Effective Synthesis of 3-(2-Furyl)Phthalides under the Friedel-Crafts Reaction Conditions

Full text of DOI:10.1007/s10593-015-1649-x

DOI 10.1007/s10593-015-1649-x
Chemistry of Heterocyclic Compounds, Vol. 50, No. 12, March, 2015 (Russian Original Vol. 50, No. 12, December, 2014)
LETTERS TO THE EDITOR
EFFECTIVE SYNTHESIS OF 3-(2-FURYL)PHTHALIDES UNDER
THE FRIEDEL–CRAFTS REACTION CONDITIONS
P. M. Shpuntov1, V. A. Shcherbinin1, and A. V. Butin1,2
*
Keywords: 2-formylbenzoic acids, furans, 3-(2-furyl)phthalides, condensation, Friedel–Crafts reaction.
3-(2-Furyl)phthalides, or 3-(2-furyl)-2-benzofuran-1(3Н)-ones, are key starting materials for the
synthesis of 2-(2-carboxybenzyl)furans [1], which can be used for the preparation of a whole range of
biologically active heterocyclic systems. In particular, such compounds include the natural naphtho[2,3-b]furan-
4,9-diones [2] possessing cytotoxic and antiparasitic activity [3], as well as isocoumarin [4], isoquinolone [5]
and pyridazinoisoquinolone [6] derivatives. The majority of currently known methods for the syntesis of
3-(2-furyl)phthalides are based on directed ortho-metalation of benzamides, achieved by the use of expensive
organometallic reagents at low temperatures (down to -78°С) and under inert atmosphere [2, 7]. These
limitations and the associated need for specific laboratory equipment present an obstacle to the wide use of
3-(2-furyl)phthalides in organic synthesis.
At the same time, it is known that 3-(aryl)phthalides can be obtained by condensation of 2-formyl-
benzoic acids and arenes under the Friedel–Crafts reaction conditions [8-10], and 3-(3-indolyl)phthalides are
synthesized similarly [11].
Previously, we have observed that synthesis of aryldifurylmethanes 4 by condensation of 2-formyl-
benzoic acids 1 with 2-(tert-butyl)furan (2d) in dioxane in the presence of HClO4 gave also 3-(2-furyl)-
phthalides 3 with 20-35% yields as by-products [12]. Addition of water to the reaction mixture (12% of the
solvent volume) allowed to increase the yields of phthalides up to 35-40%. 3-(2-Furyl)phthalides were also
successfully prepared starting from 2-methylfuran (2b), but the product yields did not exceed 25% in this case
[13].
In the current study, we found that using water as solvent and hydrochloric acid as catalyst in
combination with milder reaction conditions (room temperature) directed the process mainly towards the
formation of 3-(2-furyl)phthalides 3. Insignificant amounts (no more than 10%) of aryldifurylmethanes 4 were
formed as by-products [12], except for the reaction between 2-formylbenzoic acid (1a) and furan (2a), in which
case the formation of an insignificant amount of tarry products in the reaction mixture was observed, while the
product 4a was not detected at all.
______
*To whom correspondence should be addressed, e-mail: pasfreak@hotmail.com.
1Kuban State Technological University, 2 Moskovskaya St., Krasnodar 350072, Russia.
2Perm State National Research University, 15 Bukireva St., Perm 614990, Russia; е-mail:
alexander_butin@mail.ru.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1920-1923, December, 2014.
Original article submitted November 3, 2014.
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0009-3122/15/5012-1768©2015 Springer Science+Business Media New York

R
COOH
CHO
O
COOH
R
R
H2O, HCl
dioxane
O
R1
1a–d
O
+
+
room temp.
5–7 days
O
O
R1
R1
4a–g
(0–10%)
R1
O
2a–d
3a–g
1 a R = H, b R = Cl, c R = Br, d R = I; 2 a R1 = H, b R1 = Me, c R1 = Et, d R1 = t-Bu;
3, 4 a–d R = H, e R = Cl, f R = Br, g R = I; a R1 = H, b R1 = Me, c R1 = Et, d R1 = t-Bu, e–g R1 = Me
Although water was an acceptable solvent for unsubstituted 2-formylbenzoic acid (1a), substituted
2-formylbenzoic acids 1b-d were poorly soluble in water. Hence, the addition of a small amount of an organic
solvent was essential, otherwise the reaction time increased significantly. A series of experiments with various
solvents allowed to conclude that use of a 5:1 water–dioxane mixture facilitates better dissolution of the starting
acids and practically does not affect the target product yields. We should note that these conditions were also
suitable for the acid 1a.
Taking into account the lower reactivity of furan (2а) and 2-tert-butylfuran (2d) compared to 2-methyl-
furan (2b) and 2-ethylfuran (2с), achieving acceptable yields of reaction products required the use of more
hydrochloric acid in this case. The structures of compounds 3а-g were fully confirmed by spectral methods and
elemental analysis.
Despite the prolonged reaction time, our method enables the preparation of 3-(2-furyl)phthalides in
good yields, it is technologically convenient, does not require specific conditions and can be performed on
industrial scale.
IR spectra were recorded on a Perkin Elmer Spectrum Two instrument with ATR accessory. 1Н and 13C
NMR spectra were acquired on an Agilent 400/54 spectrometer (400 and 100 MHz, respectively) in CDCl3,
1
13
with residual solvent protons as standard (7.26 ppm for H nuclei, 77.2 ppm for C nuclei). Mass spectra were
recorded on a Kratos MS-30 instrument, EI ionization (70 eV, ionization chamber temperature 200°С).
Elemental analysis was performed on a Fisons EA-1108 CHNS analyzer. Melting points were determined on an
SMP 40 apparatus. Sorbfil plates (Sorb-polimer Ltd., Krasnodar, Russia) were used for TLC, the eluent was 5:1
petroleum ether–dioxane, visualization with vanillin stain, obtained by dissolving vanillin (6 g) in EtOH
(250 ml) with added conc. H2SO4 (2.5 ml). The products were purified by chromatography on KSK silica gel
(50-160 μm, Sorb-polimer Ltd., Krasnodar, Russia). Formylbenzoic acids 1a-d were obtained according to
published methods [12].
Preparation of 3-(2-Furyl)-2-benzofuran-1(3Н)-ones 3а-g (General Method). A mixture of formyl-
benzoic acid 1а-d (2 mmol) in dioxane (2 ml) and Н2О (10 ml) was treated by adding conc. HCl (0.5 ml, or
2.5 ml in the case of reactions with furans 2a,d) and furan 2a-d (3 mmol). The reaction mixture was stirred for
5-7 days at room temperature, then neutralized with NaHCO3, extracted with EtOAc (3×10 ml), dried over
anhydrous Na2SO4, and evaporated to dryness. The residue was purified by filtration through a silica gel layer
(40 mm diameter, 35 mm thickness), eluent 1:24 EtOAс–petroleum ether. The product was recrystallized from a
1:4 mixture of CH2Cl2–petroleum ether.
3-(2-Furyl)-2-benzofuran-1(3Н)-one (3а). Yield 0.33 g (55%), colorless needles, mp 56-57°С (mp 51.8-
52.8°С (CH2Cl2–petroleum ether) [14]). IR spectrum, ν, cm-1: 1758 (С=O), 1562, 1464, 1285, 1205, 1062, 966, 944,
798, 728. 1H NMR spectrum, δ, ppm (J, Hz): 6.37 (2H, d, J = 1.2, H Fur); 6.46 (1H, s, 3-CH); 7.43 (1H, t, J = 1.2,
H Fur); 7.45-7.47 (1H, m, H Ar); 7.57-7.61 (1H, m, H Ar); 7.68-7.73 (1H, m, H Ar); 7.94-7.97 (1H, m, H Ar).
13C NMR spectrum, δ, ppm: 75.5; 110.5; 110.6; 123.0; 125.7; 126.3; 129.8; 134.2; 144.2; 146.4; 148.8; 169.8. Mass
spectrum, m/z (Irel, %): 200 [M]+ (12), 172 (20), 156 (37), 128 (60), 106 (100), 75 (32), 51 (37), 43 (13).
3-(5-Methylfuran-2-yl)-2-benzofuran-1(3Н)-one (3b). Yield 0.47 g (73%), colorless prisms,
mp 115-116°С (mp 110-111°С (CH2Cl2–petroleum ether) [13]). IR spectrum, ν, cm-1: 1753 (С=O), 1564, 1467,
1769

1286, 1209, 1066, 1011, 951, 939, 777, 730. 1H NMR spectrum, δ, ppm (J, Hz): 2.24 (3H, s, CH3); 5.94 (1H, d,
J = 3.2, H Fur); 6.23 (1H, d, J = 3.2, H Fur); 6.39 (1H, s, 3-CH); 7.43-7.46 (1H, m, H Ar); 7.55-7.60 (1H, m,
H Ar); 7.67-7.71 (1Н, m, H Ar); 7.92-7.95 (1H, m, H Ar). 13C NMR spectrum, δ, ppm: 13.5; 75.9; 106.6; 111.8;
123.0; 125.6; 126.5; 129.6; 134.1; 146.5; 146.8; 154.3; 169.9. Mass spectrum, m/z (Irel, %): 214 [M]+ (83), 170
(100), 141 (26), 133 (35), 115 (37), 106 (32), 105 (75), 77 (58), 51 (36), 49 (46), 43 (45).
3-(5-Ethylfuran-2-yl)-2-benzofuran-1(3Н)-one (3с). Yield 0.42 g (61%), colorless needles,
1
mp 88-89°С. IR spectrum, ν, cm-1: 1754 (С=O), 1554, 1469, 1285, 1187, 1069, 1022, 941, 812, 732. H NMR
spectrum, δ, ppm (J, Hz): 1.19 (3H, t, J = 7.6, СH2СH3); 2.60 (2H, q, J = 7.6, СH2СH3); 5.95 (1H, d, J = 3.2,
H Fur); 6.22 (1H, d, J = 3.2, H Fur); 6.41 (1H, s, 3-CH); 7.44-7.48 (1H, m, H Ar); 7.56-7.61 (1Н, m, H Ar);
13
7.67-7.72 (1H, m, H Ar); 7.93-7.96 (1H, m, H Ar). C NMR spectrum, δ, ppm: 11.8; 21.3; 75.9; 105.0; 111.5;
123.0; 125.6; 126.6; 129.6; 134.1; 146.5; 146.7; 160.0; 169.9. Mass spectrum, m/z (Irel, %): 228 [M]+ (80), 199
(35), 184 (28), 169 (64), 156 (40), 155 (100), 141 (32), 128 (30), 115 (74), 106 (53), 77 (30), 63 (38), 51 (73),
49 (30), 43 (55). Found, %: C 73.74; Н 5.25. С14Н12О3. Calculated, %: С 73.67; Н 5.30.
3-(5-tert-Butylfuran-2-yl)-2-benzofuran-1(3Н)-one (3d). Yield 0.61 g (79%), white powder,
mp 77-78°С (mp 73-74°С (CH2Cl2–petroleum ether) [13]). IR spectrum, ν, cm-1: 1751 (С=O), 1502, 1469,
1286, 1152, 1064, 1013, 961, 931, 731. 1H NMR spectrum, δ, ppm (J, Hz): 1.24 (9H, s, C(CH3)3); 5.92 (1H, d,
J = 3.2, H Fur); 6.14 (1H, d, J = 3.2, H Fur); 6.43 (1H, s, 3-CH); 7.47-7.50 (1H, m, H Ar); 7.56-7.61 (1Н, m,
H Ar); 7.67-7.72 (1H, m, H Ar); 7.93-7.96 (1H, m, H Ar). 13C NMR spectrum, δ, ppm: 28.9 (3С); 32.8; 76.0;
103.0; 110.9; 123.0; 125.6; 126.6; 129.6; 134.0; 146.6; 146.8; 166.3; 170.0. Mass spectrum, m/z (Irel, %): 256
[M]+ (32), 242 (27), 241 (100), 133 (41), 111 (28), 77 (28), 57 (22), 51 (20), 43 (37), 41 (33).
6-Chloro-3-(5-methylfuran-2-yl)-2-benzofuran-1(3Н)-one (3е). Yield 0.34 g (68%), colorless prisms,
mp 119-120°С. IR spectrum, ν, cm-1: 1751 (С=O), 1562, 1467, 1422, 1291, 1204, 1059, 961, 794, 755. 1H NMR
spectrum, δ, ppm (J, Hz): 2.24 (3H, s, CH3); 5.96 (1H, d, J = 3.2, H Fur); 6.27 (1H, d, J = 3.2, H Fur); 6.38 (1H,
13
s, 3-CH); 7.39 (1H, d, J = 8.0, H-4); 7.65 (1Н, dd, J = 8.0, J = 2.0, H-5); 7.90 (1H, d, J = 2.0, H-7). C NMR
spectrum, δ, ppm: 13.5; 75.8; 106.7; 112.2; 124.3; 125.6; 128.4; 134.4; 136.0; 144.7; 146.1; 154.6; 168.4. Mass
spectrum, m/z (Irel, %): 250 [M(37Cl)]+ (10), 248 [M(35Cl)]+ (30), 204 (23), 191 (12), 189 (36), 169 (72), 141
(29), 139 (31), 126 (29), 111 (62), 75 (100), 74 (53), 53 (28), 43 (28). Found, %: C 62.70; Н 3.72. С13Н9ClО3.
Calculated, %: С 62.79; Н 3.65.
6-Bromo-3-(5-methylfuran-2-yl)-2-benzofuran-1(3Н)-one (3f). Yield 0.38 g (65%), colorless prisms,
mp 150-151°С. IR spectrum, ν, cm-1: 1750 (С=O), 1562, 1471, 1417, 1289, 1203, 1078, 960, 793, 753. 1H NMR
spectrum, δ, ppm (J, Hz): 2.24 (3H, s, CH3); 5.96 (1H, d, J = 3.2, H Fur); 6.27 (1H, d, J = 3.2, H Fur); 6.35 (1H,
13
s, 3-CH); 7.33 (1H, d, J = 8.0, H-4); 7.80 (1Н, dd, J = 8.0, J = 2.0, H-5); 8.06 (1H, d, J = 2.0, H-7). C NMR
spectrum, δ, ppm: 13.5; 75.8; 106.7; 112.2; 123.7; 124.6; 128.6 (2C); 137.2; 145.2; 146.0; 154.6; 168.3. Mass
spectrum, m/z (Irel, %): 294 [M(81Br)]+ (27), 292 [M(79Br)]+ (27), 250 (32), 248 (33), 185 (31), 183 (30), 115
(52), 111 (58), 75 (47), 63 (68), 58 (58), 53 (56), 51 (100), 43 (56). Found, %: C 53.18; Н 3.15. С13Н9BrО3.
Calculated, %: С 53.27; Н 3.09.
6-Iodo-3-(5-methylfuran-2-yl)-2-benzofuran-1(3Н)-one (3g). Yield 0.43 g (64%), white powder, mp
173-174°С (mp 169-170°С (CH2Cl2–petroleum ether) [13]). IR spectrum, ν, cm-1: 1749 (С=O), 1562, 1468,
1
1410, 1285, 1202, 1073, 956, 791, 752. H NMR spectrum, δ, ppm (J, Hz): 2.24 (3H, s, CH3); 5.96 (1H, d,
J = 3.2, H Fur); 6.26 (1H, d, J = 3.2, H Fur); 6.34 (1H, s, 3-CH); 7.21 (1H, d, J = 8.0, H-4); 7.99 (1Н, dd,
J = 8.0, J = 1.2, H-5); 8.28 (1H, d, J = 1.2, H-7). 13C NMR spectrum, δ, ppm: 13.6; 75.9; 94.7; 106.7; 112.2;
124.7; 128.7; 134.7; 142.9; 145.9; 146.0; 154.6; 168.1. Mass spectrum, m/z (Irel, %): 340 [M]+ (100), 325 (21),
296 (87), 281 (27), 230 (34), 141 (26), 115 (44), 111 (31), 75 (35), 58 (24), 53 (26), 51 (24), 43 (38).
This work was supported by the Ministry of Education and Science of the Russian Federation (subsidy
2515) and the Federal Targeted Program for Research and Development in the Priority Areas of Development of the
Russian Scientific and Technological Complex for 2014-2020 (RFMEFI57714X0046).
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