pubs.acs.org/joc Note Regioselective Synthesis of Benzofuranones and Benzofurans Xiaojie Zhang and Christopher M. Beaudry* Cite This: J. Org. Chem. 2021, 86, 6931−6936 Read Online ACCESS Metrics & More Article Recommendations *sı Supporting Information ABSTRACT: Reaction of 3-hydroxy-2-pyrones with nitroalkenes bearing ester groups gives benzofuranones. The reaction allows regioselective preparation of the benzofuranones with program- mable substitution at any position. Complex substitution patterns are readily created. The substituted benzofuranones can be converted to substituted benzofurans. enzofuranones, benzofurans, and related functional groups Scheme 1. Regiochemistry in α-Phenoxy Carbonyl B appear as substructures in natural products, pharmaceut- Cyclizations icals, biologically active food chemicals, and illicit psychoactive compounds.1 For example, amiodarone (1) is a benzofuran that is a commonly prescribed medicine for cardiac arrhythmias (Figure 1).2 Fumimycin (2) is a benzofuranone cyclization, and the product (6) is formed as a single regioisomer.9 When both ortho positions are unsubstituted, Downloaded via OREGON STATE UNIV on August 4, 2021 at 17:52:12 (UTC). the sterically less-hindered product is commonly favored. For example, cyclization of 7 leads to 3,6-disubstituted benzofuran Figure 1. Medicinal benzofurans and benzofuranones. 8, and the 3,4-disubstituted congener 9 is not observed.10 In See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles. cases where steric considerations do not provide a strong natural product that displays antibiotic activity by inhibiting 11 3 preference, regiochemical mixtures are common. Cyclization the bacterial protein deformylase enzyme. Bergamottin (3)is of 10 leads to a mixture of 11 and 12 in a ratio of 53:37, a cytochrome P450 inhibitor found in citrus fruits, and it is 12 − 4 respectively. implicated in grapefruit drug interactions. Finally, 2C-B-FLY We recently discovered a new synthesis of substituted (4) is a dihydrobenzofuran bioisostere of mescaline, which was 5 phenols from 3-hydroxy-2-pyrones (13) and nitroalkenes (14, prepared for SAR investigation of the serotonin receptors, and 13 6 Scheme 2). The reaction allows for high levels of it has been used as a recreational hallucinogen. substitution, including even hexasubstituted benzenes, and The importance of biologically active benzofuran derivatives ∼ 7 very good regioselectivity (rr = 200:1). Mechanistically, a has fueled decades of research into their chemical synthesis. A Diels−Alder cycloaddition of 13 and 14 gives 15. Elimination classical and common strategy for their synthesis is shown in Scheme 1.Anα-phenoxycarbonyl compound undergoes cyclization (e.g., intramolecular Friedel−Crafts-type condensa- Received: February 10, 2021 tion) to build the five-membered furanoid ring.8 This strategy Published: April 14, 2021 exemplifies issues of regiochemical control in the formation of benzofurans and derivatives, in that it is particularly useful when the regiochemical outcome of the reaction is predictable. For example, substrate 5 has only one ortho site available for © 2021 American Chemical Society https://doi.org/10.1021/acs.joc.1c00341 6931 J. Org. Chem. 2021, 86, 6931−6936 The Journal of Organic Chemistry pubs.acs.org/joc Note Scheme 2. Diels−Alder Based Phenol and Benzofuranone Table 1. Investigation of Conditions for the Benzofuranone Syntheses Synthesis time entry reagents T (°C) (h) yield (%)a b 1 AlCl3 (10 mol %) 150 2 53 (23) + 15 (24) 2 AlCl3 (10 mol %) 150 24 45 14 of nitrous acid gives 16. Finally, retro-cycloaddition gives the 3 AlCl3 (10 mol %), TFA 150 1 42 product phenol (17). The key to this strategy is that both (10 mol %) 4 AlCl3 (10 mol %), TFA 110 24 58 coupling partners are electronically polarized. The initial (10 mol %) Diels−Alder reaction occurs with high levels of regioselectivity, 5 i. AlCl3 (10 mol %); ii. TFA 120 20 53 and it tolerates substitution in both coupling partners. We are (20 mol %) able to prepare many phenols with complete control of the 6 AlCl3 (10 mol %), TFA 120 20 64 substitution pattern. (20 mol %) We speculated that if nitroalkenes bearing a carbomethoxy- 7 PhB(OH)2 (10 mol %), TFA 120 20 55 methyl group (18) were to participate in the reaction, phenols (20 mol %) 8BFOEt (10 mol %) 120 6 52 bearing a tethered ester (19)wouldbeformed.Such 3 2 9Me2AlCl (10 mol %), TFA 100 2.5 29 (23) + nitroalkenes are conveniently prepared using standard Henry- (20 mol %) 30 (24) 15 19 type condensations of nitroalkanes. We expected phenols 10 AlCl3 (10 mol %), pTsOH 120 6 33 would cyclize to benzofuranones 20 under the reaction (20 mol %) conditions. 11 AlCl3 (10 mol %), HCl (1 equiv) 150 1.5 32 Our investigations began with unsubstituted 3-hydroxy-2- 12 AlCl3 (10 mol %), Cl3CCO2H 150 3 35 pyrone (21) and nitroalkene 22 (Table 1). Conditions (20 mol %) 13 13 AlCl3 (10 mol %), TFA 120 27 19 previously reported for our substituted phenol synthesis (20 mol %), 4 Å MS (entry 1) promoted the desired reaction, giving phenol 23 in c 14 AlCl3 (10 mol %), TFA 120 20 64 53% yield and the desired benzofuranone product 24 in 15% (20 mol %) yield. Allowing the reaction to proceed until there was aIsolated % yield of 24, unless otherwise noted. bo-DCB (0.5 M). complete consumption of starting materials 21, 22, and phenol cBuCN (0.3 M) was used as the solvent. intermediate 23 (TLC check) gave benzofuranone 24 in 45% yield (entry 2). Apart from the desired product (24), a in an attempt to sequester the methanol byproduct gave a multitude of minor products were present, but all were ff ∼ substantially decreased yield (entry 13). Finally, di erent produced in less than 5% yield, and we were not able to solvents were evaluated but did not change the chemical yield determine their structure. fi of the reaction (entry 14). We were somewhat surprised to nd that the formation of The benzofuranone synthesis was then evaluated with other phenol 23 was faster than its conversion to benzofuranone 24 substrate combinations to explore the tolerance of the reaction under the conditions in entries 1 and 2. In a control to substitution (Scheme 3). A variety of 4-substituted-3- experiment, we found that isolation and subjection of phenol 1 ≠ ffi fl hydroxy-2-pyrones (13,R H) were e ciently converted to 23 to tri uoroacetic acid (TFA) rapidly gave 24 in 70% yield substituted benzofuranones 20. Methyl (25), branched alkyl (see Supporting Information). Combining 21 and 22 with (26), and phenyl groups (27) were all well tolerated. Pyrones both the AlCl3 Lewis acid and TFA protic acid markedly increased the rate of benzofuranone production (entry 3). Scheme 3. Regioselective Syntheses of Benzofuranones Lowering the reaction temperature gave a slightly increased chemical yield of 24 (entry 4). Conducting the Diels−Alder- based cascade first with subsequent addition of TFA after consumption of 21 and 22 did not lead to improved yields (entry 5). Finally, conducting the reaction at 120 °C with 20 mol % of TFA gave an optimal yield of benzofuranone 24 (entry 6). The benzofuranone synthesis was also evaluated using a variety of different Lewis acids. Boronic acids (entry 7), boron trifluoride (entry 8), and other aluminum Lewis acids (entry 9) all successfully promoted the reaction; however, the overall chemical yield was not improved. The protic acid used to affect ring closure was also varied. Toluenesulfonic acid (entry 10), hydrochloric acid (entry 11), and other weak acids such as trichloroacetic acid were evaluated (entry 12), but none of these acids gave superior results. Addition of molecular sieves 6932 https://doi.org/10.1021/acs.joc.1c00341 J. Org. Chem. 2021, 86, 6931−6936 The Journal of Organic Chemistry pubs.acs.org/joc Note with multiple substitution also participated in the reaction. 5,6- (heated oil or cryogenic solvent) bath temperatures were used to Disubstituted benzofuran 28 was prepared in moderate yield; record all reaction temperatures. Flash column chromatography however, note that this type of benzofuran is difficult to (FCC) was carried out with SiliaFlash P60, 60 Å silica gel. Reactions prepare as a single regioisomer using standard condensation and column chromatography were monitored with EMD silica gel 60 conditions. Trisubstituted benzofuranones 29, 30, and 31 were F254 plates and visualized with potassium permanganate stain. Reagent grade 1,4-dioxane was dried over CaH and distilled prior to all prepared in synthetically useful yields. Finally, 4,7- 2 ff use. 1,2-Dichlorobenzene (DCB) was distilled under reduced pressure disubstituted benzofurans bearing methyl groups (32), di er- and degassed using three freeze−pump−thaw cycles. Tetrahydrofuran ent alkyl groups (33), and electron-withdrawing groups (34) (THF), toluene, and benzene were dried by passage through activated were also prepared using our method. alumina columns. All other reagents and solvents were used without An advantage of preparing benzofuranones is that they are further purification from commercial sources. Unless otherwise noted, conveniently transformed into substituted benzofurans. For melting points were obtained from material that solidified after example, 34 can be olefinated under standard Wittig chromatography. conditions to give 2,4,7-trisubstituted benzofuran 35 (Scheme Instrumentation: FT-IR spectra were obtained on NaCl plates with 4).16 Benzofuran 34 can also be converted to the a PerkinElmer Spectrum Vision spectrometer. HRMS were recorded on a JEOL MS Route Magnetic Sector Instrument (EI) or a Waters Synapt HDMS TOF instrument (ESI). Proton and carbon NMR Scheme 4. Synthesis of Substiuted Benzofurans spectra (1H NMR and 13C NMR) were recorded in deuterated chloroform (CDCl3) unless otherwise noted on a Bruker 700 MHz Avance III Spectrometer with carbon-optimized cryoprobe or Bruker 400 MHz DPX-400 spectrometer. Multiplicities are abbreviated as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet. Melting points were determined with a Cole-Parmer instrument and are uncorrected.