Formylation of 5-hydroxybenzofuran derivatives and synthesis of furo-[3,2-f]coumarins based on them

Article abstract of DOI:10.1007/s10593-011-0886-x

The formylation of esters of 5-hydroxy-1-benzofuran-3-carboxylic acid has been studied. The interaction of the synthesized aldehydes with esters of β-keto acids and hetarylacetonitriles gave furo[3,2-f]coumarin-1-carboxylic acids derivatives.

Full text of DOI:10.1007/s10593-011-0886-x

Chemistry of Heterocyclic Compounds, Vol. 47, No. 9, December, 2011 (Russian Original Vol. 47, No. 9, September, 2011)
FORMYLATION OF 5-HYDROXYBENZOFURAN
DERIVATIVES AND SYNTHESIS OF FURO-
[3,2-f]COUMARINS BASED ON THEM*
M. S. Frasinyuk1**, S. P. Bondarenko2, O. V. Shablykina3, and V. P. Khilya3
The formylation of esters of 5-hydroxy-1-benzofuran-3-carboxylic acid has been studied. The
interaction of the synthesized aldehydes with esters of β-keto acids and hetarylacetonitriles gave
furo[3,2-f]coumarin-1-carboxylic acids derivatives.
Keywords: 5-hydroxybenzofuran, furo[3,2-f]coumarin, Knoevenagel condensation, Duff reaction.
Furocoumarins with the “resorcinol” position of oxygen atoms (derivatives of psoralen, allopsoralen,
and angelicin) both natural and synthetic, are widely used as photosensitizing substances, they have been used in
the treatment of skin diseases: psoriasis, fungal granulosis, vitiligo, lupus erythematosus, etc. In view of their
availability and ease of preparation, derivatives of psoralen have been the most studied.
At the same time, many authors have paid attention to the synthesis of derivatives of one of the isomers
of psoralen – isopseudopsoralen (furo[3,2-f]coumarin) and its benzoanalogs. The preparation of isopseudo-
psoralen derivatives by formation of the furan ring as a result of cyclization of 5-allyl-6-hydroxycoumarins
[4,5], 6-acetoxy-5-(2,3-dibromopropyl)coumarins [6-8], 6-(2'-oxocyclohexyloxy)coumarins [9], 6-(2-propynyl-
oxy)coumarins [10, 11], 5-acyl-6-carboxymethoxycoumarins [7], or 5-(2,2-dimethoxyethyl)-6-methoxymethyl-
oxycoumarins [12] are known. Annelation of the coumarin ring to benzofuran derivatives by cyclization of ortho-
acylhydroxybenzofurans or their esters occurs under conditions of the Perkin [8, 13], Knoevenagel [1, 14-16], or
Wittig reactions [10, 17].
Starting from the knowledge that derivatives of 3-ethoxycarbonyl-5-hydroxy-2-methyl-1-benzofuran
(1a) [18] and 3-ethoxycarbonyl-5-hydroxy-2-phenyl-1-benzofuran (1c) are used as the pharmaceutical
preparations benzofurocaine and phenicaberan [20], the objective of our investigation was the synthesis of
isopseudopsoralen derivatives containing 2-R-3-alkoxycarbonyl-5-hydroxybenzofuran units.
_______
*Dedicated to the glorious memory of Academician M. O. Lozinskii.
**To whom correspondence should be addressed, e-mail: mfras@i.kiev.ua.
1Institute of Bioorganic and Petrochemistry, National Academy of Sciences of Ukraine, 1 Murmanska St., Kyiv
02094, Ukraine.
2National University of Food Technology, 68 Volodymyrska St., Kyiv 01601, Ukraine.
3Taras Shevchenko Kyiv National University, 64 Volodymyrska St., Kyiv 01033, Ukraine.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, 1402-1410, September, 2011
Original article submitted February 6, 2011.
0009-3122/11/4709-1155©2011 Springer Science+Business Media, Inc.
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To obtain the starting ortho-hydroxy aldehydes we chose the Duff reaction in the series 3-alkoxy-
carbonyl-5-hydroxybenzofurans 1a-c. As it turned out Duff formylation of compound 1a proceeded with
formation the 4-formyl derivative 2a in low yield, since the various side processes lowered the yield
considerably and made the purification of the required aldehyde difficult (Table 1).
Introduction of the 3-alkoxycarbonyl-5-methoxy-2-methylbenzofurans 1d,e into the Duff reaction led to
1
the formation of the 6-formyl derivatives 2d,e, the structures of which were confirmed by H NMR
spectroscopy. The signals of the protons H-4 and H-7 of compounds 2d,e appeared as singlets which confirmed
the formation of the 6-formyl derivatives.
Bromination of compounds 1a-c with dioxane dibromide led exclusively to the 6-bromo derivatives
1f-h, and subsequent formylation by the Duff reaction occurred at position 4 with high yields of the aldehydes
2f-h (Table 1).
1
In the H NMR spectra of compounds 2a,f-h the signal of H-4 of the benzofuran ring was absent,
whereas the signal of the proton H-7 was observed as a doublet with a coupling constant of 9.0 Hz for
compound 2a or as a singlet for compounds 2f-h (Table 2).
O
O
O
OR1
R
OR1
R
Urotropine,
CF3CO2H
R2O
HO
R3
(1a)
O
O
2a,f–h
1a–e
Dioxane · Br2
Urotropine,
CF3CO2H
Urotropine,
CF3CO2H
(1d,e)
(1a–c)
O
O
OR1
R
OR1
Me
HO
Br
MeO
O
O
O
2d,e
1f–h
1a,b,d–g, 2a,f,g R = Me; 1c,h, 2h R = Ph; 1a,c,d,f,h, 2a,d,f,h R1 = Et;
1b,e,g, 2e,g R1 = Me; 1a–c R2 = H, d,e R2 = Me; 2a R3 = H, f–h R3 = Br
For the synthesis of derivatives of isopseudopsoralen, containing the 3-alkoxycarbonylbenzofuran group
we used aldehydes 2a,f-h.
For example, we introduced 4-formyl-5-hydroxybenzofuran 2f into the Knoevenagel condensation with
ethyl acylacetates. As a result of the subsequent intramolecular cyclization the substituted 8-acylfuro[3,2-f]-
coumarins 3a-c were synthesized. Under analogous conditions the aldehydes 2a,f-h and 2-hetarylacetonitriles
were introduced into the Knoevenagel reaction with subsequent intramolecular cyclization that led to the
formation of 7-iminofuro[3,2-f]coumarins, acid hydrolysis of which gave 8-hetarylfuro[3,2-f]coumarins 4a-j.
By this method, we have synthesized derivatives of isopseudopsoralen with various heterocyclic groups in
position 8 – 2-benzothiazole (4a,b), 2-benzimidazole (4c), 2-benzoxazole (4d), 2-(4-aryl)thiazole (4e-g), 2-pyri-
dine (4h), 2-quinoline (4i), and 2-furan (4j).
1
A characteristic of the H NMR spectra of compounds 3a-c and 4a-j is the presence of the weak field
peak of the proton H-9 of the furo[2,3-f]coumarin ring at 9.52-11.03 ppm (Table 3). It is known that the signal
of proton H-4 of 3-hetarylcoumarins is observed at 8.40-9.20 ppm [21]. This abnormal values of the chemical
shift can be explained by the proximity of proton H-9 and the anisotropic 1-alkyloxycarbonyl group in
compounds 3a-c and 4a-j.
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R4
O
R4COCH2CO2Et
O
2a,f–h
8
CO2Et
(2f)
O
1
Me
4
1) HetCH2CN,
2) H+
O
Br
3a–c
X
O
NH
O
CO2R1
R
R6
R5
R3
O
4a–d
N
S
O
CO2Et
O
(2f)
Me
O
Br
Het
4e–g
O
CO2Et
O
Me
O
Br
(2f)
4h–j
3a R4 = Me, b R4 = Et, c R4 = Pr; 4a R = Me, R1 = Et, R3 = H, X = S; 4b R = Ph,
R1 = Et, R3 = Br, X = S; 4c R = R1 = Me, R3 = Br, X = NH; 4d R = Me, R1 = Et,
R3 = Br, X = O, e R5 = NO2, R6 = H; 4f R5 = H, R6 = OMe; 4g R5 + R6 = OCH2O;
4h Het = 2-Py; 4i Het = 2-quinolinyl; 4j 5-ethoxycarbonyl-2-furyl
So we have studied the formylation and bromination of 2-substituted 3-alkoxycarbonyl-5-hydroxy-
benzofurans. It is shown that bromination of 2,3-disubstituted 5-hydroxybenzofurans with dioxane dibromide
occurs at position 6, whereas Duff formylation occurs at positions 4 and 6 of the benzofuran ring of 5-hydroxy
and 5-methoxy derivatives respectively. The desired furo[3,2-f]coumarins with acyl and hetaryl substituents in
position 8 were obtained by the interaction of the synthesized 4-formyl-5-hydroxybenzofurans with ethyl
acetoacetate derivatives and hetarylacetonitriles.
EXPERIMENTAL
1H NMR spectra were recorded in DMSO-d6 (compounds 1b,d-h, 2a,d-g, 3a-d, 4a,d,f-i) or CF3CO2D
solutions (compounds 4b,c,e,j) with TMS as internal standard on a Varian VXR 300 (300 MHz) instrument.
Mixtures of 9:1 and 19:1 chloroform−methanol were used as eluents. Benzofuran derivative 1b was synthesized
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by a known method [18], and its 5-methoxy derivative 1e was synthesized analogously to compound 1d [22].
Melting points were measured in a sealed capillary with a Buchi B-535 instrument. Monitoring of the course of
reactions and purity of the compounds synthesized was by TLC on Silufol UV-254 and Merck 60 F254 plates.
6-Bromo-5-hydroxy-1-benzofuran-3-carboxylates 1f-h (General Method). To a solution of benzo-
furan 1-c (100 mmol) in a minimum amount of dioxane, a solution of bromine (105 mmol) in dioxane (100 ml)
was added in one amount and the mixture was kept for 30 min. The reaction mixture was poured into iced water
(500 ml), the precipitate was filtered off and purified by recrystallization from ethanol.
4- and 6-Formyl-1-benzofuran-3-carboxylates 2a,d-h (General Method). A mixture of compound
1a,d-h (10 mmol) and urotropine (15 mol) in trifluoroacetic acid (25 ml) was boiled for 6-8 h. The reaction
mixture was diluted with water (100 ml), the precipitate was filtered off and recrystallized from methanol.
Ethyl 8-Acyl-5-bromo-2-methyl-7-oxo-7H-furo[3,2-f]chromene-1-carboxylates 3a-c (General
Method). Aldehyde 2f (5 mmol) was dissolved in a minimum amount of ethanol at 40-50°C and ethyl
acylacetate (7.5 mmol) and piperidine (0.1 ml) were added. The reaction mixture was boiled for 4-6 h
(completion of the reaction was determined by TLC), cooled to room temperature, the precipitate was filtered
off and recrystallized from ethanol.
8-Hetaryl-7-oxo-7H-furo[3,2-f]chromene-1-carboxylates 4a-j (General Method). The corresponding
substituted 4-formyl-5-hydroxy-1-benzofuran 1a,f-h (3 mmol) and hetarylacetonitrile (3 mmol) were dissolved
in the minimum amount of ethanol at 40-50°C and 2 drops of piperidine were added. The reaction mixture was
kept for 24 h at room temperature, the precipitate of 2-iminocoumarin was filtered off and washed with ethanol.
The residue was transferred to water (50 ml) containing conc. H2SO4 (0.5-1 ml), boiled for 2-3 h to hydrolyze
the 2-imino group, after which the precipitate was filtered off, dried, and recrystallized from DMF (compounds
4a-g) or a mixture of DMF and 2-propanol (compounds 4h,j)
REFERENCES
1.
2.
G. A. Kuznetsova, Natural Coumarins and Furocoumarins [in Russian], Nauka, Leningrad, 1967.
A. M. A. G. Oliveira, M. M. M. Raposo, A. M. F. Oliveira-Campos, A. E. H. Machado, P. Puapairoj,
M. Pedro, M. S. J. Nascimento, C. Portela, C. Afonso, and M. Pinto, Eur. J. Med. Chem., 41, 367
(2006).
3.
4.
A. Chilin, C. Marzano, A. Guiotto, P. Manzini, F. Baccichetti, F. Carlassare, and F. Bordin, J. Med.
Chem., 42, 2936 (1999).
A. Guiotto, P. Manzini, A. Chilin, G. Pastorini, and P. Rodighiero, J. Heterocycl. Chem., 22, 649
(1985).
5.
6.
7.
8.
K. C. Majumdar and P. Chatterjee, Synth. Commun, 28, 3633 (1998).
S. M. Desai and K. N. Trivedi, Indian J. Chem., 24B, 47 (1985).
P. Rodighiero, A. Chilin, and A. Guiotto, Gazz. Chim.. Ital., 114, 509 (1984).
K. D. Kaufman, J. F. W. Keanu, R. C. Kelly, D. W. McBride, and G. Slump, J. Org. Chem., 27, 2567
(1962).
9.
P. Rodighiero, M. Palumbo, S. Marciani Magno, P. Manzini, O. Gia, R. Pirro, and A. Guiotto,
J. Heterocycl. Chem., 23, 1405 (1986).
10.
H. Ishii, T. Ishikawa, H. Wada, H. Miyazaki, Y. Kaneko, and T. Harayana, Chem. Pharm. Bull., 40,
2614 (1992).
11.
12.
13.
14.
C. P. Rao, A. Prashant, and G. L. D. Krupadanam, Indian J. Chem., 33B, 593 (1994).
T. Harayama and Y. Nishita, Chem Pharm. Bull., 44, 2986 (1996).
W. Limontschew and O. Dischendorfer, Monatsh. Chem., 81, 737 (1950).
G. Bastian, L. Rene, J.-P. Buisson, R. Royer, D. Averbeck, and S. Averbeck Eur. J. Med. Chem., 16,
563 (1981).
1162

15.
16.
F. Rouessac and A. Leclerc, Synth. Commun., 23, 2709 (1993).
A. M. A. G. Oliveira, M. M. M. Raposo, A. M. F. Oliveira-Campos, J. Griffiths, and A. E. H. Machado,
Helv. Chim. Acta, 86, 2900 (2003).
17.
18.
19.
20.
21.
H. Ishii, Y. Kaneko, H. Miyazaki, and T. Harayama, Chem. Pharm. Bull., 39, 3100 (1991).
E. Bernatek and T. Ledaal, Acta Chem. Scand., 2053 (1958).
A. N. Grinev and N. K. Venevtseva, Zh. Obshch. Chem., 33, 820 (1963).
N. D. Mashkovskii, Drugs [in Russian],Torsing, Kharkiv (1977).
O. V. Khilya, M. S. Frasinyuk, A. V. Turov, and V. P. Khilya, Khim. Geterotsikl. Soed., 1120 (2001).
[Chem. Heterocycl. Comp., 37, 1029 (2001)].
22.
H. L. McPherson and B. W. Ponder, J. Heterocycl. Chem., 15, 43 (1978).
1163