Facile synthetic route to benzo[c]chromenones and thieno[2,3-c]chromenones

Article abstract of DOI:10.1080/00397911.2017.1380833

Convenient two-step procedure for the synthesis of fused chromenone derivatives was developed. Reduction of the obtained in the Meerwein arylation reaction aryl- and thienylquinones allowed to construct 6H-benzo[c]chromene-6-ones and 4H-thieno[2,3-c]chrom

Full text of DOI:10.1080/00397911.2017.1380833

Synthetic Communications
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Facile synthetic route to benzo[c]chromenones
and thieno[2,3-c]chromenones
Olga Ya. Shyyka, Roman L. Martyak, Mykola A. Tupychak, Nazariy T.
Pokhodylo & Mykola D. Obushak
To cite this article: Olga Ya. Shyyka, Roman L. Martyak, Mykola A. Tupychak, Nazariy T.
Pokhodylo & Mykola D. Obushak (2017): Facile synthetic route to benzo[c]chromenones and
thieno[2,3-c]chromenones, Synthetic Communications, DOI: 10.1080/00397911.2017.1380833
To link to this article: http://dx.doi.org/10.1080/00397911.2017.1380833
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Date: 04 October 2017, At: 01:45

Facile synthetic route to benzo[c]chromenones and
thieno[2,3-c]chromenones
Olga Ya. Shyyka
Department of Organic Chemistry, Ivan Franko National University of Lviv, Lviv, Ukraine
Roman L. Martyak
Department of Organic Chemistry, Ivan Franko National University of Lviv, Lviv, Ukraine
Mykola A. Tupychak
Department of Organic Chemistry, Ivan Franko National University of Lviv, Lviv, Ukraine
Nazariy T. Pokhodylo
Department of Organic Chemistry, Ivan Franko National University of Lviv, Lviv, Ukraine
Mykola D. Obushak
Department of Organic Chemistry, Ivan Franko National University of Lviv, Lviv, Ukraine
Address correspondence to Olga Ya. Shyyka, Department of Organic Chemistry, Ivan Franko
National University of Lviv, Kyryla i Mefodiya St. 6, Lviv 79005, Ukraine. E-mail:
shiyka.olya@gmail.com
1H and 13C NMR spectra of all new compounds can be found via the ‘‘Supplementary Content’’
section of this article’s webpage.
1

ABSTRACT
Convenient two-step procedure for the synthesis of fused chromenone derivatives was
developed. Reduction of the obtained in the Meerwein arylation reaction aryl- and
thienylquinones allowed to construct 6H-benzo[c]chromene-6-ones and 4H-thieno[2,3-
c]chromen-4-one in a cost and time- more effective manner in comparison with already known
methods. The obtained products have provided a new entry to chromenone derivatives.
GRAPHICAL ABSTRACT
KEYWORDS: 4H-thieno[2,3-c]chromen-4-one, 6H-benzo[c]chromene-6-ones, diazonium salts,
meerwein arylation reaction, quinone
Introduction
Recently, special attention is paid to the research in medicine, particularly to the synthetic
drug development for the numerous diseases treatment. Strong interest of researchers in
functionalized 6H-benzo[c]chromenone derivatives is determined by the broad spectrum of their
[1
biological activity and occurrence in pharmacologically relevant natural compounds
and
articles cited therein]. Moreover, substituted 6H-benzo[c]chromenones are of considerable
pharmacological importance due to the presence of chromenone core in a number of anticancer
[2
agents and antibiotics
and articles cited therein]. Taking into account the above stated,
development of methods for the synthesis of new hydroxy-chromenone derivatives is encouraged
and was in our focus.
2

However, synthesis of diverse heterocyclic molecules from the readily available starting
materials in a cost and time-effective manner is an enduring challenge for organic chemists. The
typical key approaches in the synthesis of 2-hydroxy-6H-benzo[c]chromene-6-ones or 8-
hydroxy-4H-thieno[2,3-c]chromen-4-ones are as follows: a) Suzuki coupling of
boronates/boronic acids with the corresponding aryl-/hetaryl- bromides [3–5]; b) Packmann
condensation between 1,5-dihydronaphtalene and corresponding β-ketoesters to generate desired
carbon framework with further two-step functionalization [6]; c) domino retro-Michael-aldol
lactonization [7]; d) Hauser-initiated annulation [8,9]; e) catalytic intramolecular oxidation reaction
of quinone with benzoic acids [10]; f) Rh(III)-, Ru(II) - and Copper- catalysed C−H bond arylation
with phenol, quinone or arene derivatives.[11–14] The last approaches [13,14] present convenient and
facile chromenone synthesis using modified Meerwein arylation method as a key step. Despite
the vast amount of literature on synthetic routes to hydroxy chromenone derivatives, all
mentioned above methods require the use of expensive or not readily available starting reactants,
metal catalysts (Pd, Rh, Ir compounds), longer reaction times, high temperatures and sometimes
give poor or moderate yields in multi-step procedures.
Due to the importance of fused chromenone derivatives the development of new efficient
synthetic paths for their preparation still remains an actual task. Thus, considering the above
synthetic methodology to prepare chromenones and its biological importance it was thought
worthwhile to elaborate convenient synthetic protocol allowing to construct hydroxy
chromenone derivatives under mild Meerwein arylation conditions from the readily available
starting material.
Results and Discussion
3

Arylation of unsaturated compounds with arenediazonium salts under typical Meerwein
conditions provides a convenient method for the synthesis of polyfunctional substrates. In our
previous works, we demonstrated the synthetic potential of aryldiazonium salts in the
construction of valuable heterocyclic compounds via the Meerwein arylation reactions with
further cyclization.[15,16] Moreover, a wide variety of novel fused polyheterocyclic systems were
successfully obtained in cyclocondensation reactions of thienyldiazonium salts.[17–19] Thus, we
have used Meerwein arylation approach to obtain a number of substituted 2-hydroxy-6H-
benzo[c]chromen-6-ones and 8-hydroxy-4H-thieno[2,3-c]chromen-4-one. Benzo[c]chromen-6-
ones and thieno[2,3-с]chromenone were obtained via metal-free protocol in a cost and time-
more effective manner in comparison with already known methods.
Firstly, it was found out that readily available substituted anthranilates 1 could be easily
converted into corresponding diazonium salts 2, which in the Meerwein arylation reaction with
quinone give arylquinones 3in high yields under mild conditions (Scheme 1). The reaction of
arenediazonium chlorides 2a–d with quinone were carried out in aqueous suspension in the
presence of sodium acetate. The peculiarity of the 1,4-benzoquinone arylation is that it occurs in
the absence of a catalyst, which is nearly always required in all other variants of the Meierwein
reaction.
Next the reduction of obtained arylquinones 3 was performed resulting into 2',5'-
dihydroxy-[1,1'-biphenyl]-2-carboxylate intermediate A formation. Obviously, the last
intermediate A undergoes cyclization by intermolecular transesterification and the chromenone
ring closure products 4 were isolated in high yields. It should be mentioned, that both reduction
systems: sodium sulfide in aqueous ethanol (Method A) or zinc powder in glacial acetic acid
(Method B) gave successful result yielding a number of desired benzo[c]chromen-6-ones 4.
4

Additionally, we were interested to develop synthetic paths for 4H-thieno[2,3-c]
chromen-4-one formation. Further to extend the application of proposed Meerwein methodology,
we examined thienyldiazonium salts. Thus, new reaction partner: thienyldiazonium salt 2e was
involved in Meerwein arylation of quinone. Obtained in Meerwein thienylquinone 3e was
reduced in the same, mentioned earlier, protocol using sodium sulphide in aqueous ethanol
affording desired fused thienochromenone 4e formation in high yield.
It should be noted, that usage of diazonium salts based on 2-aminothiophenes in this
scheme failed due to the polymerization, destruction processes and rapid cleavage of such labile
diazonium salts.
Moreover, it is well-known that presence of quinone moiety opens a possibility for
further modifications allowing to construct polyfused heterocycles based on 1,4-addition
reactions and cyclocondensations. Taking into account this fact, we decided to provide 1,4-
addition of the thiourea to thienyl-quinone 3e according to method originally proposed by Lau
and Kestner.[20] It was found that formation of 2-oxobenzo[d][1,3]oxathiol-thiophene involved
three stages: 1,4 addition of thiourea to protonated form of substituted quinone giving first
thiouronium salt with the next cyclisation and hydrolyses. Finally, to generate chromenone cycle
additional heating in toluene with p-toluenesulfonic acid catalysis was performed without
isolation of product B. As a result polyfused 4H-[1,3]oxathiolo[5,4-g]thieno[2,3-c]chromene-
4,8-dione system 5 was constructed.
Experimental
1H NMR spectra and 13C NMR spectra were recorded on a Varian Mercury 400
1
13
instrument (400MHz for H, 125MHz for 13C). The 1H and C chemical shifts were reported in
5

parts per million relative to tetramethylsilane or the deuterated solvent as an internal reference.
Mass spectra were performed using Agilent 1100 series LC/MSD with an API-ES/APCI
ionization mode and low-resolution electron impact mass spectra (EIMS) on an Agilent 6890N
gas chromatograph equipped with a 5973N mass selective detector and a 7683B automatic liquid
sampler (Agilent Technologies). The evolution of reactions and purity of the synthesized
compounds were monitored chromatographically on Silufol UV-254 plates.
General procedure for the synthesis of aryl- and thienylquinones 3a-e
Appropriate amine 1 (0.02mol ) was dissolved in concentrated hydrochloric acid (5mL )
and ice (15g ) was added. When the mixture was cooled to 0˚C, saturated sodium nitrite (1.73g;
0.025mol ) aqueous solution was added keeping the temperature below 5˚C. After 10min,
resinous sediment (in case it was formed) should be filtered. Filtrated solution of the diazonium
salt was added dropwise into quinone (2.5g; 0.024mol ), AcONa3H2O (6.84g; 0.045mol ) water
(150ml ) suspension keeping the temperature at 15-20˚C. The reaction mixture was left stirring
for 2hours . The formed solid product was filtered and recrystallized from ethanol or
ethanol/DMF solution.
Methyl 2-(3,6-dioxocyclohexa-1,4-dienyl)benzoate (3a)
(This compound was previously reported by Honraedt at al. [14]): Yield: 86% as a light
brown solid; mp 114–115 ºС; 1H NMR (400MHz, DMSO-d6): δ 7.98 (1H, d, J = 7.4Hz, НAr-6),
7.72 (1H, t, J = 7.4Hz, НAr-4), 7.62 (1H, t, J = 7.4Hz, НAr-5), 7.45 (1H, d, J = 7.4Hz, НAr-3),
13
6.98 (2H, br.s, HQuinone), 6.83 (1H, s, HQuinone), 3.70 (3H, s, MeO). C NMR (125MHz, DMSO-
d6): δ 188.06 (COQuinone), 186.46 (COQuinone), 166.80 (COOMe), 149.35 (CQuinone), 137.35 (CH),
137.30 (CH), 134.89 (CAr-2), 133.44 (CH), 131.39 (CH), 131.04 (CH), 130.25 (CH), 130.20
6

+
(CAr-1), 130.08 (CH), 52.71 (OMe). MS (m/z): 243 (M + 1). Anal. calcd. for C14H10O4: C,
69.42; H, 4.16; found: C, 69.49; H, 4.25.
General procedure for the synthesis of 2-hydroxy-6H-benzo[c]chromen-6-ones
4a-d and 8-hydroxy-4H-thieno[2,3-c]chromen-4-one 4e
Method A
Sodium sulfide nonahydrate (1.44g; 0.006mol ) was added to the solution of compound 3
(0.002mol ) in ethanol (10ml ) – water (2ml ). The reaction mixture is heated at 60°С for 2hours .
Solvent is evaporated under reduced pressure and the residue is extracted with dichloromethane.
Dichloromethane is evaporated in vacuum, the solid product was recrystallized from ethanol or
ethanol/DMF solution.
Method B
A solution of compound 3 (0.002mol ) in glacial acetic acid (5ml ) was added to the well-
stirred mixture of zinc dust (0.13g; 0.01mol ) in glacial acetic acid (5ml ). After the mixture was
refluxed for 30min, zinc compounds and excess of zinc dust were filtrated off. The filtrate was
concentrated under reduced pressure to remove acetic acid and the residue was purified by
recrystallization from ethanol or ethanol/DMF solution.
2-Hydroxy-6H-benzo[c]chromen-6-one (4a)
[10]
(This compound was previously reported by Engelman et al.
and Yang at al. [11,
12a]): Yield: 89% as a grey solid; mp 215–216 ºС; 1H NMR (400MHz, DMSO-d6) δ 9.72 (1H, s,
OH), 8.22 (2H, br.s, H-10,7), 7.89 (1H, t, J = 7.7Hz, H-9), 7.63 (1H, t, J = 7.6Hz, H-8), 7.57
(1H, s, H-1), 7.23 (1H, d, J = 8.8Hz, H-4), 6.98 (1H, dd, J = 8.9, 2.8Hz, H-3). 13C NMR
7

(125MHz, DMSO-d6): δ 160.87 (COO), 154.81 (COH), 144.35 (COC), 135.68 (CH), 134.74 (C-
10a), 130.21 (CH), 129.61 (CH), 122.91 (CH), 121.03 (C-6a), 118.91 (CH), 118.63 (C-1a),
+
118.56 (CH), 108.64 (CH). MS (m/z): 213 (M + 1). Anal. calcd. for C13H8O3: C, 73.58; H,
3.80; found: C, 73.51; H, 3.75.
4H[1,3]Oxathiolo[5,4-g]thieno[2,3-c]chromene-4,8-dione (5)
To a solution of 0.15mol of thiourea in 100ml of 2N hydrochloric acid 0.1mol (g) of
thienylquinone 3e in 60ml of glacial acetic acid was added with stirring. The mixture was stirred
at room temperature for 30min, during which time a mass of crystalline thiouronium salt
precipitated. Upon heating on a steam bath, the salt re-dissolved to give a clear solution. The
mixture was heated for 1 hr, then chilled in an ice bath until crystallization was complete. The
solid was collected, washed with water, the resulted precipitate without recrystallization was
dissolved in 50ml of toluene and p-TSA was added as a catalyst. The reaction mixture was
heated under reflux for 4hours, then chilled at room temperature and washed with aqueous 2N
NaOH solution. The toluene layer was collected and the solvent was evaporated under reduced
1
pressure. Yield: 88% as a light purple solid; mp 252–253 ºС; H-NMR (400MHz, DMSO-d6): δ
8.43 (1H, d, J = 4.8Hz, H-2), 8.04 (1H, d, J = 4.8Hz, H-1), 7.78 (1H, d, J = 2.2Hz, H-10), 7.28
(1H, d, J = 2.3Hz, H-6). 13C NMR (125MHz, DMSO-d6): δ 171.43 (SCO), 158.02 (CO), 156.11
(C), 146.50 (CH), 145.25 (C), 139.65 (CH), 125.52 (C), 124.41 (C), 124.37 (C), 120.02 (C),
+
114.72 (CH), 111.82 (CH). MS (m/z): 277 (M + 1). Anal. calcd. for C12H4O4S2: C, 52.17; H,
1.46; found: C, 52.05; H, 1.63.
Conclusion
8

In summary, we have described a simple efficient method for the synthesis of the
substituted 6H-benzo[c]chromene-6-ones and 4H-thieno[2,3-c]chromen-4-one, which are
suitable for the evaluation of biological activity and further drug discovery.
Acknowledgements
The authors are grateful to the Ministry of Education and Science of Ukraine for financial
support of this project (No 0116U008067).
References
[1] Sun, J.; Awakawa, T.; Noguchi, H.; Abe, I. Induced Production of Mycotoxins in an
Endophytic Fungus from the Medicinal Plant Datura stramonium L. Bioorg. Med. Chem.
Lett. 2012, 22(20), 6397–6400.
[2] Mazimba, O. Synthetic Protocols on 6h-Benzo[C]Chromen-6-Ones: A Review. Turk. J.
Chem. 2016, 40, 1–27.
[3] Nemecek, G.; Cudaj, J.; Podlech, J. Revision of the Structure and Total Synthesis of
Altenuisol. Eur. J. Org. Chem. 2012, 20, 3863–3870.
[4] Kym, P. R.; Kort, M. E.; Coghlan, M. J.; Moore, J. L.; Tang, R.; Ratajczyk, J. D.; Larson, D.
P.; Elmore, S. W.; Pratt, J. K.; Stashko, M. A. et al. Nonsteroidal Selective
Glucocorticoid Modulators: The Effect of C-10 Substitution on Receptor Selectivity and
Functional Potency of 5-Allyl-2,5-dihydro-2,2,4-trimethyl-1H-[1]benzopyrano[3,4-
f]quinolones. J. Med. Chem. 2003, 46, 1016–1030.
[5] Iaroshenko, V. O.; Ali, S.; Mkrtchyan, S.; Gevorgyan, A.; Babar, T. M.; Semeniuchenko, V.;
Hassan, Z.; Villinger, A.; Langer, P. Design and Synthesis of Condensed
Thienocoumarins by Suzuki–Miyaura Reaction/Lactonization Tandem Protocol.
Tetrahedron Lett. 2012, 53(52), 7135–7139.
[6] McGee, L. R.; Confalone, P. N. On the Photobiology of the Gilvocarcins. Total Synthesis of
Defucogilvocarcin V and a Related Photoactive Vinyl Phenol. J. Org. Chem. 1988,
53(16), 3695–3701.
[7] Appel, B.; Saleh, N.N.R.; Langer, P. Domino Reactions of 1,3-Bis-Silyl Enol Ethers with
Benzopyrylium Triflates: Efficient Synthesis of Fluorescent 6H-Benzo[c]Chromen-6-
Ones, Dibenzo[c,d]Chromen-6-Ones, and 2,3-Dihydro-1H-4,6-Dioxachrysen-5-Ones.
Chem. Eur. J. 2006, 12, 1221–1236.
[8] Ray, S.; Patra, A.; Mal, D. Tandem Annulation Strategy for the Convergent Synthesis of
Benzonaphthopyranones: Total Synthesis of Chartarin and O-Methylhayumicinone.
Tetrahedron 2008, 64, 3253–3267.
[9] Ueberschaar, N.; Dahse, H.-M.; Bretschneider, T.; Hertweck, C. Rational Design of an
Apoptosis-Inducing Photoreactive DNA Intercalator. Angew. Chem. Int. Ed. 2013, 52,
6185–6189.
9

[10] Engelman, K .L.; Feng, Y.; Ison, E. A. C–H Bond Functionalization of Benzoic Acid:
Catalytic Synthesis of 2-Hydroxy-6H-Benzo[c]Chromen-6-Ones Using (Cp*IrCl2)2.
Organometallics 2011, 30, 4572–4577.
[11] Yang, W.; Wang, S.; Zhang, Q.; Liua, Q.; Xu, X. Rh(III)-Catalyzed Oxidative C–H Bond
Arylation with Hydroquinones: Sustainable Synthesis of Dibenzo[b,d]Pyran-6-Ones and
Benzo[d]Naphtho[1,2-b]Pyran-6-Ones. Chem. Commun. 2015, 51, 661–664.
[12] a) Yang, W.; Wang, J.; Wei, Z., Zhang, Q.; Xu, X. Kinetic Control of Rh(III)-Catalyzed
Annulation of C–H Bonds with Quinones: Chemoselective Synthesis of
Hydrophenanthridinones and Phenanthridinones. J. Org. Chem., 2016, 81(4), 1675–1680.
(b) Qi, Z.; Li, X. Rh(III)-Catalyzed C–H Activation of Benzamides: Coupling with
Quinones. Chin. J. Catal. 2015, 36, 48–56.
[13] Crespi, S.; Jäger, S.; König, B.; Fagnoni, M. A Photocatalytic Meerwein Approach to the
Synthesis of Isochromanones and Isochromenones. Eur. J. Org. Chem., 2017, 15, 2147–
2153.
[14] Honraedt, A.; Callonnec, F. L;̧ Grognec, E. L; Fernandez, V.; Felpin, F.-X. C−H Arylation
of Benzoquinone in Water through Aniline Activation: Synergistic Effect of Graphite-
Supported Copper Oxide Nanoparticles. J. Org. Chem. 2013, 78(9), 4604–4609.
[15] Obushak, N. D.; Martyak, R. L.; Matiichuk V. S. Heterocycles Synthesis Based on
Arylation Products of Unsaturated Compounds: XII.* Reactions of 2-Aryl-1,4-
benzoquinones with Dithiol Compounds. Russ. J. Org. Chem. 2005, 41(5), 748–752.
[16] Martyak, R. L.; Obushak, N. D.; Matiichuk V. S. Synthesis of Heterocycles on the Basis of
Arylation Products of Unsaturated Compounds: XX.* Reaction of 2-Aryl-1,4-
Benzoquinones with Potassium O-Butyl Carbonodithioate. Russ. J. Org. Chem. 2010,
46(3), 394–398.
[17] Pokhodylo, N. T.; Shyyka, O. Y.; Obushak M. D. Facile and Efficient One-Pot Procedure
for Thieno[2,3-e][1,2,3]Triazolo[1,5-a] Pyrimidines Preparation. Synth. Commun. 2014,
44(7), 1002–1006.
[18] Pokhodylo, N. T.; Shyyka, O. Y.; Obushak N. D. Ethyl 2-Aminothiophene-3-Carboxylates
in the Synthesis of Isomeric Thienopyridines. Chem. Heterocycl. Compd. 2014, 50(12),
1748–1755.
[19] Pokhodylo, N. T.; Shyyka, O. Y.; Savka, R. D.; Obushak M. D. Novel Selected Tandem
Transformations of the Amino and Carbonyl/Nitrile Groups in the Gewald Thiophenes.
Phosphorus Sulfur Silicon Relat Elem. 2010, 185(10), 2092–2100.
[20] Lau, P. T. S.; Kestner, M. A. One- Step Synthesis of 5-Hydroxy-1,3-Benzoxathiol-2-Ones
from Quinones and Thiourea. J. Org. Chem. 1968, 33(12), 4426–4431.
10

Scheme 1. Synthesis of 2-hydroxy-6H-benzo[c]chromen-6-ones 4a-d.
11

Scheme 2. Synthesis of 4H-thieno[2,3-c]chromen-4-one 4e and 2-oxobenzo[d][1,3]oxathiol-
thiophene 5.
12