One-pot practical method for synthesis of functionalized 4H-chromen-5-one derivatives under catalyst and solvent-free conditions

Article abstract of DOI:10.1080/00397911.2018.1517218

A facile and practical method was described for the synthesis of 4H-chromen-5-ones under catalyst- and solvent-free conditions by one-pot stirring of starting materials at 110 °C. The products were obtained by the reaction between cyclic 1,3-dicarbonyl compounds, aromatic aldehydes and (E)-N-methyl-1-(methylthio)-2-nitroethenamine (NMSM) in short duration with good to excellent yields. This simple and environmentally benign method eliminates the use of expensive, metallic and corrosive catalysts, hazardous organic solvents, and chromatographic separation.

Full text of DOI:10.1080/00397911.2018.1517218

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
One-pot practical method for synthesis of
functionalized 4H-chromen-5-one derivatives
under catalyst and solvent-free conditions
M. Musawwer Khan, Biswas Saigal, Sumbulunnisan Shareef, Sarfaraz Khan &
Subash C. Sahoo
To cite this article: M. Musawwer Khan, Biswas Saigal, Sumbulunnisan Shareef, Sarfaraz Khan &
Subash C. Sahoo (2018): One-pot practical method for synthesis of functionalized 4H-chromen-5-
one derivatives under catalyst and solvent-free conditions, Synthetic Communications, DOI:
10.1080/00397911.2018.1517218
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https://doi.org/10.1080/00397911.2018.1517218
One-pot practical method for synthesis of functionalized
4H-chromen-5-one derivatives under catalyst and
solvent-free conditions
M. Musawwer Khana, Biswas Saigala, Sumbulunnisan Shareefa, Sarfaraz Khana, and
Subash C. Sahoob
b
aDepartment of Chemistry, Aligarh Muslim University, Aligarh, India; Department of Chemistry and
Center of Advanced Studies in Chemistry, Panjab University, Chandigarh, India
ABSTRACT
ARTICLE HISTORY
Received 21 March 2018
A facile and practical method was described for the synthesis of 4H-
chromen-5-ones under catalyst- and solvent-free conditions by one-
pot stirring of starting materials at 110 ꢀC. The products were
obtained by the reaction between cyclic 1,3-dicarbonyl compounds,
aromatic aldehydes and (E)-N-methyl-1-(methylthio)-2-nitroethen-
amine (NMSM) in short duration with good to excellent yields. This
simple and environmentally benign method eliminates the use of
expensive, metallic and corrosive catalysts, hazardous organic sol-
vents, and chromatographic separation.
KEYWORDS
Catalyst-free; multicompo-
nent reaction; solvent-free;
4H-Chromen-5-ones; (E)-N-
methyl-1-(methylthio)-2-
nitroethenamine (NMSM)
GRAPHICAL ABSTRACT
Introduction
In the mainstream of current research, green techniques or processes have recently
gained significant economic and ecological interest, as they focused on approaches,
which minimize the uses and generation of hazardous substances.[1,2] The main focus of
green chemistry is to reshape the way and design different synthetic strategies to include
the environment as a major concern. Therefore, the green chemistry provides modern
synthetic pathways to architecting the molecules in a more economical and proficient
manner. The replacement of either toxic solvent with eco-friendly solvent or catalyst-
and solvent-free chemical processes have been a promising interest in academia and
industry. Catalyst- and solvent-free multicomponent synthesis is particularly more
CONTACT M. Musawwer Khan
musawwer@gmail.com
Department of Chemistry, Aligarh Muslim University,
Aligarh 202002, India.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2018 Taylor & Francis Group, LLC

2
M. M. KHAN ET AL.
Figure 1. 4H-Chromenone and 4H-chromen containing biologically active compounds.
attractive because they incorporate many green chemistry principles.[3] In this specific
circumstance, multicomponent reactions (MCRs) have emerged as a powerful strategy
for the synthesis of biologically active compounds in green synthetic frameworks with-
out isolation of unwanted intermediates,[4] which offered high atom economy, high
selectivity, less waste production, and good yields.[5,6]
4H-Chromenone and its analogs exhibit a broad spectrum of biological and pharma-
[10]
cological activities such as anticancer,[7] anticoagulant,[8] antimicrobial,[9] anti-HIV,
[11]
antimalarial,
anti-tumour,[12] antidyslipidemic,[13] anticonvulsant,[14] and diuretic.
[15]
Compounds with 4H-chromenone framework are not only biologically and pharma-
cologically active, but also widely distributed as a key structural motif in many natural
products and structure related to plant pigments.[16,17] In addition, these derivatives
have also played promising roles in the field of agrochemicals and cosmetics indus-
tries.[18] Moreover, 4H-chromenone derivatives have also been applied for the treatment
of human inflammatory TNFa-mediated diseases such as rheumatoid, psoriatic arthritis,
as apoptosis inducers, and inhibitors for excitatory amino acid transport.[19] For
example, compound A possesses antirheumatic activity[20] and compound B act as an
antibacterial,[21] whereas anticancer activities shown by compounds C and D[22] (Figure
1). These diverse applications of 4H-chromenone derivatives in medicinal and pharma-
ceutical chemistry have dragged substantial interest among synthetic chemists to develop
useful synthetic routes for their preparation. A number of synthetic methods for the
construction of 2-aminochromenone and 4H-chromenone derivatives have
been reported.[23]
Recently, synthetic chemists explored (E)-N-methyl-1-(methylthio)-2-nitroethenamine
(NMSM) and synthesized a variety of oxygen and nitrogen-containing heterocyclic com-
[24]
pounds.
However, for the synthesis of substituted 4H-chromen-5-one derivatives by
using NMSM, there were only two methods reported using 20 mol% piperidine and
1.5 mol% 6, 60-thiobis(methylene)-b-cyclodextrin dimer as a catalyst.[25] Although this
method is useful but associated with some demerits such as longer reaction time and
use of catalysts as well as solvents. Therefore, it is need of time to develop an efficient
and greener protocol for the synthesis of these important compounds, which might be a
better alternative.
In continuation of our research work towards the synthesis of functionalized hetero-
cycles by using green and sustainable approaches via MCRs,[26] herein, we wish to
report a sustainable and efficient protocol for the synthesis of 4H-chromene-5-one

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3
Scheme 1. Comparison of present work with reported method.
Table 1. Optimization of reaction conditions for the synthesis of compound 4aa.
Entry
Catalyst (mol%)
Solvent
Temp.
Time
Yieldb (%)
1
2
3
4
5
6
7
6
9
Nano ZnO (10)
Nano ZnO (10)
Nano ZnO (10)
Nano ZnO (10)
No Catalyst
No Catalyst
No Catalyst
No Catalyst
No Catalyst
EtOH
EtOH
CH3CN
Neat
Neat
Neat
Neat
Neat
Neat
rt
3 h
2 h
2.5 h
1 h
40 min
20 min
20 min
18 min
15 min
40
65
60
72
84
90
90
88
86
78ꢀC
80ꢀC
100ꢀC
100ꢀC
110ꢀC
115ꢀC
120ꢀC
130ꢀC
aGeneral reaction conditions: NMSM 1a (1 mmol), dimedone 2a (1 mmol) and 4-chlorobenzaldehyde 3a (1 mmol).
bIsolated yields. Bold values in entry 6 signifies the optimized raction conditions.
derivatives in high yields by the reaction of cyclic-1,3-diketones and aromatic aldehydes
with NMSM under neat conditions (Scheme 1).
Results and discussion
To optimize the reaction conditions, we first conducted a series of trial reactions with
NMSM 1a (1.0 mmol), dimedone 2a (1.0 mmol), and 4-chlorobenzaldehyde 3a
(1.0 mmol) in the presence of recyclable heterogeneous nano ZnO (10 mol%) as a cata-
lyst using ethanol at room temperature, ethanol at 78 ꢀC, acetonitrile at 80 ꢀC and with-
out solvent at 100 ꢀC, respectively (Table 1, entries 1–4). Again, the same reaction was

4
M. M. KHAN ET AL.
performed under catalyst- and solvent-free conditions at 100 ꢀC (Table 1 entry 5). From
the above preliminary experiments, we have noticed that catalyst- and solvent-free con-
ditions at 100 ꢀC afforded the comparably good result in terms of yield and time for
exclusive formation of the desired product 4a.
The product 4a was characterized by the physical and spectral properties, which gives
the good agreement with the reported data.[25] Encouraged by this result and in a quest
to develop a green and sustainable method, we further commenced the same reaction at
different temperature viz. 110 ꢀC, 115 ꢀC, 120 ꢀC, and 130 ꢀC at neat conditions and
without a catalyst, which furnished the product in 90%, 90%, 88%, and 86% yields,
respectively (Table 1, entries 6–9). The best result was achieved at 110 ꢀC, which gives
the desired product 4a in 90% yield within 20 min of stirring. We have observed that
there is no significant increase in yield while further increasing the temperature.
From the above observations (Table 1, entry 6), the catalyst- and solvent-free
conditions at 110 ꢀC came out as the optimized reaction conditions in terms of best
yield and time.
After optimizing the reaction conditions, we explored the scope of the synthetic
protocol. For this, we started our reactions with benzaldehyde, dimedone, and NMSM
under the same reaction conditions and it furnished the product 4 b in 86% yields
within 30 min. After getting these encouraging results, the reaction of various substi-
tuted aromatic aldehydes having electron donating groups such as 4-Et and 4-Me and
withdrawing groups such as 4-Cl, 4-Br, 4-F, 4-NO2, 4-OMe, 3-Cl, 3-Br, 3-OMe, 2-NO2
and 2-F with dimedone and NMSM were performed under optimized conditions. The
reaction proceeds effectively to afford a series of chromen-5-one derivative 4a–4q in
85–94% yields (Table 2). We have noticed that the aromatic aldehydes having electron
withdrawing groups afforded the products with good to excellent yields. Electron donat-
ing substituted aromatic aldehydes also shows equal ease towards the product formation
in good yields.
Further, the scope of this protocol was extended by the reaction of cyclohexane-1,3-
dione with aromatic aldehydes and NMSM under optimized reaction conditions, which
afforded the formation of desired products 4r–4u in very good yields (Table 2).
Subsequently, to create more complexity, we performed the reaction of terephthalalde-
hyde with cyclic-1,3-diketones and NMSM under optimized conditions, which furnished
the corresponding novel bis 4H-chromen-5-one derivatives 6a and 6b as shown in
Scheme 2.
Next, we moved to validate our protocol on gram-scale under the optimized condi-
tions and compounds 4i and 4q were synthesized in gram scale by the reaction of
NMSM, dimedone with corresponding aldehydes as depicted in Scheme 3.
All the newly synthesized compounds were fully characterized by its melting point
1
and spectroscopic techniques like IR, H & 13C NMR, HRMS and also by CHNS ana-
lysis. Reported compounds 4f, 4i, 4j, 4l, and 4n were also fully characterized and the
spectroscopic data are in good agreement with the proposed structure.25 Moreover, the
structure and configuration of one of the compound were confirmed by single crystal-
XRD analysis and the ORTEP diagram of compound 4m is shown in Figure 2.
Finally, a plausible reaction mechanism for the formation of 4H-chromene-5-ones
was outlined in Scheme 4. The first step is Knoevenagel condensation of dimedone and

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Table 2. Substrate scope for the synthesis of functionalized 4H-chromen-5-one derivtivesa.
aReactions were performed with NMSM (1 mmol), cyclic-1,3-dikeone (1 mmol) and aromatic aldehydes (1 mmol) at
110 ꢀC.
bIsolated yields.

6
M. M. KHAN ET AL.
Scheme 2. Synthesis of novel bis 4H-chromen-5-one derivtives.
Scheme 3. Gram scale synthesis of 4H-chromen-5-one 4i and 4q.
Figure 2. ORTEP diagram of compound 4m (CCDC 1814849).
aromatic aldehyde to give an intermediate I, which undergoes Michael-type
addition with NMSM to form species II. Then, the species II undergoes intra-molecular
O-cyclization to afford the desired compound via species III by the elimination
of –MeSH.

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7
Scheme 4. Plausible reaction mechanism for the formation of 4H-chromen-5-ones.
Conclusion
In summary, we have developed an expedient and sustainable greener method for the
synthesis of 4H-chromen-5-one derivatives from the reaction of cyclic-1,3-diketones,
aromatic aldehydes, and NMSM in catalyst-free under neat conditions at 110 ꢀC. The
significant features of this presented method are simple, clean reaction profile, good to
excellent yields, reduced reaction time, avoidance of toxic catalyst and no need of col-
umn chromatographic separation. We believe that these prominent features will facili-
tate this protocol to find wide applications in the field of synthetic organic chemistry
and medicinal chemistry.
Experimental
Synthetic grade chemicals and all solvents were obtained from Sigma-Aldrich, Merck,
Otto Chemie and used for carrying out this work as received. Infrared spectra were
recorded in potassium bromide pellets in reflection mode on a Perkin-Elmer 10.4.00 IR
spectrophotometer. 1H-NMR and 13C-NMR spectral analysis were carried out on
Bruker (Avance-II 400 MHz), Varian-AS400 NMR, and Bruker BioSpin GmbH spec-
trometers using tetramethylsilane (TMS) as an internal standard and DMSO-d6 or
CDCl3 as a solvent. Melting points were measured on a Labtronics apparatus and are
uncorrected. Crystal data were collected with a SuperNova, single source at offset/far,
HyPix3000 diffractometer (CCD) using graphite monochromated MoKa radiation
(k ¼ 0.71073 Å) at 296 K. High-Resolution Mass Spectra (ESI) were obtained on
ORBITRAP mass analyzer (Thermo Scientific, Q Exactive) by the ESI method, while the
elemental analysis of the compounds was performed on a Perkin-Elmer-2400 CHN/S
analyzer and Thermo Scientific (FLASH 2000) analyzer.

8
M. M. KHAN ET AL.
General procedure for the preparation of functionalized 4H-chromen-5-one
derivatives (4a–4u)
In a dried 5 mL round-bottomed flask was charged with a mixture of aromatic alde-
hydes (1.0 mmol), cyclic-1,3-diketones (1.0 mmol) and NMSM (1.0 mmol) at 110ꢀC. The
resulting mixture was stirred for 15–30 min and the reaction progress was checked by
TLC. After completion of the reaction as indicated by TLC, the resulting precipitate was
cooled and added 2 ml of ethanol and stirred for 5 min. Then, the precipitate was fil-
tered and washed with cold ethanol. Recrystallization was performed from hot aceto-
nitrile to give the pure products.
4-(4-chlorophenyl)-7,7-dimethyl-2-(methylamino)-3-nitro-7,8-dihydro-4H-chromen-
5(6H)-one (4a). Isolated as light yellow solid; Yield: 90%; m.p: 240–242ꢀC; IR (KBr, cmꢁ1)
1
3285, 3021, 2963, 1678, 1638, 1560, 1487, 1469, 1254, 1195, 1086, 812; H NMR (400 MHz,
DMSO-d6) d 0.91 (s, 3H), 1.05 (s, 3H), 2.09 (d, J¼ 16 Hz, 1H), 2.27 (d, J¼ 16.4 Hz, 1H),
2.62 (dd, J¼ 16.8Hz, 2H), 3.09 (d, J¼ 5.2 Hz, 3H), 4.87 (s, 1H), 7.23 (d, J¼ 8 Hz, 2H), 7.29
(d, J¼ 8 Hz 2H), 10.25 (t, J¼ 4.8 Hz, 1H); 13C NMR (400 MHz, DMSO-d6) d 26.6, 28.3,
31.9, 35.2, 39.5, 49.7, 108.1, 114.8, 127.8, 129.9, 131.0, 141.4, 157.2, 161.1, 195.3; Anal.
Calcd (%) for C18H19ClN2O4: C, 59.59; H, 5.28; N, 7.72 Found: C, 59.64; H, 5.20; N, 7.80;
EI-HRMS: Anal. Calcd for [C18H19ClN2O4 þ Hþ]: Cacld: 363.1106, Found: 363.1103.
Typical procedure for the synthesis of bis 4H-chromen-5-one
derivatives (6a and 6b)
In a dried 10 mL round-bottomed flask was charged with a mixture of terephthalalde-
hyde (1.0 mmol), cyclic-1,3-diketones (2.0 mmol) and NMSM (2.0 mmol) at 110 ꢀC. The
resulting mixture was stirred for 15–20 min and after completion of the reaction as indi-
cated by TLC, the resulting precipitate was cooled and added 3 ml of ethanol and stirred
for 5 min. Then, the precipitate was filtered and washed with cold ethanol.
Recrystallization was performed from hot acetonitrile to give the pure products.
4,4’-(1,4-phenylene)bis(7,7-dimethyl-2-(methylamino)-3-nitro-7,8-dihydro-4H-chro-
men-5(6H)-one) (6a). Isolated as white solid; Yield: 88%; m.p: 290–292 ꢀC; IR (KBr,
1
cmꢁ1): 3278, 3223, 3024, 2958, 1671, 1634, 1564, 1472, 1368, 1236, 1163, 1052; H
NMR (500 MHz, DMSO-d6) d 0.89 (s, 3H) 0.90 (s, 3H), 1.02 (s, 3H), 1.05 (s, 3H),
2.10–2.15 (m, 2H), 2.18–2.28 (m, 2H), 2.58–2.64 (m, 4H), 3.06 (d, J ¼ 5.0 Hz, 3H), 3.09
(d, J ¼ 5.0 Hz, 3H), 4.84 (s, 1H), 4.86 (s, 1H) 7.05 (s, 2H), 7.45 (d, J ¼ 8.0 Hz, 1H), 7.78
(d, J ¼ 8.0 Hz, 1H), 10.18 (s, 1H), 10.19 (s, 1H); 13C NMR (400 MHz, DMSO-d6) 13C
NMR (100 MHz, DMSO-d6) d 27.0, 27.6, 28.5, 28.7, 28.8, 28.9, 31.1, 32.4, 32.5, 35.3,
35.3, 36.7, 50.2, 50.3, 108.3, 108.9, 115.1, 115.9, 127.9 129.4, 129.7, 135.3, 141.1, 149.6,
1577, 158.0, 161.8, 161.9, 195.8, 195.9; Anal. Calcd (%) for C30H34N4O8: C, 62.27; H,
5.92; N, 9.68. Found: C, 62.20; H, 5.87; N, 9.58; EI-HRMS: Anal. Calcd for
[C30H34N4O8 þ Hþ]: Cacld: 579.2449, Found: 579.2452.
Acknowledgment
Saigal thanks CSIR, New Delhi, India, for the junior research fellowship (JRF). The authors
acknowledge the SAIF, PU, Chandigarh, IIT Guwahati and NCL Pune for providing NMR

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9
spectra, HRMS S. C. Sahoo thanks to DST-FIST for single crystal-XRD facility. The authors are
also grateful to the Chairman, Department of Chemistry, AMU, Aligarh, for providing necessary
research facilities to execute this work. We are also obliged to the referees for their valuable
suggestions.
References
[1] Cioc, R. C.; Ruijter, E.; Orru, R. V. A. Multicomponent Reactions: Advanced Tools for
Sustainable Organic Synthesis. Green Chem. 2014, 16, 2958–2975. DOI: 10.1039/
C4GC00013G. (b) Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice.
Oxford University Press: New York, 1998. (c) Dunn, P. J. The Importance of Green
Chemistry in Process Research and Development. Chem. Soc. Rev. 2012, 41, 1452–1461.
DOI: 10.1039/c1cs15041c.
[2] (a) Kirchhoff, M. M. Promoting Green Engineering through Green Chemistry. Environ.
Sci. Technol. 2003, 37, 5349–5353. DOI: 10.1021/es0346072. (b) Horvath, I. T.; Anastas, P.
T. Innovations and Green Chemistry. Chem. Rev. 2007, 107, 2169–2173. DOI: 10.1021/
cr078380v.
[3] (a) Singh, M. S.; Chowdhury, S. Recent Developments in Solvent-Free Multicomponent
Reactions: A Perfect Synergy for Eco-Compatible Organic Synthesis. RSC Adv. 2012, 2,
4547–4592. DOI: 10.1039/C2RA01056A. (b) Kumar, A.; Sharma, S. A. Grinding-Induced
Catalyst- and Solvent-Free Synthesis of Highly Functionalized 1,4-Dihydropyridines via a
Domino Multicomponent Reaction. Green Chem. 2011, 13, 2017–2020. DOI: 10.1039/
C1GC15223H.
[4] (a) Khan, M. M.; Khan, S.; Saigal, Iqbal, S. Recent Developments in Multicomponent
Synthesis of Structurally Diversified Tetrahydropyridines. RSC Adv. 2016, 6, 42045–42061.
DOI: 10.1039/C6RA06767K. (b) Khan, M. M.; Yousuf, R.; Khan, S.; Shafiullah. Recent
Advances in Multicomponent Reactions Involving Carbohydrates. RSC Adv. 2015, 5,
57883–57905. DOI: 10.1039/C5RA08059B. (c) Zhu, J.; Bienayme, H. Multicomponent
Reactions, 1st ed.; Wiley-VCH: Weinheim, Germany, 2005.
[5] (a) Metzger, J. O. Solvent-Free Organic Syntheses. Angew. Chem. Int. Ed. Engl. 1998, 37,
2975–2978. DOI: 10.1002/(SICI)1521-3773(19981116)37:21<2975::AID-ANIE2975 > 3.0.CO;
2-A. (b) Varma, R. S. Solvent-Free Organic Syntheses. Green Chem. 1999, 1, 43–55. DOI:
10.1039/A808223E. (c) Tanaka, K.; Toda, F. Solvent-Free Organic Synthesis. Chem. Rev.
2000, 100, 1025–1074. DOI: 10.1021/cr940089p
[6] (a) Haji, M. Multicomponent Reactions: A Simple and Efficient Route to Heterocyclic
Phosphonates. Beilstein J Org Chem. 2016, 12, 1269–1301. DOI: 10.3762/bjoc.12.121. (b)
Carlone, A.; Cabrera, S.; Marigo, M.; Jorgensen, K. A. A New Approach for an
Organocatalytic Multicomponent Domino Asymmetric Reaction. Angew. Chem. Int. Ed.
2007, 46, 1101–1104. DOI: 10.1021/ol9024293.
[7] (a) Hatakeyama, S.; Ochi, N.; Numata, H.; Takano, S. A new route to substituted 3-
methoxycarbonyldihydropyrans; enantioselective synthesis of (–)-methyl elenolate. J.
Chem. Soc. Chem. Commun. 1988, 1202–1204. DOI:10.1039/C39880001202. (b) Armesto,
D.; Horspool, W. M.; Martin, N.; Ramos, A.; Seaone, C. Synthesis of cyclobutenes by the
novel photochemical ring contraction of 4-substituted 2-amino-3,5-dicyano-6-phenyl-4H-
pyrans. J. Org. Chem. 1989, 54, 3069–3072. DOI: 10.1021/jo00274a021.
[8] Rajasekhar, M.; Rao, K. U. M.; Sundar, C. S.; Reddy, N. B.; Nayak, S. K.; Reddy, C. S.
Green Synthesis and Bioactivity of 2-Amino-4H-Chromen-4-yl-Phosphonates. Chem.
Pharm. Bull. 2012, 60, 854–858. DOI: 10.1248/cpb.c12-00160.
[9] Wu, J. Y. C.; Fong, W. F.; Zhang, J. X.; Leung, C. H.; Kwong, H. L.; Yang, M. S.; Li, D.;
Cheung, H. Y. Reversal of Multidrug Resistance in Cancer Cells by Pyranocoumarins
Isolated from Radix Peucedani. Eur. J. Pharmacol. 2003, 473, 9–17. DOI: 10.1016/S0014-
2999(03)01946-0.

10
M. M. KHAN ET AL.
[10] (a) Flavin, M. T.; Rizzo, J. D.; Khilevich, A.; Kucherenko, A.; Sheinkman, A. K.;
Vilaychack, V.; Lin, L.; Chen, W.; Greenwood, E. M.; Pengsuparp, T.; et al. Synthesis,
Chromatographic Resolution, and anti-Human Immunodeficiency Virus Activity of
(+/–)-Calanolide a and Its Enantiomers. J. Med. Chem. 1996, 39, 1303–1313. DOI:
10.1021/jm950797i. (b) Rueping, M.; Sugiono, E.; Merino, E. Asymmetric Organocatalysis:
An Efficient Enantioselective Access to Benzopyranes and Chromenes. Chem. Eur. J. 2008,
14, 6329–6332. DOI: 10.1002/chem.200800836.
[11] Morgan, L. R.; Jursic, B. S.; Hooper, C. L.; Neumann, D. M.; Thangaraj, K.; LeBlanc, B.
Anticancer Activity for 4,4'-Dihydroxybenzophenone-2,4-Dinitrophenylhydrazone (A-007)
Analogues and Their Abilities to Interact with Lymphoendothelial Cell Surface Markers.
Bioorg. Med. Chem. Lett. 2002, 12, 3407–3411. DOI: 10.1016/S0960-894X(02)00725-4.
[12] Rueping, M.; Sugiono, E.; Merino, E. Asymmetric Organocatalysis: an Efficient
Enantioselective Access to Benzopyranes and Chromenes. Chemistry. 2008, 14, 6329–6332.
DOI: 10.1002/chem.200800836.
[13] Elisa, P. S.; Ana, E. B.; Ravelo, A. G.; Yapu, D. J.; Turba, A. G. Antiplasmodial Activity of
Naphthoquinones Related to Lapachol and Beta-Lapachone. Chem. Biodivers. 2005, 2,
264–274. DOI: 10.1002/cbdv.200590009.
[14] Baraldi, P. G.; Manfredini, S.; Simoni, D.; Tabrizi, M. A.; Balzarini, J.; Clercq, E. D.
Geiparvarin Analogues. 3. Synthesis and Cytostatic Activity of 3(2H)-Furanone and 4,5-
Dihydro-3(2H)-Furanone Congeners of Geiparvarin, Containing a Geraniol-like Fragment
in the Side Chain. J. Med. Chem. 1992, 35, 1877–1882. DOI: 10.1021/jm00088a025.
[15] Kumar, A.; Maurya, R. A.; Sharma, S. A.; Ahmad, P.; Singh, A. B.; Bhatia, G.; Srivastava,
A. K. Pyranocoumarins: A New Class of anti-Hyperglycemic and anti-Dyslipidemic
Agents. Bioorg. Med. Chem. Lett. 2009, 19, 6447–6451. DOI: 10.1016/j.bmcl.2009.09.031.
[16] Moon, D. O.; Kim, K. C.; Jin, C. Y.; Han, M. H.; Park, C.; Lee, K. J.; Park, Y. M.; Choi, Y.
H.; Kim, G. Y. Inhibitory Effects of Eicosapentaenoic Acid on Lipopolysaccharide-Induced
Activation in BV2 Microglia. Int. Immunopharmacol. 2007, 7, 222–229. DOI: 10.1016/
j.intimp.2006.10.001.
[17] (a) Elinson, M. N.; Dorofeev, A. S.; Miloserdov, F. M.; Ilovaisky, A. I.; Feducovich, S. K.;
Belyakov, P. A.; Nikishin, G. I. Catalysis of Salicylaldehydes and Two Different C-H Acids
with Electricity: First Example of an Efficient Multicomponent Approach to the Design of
Functionalized Medicinally Privileged 2-Amino-4H-Chromene Scaffold. Adv. Synth. Catal.
2008, 350, 591–601. DOI: 10.1002/adsc.200700493. (b) Atwal, K. S. Mycocardial protection
with the ATP-sensitive potassium channel openers. Curr. Med. Chem. 1996, 3, 227–238.
[18] Adbel Aziz Hafez, E.; Abdel Aziz Hafez, E.; Hilmy Elnagdi, M.; Ghani Ali Elagamey, A.;
Mohamed Abdel Aziz El-Taweel, F. Nitriles in Heterocyclic Synthesis: Novel Synthesis of
Benzo[c]Coumarin and of Benzo[c]Pyrano[3,2-c]Quinoline Derivatives. Heterocycles. 1987,
26, 903–907. DOI: 10.3987/R-1987-04-0903.
[19] (a) Kemnitzer, W.; Kasibhatla, S.; Jiang, S.; Zhang, H.; Zhao, J.; Jia, S.; Xu, L.; Crogan-
Grundy, C.; Denis, R.; Barriault, N.; et al. Discovery of 4-Aryl-4H-Chromenes as a New
Series of Apoptosis Inducers Using a Cell- and Caspase-Based High-Throughput
Screening Assay. 2. Structure-Activity Relationships of the 7- and 5-, 6-, 8-Positions.
Bioorg. Med. Chem. Lett. 2005, 15, 4745–4751. DOI: 10.1016/j.bmcl.2005.07.066. (b) Tian,
D.; Das, S. G.; Doshi, J. M.; Peng, J.; Lin, J.; Xing, J. C. sHA14-1, a Stable and ROS-Free
Antagonist against Anti-Apoptotic Bcl-2 Proteins, Bypasses Drug Resistances and
Synergizes Cancer Therapies in Human Leukaemia Cell. Cancer Lett. 2008, 259, 198–208.
DOI: 10.1016/j.canlet.2007.10.012.
[20] Smith, C. W.; Bailey, J. M.; Billingham, M. E. J.; Chandrasekhar, S.; Dell, C. P.; Harvey, A.
K.; Hicks, C. K.; Kingston, A. E.; Wishart, G. N. The anti-Rheumatic Potential of a Series
of 2,4-di-Substituted-4H-Naphtho[1,2-b]Pyran-3-Carbonitriles. Bioorg. Med. Chem. 1995,
5, 2783–2788. DOI: 10.1016/0960-894X(95)00487-E.
[21] Kumar, D.; Reddy, V. B.; Sharad, S.; Dube, U.; Kapur, S. A Facile One-Pot Green
Synthesis and Antibacterial Activity of 2-Amino-4H-Pyrans and 2-Amino-5-Oxo-5,6,7,8-

R
SYNTHETIC COMMUNICATIONSV
11
Tetrahydro-4H-Chromenes. Eur. J. Med. Chem. 2009, 44, 3805–3809. DOI: 10.1016/
j.ejmech.2009.04.017.
[22] (a) Amr, A.-G. E.; Mohamed, A. M.; Mohamed, S. F.; Abdel-Hafez, N. A.; Hammam, A.
E.-F. G. Anticancer Activities of Some Newly Synthesized Pyridine, Pyrane, and
Pyrimidine Derivatives. Bioorg. Med. Chem. 2006, 14, 5481–5488. DOI: 10.1016/
j.bmc.2006.04.045. (b) Abdelrazeka, F. M.; Metza, P.; Farrag, E. K. Synthesis and
Molluscicidal Activity of 5-oxo-5,6,7,8-Tetrahydro-4H-Chromene Derivatives. Arch.
Pharm. Pharm. Med. Chem. 2004, 337, 482–485. DOI: 10.1002/ardp.200400881.
[23] (a) Khan, A. T.; Lal, M.; Ali, S.; Khan, M. M. One-Pot Three-Component Reaction for the
Synthesis of Pyran Annulated Heterocyclic Compounds Using DMAP as a Catalyst.
Tetrahedron lett., 2011, 52, 5327–5332. DOI: 10.1016/j.tetlet.2011.08.019. (b) Shirini, F.;
Daneshvar, N. Introduction of Taurine (2-Aminoethanesulfonic Acid) as a Green Bio-
Organic Catalyst for the Promotion of Organic Reactions under Green Conditions. RSC
Adv., 2016, 6, 110190–110205. DOI: 10.1039/C6RA15432H. (c) Maleki, B.; Nasiri, N.;
Tayebee, R.; Khojastehnezhad, A.; Ali, H.; Akhlaghi. Green Synthesis of
Tetrahydrobenzo[b]Pyrans, Pyrano[2,3-c]Pyrazoles and Spiro[Indoline-3,4,-Pyrano[2,3-
c]Pyrazoles Catalyzed by Nano-Structured Diphosphate in Water. RSC Adv., 2016, 6,
79128–79134. DOI: 10.1039/C6RA15800E.
[24] (a) Kanchithalaivan, S.; Sivakumar, S.; Kumar, R. R.; Elumalai, P.; Ahmed; Q. N. Padala,
A. K. K. Four-Component Domino Strategy for the Combinatorial Synthesis of Novel 1,4-
Dihydropyrano[2,3-c]Pyrazol-6-Amines. ACS Comb. Sci., 2013, 15, 631–638. DOI:
10.1021/co4000997. (b) Gunasekaran, P.; Prasanna, P.; Perumal, S. L-Proline-Catalyzed
Three-Component Domino Reactions for the Synthesis of Highly Functionalized
Pyrazolo[3,4-b]Pyridines. Tetrahedron Lett., 2014, 55, 329–332. DOI: 10.1016/j.tet-
let.2013.11.016. (c) Rao; H. S. P.; Parthiban, A. One-Pot Pseudo Three-Component
Reaction of nitroketene-N,S-Acetals and Aldehydes for Synthesis of Highly Functionalized
Hexa-Substituted 1,4-Dihydropyridines. Org. Biomol. Chem., 2014, 12, 6223–6238. DOI:
10.1039/C4OB00628C. (d) Gunasekaran, P.; Prasanna, P.; Perumal, S.; Almansour, A. I.
ZnCl2-Catalyzed Three-Component Domino Reactions for the Synthesis of Pyrano[3,2-
c]Quinolin-5(6H)-Ones. Tetrahedron Lett., 2013, 54, 3248–3252. DOI: 10.1016/j.tet-
let.2013.04.022. (e) Reddy, M. V.; Reddy, G. D.; Kim; J. T.; Jeong, Y. T. An Efficient and
Green Synthesis of Highly Functionalized N -Methyl-2-Nitro-Aryl-1 H -Benzo[f]Chromen-
3-Amine Derivatives under Catalyst-Free Conditions. Tetrahedron, 2016, 72, 6484–6491.
DOI: 10.3390/molecules23010235. (f) Mao, J.; Wang, J.; Zhang, W.; Li, Z.; Zhu, J.; Guo, C.
Convenient multicomponent reaction synthesis of novel pyrano[4,3-b]pyran derivatives
via a domino reaction under microwave irradiation. Arkivoc, 2016, (iii), 171–186. DOI:
10.3998/ark.5550190.p009.398. (g) Sivakumar, S.; Kanchithalaivan, S.; Kumar, R. R. A
One-Pot Three-Component Domino Protocol for the Synthesis of Penta-Substituted 4H-
Pyrans. RSC Adv., 2013, 3, 13357–13364. DOI: 10.1039/C3RA41510D. (h) Poomathi, N.;
Kamalraja, J.; Mayakrishnan, S.; Muralidharan; D.; and Perumal, P. T. Indium Trichloride
Catalysed Domino Reactions of Isatin: A Facile Access to the Synthesis of Spiro(Indoline-
3,4,-Pyrano[2,3-c]Pyrazol)-2-One Derivatives. Synlett. 2014, 25, 0708–0712. DOI: 10.1055/
s-0033-1340666. (i) Balachandra, B.; Shanmugam, S.; Muneewarahand, T.; Ramakritinan,
M. Iodine Catalyzed One-Pot Synthesis of Highly Substituted N-Methyl Pyrroles via
[3 + 2] Annulation and Their In Vitro Evaluation as Antibacterial Agents. RSC Adv., 2015,
5, 64781–64789. DOI: 10.1039/C5RA11094G. (j) Jadhav, A. M.; Krishnammagari, S. K.;
Kim, J. T.; Jeong, Y. T. A Highly Efficient and Recyclable Silica-Supported Tungstic Acid
(STA) Catalyst for the Synthesis of Pyrano[3,2- c]Chromen-5-Ones under Solvent Free
Conditions. Tetrahedron, 2017, 73, 5163–5169. DOI: 10.1016/j.tet.2017.07.008. (k) Jadhav,
A. M.; Kim, Y. I.; Lim, K. T.; Jeong, Y. T. Application of p-TSA in the One Pot Synthesis
of
2018, 59, 554–557. DOI: 10.1002/cjoc.200890376. (l) Rahimi, F.; Hosseini, H.; Bayat, M.;
Jeong, Y. T. One-Pot Three-Component Approach to Synthesis of Novel
N
-Methyl-3-Nitro-Aryl-Benzo[4,5]Imidazo[1,2-a]Pyrimidin-2-Amine. Tetrahedron,
A

12
M. M. KHAN ET AL.
Dihydroxyoxoindeno[1,2-b]Pyrrole Derivatives. Tetrahedron, 2018, 59, 818–822. DOI:
/10.1016/j.tetlet.2018.01.050.
[25] (a) Kamalraja, J.; Muralidharan; D.; Perumal, P. T. An Efficient, One-Pot Regioselective
Synthesis of Highly Functionalized Chromen-5-Ones and Pyrano[3,2-c]Chromen-5-Ones
via a Tandem Knoevenagel–Michael–Cyclization Sequence. Synlett., 2012, 23, 2894–2898.
DOI: 10.1055/s-0032-1317543. (b) Shinde, V. V.; Jeong, D.; Cho, E.; Jung, S. 6,6,-
Thiobis(Methylene)-β-Cyclodextrin Dimer as a Dimeric Host and Reusable Promoter for
Synthesis of Chromenones in Water. Tetrahedron, 2018, 74, 194–198. DOI: 10.1016/
j.tet.2017.11.065.
[26] (a) Khan, M. M.; Saigal; Khan, S.; Shareef, S.; Hussain, S. ChemistrySelect, 2018, 3,
2261–2266. A Facile and Green Approach for One-Pot Synthesis of Functionalized
Chromeno[3, 4-b]quinolines and Spiro Chromeno[3, 4-b]quinolines by Using Molecular
Iodine as a Catalyst. DOI: 10.1002/slct.201702810. (b) Khan, M. M.; Khan, S.; Saigal;
Sahoo, S. C. Organocatalyzed Synthesis and Antifungal Activity of Fully Substituted 1,
4-Dihydropyridines. ChemistrySelect, 2018, 3, 1371–1380. DOI: 10.1002/slct.201800709. (c)
Khan, M. M.; Khan, S.; Iqbal, S.; Saigal; Yousuf, R. New J. Chem., 2016, 40, 7504–7512.
Synthesis of Functionalized Dihydro-2-Oxypyrroles and Tetrahydropyridines Using 2,6-
Pyridinedicarboxylic Acid as an Efficient and Mild Organocatalyst. New J. Chem. 2016,
40, 7504–7512. DOI: 10.1039/C6NJ01170E.