Microwave-Assisted Preparation of Benzo[b]furans under Solventless
Phase-Transfer
Catalytic Conditions
Dariusz Bogdal* and Marek Warzala
Department of Chemistry, Politechnika Krakowska, ul. Warszawska 24, 31-155 Krakow, Poland. Tel./Fax: +48 12 634-24-25, e-mail: pcbogdal@cyf-kr.edu.pl
Abstract: Condensation of salicylaldehyde and its derivatives with various esters of
chloroacetic acids in the presence of tetrabutylammonium bromide (TBAB) leads to the synthesis of benzo[b]furans by a solventless phase-transfer catalytic (PTC) reaction under microwave irradiation.
Keywords: microwave, benzofurans, condensation, phase-transfer catalysis
Benzofuran derivatives are nowadays an important class of organic compounds that occur in a great number of natural products [1], are used in cosmetics [2] and are used as synthetic pharmaceuticals [3]. Moreover, benzo[b]furans are building blocks for optical brighteners and are applied, for example, in combination with benzimidazoles as biphenyl end groups [4]. Many of the natural benzo[b]furans have physiological, pharmacological and toxic properties, and as a result there is continuing interest in their chemical synthesis [5].
Cyclization reactions of various types have been used to produce substituted benzo[b]furans [6,7]. In the present paper, we report on the modification of one of the most popular routes to substituted benzo[b]furans, i.e. O-alkylation of o-hydroxylated aromatic carbonyl compounds with a-halogenated carbonyl compounds, followed by intramolecular cyclization. The reactions are usually catalyzed by potassium carbonate in acetone or by potassium hydroxide in ethanol [8].
RESULT AND DISCUSSION
The use of inorganic solid materials for the
support of organic reactants and catalysts has been broadly exemplified and
well established as an environmental benign technology [9]. In recent years, it
has been shown that microwave irradiation is of particular benefit for such
reactions, particularly for these reactions carried out in the absence of solvents
[10]. The solventless reactions offer a number of advantages: solvents are
often expensive, toxic, and difficult to remove in the case of aprotic solvents
with high boiling points. Moreover, the absence of solvent reduces the risk of
an explosion when the reaction takes place in a microwave oven, and
liquid-liquid extraction can be avoided in the isolation of reaction products.
At present, the reactions under solid-liquid phase-transfer
catalytic (PTC) conditions which are specially useful for anionic
activation processes are numbered among the ‘dry’
reactions [11].
Recently, it has been
shown that under microwave irradiation in dry media a number alcohols
and phenols could be easily O-alkylated [12], and aromatic aldehydes could
undergo condensation [13] and cyclocondensation reactions [14]. Since, more
recently, Varma et al. have reported the preparation of 2-aroylbenzo[b]furans
using microwave irradiation to drive
the condensation of a-tosyloxyketones with
salicylaldehyde derivatives on potassium fluoride doped alumina [15], we have
been prompted to present our results on the synthesis of benzo[b]furans under solid-liquid phase-transfer catalytic (PTC) conditions (Scheme 1).
Scheme 1
In a typical experiment, the reactions were
carried out by simply mixing a salicylaldehyde derivative with a two fold
excess of a chloroacetic acid ester and a catalytic amount of
tetrabutylammonium bromide (TBAB). The mixtures were adsorbed on potassium carbonate, then irradiated in an open vessel in a
domestic microwave oven for 8-10 min. The results and conditions of the
reactions are summarized in Table 1.
We found that the shape and size of the
reaction vessel are important factors for microwave heating, the preferred
reaction vessel was a conical flask of much larger capacity than the volume of
the reaction mixture, bearing a loose
cotton cover. Due to difficulties with adjusting temperature in a domestic microwave oven, one of the best
solutions is to repeat an experiment a couple of times increasing the power slowly so that vapors do not escape
the flask. Furthermore, at the end of such an experiment, temperature can be
measured with a thermocouple.
Table 1. Results and conditions of the synthesis of benzo[b]furans derivatives 3a-i and 5a-ca).
|
Product |
Number |
Time [min] |
Powerb) [W] |
Temp.c) [°C] |
Yieldd) [%] |
|
|
3a |
8 |
175 |
175 |
65 |
|
|
3b |
8 |
250 |
145 |
68 |
|
|
3c |
8 |
250 |
138 |
82 |
|
|
3d |
10 |
160 |
120 |
85 |
|
|
3e |
10 |
160 |
245 |
91 |
|
|
3f |
10 |
160 |
245 |
72 |
|
|
3g |
10 |
250 |
175 |
96 |
|
|
3h |
8 |
300 |
175 |
78 |
|
|
3i |
10 |
160 |
148 |
88 |
|
|
5a |
8 |
250 |
191 |
69 |
|
|
5b |
10 |
160 |
140 |
79 |
|
|
5c |
8 |
300 |
162 |
94 |
a) in all the reaction under microwave
irradiation full conversions of aromatic aldehydes were achieved; under
conventional conditions (oil bath) full conversion of an aldehyde was usually
observed after 3 h; b) the reactions were carried out in a Philips
household microwave oven with maximum power 900 W which was reduced to the
range 175-300W; c) the final temperature of the reaction mixture
measured with a thermocouple after the completion; d) the final
yield after product separation.
CONCLUSION
In conclusion, we
have described a highly efficient microwave-induced procedure for the preparation
of various benzo[b]furan derivatives, that occurs remarkably fast, under mild
conditions, using inexpensive reagents and a household microwave oven as the
irradiation source. The advantages of this environmentally benign
and safe protocol include a simple reaction set-up, application of commercially
available reagents and catalysts, high
product yields, short reaction times as well as the elimination of solvents.
EXPERIMENTAL
General methods: Elemental analyses were performed on a Perkin-Elmer 2400 microanalyzer. Melting points, measured on a Boetius-PHMK 05 microscope plates, are uncorrected. The progress of reactions was monitored by a gas chromatography (GC) 5890 Hewlett-Packard coupled with a mass detection (MS) 5971 Hewlett-Packard. 1H-NMR spectra were recorded with a TESLA 487 C spectrometer, TMS being used as a internal standard; the chemical shifts are expressed in d values downfield from TMS. Multiplicities are recorded as s (single), d (doublet), t (triplet), dt (doublet of triplet , and m (multiplet). IR spectra were obtained on a Bio-Rad FT-IR spectrophotometer FTS 165, and the wave numbers were given with a precision of 2 cm-1. Silica gel column chromatography was performed with Fluka Kieselgel 60, using mixtures of cyclohexane and methylene chloride as eluants.
Starting materials: Allyl and cycloheksyl chloracetates were prepared by the standard esterification method from chloracetic acid and allyl alcohol and cyclohexanol, respectively. All other reagent were purchased from Aldrich and used as received.
Standard Procedure for the preparation of benzo[b]furan derivatives: Potassium carbonate (2.70g, 20mmol), TBAB (0.16g, 0.50mmol), and a salicylaldehyde derivative (5.0mmol) were thoroughly mixed and placed in an open conical, glass flask. Then a chloroacetate ester (10mmol) was added dropwise, the mixture was thoroughly stirred with a spatula for a few seconds, placed in a domestic microwave oven, and irradiated for 8-10 min (Table 1). The final temperature of the reaction mixture was measured with a termocouple at the end of the reaction. Upon completion of the reaction, monitored by GC/MS, the mixture was extracted with methylene chloride, and the solvent was then removed. A crude product was purified by column chromatography.
Ethyl 2-benzo[b]furancarboxylate (3a). Colourless oil, nD20-1.5503; [Found: C, 69.24; H, 5.08 C11H10O3 requires C, 69.46; H, 5.29%]; nmax(liquid film) 2983(m), 1731(s), 1614(w), 1447(m), 1370(m), 1329 (w), 1297(s), 1259(m), 1225(m), 1210(m), 1181(s), 1146(m), 1020(m), 946(w), 888(w), 840(w), 750(s) cm-1; dH (80 MHz CDCl3) 7.66-6.91 (5H, m aromatic protons), 4.37 (2H, k, J 7.1 Hz, CH2-Me), 1.35 (3H, t, J 7.1 Hz, CH2-Me); m/z (70eV) 191 ((M+1)+, 11), 190 (M+, 82), 162 (83), 145 (100), 118 (27), 89 (34), 63 (14 %).
Ethyl methoxy-2-benzo[b]furancarboxylate (3b). White solid, m.p. 73-75°C; [Found: C, 65.31; H, 5.51 C12H12O4 requires C, 65.49; H, 5.49%]; nmax(KBr) 1711(s), 1621(m), 1578(m), 1494(m), 1370(m), 1327(m), 1272(m), 1227(m), 1195(m), 1091(m), 1057(m), 1027(m), 974(s), 942(s), 857(s), 781(s), 761(s), 733(s), 703(m), 624(m), 574(w), 537(s) cm-1; dH (80 MHz CDCl3) 7.51-6.91 (4H, m aromatic protons), 4.43 (2H, k, J 7.0 Hz, CH2-Me), 4.02 (3H, s, OMe) 1.42 (3H, t, J 7.1 Hz, CH2-Me); m/z (70eV) 221 ((M+1)+, 13), 220 (M+, 100), 193 (7.5), 192 (66), 175 (33), 149 (11 %).
Ethyl 6-diethylamino-2-benzo[b]furancarboxylate (3c). Red oil, nD20-1.6163; [Found: C, 68.69 ; H, 7.29; N, 5.38 C15H19NO3 requires C, 68.95; H, 7.33; N, 5.36%]; nmax(liquid film) 2973(s), 2931(m), 2899(m), 2872(w), 1716(s), 1626(s), 1578(m), 1556(m), 1509(s), 1398(m), 1372(s), 1357(m), 1303(m), 1270(s),1241(s), 1180(s), 1120(s), 1095(m), 1017(m), 844(w), 795(m), 759(m) cm-1; dH (80 MHz CDCl3) 7.49-7.26 (2H, m, aromatic protons), 6.77-6.40 (2H, m aromatic protons), 4.40 (2H, k, J 7.0 Hz, CH2-Me), 3.40 (4H, k, J 7.1 Hz, CH2Me) 1.40 (3H, t, J 7.2 Hz, CH2-Me), 1.19 (6H, t, J 7.0 Hz, NCH2Me); m/z (70eV) 261 (M+, 42), 247 (16), 246 (100), 218 (23), 190 (10), 116 (6.7 %).
Allyl 2-benzo[b]furancarboxylate(3d). White
solid, m.p. 82-83 °C; [Found: C, 71.05; H, 4.92 C12H10O3
requires C, 71.28; H, 4.98%]; nmax(KBr) 3086(w), 2943(w),
1731(s), 1564(m), 1447(m), 1368(m), 1297(s), 1259(w), 1222(m), 1210(w),
1178(s), 1145(m), 1096(m), 977(m), 936(m), 885(w), 835(w), 750(s) cm-1;
dH (80 MHz CDCl3) 7.74-7.26 (5H, m,
aromatic protons), 6.35 – 5.85 (1H, m, CH2-CH=CH2),
5.65 – 5.26 (2H, m, CH2-CH=CH2), 4.88 (2H, dt, J 7.0 1.2 Hz, CH2-CH=CH2);
m/z (70eV) 203 ((M+1)+, 4.5), 202 (M+, 33), 158 (8.7),
157(9.4), 146(11), 145 (100), 131 (7.4), 118 (17.8), 89 (32), 63 (16 %).
Allyl 7-methoxy-2-benzo[b]furancarboxylate(3e). Colourless oil, nD20-1.5107; [Found: C, 67.48; H, 5.29 C13H12O4 requires C, 67.24; H, 5.21%]; nmax(KBr) 2942(w), 1731(s), 1622(w), 1594(m), 1577(m), 1492(s), 1325(w), 1302(m), 1272(m), 1227(w), 1185(s), 1094(s), 974(m), 779(m), 731(m) cm-1; dH (80 MHz CDCl3) 7.57 – 6.97 (4H, m, aromatic protons), 6.40 - 5.77 (1H, m, CH2-CH=CH2), 5,52-5,15(2H, m, CH-CH=CH2), 4.88 (2H, dt, J 5.4, 1.2 Hz, CH2-CH=CH2), 4.02(3H, s, OMe); m/z (70eV) 233 ((M+1)+, 12), 232 (M+, 85), 175 (100), 148 (18), 119 (12), 89(11%).
Allyl 6-Diethylamino-2-benzo[b]furancarboxylate (3f). Red oil; nD20-1.6228; [Found: C, 70.21; H, 7.02; N, 5.14 C16H19NO3 requires C, 70.31; H, 7.01; N, 5.12%]; nmax(KBr) 3086(w), 2973(m), 1719(s), 1626(s), 1577(w), 1554(m), 1510(s), 1356(m), 1304(m), 1270(s), 1240(s), 1175(s), 1121(s), 978(m), 793(m), 758(m) cm-1; dH (80 MHz CDCl3) 7.50-7.02 (2H, m, aromatic protons), 6.78-6.69 (2H, m, aromatic protons), 6.40-5.84 (1H, m, CH2-CH=CH2), 5,54-5.32 (2H, m, CH=CH2), 4.84 (2H, dt, J 5.4, 1.3 Hz, CH2-CH=CH2), 3.41 (4H, k, J 7.0 Hz, CH2-CH3), 1.20 (6H, t, J 7.0 Hz, CH2-Me); m/z (70eV) 274 ((M+1)+, 6.6), 273 (M+, 37), 259 (17), 258 (100), 230 (7.7 %).
Cyclohexyl 2-benzo[b]furancarboxylate (3g). White solid, m.p. 70–71 °C; [Found: C, 73.72; H, 6.70 C15H16O3 requires C, 73.75; H, 6.60 %]; nmax(KBr) cm-1; 2949(m), 2859(m), 1929(s), 1818(s), 1714(s), 1614(m), 1561(s), 1477(m), 1453(s), 1376(s), 1327(s), 1297(s), 1261(s), 1216(s), 1185(s), 1148(m), 1096(s), 1009(s), 954(m), 885(m), 834(m), 760(s) cm-1; dH (80 MHz CDCl3) 7.73-7.26 (5H, m, aromatic protons), 5.25-4.84 (1H, m, OCH), 2.20-0.95 (10H, m, (CH2)5 -cyclohexyl); m/z (70eV) 245 [(M+1)+, 1.8%], 244 (M+, 9.7), 163 (19), 162 (100), 89 (14 %).
Cycloheksyl 7-methoxy-2-benzo[b]furancarboxylate (3h). Colourless oil, nD20-1.5551; [Found: C, 69.68; H, 6.58 C16H18O4 requires C, 70.06; H, 6.61 %]; nmax(KBr) 2938(s), 2860(s), 1727(s), 1622(w), 1595(m), 1578(m), 1492(s), 1453(m), 1325(m), 1299(s), 1272(m), 1229(w), 1190(s), 1095(s), 1013(m), 977(w), 956(m), 842(w), 780(m), 731(m) cm-1;
dH (80 MHz CDCl3) 7.49-6.84 (4H, m, aromatic protons), 5.20-4.45 (1H, m, OCH), 4.02 (3H, s, OMe), 2.20-0.95 (10H, m, (CH2)5 cyclohexyl); m/z (70eV) 275 ((M+1)+, 5.5), 274 (M+, 28), 193 (11), 192 (100), 177 (12), 175 (9.5 %).
Cycloheksyl 6-diethylamino-2-benzo[b]furancarboxylate (3i). Red oil, nD20-1.6022 [Found: C, 72.12; H, 7.65; N, 4.08 C19H25NO3 requires C, 72.35; H, 7.99; N, 4.44 %]; nmax(KBr) 3086(w), 2970(m), 2937(s), 2861(m), 1715(s), 1627(s), 1577(m), 1556(m), 1510(s), 1450(m), 1356(m), 1324(m), 1301(m), 1270(s), 1240(s), 1179(s), 1120(s), 1093(w), 1013(m), 963(m), 842(w), 801(m), 793(m), 759(m) cm-1; dH (80 MHz CDCl3) 7.48-7.38 (2H, m aromatic protons), 6.76-6.67 (2H, m aromatic protons), 5.25-4.77 (1H, m, OCH), 3.40 (4H, k, J 7.0 Hz, 2 ´ N-CH2-CH3), 2.15-0.85 (10H, m, (CH2)5 cyclohexyl), 1.28-1.19 (6H, t, J 7.0 Hz, -CH2-Me); m/z (70eV) 316 ((M+1)+, 5.6), 315 (M+, 26), 300 (7.5), 233 (16), 219 (13), 218 (100), 190 (7.7 %).
Ethyl naphto[2,1-b]furan-2-carboxylate (5a). White solid, m.p. 85–88 °C; [Found: C, 74.71; H, 5.24 C15H12O3 requires C, 74.99; H, 5.03 %;]; nmax(KBr) 3086(w), 3060(w), 2987(m), 1728(s), 1586(m), 1552(s), 1367(m), 1326(s), 1281(m), 1224(m), 1172(s), 1124(m), 1020(s), 823(s), 803(m), 761(s), 743(m)cm-1; dH (80 MHz CDCl3) 8.23-7.59 (7H, m, aromatic protons), 4.62-4.35 (2H, k, J 7.1 Hz, CH2-Me), 1.55-1.37 (3H, t, J 7.1 Hz, -CH2-Me); m/z (70eV) 241 ((M+1)+, 16), 240 (M+, 100), 213 (12), 212 (79), 196 (6.6), 195 (27), 168 (24), 139(52);
Allyl naphto[2,1-b]furan-2-carboxylate (5b) White solid, m.p. 72–74 °C; [Found: C, 75.95; H, 4.88 C16H12O3 requires C, 76.18; H, 4.79 %;]; nmax(KBr) 3084(w), 3051(w), 2932(w), 1731(s), 1646(w), 1585(m), 1554(w), 14529w), 1378(m), 1331(m), 1283(m), 1224(m), 1175(s), 1123(m), 914(s), 873(m), 830(s), 759(s), 751(s), 562(m) cm-1; dH (80 MHz CDCl3) 8.23-7.55 (7H, m, aromatic protons), 6.28 – 5.88 (1H, m, CH2-CH=CH2), 5.60 – 5.29 (2H, m, CH2-CH=CH2), 4.97-4.42(2H, m, CH2-CH=CH2); m/z (70eV) 253 ((M+1)+, 18), 252 (M+, 100), 212 (9.8), 208 (8.8), 207 (9.0), 196 (13), 195 (86), 181(8.8), 168 (68), 139 (82 %).
Cycloheksyl naphto[2,1-b]furan-2-carboxylate (5c). White solid, m.p. 134–136 °C; [Found: C, 77.50; H, 6.16 C19H18O3 requires C, 77.53; H, 6.16 %;]; nmax(KBr) 3106(m), 3050(w), 2933(s), 2857(s), 1713(s), 1627(w), 1589(m), 1562(w), 1450(m), 1354(m), 1307(m), 1320(m), 1283(s), 1237(s), 1170(s), 1116(s), 1014(s), 990(m), 960(m), 930(m), 881(m), 827(w), 807(s), 762(m), 741(m) cm-1; dH (80 MHz CDCl3) 8.02-7.54 (7H, m, aromatic protons), 5.25-4.95 (1H, m, OCH), 2.15-1.10 (10H, m, (CH2)5 -cyclohexyl); m/z (70eV) 295 ((M+1)+, 4.7), 294 (M+, 21), 212 (100), 213 (15), 195 (9.0), 139 (21 %).
ACKNOWLEDGMENTS
This work was
undertaken as part of the EU sponsored D10 COST Program (Innovative Methods and
Techniques for Chemical Transformations).
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