS calcd for C27
H
20
O
5
: 424.4447, found: 425.1480. Anal.
C
C
26
26
H
16Cl
2
2
O
O
4
:
462.0426, found: 463.0390. Anal. calcd for
calcd for C27
H
20
O
5
: C, 76.40; H, 4.75. Found: C, 76.39; H, 4.76.
H
16Cl
4
: C, 67.40; H, 3.48. Found: C, 67.42; H, 3.52.
0
0
0
0
0
0
0
0
0
0
0
0
7
-Ethoxy-5 -phenyl-5 ,10b -dihydro-3 H-spiro[indene-2,2 -pyr-
9 -Bromo-7 -chloro-5 -phenyl-5 ,10b -dihydro-3 H-spiro[indene-
0
ano[3,2-c]chromene]-1,3-dione (3d). White solid (85%); IR (KBr) 2,2 -pyrano[3,2-c]chromene]-1,3-dione (3h). White solid (78%); IR
ꢂ1
ꢂ1
(nmax/cm ): 2980, 2902, 1741, 1709, 1579, 1489, 1249, 1203, (KBr) (nmax/cm ): 2919, 2853, 1748, 1701, 1609, 1460, 1367,
1
1
1074, 1054, 892, 736, 710. H NMR (400 MHz, CDCl
3
): d
H
8.06– 1284, 1227, 1190, 1126, 995, 931, 745, 707, 587. H NMR (400
): d 7.99–7.96 (2H, m, H–Ar), 7.88–7.85 (2H, m, H–
8.02 (2H, m, H–Ar), 7.92–7.89 (2H, m, H–Ar), 7.59–7.56 (2H, m, MHz, CDCl
3
H
H–Ar), 7.42–7.36 (2H, m, H–Ar), 7.32–7.28 (1H, m, H–Ar), 6.82– Ar), 7.49 (2H, d, J ¼ 6.8 Hz, H–Ar), 7.36–7.32 (3H, m, H–Ar), 7.28–
.72 (3H, m, H–Ar), 6.28–6.22 (1H, m, CH), 5.94 (1H, s, CH), 5.51 7.22 (1H, m, H–Ar), 7.08–7.07 (1H, m, H–Ar), 6.27–6.25 (1H, m,
1H, s, CH), 4.18 (2H, q, J ¼ 14.0 Hz, CH ), 2.86–2.81 (1H, m, CH), 5.91 (1H, s, CH), 5.44–5.40 (1H, m, CH), 2.80–2.74 (1H, m,
CH ), 2.32–2.30 (1H, m, CH ), 1.50 (3H, t, J ¼ 6.8 Hz, CH );
6
(
2
1
3
13
C
CH ), 2.28–2.22 (1H, m, CH ); C NMR (100 MHz, CDCl ): dC
2 2 3
2
2
3
NMR (100 MHz, CDCl ): d 197.9, 196.6, 147.4, 142.6, 140.4, 197.6, 196.2, 148.2, 140.3, 137.7, 136.8, 136.7, 132.1, 130.7,
3
C
1
1
2
4
7
40.3, 138.8, 136.6, 136.4, 132.2, 128.4, 127.6, 125.6, 124.2, 128.7, 128.0, 126.7, 126.2, 125.6, 124.4, 124.3, 124.2, 121.3,
+
24.0, 122.5, 120.6, 119.9, 119.1, 112.2, 80.0, 74.4, 66.2, 64.4, 111.2, 80.8, 74.3, 65.8, 25.9. HRMS [M + H] calcd for C26
H
H
16
16
-
-
5.9, 14.8. HRMS calcd for C28
H
22
O
5
: 438.4713, found: BrClO
4
4
: 507.7598, found: 508.9917. Anal. calcd for C26
: C, 61.50; H, 3.18. Found: C, 61.53; H, 3.17.
39.1497. Anal. calcd for C28
6.72; H, 5.09.
H
22
O
5
: C, 76.70; H, 5.06. Found: C, BrClO
0
0
0
0
5 ,10b -Dihydro-3 H-spiro[indene-2,2 -pyrano[3,2-c]chromene]-
0
0
0
0
0
0
0
ꢂ1
9
-Bromo-5 -phenyl-5 ,10b -dihydro-3 H-spiro[indene-2,2 -
1,3-dione (3 a). White solid (80%); IR (KBr) (nmax/cm ): 2974,
pyrano[3,2-c]chromene]-1,3-dione (3e). White solid (72%); IR 2908, 1754, 1709, 1579, 1469, 1262, 1210, 1086, 989, 879, 769,
ꢂ1
1
(
1
KBr) (nmax/cm ): 3064, 2941, 2853, 1761, 1709, 1586, 1469, 710, 645. H NMR (400 MHz, CDCl ): d 8.06–8.04 (2H, m, H–
3 H
1
405, 1287, 1203, 1132, 989, 866, 743, 691, 600. H NMR (400 Ar), 7.96–7.91 (2H, m, H–Ar), 7.34–7.32 (1H, m, H–Ar), 7.19–7.13
): d 8.06–8.01 (2H, m, H–Ar), 7.93–7.90 (2H, m, H– (1H, m, H–Ar), 6.90–6.80 (2H, m, H–Ar), 6.08–6.05 (1H, m, CH),
Ar), 7.53–7.52 (2H, m, H–Ar), 7.42–7.36 (2H, m, H–Ar), 7.38–7.31 5.88 (1H, d, J ¼ 2.4 Hz, CH), 4.73–4.58 (2H, m, CH ), 2.78–2.73
); C NMR (100 MHz,
198.2, 196.6, 154.1, 140.3, 136.6, 136.5, 130.7, 128.9,
197.6, 127.7, 124.3, 124.1, 122.1, 120.9, 118.4, 116.4, 74.5, 68.3, 67.6,
MHz, CDCl
3
H
2
1
3
(
3H, m, H–Ar), 6.88 (1H, d, J ¼ 8.8 Hz, H–Ar), 6.28–6.27 (1H, m, (1H, m, CH
2 2
), 2.24–2.18 (1H, m, CH
CH), 5.82 (1H, s, CH), 5.47 (1H, s, CH), 2.86–2.80 (1H, m, CH ), CDCl ): d
2
3
C
1
3
2
1
.33–2.27 (1H, m, CH
2 3 C
); C NMR (100 MHz, CDCl ): d
+
96.4, 151.9, 140.3, 138.5, 136.7, 136.6, 132.0, 131.5, 130.1, 25.7. HRMS [M + H] calcd for C H O : 318.3228, found:
2
0
14 4
1
28.5, 127.8, 125.7, 124.3, 124.1, 123.8, 120.4, 118.5, 113.2, 79.9, 319.1013. Anal. calcd for C H O : C, 75.46; H, 4.43. Found: C,
20 14 4
+
74.2, 65.7, 25.8. HRMS [M + H] calcd for C H BrO : 472.0310, 75.47; H, 4.41.
26 17 4
0
0
0
0
0
found: 473.0364. Anal. calcd for C26
Found: C, 65.96; H, 3.65.
H
17BrO
4
: C, 65.98; H, 3.62.
7 -Methoxy-5 ,10b -dihydro-3 H-spiro[indene-2,2 -pyrano[3,2-
0
c]chromene]-1,3-dione (3 b). White solid (78%); IR (KBr) (nmax
/
0
0
0
0
0
0
ꢂ1
9
-Chloro-5 -phenyl-5 ,10b -dihydro-3 H-spiro[indene-2,2 -pyr-
cm ): 2928, 2844, 1748, 1701, 1581, 1478, 1357, 1274, 1227,
1
ano[3,2-c]chromene]-1,3-dione (3f). White solid (75%); IR (KBr) 1107, 1051, 1014, 874, 745, 707, 652. H NMR (400 MHz, CDCl
3
):
ꢂ1
(n
max/cm ): 2910, 1739, 1701, 1600, 1469, 1414, 1274, 1218,
098, 986, 884, 735, 698, 596, 466. H NMR (400 MHz, CDCl ): d
d
H
8.06–8.04 (2H, m, H–Ar), 7.94–7.93 (2H, m, H–Ar), 6.96 (1H,
1
1
8
d, J ¼ 8.0 Hz, H–Ar), 6.85–6.76 (2H, m, H–Ar), 6.07 (1H, s, CH),
3
H
.06–8.01 (2H, m, H–Ar), 7.98–7.90 (2H, m, H–Ar), 7.53–7.52 5.88 (1H, s, CH), 4.77–4.70 (2H, m, CH ), 3.86 (3H, s, CH ), 2.78–
2
3
1
3
(2H, m, H–Ar), 7.42–7.36 (2H, m, H–Ar), 7.38–7.21 (3H, m, H– 2.73 (1H, m, CH ), 2.22–2.15 (1H, m, CH ); C NMR (100 MHz,
2
2
Ar), 6.98 (1H, d, J ¼ 8.8 Hz, H–Ar), 6.38–6.32 (1H, m, CH), 5.82 CDCl
3 C
): d 198.3, 196.4, 148.1, 143.9, 140.5, 136.8, 136.7, 130.5,
1H, s, CH), 5.48 (1H, s, CH), 2.86–2.80 (1H, m, CH ), 2.38–2.26 124.4, 124.2, 122.9, 120.7, 119.4, 118.7, 110.7, 78.8, 68.8, 68.2,
2
(
(
1
3
1H, m, CH
1
1
6
2
); C NMR (100 MHz, CDCl
40.4, 140.3, 138.6, 136.7, 136.6, 131.7, 129.2, 128.6, 127.8, 349.1124. Anal. calcd for C21
27.2, 126.0, 125.9, 124.4, 124.1, 123.3, 120.4, 118.0, 79.9, 74.2, 72.43; H, 4.61.
3 C 16 5
): d 197.7, 196.4, 151.4, 56.0, 25.9. HRMS calcd for C21H O : 348.3487, found:
H
16
O
5
: C, 72.41; H, 4.63. Found:
0
0
0
0
0
5.8, 25.9. HRMS calcd for C H ClO : 428.8638, found:
7 -Ethoxy-5 ,10b -dihydro-3 H-spiro[indene-2,2 -pyrano[3,2-c]
2
6
17
4
0
4
29.0905. Anal. calcd for C H ClO : C, 72.82; H, 4.00. Found: chromene]-1,3-dione (3 c). White solid (78%); IR (KBr) (nmax/
2
6
17
4
ꢂ1
C, 72.84; H, 4.03.
cm ): 2974, 2908, 1754, 1709, 1579, 1469, 1262, 1210, 1086,
,9 -Dichloro-5 -phenyl-5 ,10b -dihydro-3 H-spiro[indene-2,2 - 989, 879, 769, 710, 645. H NMR (400 MHz, CDCl
0
0
0
0
0
0
0
1
7
3
): d
H
8.08–8.04
pyrano[3,2-c]chromene]-1,3-dione (3g). White solid (70%); IR (2H, m, H–Ar), 7.96–7.93 (2H, m, H–Ar), 6.92–6.90 (1H, m, H–
ꢂ1
(
1
KBr) (nmax/cm ): 2919, 2853, 1748, 1701, 1609, 1460, 1367, Ar), 6.87–6.79 (2H, m, H–Ar), 6.12 (1H, s, CH), 5.83 (1H, s, CH),
1
284, 1227, 1190, 1126, 995, 931, 745, 707, 587. H NMR (400 4.77 (2H, s, CH
MHz, CDCl ): d 8.07–8.03 (2H, m, H–Ar), 7.94–7.92 (2H, m, H– 28.8 Hz, CH
2
), 4.12 (2H, q, J ¼ 8.0 Hz, CH
2
), 2.80 (1H, d, J ¼
3
2
), 2.25 (1H, d, J ¼ 20.8 Hz, CH
2
), 1.48 (3H, t, J ¼
16812 | RSC Adv., 2018, 8, 16802–16814
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RSC Advances
1
3
8
1
1
.0 Hz, CH
3
); C NMR (100 MHz, CDCl
3
): d
C
198.2, 196.6, 147.2, 74.5, 68.7, 67.6, 25.8. Anal. calcd for C27
H
18
O
6
: C, 73.97; H, 4.14.
44.0, 140.3, 136.6, 136.5, 130.5, 124.3, 124.1, 122.9, 120.5, Found: C, 73.99; H, 4.11.
19.3, 118.8, 118.4, 112.1,74.5, 68.7, 67.7, 64.3, 25.7, 14.7. HRMS
M + H] calcd for C H O : 362.3753, found: 363.1278. Anal.
+
[
2
2
18 5
Methodology for biological
calcd for C22
H
18
0
O
5
: C, 72.92; H, 5.01. Found: C, 72.90; H, 5.03.
0
0
0
0
9
-bBomo-5 ,10b -dihydro-3 H-spiro[indene-2,2 -pyrano[3,2- experiments
c]chromene]-1,3-dione (3 d). White solid (72%); IR (KBr) (nmax
cm ): 2921, 2843, 1748, 1715, 1593, 1469, 1411, 1287, 1229,
177, 1048, 989, 853, 820, 691, 626, 548. H NMR (400 MHz,
0
/
Cell culture and reagents
ꢂ1
1
Breast cancer (MDA-MB-231, MCF-7), colon cancer (HCT-116)
and oral squamous cell carcinoma (H357) cells were grown
and cultured in DMEM supplemented with 10% FBS, 1.5 mM L-
1
CDCl ): d 8.00–7.97 (2H, m, H–Ar), 7.88–7.86 (2H, m, H–Ar),
3
H
7
(
4
.36 (1H, d, J ¼ 2.8 Hz, H–Ar), 7.29–7.12 (1H, m, H–Ar), 6.63
ꢂ1
glutamine and 1% antibiotic (100 U ml of penicillin, 10 mg
1H, d, J ¼ 8.8 Hz, H–Ar), 6.00 (1H, s, CH), 5.74 (1H, s, CH),
ꢂ1
ꢀ
ml of streptomycin) at 37 C in a humidied atmosphere of
5% CO . Cell culture reagents and other growth supplements
.63–4.51 (2H, m, CH
2
), 2.71–2.65 (1H, m, CH
2
), 2.16–2.10 (1H,
1
3
2
m, CH
1
1
2
); C NMR (100 MHz, CDCl ): d 198.0, 196.4, 153.2,
40.3, 136.7, 136.6, 131.8, 130.2, 129.7, 124.4, 124.2, 124.0,
3
C
were procured from Himedia, India.
+
19.0, 118.2, 113.1, 74.4, 68.4, 67.2, 25.7. HRMS [M + H] calcd
13BrO
: 397.2188, found: 398.9998. Anal. calcd for Cell viability assay
C H BrO : C, 60.47; H, 3.30. Found: C, 60.49; H, 3.27.
for C20
H
4
2
0
13
4
The anchorage dependant cell viability of the investigational
compounds, parent compound and 5-FU (commonly used anti-
cancer agent) were measured using MTT cell viability assay. In
brief, 8000–10 000 cells per well were seeded in 96 well at
bottom tissue culture plates and grown to 70–80% conuence.
Then cells were treated with increasing concentrations of the
compounds for 48 h prior to harvest. Then media was aspirated
and washed once with 1XPBS. Then 0.05% MTT solution was
0
0
0
0
0
9
-Chloro-5 ,10b -dihydro-3 H-spiro[indene-2,2 -pyrano[3,2-c]
0
chromene]-1,3-dione (3 e). White solid (74%); IR (KBr) (nmax/
cm ): 2915, 2857, 1741, 1722, 1579, 1469, 1417, 1287, 1229,
190, 96, 866, 820, 704, 633, 561. H NMR (400 MHz, CDCl
.06–8.02 (2H, m, H–Ar), 7.94–7.92 (2H, m, H–Ar), 7.28–7.27
1H, m, H–Ar), 7.19–7.06 (1H, m, H–Ar), 6.72 (1H, d, J ¼ 8.8 Hz,
H–Ar), 6.07–6.06 (1H, m, CH), 5.81 (1H, d, J ¼ 2.4 Hz, CH), 4.70–
.57 (2H, m, CH ), 2.77–2.71 (1H, m, CH ), 2.23–2.16 (1H, m,
ꢂ1
1
1
8
(
3
): d
H
4
ꢀ
2
2
added to each well and incubated in 37 C for 5–6 h to allow
1
3
CH2); C NMR (100 MHz, CDCl ): d 198.0, 196.4, 152.7, 140.3,
3
C
formation of formazan crystals. The formazan crystals were
dissolved by adding 100 mL of 0.2% NP-40 detergent solution
and incubated in dark for 1 h. The colour intensity was
measured spectrophotometrically at 570 nm by using micro-
plate reader (Mithras LB 940, Berthold Germany). Each data
point was calculated in triplicate and all the assays were per-
formed at least thrice.
1
1
3
36.7, 136.6, 129.7, 128.9, 127.3, 125.7, 124.3, 124.1, 123.5,
18.9, 117.8, 74.4, 68.4, 67.3, 25.7. HRMS calcd for C20 13ClO
52.7678, found: 353.0492. Anal. calcd for C20 13ClO : C, 68.09;
H, 3.71. Found: C, 68.07; H, 3.74.
,9 -Dichloro-5 ,10b -dihydro-3 H-spiro[indene-2,2 -pyrano
3,2-c]chromene]-1,3-dione (3 f). White solid (75%); IR (KBr)
H
4
:
H
4
0
0
0
0
0
0
7
0
[
ꢂ1
(n
max/cm ): 3103, 2934, 2857, 1748, 1709, 1586, 1489, 1462,
352, 1274, 1223, 1177, 1093, 976, 918, 860, 704, 626, 535. H
1
1
Conflicts of interest
NMR (400 MHz, CDCl ): dH 8.08–8.04 (2H, m, H–Ar), 7.96–7.93
3
(
(
(
1
1
+
2H, m, H–Ar), 7.27–7.20 (2H, m, H–Ar), 6.12 (1H, s, CH), 5.83
There are no conicts to declare.
1H, s, CH), 4.77 (2H, s, CH
2
3
), 2.80 (1H, d, J ¼ 28.8 Hz, CH
2
), 2.25
1
1H, d, J ¼ 20.8 Hz, CH
2 3 C
); C NMR (100 MHz, CDCl ): d 197.9,
96.2, 148.6, 140.2, 136.8, 136.7, 129.2, 128.9, 125.9, 125.6, Acknowledgements
24.7, 124.4, 124.2, 121.9, 119.6, 74.4, 68.9, 67.2, 25.7. HRMS [M
+
SN and SRM are thankful to CSIR New Delhi [02(0218)/14/EMR-
H] calcd for C H Cl O : 386.0113, found: 387.0100. Anal.
2
0
12
2 4
II] and DRDO New Delhi ERIP/ER/1203083/M/01 for providing
research grant. SN thanks to CSIR, New Delhi for providing
research grant. PP thanks to DST, Odisha for providing research
fellowship. Authors are also thankful to DST, FIST, New Delhi
for providing NMR facility in Ravenshaw University.
calcd for C H Cl O : C, 62.04; H, 3.12. Found: C, 62.02; H,
2
0
12
2 4
3
.15.
0
0
0
0
0
(R)-1,3-Dioxo-1,3,5 ,10b -tetrahydro-3 H-spiro[indene-2,2 -pyr-
0
ano[3,2-c]chromen]-7 -yl benzoate (3 g). White solid (75%); IR
ꢂ1
(KBr) (nmax/cm ): 2919, 2844, 1757, 1710, 1600, 1478, 1265, 1089,
1
9
86, 865, 773, 707, 642, 540. H NMR (400 MHz, CDCl
3 H
): d 8.22–
8
.20 (2H, m, H–Ar), 8.06–8.04 (2H, m, H–Ar), 7.94–7.92 (2H, m, H–
Notes and references
Ar), 7.64–7.60 (1H, m, H–Ar), 7.52–7.48 (2H, m, H–Ar), 7.28–7.26
(
8
1
CH
1
1
1H, m, H–Ar), 7.05–7.03 (1H, d, J ¼ 8.0 Hz, H–Ar), 6.91 (1H, t, J ¼
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Z.-W. Tang, G. He, L. Ouyang, W. Huang and B. Han,
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), 4.61 (1H, d, J ¼ 12.0 Hz, CH
), 2.21–2.16 (1H, m, CH ); C NMR (100 MHz, CDCl ): d
98.1, 196.5, 164.6, 146.2, 140.3, 138.7, 136.6, 136.5, 133.4, 130.3,
30.3, 129.3, 128.4, 125.1, 124.3, 124.1, 124.0, 122.2, 120.6, 118.9,
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13
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C
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16814 | RSC Adv., 2018, 8, 16802–16814
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