Selective Syntheses of Coumarin and Benzofuran Derivatives Using Phenols and α-Methoxy-β-ketoesters

Ryo Miyata; Takashi Shigeta; Shigenori Kumazawa; Masahiro Egi

doi:10.1055/s-0042-1751408

SynOpen, Inhaltsverzeichnis

CC BY 4.0 · SynOpen 2023; 07(01): 8-16
DOI: 10.1055/s-0042-1751408

paper

Selective Syntheses of Coumarin and Benzofuran Derivatives Using Phenols and α-Methoxy-β-ketoesters

Ryo Miyata‡

,

Takashi Shigeta‡

,

Shigenori Kumazawa

,

Masahiro Egi ∗

Abstract

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Key words

coumarin - benzofuran - selective syntheses - phenol - α-methoxy-β-ketoester - α-methoxyacetophenone

Coumarins and benzofurans are widely distributed in nature and are important heterocyclic compounds in medicinal and materials chemistry.[1] Coumarins exhibit various biological activities, including antioxidant,[2] antiprotozoal,[3] and anti-HIV activities.[4] Their derivatives are used as cosmetic ingredients[5] and dispersed fluorescent dyes.[6] Benzofurans also exhibit interesting activities, including as antitumors,[7] lipid peroxidation inhibitors,[8] and non-nucleoside adenosine A₁ antagonists.[9] They are widely used as fluorescent materials, such as fluorescent organic nanoparticles.[10] Therefore, many researchers are investigating the development of efficient synthetic methods for both coumarins and benzofurans.

Scheme 1 Various synthetic methods for coumarin and benzofuran derivatives

Pechmann and Knoevenagel condensations are typical methods used for the synthesis of coumarin derivatives (Scheme [1]A).[11] [12] In recent years, new methodologies using transition metal catalysts have been developed, such as the hydroarylation of alkynes and the carbonylation of ortho-vinylphenols.[13] However, only a few studies have reported on the synthesis of 3-heteroatom-substituted coumarins.[14] The introduction of functional groups at the C3-position has attracted much attention for improving the physical properties of coumarin-based molecules and enriching the library of their derivatives.[15] Therefore, a convenient synthetic approach to 3-heteroatom-substituted coumarins is required.

Table 1 Preliminary Survey for the Synthesis of Coumarin 3a Starting from 1a and 2a

Entry	1a (equiv)	Acid (equiv)	Solvent	Temp. (°C)	Time (h)	NMR yield of 3a (%)^a	3a/4a ratio^a
1	1.1	HCl (6.0)	EtOH	rt	72	57	1:0
2	1.1	H₂SO₄ (6.0)	EtOH	rt	72	24	1:0
3	1.1	TfOH (6.0)	EtOH	rt	72	70	1:0
4	1.1	TfOH (0.1)	EtOH	90	24	22	4.4:1
5	3.0	TfOH (0.1)	EtOH	90	24	32	3.4:1
6	3.0	TfOH (0.1)	i-PrOH	90	24	28	5.8:1
7	3.0	TfOH (0.1)	DMSO	90	24	trace	–
8	3.0	TfOH (0.1)	DCE	90	24	<56	1:0
9	3.0	TfOH (0.1)	1,4-dioxane	90	24	66	3.2:1
10	3.0	HClO₄ (0.1)	1,4-dioxane	90	24	68	3.2:1

^a Determined by ¹H NMR using 1,4-dimethoxybenzene as an internal standard.

Benzofurans are often constructed by the cyclization of ortho-functionalized phenols, including phenols bearing carbon–carbon multiple bonds and salicylaldehyde derivatives.[16] For example, transition-metal-catalyzed hydroalkoxylation of ortho-alkynylphenols has been used successfully to synthesize 2-substituted benzofurans (Scheme [1]B).[17] Considering the wide availability of substrates, it is desirable to develop the reactions using simple phenols.[18] Li et al. presented the iron-catalyzed oxidative reaction of phenols with β-ketoesters to form ethyl 2-arylbenzofuran-3-carboxylates (Scheme [1]C).[19] Cossío et al. demonstrated the synthesis of 2- and 3-substituted benzofurans from phenols and α-bromoacetophenones, respectively.[20] Nonetheless, practical methods using readily available substrates are still limited. Herein, we describe the novel selective syntheses of 3-methoxy-4-arylcoumarins and 2-arylbenzofurans using phenols 1 and α-methoxy-β-ketoesters 2 (Scheme [1]D).

Using phloroglucinol (1a) and ethyl 2-methoxy-3-oxo-3-phenylpropanoate (2a) as substrates, the reaction conditions for the synthesis of 3-methoxy-4-phenylcoumarin 3a were investigated. First, 2a was synthesized by the reaction of β-ketoester with MeOH using iodobenzene diacetate.[21] The reaction of 1a with 2a was carried out in the presence of Brønsted acids, which are commonly employed in the Pechmann reaction,[22] and the desired 3-methoxycoumarin 3a was successfully obtained (Table [1], entries 1–3). Among these acids, trifluoromethanesulfonic acid (TfOH) gave the best results, affording 3a in 70% NMR yield. We aimed to use catalytic amounts of TfOH, but the yield of 3a was low, even under heating conditions (entry 4). Unexpectedly, 2-phenylbenzofuran (4a) was obtained as a byproduct.[23] While it has been reported that acid treatment of α-methoxy-β-ketoester at high temperature leads to demethoxylation to β-ketoester,[24] the reaction of 1a with 2a did not give 4-phenylcoumarin 5. To proceed with the reaction, substrate 1a was increased to 3.0 equiv and the use of various solvents was examined (entries 5–9). Polar solvents, such as i-PrOH and DMSO, did not affect the yield (entries 6 and 7). 1,2-Dichloroethane (DCE) was a potential solvent that produced 3a in good yields, along with side reactions (entry 8). The screening of solvents revealed that 1,4-dioxane was a suitable solvent (entry 9). Furthermore, the reaction in 1,4-dioxane was found to have an effect comparable with that observed using HClO₄ as an acid (entries 9 and 10).[25]

H₂O was released during the formation of 3a. It was assumed that H₂O inhibits the transesterification of 1a and 2a. Therefore, the effects of drying agents were investigated (Table [2]). In the case of molecular sieves (4Å) or trimethyl orthoformate, no reaction occurred (entries 2 and 3). When 2,2-dimethoxypropane was used, 3a was obtained in 71% NMR yield. However, it could not be separated from the byproducts by column chromatography (entry 4). Silica gel was more effective, generating 3a in 70% isolated yield (entry 5).[26] In contrast, the combination of TfOH and silica gel resulted in lower yields (entry 5 vs entry 6).

Table 2 Effects of Drying Agents on the Formation of 3a

Entry	Acid (equiv)	Drying agent	Isolated yield (%)
1	HClO₄ (0.1)	–	60
2	HClO₄ (0.1)	molecular sieves 4Å	no reaction
3	HClO₄ (0.1)	HC(OMe)₃	no reaction
4	HClO₄ (0.1)	Me₂C(OMe)₂	71^a
5	HClO₄ (0.1)	silica gel	70
6	TfOH (0.1)	silica gel	58

^a Determined by ¹H NMR using 1,4-dimethoxybenzene as an internal standard.

With the optimized conditions in hand, the substrate scope was evaluated. The results are shown in Scheme [2]. This method allowed for the isolation of 3-methoxy-4-arylcoumarins in good yields. Phenols 1 with varying numbers of substituents at different positions afforded the corresponding products 3b–d in 57–72% yields. In particular, resorcinol was converted into 7-hydroxycoumarins 3d and 3e without the formation of 5-hydroxy compounds. α-Methoxy-β-ketoesters 2 with different substituent patterns were applied for the synthesis of coumarins 3f–h. Furthermore, 4-alkylcoumarin 3i could be also synthesized in 35% yield.

Scheme 2 HClO₄-mediated intermolecular annulation of 1 and 2 into coumarins 3. Reaction conditions: 1 (3.0 mmol), 2 (1.0 mmol), silica gel (~1.3 g), HClO₄ (0.1 M in 1,4-dioxane; 1.0 mL), 1,4-dioxane (4.0 mL), 90 °C, 24 h. Isolated yields based on 2.

Next, focusing on the observation of benzofuran 4a during coumarin synthesis, we investigated whether water was involved in the formation of benzofuran 4 (Table [3]). In the presence of excess H₂O, the HClO₄-mediated reaction between 1a and 2a did not proceed at all (entry 1). In contrast, the reaction using 3 equiv of H₂O gave benzofuran 4a in higher yield than coumarin 3a (entry 2). Simultaneously, α-methoxyacetophenone (9) was also observed. It was assumed that α-methoxy-β-ketoester 2a was hydrolyzed and decarboxylated to 9, which then underwent intermolecular annulation with phenol 1a to afford benzofuran 4a. On the other hand, Yonezawa et al. have reported the reaction of α-methoxy-carboxylic acids with aromatic compounds under acidic conditions, in which case the carboxyl and methoxy groups are replaced by two aryl groups.[27] In order to proceed with decarboxylation, the reaction procedure was modified as follows: to a solution of 2a in 1,4-dioxane were added H₂O and catalytic HClO₄, and after stirring at 90 °C for 7 h, 1a was added. As shown in entry 3, the reaction gave 4a in 53% NMR yield, with a 4a/3a ratio of 3.8:1. The change to 0.3 equiv of HClO₄ afforded good product selectivity, but excess use of H₂O reduced the yield of 4a (entries 4–6). Finally, increasing the amount of 1a and the reactant concentration afforded only 4a in 73% isolated yield (entries 7 and 8, see the Supporting Information for details).

Table 3 Optimizing the Conditions for the Synthesis of Benzofuran 4a

Entry	HClO₄ (equiv)	H₂O (equiv)	Time 1 (h)	1a (equiv)	Time 2 (h)	NMR yield of 4a (%)^a	4a/3a ratio^a
1	0.1	excess	–	3.0	24	no reaction	–
2	0.1	3.0	–	3.0	24	33	1.5:1
3	0.1	3.0	7	3.0	17	53	3.8:1
4	0.3	3.0	7	3.0	17	60	15:1
5	0.3	7.0	7	3.0	17	69	12:1
6	0.3	15.0	7	3.0	17	54	1:0
7	0.3	7.0	7	5.0	13	75	1:0
8^b,c	0.3	7.0	7	5.0	13	80 (73)^d	1:0

^a Determined by ¹H NMR using 1,4-dimethoxybenzene as an internal standard.

^b 0.33 M solution of 2a in 1,4-dioxane.

^c Ar gas was bubbled through the solvent.

^d Isolated yield in parenthesis.

The developed protocol was applied to phenols 1 and α-methoxy-β-ketoesters 2 (Scheme [3]). Treatment of 2 with HClO₄ and H₂O, followed by the addition of 1, produced the desired benzofurans 4 in good to excellent yields. Additional substituents on the aromatic ring of 2 increased the yields. Benzofurans with heterocyclic as well as aryl groups in the C2-position could be synthesized in good yields, while 2-alkylbenzofuran 4f was synthesized in a low yield. The use of 3,5-dimethoxyphenol instead of phloroglucinol required a long reaction time; however, products 4h and 4i were obtained in good yields.

Scheme 3 HClO₄-mediated intermolecular annulation of 1 and 2 into benzofurans 4. Reaction conditions: 2 (0.33 mmol), HClO₄ (0.1 M in 1,4-dioxane; 1.0 mL), H₂O (2.3 mmol), 90 °C, 7 h, then 1 (1.7 mmol), 90 °C for the time indicated in parentheses. Isolated yields based on 2.

Control experiments were performed to elucidate the reaction mechanism. Using β-ketoester 6a without the α-substituent, the reaction with 1a gave acetophenone (8) as the main product, instead of benzofuran 4a (Scheme [4a]). α-Ethoxy-β-ketoester 7 exhibited a reactivity comparable to that of α-methoxy derivative 2a, although with a slightly low yield of 4a (Scheme [4b]). This phenomenon indicates that the α-alkoxy group in β-ketoester 2 is essential for benzofuran formation.

Scheme 4

Therefore, we were interested in at what step of the intermolecular annulation process the ester group was decarboxylated. α-Methoxyacetophenone (9) was reacted with 1a under the optimal condition, without water. The reaction proceeded smoothly to form benzofuran 4a in 73% NMR yield (Scheme [5]). Even in acetophenone, the absence of the methoxy group did not lead to the formation of benzofuran 4a. It was found that the ester group was initially decarboxylated and the resulting α-methoxyacetophenone underwent intermolecular annulation.

Scheme 5 Conversion of acetophenones 8 and 9 into benzofuran 4a

Based on our experimental findings, we propose the following mechanism for benzofuran formation (Scheme [6]). First, α-methoxy-β-ketoester is hydrolyzed by HClO₄ and H₂O, followed by decarboxylation to form α-methoxyacetophenone (9). The hydroxy group of phenol 1a undergoes nucleophilic addition to the carbonyl carbon of protonated 9, resulting in the formation of intermediate 10. Finally, the intramolecular cyclization of 10 gives the corresponding benzofuran 4a.

Scheme 6 Proposed mechanism for the formation of benzofuran

In conclusion, we have developed a method for selective syntheses of coumarin and benzofuran derivatives starting from common substrates 1 and 2. Both reactions are facilitated by HClO₄, and the choice of route depends on the water content. During the synthesis of benzofurans, H₂O induces the decarboxylation of α-methoxy-β-ketoester. The resulting α-methoxyacetophenone undergoes intermolecular annulation with phenols. To the best of our knowledge, this is the first successful conversion of phenols and α-methoxyacetophenones into benzofurans.[28] Further investigation of the practical extension and elucidation of this mechanism is currently in progress in our laboratory.

Melting points were determined on a Yanaco Micro Melting Point Apparatus and are uncorrected. Infrared (IR) absorption spectra were obtained using a Jasco FT/IR-4200 or FT/IR-4700 spectrometer. ¹H and ¹³C NMR spectra were recorded on a Bruker BioSpin AVANCE III 400 or a JEOL JNM-ECZ500R spectrometer. NMR spectra were referenced to residual solvent peaks (acetone-d ₆: ¹H NMR δ = 2.05, ¹³C NMR δ = 29.84). Mass spectra were determined with a Thermo Fisher Scientific Q-Exactive HR-ESI-Orbitrap-MS mass spectrometer. For preparative HPLC, a Jasco PU-1586 Intelligent HPLC Pump, a Tosoh UV-8010 detector, a Shiseido Capcell Pak UG 120 C18 column (5 μm, 20 × 250 mm), and HPLC grade solvents were used.

Kanto Chemical silica gel (silica gel 60N, spherical neutral, particle size 40–50 μm) was directly used for column chromatography. Silica gel was activated by heating with a heat gun when used as a drying agent. 0.1 M HClO₄ in 1,4-dioxane (CAS: 7601-90-3) was purchased from Hayashi Pure Chemicals Ind., Ltd. Other commercial reagents were directly used without further purification.

General Procedure for the Synthesis of Coumarin Derivatives 3

To the solution of phenol 1 (3.0 mmol, 3.0 equiv) and α-methoxy-β-ketoester 2 (1.0 mmol, 1.0 equiv) in 1,4-dioxane (4.0 mL, 0.2 M) was added silica gel (~1.3 g) under a N₂ atmosphere. HClO₄ (0.1 M in 1,4-dioxane; 1.0 mL, 0.1 equiv) was dropwise added to the mixture at rt. The reaction mixture was heated at 90 °C (oil bath) for 24 h. The resulting mixture was filtered through Celite. The filtrate was quenched with sat. aq NaHCO₃ and extracted with EtOAc (100 mL × 3). The combined organic layers were dried (Na₂SO₄) and evaporated in vacuo. The residue was purified by flash column chromatography or reverse phase preparative HPLC to give the corresponding coumarin 3.

5,7-Dihydroxy-3-methoxy-4-phenylcoumarin (3a)

Phloroglucinol (1a; 380 mg, 3.0 mmol, 3.0 equiv), ethyl 2-methoxy-3-oxo-3-phenylpropanoate (2a; 230 mg, 1.0 mmol, 1.0 equiv), silica gel (1.1 g), and HClO₄ (0.1 M in 1,4-dioxane; 1.0 mL, 0.1 mmol, 0.1 equiv) in 1,4-dioxane (4.0 mL) were heated. The residue was purified by flash column chromatography (n-hexane/EtOAc = 1:1) to afford 3a (200 mg, 70%) as a white solid; mp 245–248 °C.

IR (KBr): 3497, 3262, 1705, 1623, 1596, 1573, 1461, 1380, 1300, 1243, 1201 cm^–1.

¹H NMR (acetone-d ₆, 400 MHz): δ = 7.42–7.27 (m, 5 H), 6.36 (d, J = 2.3 Hz, 1 H), 6.25 (d, J = 2.3 Hz, 1 H), 3.57 (s, 3 H).

¹³C NMR (acetone-d ₆, 100 MHz): δ = 160.7, 158.6, 157.2, 154.9, 142.1, 138.4, 136.7, 128.9, 128.2, 128.1, 102.4, 100.5, 95.8, 60.1.

HRMS (ESI): m/z [M – H]^– calcd for C₁₆H₁₁O₅: 283.0612; found: 283.0616.

7,8-Dihydroxy-3-methoxy-4-phenylcoumarin (3b)

Pyrogallol (1b; 430 mg, 3.4 mmol, 3.0 equiv), ethyl 2-methoxy-3-oxo-3-phenylpropanoate (2a; 250 mg, 1.1 mmol, 1.0 equiv), silica gel (1.1 g), and HClO₄ (0.1 M in 1,4-dioxane; 1.0 mL, 0.1 mmol, 0.1 equiv) in 1,4-dioxane (4.0 mL) were heated. The residue was purified by reverse phase preparative HPLC (H₂O/MeCN = 1:1, 0.1% TFA) to afford 3b (180 mg, 57%) as a brown solid; mp 93–95 °C.

IR (KBr): 3557, 3485, 3179, 1710, 1702, 1600, 1469, 1340, 1275 cm^–1.

¹H NMR (acetone-d ₆, 400 MHz): δ = 7.59–7.46 (m, 3 H), 7.38 (d, J = 7.6 Hz, 2 H), 6.78 (d, J = 8.7 Hz, 1 H), 6.46 (d, J = 8.7 Hz, 1 H), 3.69 (s, 3 H).

¹³C NMR (acetone-d ₆, 100 MHz): δ = 158.5, 148.3, 142.1, 141.6, 138.7, 133.5, 133.0, 129.9, 129.4, 129.2, 118.2, 114.6, 113.2, 60.3.

HRMS (ESI): m/z [M – H]^– calcd for C₁₆H₁₁O₅: 283.0612; found: 283.0615.

7-Hydroxy-3-methoxy-8-methyl-4-phenylcoumarin (3c)

2-Methylresorcinol (1c; 380 mg, 3.1 mmol, 3.0 equiv), ethyl 2-methoxy-3-oxo-3-phenylpropanoate (2a; 220 mg, 1.0 mmol, 1.0 equiv), silica gel (1.1 g), and HClO₄ (0.1 M in 1,4-dioxane; 1.0 mL, 0.1 mmol, 0.1 equiv) in 1,4-dioxane (4.0 mL) were heated. The residue was purified by reverse phase preparative HPLC (H₂O/MeCN = 1:1, 0.1% TFA) to afford 3c (200 mg, 72%) as a white solid; mp 214–217 °C.

IR (ATR): 3283, 2928, 1672, 1611, 1571, 1458, 1356, 1256 cm^–1.

¹H NMR (acetone-d ₆, 500 MHz): δ = 9.15 (s, 1 H), 7.59–7.47 (m, 3 H), 7.43–7.37 (m, 2 H), 6.81 (d, J = 9.0 Hz, 1 H), 6.76 (d, J = 9.0 Hz, 1 H), 3.70 (s, 3 H), 2.30 (s, 3 H).

¹³C NMR (acetone-d ₆, 125 MHz): δ = 158.9, 158.1, 151.6, 141.9, 138.6, 133.5, 129.9, 129.4, 129.3, 125.4, 113.8, 112.8, 112.2, 60.2, 8.3.

HRMS (ESI): m/z [M – H]^– calcd for C₁₇H₁₃O₄: 281.0819; found: 281.0816.

7-Hydroxy-3-methoxy-4-phenylcoumarin (3d)

Resorcinol (1d; 410 mg, 3.7 mmol, 3.0 equiv), ethyl 2-methoxy-3-oxo-3-phenylpropanoate (2a; 270 mg, 1.2 mmol, 1.0 equiv), silica gel (1.2 g), and HClO₄ (0.1 M in 1,4-dioxane; 1.0 mL, 0.1 mmol, 0.1 equiv) in 1,4-dioxane (4.0 mL) were heated. The residue was purified by flash column chromatography (CH₂Cl₂/EtOAc = 10:1 to 5:1) to afford 3d (200 mg, 61%) as a white solid; mp 196–200 °C.

IR (KBr): 3340, 1699, 1616, 1557, 1511, 1464, 1350, 1321, 1257 cm^–1.

¹H NMR (acetone-d ₆, 400 MHz): δ = 9.26 (brs, 1 H), 7.60–7.48 (m, 3 H), 7.39 (d, J = 6.6 Hz, 2 H), 6.95 (d, J = 8.7 Hz, 1 H), 6.82 (d, J = 2.4 Hz, 1 H), 6.77 (dd, J = 8.7, 2.4 Hz, 1 H), 3.70 (s, 3 H).

¹³C NMR (acetone-d ₆, 100 MHz): δ = 160.4, 158.8, 153.6, 141.5, 138.9, 133.3, 129.9, 129.5, 129.3, 128.7, 113.83, 113.81, 103.3, 60.3.

HRMS (ESI): m/z [M – H]^– calcd for C₁₆H₁₁O₄: 267.0663; found: 267.0666.

7-Hydroxy-3-methoxy-4-(3-methoxyphenyl)coumarin (3e)

Resorcinol (1d; 340 mg, 3.1 mmol, 3.0 equiv), ethyl 2-methoxy-3-(3-methoxyphenyl)-3-oxopropanoate (2c; 250 mg, 0.99 mmol, 1.0 equiv), silica gel (1.3 g), and HClO₄ (0.1 M in 1,4-dioxane; 1.0 mL, 0.1 mmol, 0.1 equiv) in 1,4-dioxane (4.0 mL) were heated. The residue was purified by reverse phase preparative HPLC (H₂O/MeCN = 2:3, 0.1% TFA) to afford 3e (150 mg, 51%) as a white solid; mp 179–182 °C.

IR (ATR): 3272, 1684, 1610, 1451, 1362, 1238 cm^–1.

¹H NMR (acetone-d ₆, 500 MHz): δ = 9.33 (s, 1 H), 7.47 (t, J = 8.2 Hz, 1 H), 7.09–7.04 (m, 1 H), 6.97 (d, J = 8.7 Hz, 1 H), 7.01–6.93 (m, 2 H), 6.81 (d, J = 2.4 Hz, 1 H), 6.78 (dd, J = 8.7, 2.4 Hz, 1 H), 3.86 (s, 3 H), 3.71 (s, 3 H).

¹³C NMR (acetone-d ₆, 125 MHz): δ = 160.7, 160.4, 158.8, 153.5, 141.5, 138.8, 134.6, 130.5, 128.8, 121.9, 115.4, 114.9, 113.8, 113.7, 103.2, 60.3, 55.7.

HRMS (ESI): m/z [M – H]^– calcd for C₁₇H₁₃O₅: 297.0768; found: 297.0765.

5,7-Dihydroxy-3-methoxy-4-(3-methoxyphenyl)coumarin (3f)

Phloroglucinol (1a; 380 mg, 3.0 mmol, 3.0 equiv), ethyl 2-methoxy-3-(3-methoxyphenyl)-3-oxopropanoate (2c; 260 mg, 1.0 mmol, 1.0 equiv), silica gel (1.3 g), and HClO₄ (0.1 M in 1,4-dioxane; 1.0 mL, 0.1 mmol, 0.1 equiv) in 1,4-dioxane (4.0 mL) were heated. The residue was purified by reverse phase preparative HPLC (H₂O/MeCN = 3:2, 0.1% TFA) to afford 3f (260 mg, 83%) as an orange solid; mp 198–200 °C.

IR (KBr): 3509, 3223, 1684, 1627, 1599, 1558, 1468, 1395, 1371, 1296, 1249, 1200 cm^–1.

¹H NMR (acetone-d ₆, 400 MHz): δ = 9.17 (brs, 1 H), 8.45 (brs, 1 H), 7.30 (t, J = 7.4 Hz, 1 H), 6.95–6.84 (m, 3 H), 6.35 (d, J = 2.4 Hz, 1 H), 6.25 (d, J = 2.4 Hz, 1 H), 3.80 (s, 3 H), 3.59 (s, 3 H).

¹³C NMR (acetone-d ₆, 100 MHz): δ = 160.7, 160.2, 158.6, 157.1, 154.9, 141.9, 138.3, 137.9, 129.4, 121.1, 114.5, 113.7, 102.4, 100.5, 95.8, 60.2, 55.5.

HRMS (ESI): m/z [M – H]^– calcd for C₁₇H₁₃O₆: 313.0718; found: 313.0719.

5,7-Dihydroxy-3-methoxy-4-(4-methoxyphenyl)coumarin (3g)

Phloroglucinol (1a; 420 mg, 3.3 mmol, 3.0 equiv), ethyl 2-methoxy-3-(4-methoxyphenyl)-3-oxopropanoate (2b; 280 mg, 1.1 mmol, 1.0 equiv), silica gel (1.1 g), and HClO₄ (0.1 M in 1,4-dioxane; 1.0 mL, 0.1 mmol, 0.1 equiv) were heated in 1,4-dioxane (4.0 mL). The residue was purified by reverse phase preparative HPLC (H₂O/MeCN = 1:1, 0.1% TFA) to afford 3g (240 mg, 68%) as an orange solid; mp 268–270 °C.

IR (KBr): 3233, 1687, 1612, 1556, 1513, 1471, 1372, 1297, 1234 cm^–1.

¹H NMR (acetone-d ₆, 400 MHz): δ = 8.29 (brs, 1 H), 7.24 (d, J = 8.8 Hz, 2 H), 6.96 (d, J = 8.8 Hz, 2 H), 6.35 (d, J = 2.4 Hz, 1 H), 6.25 (d, J = 2.4 Hz, 1 H), 3.84 (s, 3 H), 3.57 (s, 3 H).

¹³C NMR (acetone-d ₆, 100 MHz): δ = 160.6, 160.2, 158.6, 157.3, 154.9, 141.8, 138.7, 130.3, 128.2, 113.8, 102.6, 100.6, 95.9, 60.0, 55.5.

HRMS (ESI): m/z [M – H]^– calcd for C₁₇H₁₃O₆: 313.0718; found: 313.0722.

5,7-Dihydroxy-3-methoxy-4-(2-methoxyphenyl)coumarin (3h)

Phloroglucinol (1a; 380 mg, 3.0 mmol, 3.0 equiv), ethyl 2-methoxy-3-(2-methoxyphenyl)-3-oxopropanoate (2d; 260 mg, 1.0 mmol, 1.0 equiv), silica gel (1.3 g), and HClO₄ (0.1 M in 1,4-dioxane; 1.0 mL, 0.1 mmol, 0.1 equiv) were heated in 1,4-dioxane (4.0 mL). The residue was purified by reverse phase preparative HPLC (H₂O/MeCN = 3:2, 0.1% TFA) to afford 3h (200 mg, 62%) as a brown solid; mp 207–210 °C.

IR (KBr): 3466, 3400, 1703, 1624, 1566, 1493, 1464, 1432, 1351, 1292, 1238 cm^–1.

¹H NMR (acetone-d ₆, 400 MHz): δ = 9.13 (brs, 1 H), 8.50 (brs, 1 H), 7.32 (t, J = 8.2 Hz, 1 H), 7.15 (d, J = 7.5 Hz, 1 H), 7.01 (d, J = 8.2 Hz, 1 H), 6.96 (t, J = 7.5 Hz, 1 H), 6.34 (d, J = 2.3 Hz, 1 H), 6.23 (d, J = 2.3 Hz, 1 H), 3.73 (s, 3 H), 3.57 (s, 3 H).

¹³C NMR (acetone-d ₆, 100 MHz): δ = 160.3, 158.7, 157.6, 157.3, 154.8, 139.5, 138.4, 129.8, 129.7, 125.9, 120.6, 111.3, 102.9, 100.2, 95.6, 59.8, 55.8.

HRMS (ESI): m/z [M – H]^– calcd for C₁₇H₁₃O₆: 313.0718; found: 313.0721.

5,7-Dihydroxy-3-methoxy-4-phenethylcoumarin (3i)

Phloroglucinol (1a; 350 mg, 2.8 mmol, 3.0 equiv), ethyl 2-methoxy-3-oxo-5-phenylpentanoate (2g; 230 mg, 0.92 mmol, 1.0 equiv), silica gel (1.3 g), and HClO₄ (0.1 M in 1,4-dioxane; 1.0 mL, 0.1 mmol, 0.1 equiv) were heated in 1,4-dioxane (4.0 mL). The residue was purified by flash column chromatography (n-hexane/EtOAc = 1:1) to afford 3i (100 mg, 35%) as a brown solid; mp 216–219 °C.

IR (ATR): 3437, 3154, 1659, 1610, 1460, 1362, 1282, 1241 cm^–1.

¹H NMR (acetone-d ₆, 500 MHz): δ = 9.66 (s, 1 H), 9.16 (s, 1 H), 7.32–7.25 (m, 4 H), 7.23–7.15 (m, 1 H), 6.46 (d, J = 2.6 Hz, 1 H), 6.33 (d, J = 2.6 Hz, 1 H), 3.74 (s, 3 H), 3.40–3.33 (m, 2 H), 3.30–2.83 (m, 2 H).

¹³C NMR (acetone-d ₆, 125 MHz): δ = 160.3, 157.9, 157.4, 155.2, 143.2, 143.0, 138.5, 129.22, 129.18, 126.8, 102.5, 100.7, 96.1, 60.0, 36.8, 30.7.

HRMS (ESI): m/z [M – H]^– calcd for C₁₈H₁₅O₅: 311.0925; found: 311.0924.

General Procedure for the Synthesis of Benzofuran Derivatives 4

α-Methoxy-β-ketoester 2 (0.33 mmol, 1.0 equiv) was placed in a glass vessel, and HClO₄ (0.1 M in 1,4-dioxane; 1.0 mL, 0.1 mmol, 0.3 equiv) and H₂O (42 μL, 2.3 mmol, 7.0 equiv) were added. The mixture was stirred at rt for 5 min while bubbling with argon. After stirring at 90 °C (oil bath) for 7 h, phenol 1 (1.7 mmol, 5.0 equiv) was added at rt. The reaction mixture was stirred at 90 °C (oil bath) for 13–36 h, quenched with H₂O, and extracted with EtOAc (50 mL × 2). The combined organic layers were dried (Na₂SO₄) and evaporated in vacuo. The residue was purified by flash column chromatography. Further purification of the desired combined fractions was performed by reverse phase preparative HPLC to give the corresponding benzofuran 4.

4,6-Dihydroxy-2-phenylbenzofuran (4a)

Ethyl 2-methoxy-3-oxo-3-phenylpropanoate (2a; 74 mg, 0.33 mmol, 1.0 equiv), HClO₄ (0.1 M in 1,4-dioxane; 1.0 mL, 0.1 mmol, 0.3 equiv), and H₂O (42 μL, 2.3 mmol, 7.0 equiv) were heated. Phloroglucinol (1a; 210 mg, 1.7 mmol, 5.0 equiv) was added and the reaction mixture was heated for 13 h. The residue was purified by flash column chromatography (n-hexane/EtOAc = 2:1 to 3:2) followed by reverse phase preparative HPLC (H₂O/MeCN = 1:1, 0.1% TFA) to afford benzofuran 4a (55 mg, 73%) as a white solid; mp 168–170 °C.

IR (KBr): 3317, 1698, 1610, 1507, 1488, 1442, 1345, 1254 cm^–1.

¹H NMR (acetone-d ₆, 400 MHz): δ = 8.83 (brs, 1 H), 8.41 (brs, 1 H), 7.83 (d, J = 7.8 Hz, 2 H), 7.44 (t, J = 7.8 Hz, 2 H), 7.31 (t, J = 7.8 Hz, 1 H), 7.21 (s, 1 H), 6.56 (s, 1 H), 6.32 (s, 1 H).

¹³C NMR (acetone-d ₆, 100 MHz): δ = 158.2, 157.8, 153.5, 152.1, 131.8, 129.7, 128.5, 124.8, 112.3, 99.9, 98.7, 90.6.

HRMS (ESI): m/z [M – H]^– calcd for C₁₄H₉O₃: 225.0557; found: 225.0555.

4,6-Dihydroxy-2-(4-methoxyphenyl)benzofuran (4b)

Ethyl 2-methoxy-3-(4-methoxyphenyl)-3-oxopropanoate (2b; 82 mg, 0.33 mmol, 1.0 equiv), HClO₄ (0.1 M in 1,4-dioxane; 1.0 mL, 0.1 mmol, 0.3 equiv), and H₂O (41 μL, 2.3 mmol, 7.0 equiv) were heated. Phloroglucinol (1a; 210 mg, 1.7 mmol, 5.0 equiv) was added and the reaction mixture was heated for 13 h. The residue was purified by flash column chromatography (n-hexane/EtOAc = 3:2) followed by reverse phase preparative HPLC (H₂O/MeCN = 1:1, 0.1% TFA) to afford benzofuran 4b (66 mg, 79%) as an orange solid; mp 185–188 °C.

IR (KBr): 3329, 1645, 1612, 1501, 1450, 1398, 1343, 1301, 1253 cm^–1.

¹H NMR (acetone-d ₆, 400 MHz): δ = 8.74 (brs, 1 H), 8.33 (brs, 1 H), 7.75 (d, J = 8.5 Hz, 2 H), 7.04 (s, 1 H), 7.01 (d, J = 8.5 Hz, 2 H), 6.54 (s, 1 H), 6.30 (s, 1 H), 3.84 (s, 3 H).

¹³C NMR (acetone-d ₆, 100 MHz): δ = 160.5, 157.9, 157.3, 153.8, 151.9, 126.3, 124.6, 115.1, 112.5, 98.7, 98.0, 90.7, 55.7.

HRMS (ESI): m/z [M – H]^– calcd for C₁₅H₁₁O₄: 255.0663; found: 255.0664.

4,6-Dihydroxy-2-(3-methoxyphenyl)benzofuran (4c)

Ethyl 2-methoxy-3-(3-methoxyphenyl)-3-oxopropanoate (2c; 85 mg, 0.34 mmol, 1.0 equiv), HClO₄ (0.1 M in 1,4-dioxane; 1.0 mL, 0.1 mmol, 0.3 equiv), and H₂O (42 μL, 2.3 mmol, 7.0 equiv) were heated. Phloroglucinol (1a; 210 mg, 1.7 mmol, 5.0 equiv) was added and the reaction mixture was heated for 13 h. The residue was purified by flash column chromatography (n-hexane/EtOAc = 2:1 to 3:2) followed by reverse phase preparative HPLC (H₂O/MeCN = 1:1, 0.1% TFA) to afford benzofuran 4c (70 mg, 81%) as a red amorphous solid.

IR (KBr): 3377, 1686, 1611, 1489, 1340, 1258, 1213 cm^–1.

¹H NMR (acetone-d ₆, 400 MHz): δ = 7.45–7.32 (m, 3 H), 7.23 (s, 1 H), 6.88 (dd, J = 8.1, 2.4 Hz, 1 H), 6.57 (s, 1 H), 6.33 (s, 1 H), 3.87 (s, 3 H).

¹³C NMR (acetone-d ₆, 100 MHz): δ = 161.1, 158.1, 157.7, 153.4, 152.1, 133.0, 130.8, 117.2, 114.3, 112.2, 109.9, 100.2, 98.6, 90.6, 55.6.

HRMS (ESI): m/z [M – H]^– calcd for C₁₅H₁₁O₄: 255.0663; found: 255.0664.

4,6-Dihydroxy-2-(3,4-dimethoxyphenyl)benzofuran (4d)

Ethyl 2-methoxy-3-(3,4-dimethoxyphenyl)-3-oxopropanoate (2e; 95 mg, 0.34 mmol, 1.0 equiv), HClO₄ (0.1 M in 1,4-dioxane; 1.0 mL, 0.1 mmol, 0.3 equiv), and H₂O (42 μL, 2.3 mmol, 7.0 equiv) were heated. Phloroglucinol (1a; 210 mg, 1.7 mmol, 5.0 equiv) was added and the reaction mixture was heated for 13 h. The residue was purified by flash column chromatography (n-hexane/EtOAc = 3:2 to 1:1) to afford benzofuran 4d (89 mg, 92%) as a colorless amorphous solid.

IR (ATR): 3369, 1687, 1610, 1503, 1447, 1338, 1241 cm^–1.

¹H NMR (acetone-d ₆, 400 MHz): δ = 8.75 (brs, 1 H), 8.35 (brs, 1 H), 7.40–7.35 (m, 2 H), 7.07 (s, 1 H), 7.02 (d, J = 8.4 Hz, 1 H), 6.54 (s, 1 H), 6.31 (s, 1 H), 3.91 (s, 3 H), 3.85 (s, 3 H).

¹³C NMR (acetone-d ₆, 100 MHz): δ = 157.9, 157.4, 153.8, 151.9, 150.7, 150.4, 124.9, 117.6, 113.0, 112.5, 108.8, 98.7, 98.4, 90.6, 56.17, 56.16.

HRMS (ESI): m/z [M – H]^– calcd for C₁₆H₁₃O₅: 285.0768; found: 285.0769.

4,6-Dihydroxy-2-(thiophen-2-yl)benzofuran (4e)

Ethyl 2-methoxy-3-oxo-3-(thiophen-2-yl)propanoate (2f; 72 mg, 0.32 mmol, 1.0 equiv), HClO₄ (0.1 M in 1,4-dioxane; 1.0 mL, 0.1 mmol, 0.3 equiv), and H₂O (40 μL, 2.2 mmol, 7.0 equiv) were heated. Phloroglucinol (1a; 220 mg, 1.7 mmol, 5.0 equiv) was added and the reaction mixture was heated for 13 h. The residue was purified by flash column chromatography (n-hexane/EtOAc = 1:1) followed by reverse phase preparative HPLC (H₂O/MeCN = 3:2, 0.1% TFA) to afford benzofuran 4e (37 mg, 50%) as a white solid; mp 155–158 °C.

IR (ATR): 3327, 2482, 1685, 1604, 1497, 1439, 1331, 1250 cm^–1.

¹H NMR (acetone-d ₆, 500 MHz): δ = 7.47 (d, J = 4.3 Hz, 1 H), 7.45 (d, J = 4.3 Hz, 1 H), 7.13 (t, J = 4.3 Hz, 1 H), 7.02 (d, J = 2.0 Hz, 1 H), 6.53 (d, J = 2.5 Hz, 1 H), 6.32 (d, J = 2.5 Hz, 1 H).

¹³C NMR (acetone-d ₆, 125 MHz): δ = 157.8, 157.7, 152.0, 149.1, 134.3, 128.8, 125.8, 124.2, 112.0, 99.5, 98.9, 90.6.

HRMS (ESI): m/z [M – H]^– calcd for C₁₂H₇O₃S: 231.0121; found: 231.0117.

4,6-Dihydroxy-2-phenethylbenzofuran (4f)

Ethyl 2-methoxy-3-oxo-5-phenylpentanoate (2g; 80 mg, 0.32 mmol, 1.0 equiv), HClO₄ (0.1 M in 1,4-dioxane; 1.0 mL, 0.1 mmol, 0.3 equiv), and H₂O (40 μL, 2.2 mmol, 7.0 equiv) were heated. Phloroglucinol (1a; 200 mg, 1.6 mmol, 5.0 equiv) was added and the reaction mixture was heated for 13 h. The residue was purified by flash column chromatography (n-hexane/EtOAc = 1:1) followed by reverse phase preparative HPLC (H₂O/MeCN = 1:1, 0.1% TFA) to afford benzofuran 4f (10 mg, 12%) as a white solid; mp 132–134 °C.

IR (ATR): 3331, 2914, 1679, 1637, 1509, 1448, 1410, 1341, 1260 cm^–1.

¹H NMR (acetone-d ₆, 500 MHz): δ = 8.60 (s, 1 H), 8.23 (s, 1 H), 7.34–7.14 (m, 5 H), 6.45 (d, J = 1.3 Hz, 1 H), 6.41 (s, 1 H), 6.25 (d, J = 1.3 Hz, 1 H), 3.12–2.80 (m, 4 H).

¹³C NMR (acetone-d ₆, 125 MHz): δ = 157.9, 156.7, 155.7, 151.3, 142.1, 129.22, 129.18, 126.9, 111.4, 100.2, 98.3, 90.5, 34.6, 30.8.

HRMS (ESI): m/z [M – H]^– calcd for C₁₆H₁₃O₃: 253.0870; found: 253.0866.

6-Hydroxy-7-methyl-2-phenylbenzofuran (4g)

Ethyl 2-methoxy-3-oxo-3-phenylpropanoate (2a; 74 mg, 0.33 mmol, 1.0 equiv), HClO₄ (0.1 M in 1,4-dioxane; 1.0 mL, 0.1 mmol, 0.3 equiv), and H₂O (42 μL, 2.3 mmol, 7.0 equiv) were heated. 2-Methylresorcinol (1c; 210 mg, 1.7 mmol, 5.0 equiv) was added and the reaction mixture was heated for 13 h. The residue was purified by flash column chromatography (n-hexane/EtOAc = 6:1 to 3:1) followed by reverse phase preparative HPLC (H₂O/MeCN = 2:3, 0.1% TFA) to afford benzofuran 4g (39 mg, 53%) as a white solid; mp 102–105 °C.

IR (ATR): 3266, 2923, 1603, 1417, 1313, 1216 cm^–1.

¹H NMR (acetone-d ₆, 500 MHz): δ = 8.46 (s, 1 H), 8.00 (s, 1 H), 7.71 (d, J = 7.7 Hz, 2 H), 7.52 (d, J = 8.6 Hz, 1 H), 7.47 (t, J = 7.7 Hz, 2 H), 7.35 (t, J = 7.7 Hz, 1 H), 6.94 (d, J = 8.6 Hz, 1 H), 2.37 (s, 3 H).

¹³C NMR (acetone-d ₆, 125 MHz): δ = 157.0, 154.1, 141.4, 133.4, 129.8, 128.0, 127.9, 123.0, 119.2, 118.0, 112.9, 108.5, 8.6.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₅H₁₃O₂: 225.0910; found: 225.0909.

4,6-Dimethoxy-2-phenylbenzofuran (4h)

Ethyl 2-methoxy-3-oxo-3-phenylpropanoate (2a; 72 mg, 0.32 mmol, 1.0 equiv), HClO₄ (0.1 M in 1,4-dioxane; 1.0 mL, 0.1 mmol, 0.3 equiv), and H₂O (41 μL, 2.3 mmol, 7.0 equiv) were heated. 3,5-Dimethoxyphenol (1e; 250 mg, 1.6 mmol, 5.0 equiv) was added and the reaction mixture was heated for 36 h. The residue was purified by flash column chromatography (n-hexane/EtOAc = 10:1) to afford benzofuran 4h (56 mg, 68%) as a white solid; mp 62–64 °C.

IR (ATR): 3376, 1687, 1610, 1500, 1446, 1329, 1220 cm^–1.

¹H NMR (acetone-d ₆, 400 MHz): δ = 7.86 (d, J = 7.3 Hz, 2 H), 7.45 (t, J = 7.3 Hz, 2 H), 7.33 (t, J = 7.3 Hz, 1 H), 7.20 (s, 1 H), 6.78 (s, 1 H), 6.41 (s, 1 H), 3.93 (s, 3 H), 3.86 (s, 3 H).

¹³C NMR (acetone-d ₆, 100 MHz): δ = 160.6, 157.5, 154.6, 154.3, 131.6, 129.7, 128.7, 124.9, 113.8, 99.8, 95.3, 89.0, 56.1, 56.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₆H₁₅O₃: 255.1016; found: 255.1015.

4,6-Dimethoxy-2-(3-methoxyphenyl)benzofuran (4i)

Ethyl 2-methoxy-3-(3-methoxyphenyl)-3-oxopropanoate (2c; 82 mg, 0.33 mmol, 1.0 equiv), HClO₄ (0.1 M in 1,4-dioxane; 1.0 mL, 0.1 mmol, 0.3 equiv), and H₂O (41 μL, 2.3 mmol, 7.0 equiv) were heated. 3,5-Dimethoxyphenol (1e; 250 mg, 1.6 mmol, 5.0 equiv) was added and the reaction mixture was heated for 36 h. The residue was purified by flash column chromatography (n-hexane/EtOAc = 9:1) to afford benzofuran 4i (72 mg, 78%) as a white solid; mp 78–80 °C.

IR (ATR): 1602, 1560, 1495, 1478, 1461, 1425, 1324, 1273, 1204 cm^–1.

¹H NMR (acetone-d ₆, 400 MHz): δ = 7.47–7.33 (m, 3 H), 7.22 (s, 1 H), 6.90 (d, J = 8.1 Hz, 1 H), 6.78 (s, 1 H), 6.41 (s, 1 H), 3.93 (s, 3 H), 3.88 (s, 3 H), 3.87 (s, 3 H).

¹³C NMR (acetone-d ₆, 100 MHz): δ = 161.1, 160.7, 157.5, 154.6, 154.2, 132.9, 130.8, 117.4, 114.7, 113.8, 110.1, 100.2, 95.3, 89.0, 56.1, 56.0, 55.7.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₇H₁₇O₄: 285.1121; found: 285.1119.

Referenzen

References and Notes

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Abbildungen

Scheme 1 Various synthetic methods for coumarin and benzofuran derivatives

Scheme 2 HClO₄-mediated intermolecular annulation of 1 and 2 into coumarins 3. Reaction conditions: 1 (3.0 mmol), 2 (1.0 mmol), silica gel (~1.3 g), HClO₄ (0.1 M in 1,4-dioxane; 1.0 mL), 1,4-dioxane (4.0 mL), 90 °C, 24 h. Isolated yields based on 2.

Scheme 3 HClO₄-mediated intermolecular annulation of 1 and 2 into benzofurans 4. Reaction conditions: 2 (0.33 mmol), HClO₄ (0.1 M in 1,4-dioxane; 1.0 mL), H₂O (2.3 mmol), 90 °C, 7 h, then 1 (1.7 mmol), 90 °C for the time indicated in parentheses. Isolated yields based on 2.

Scheme 4

Scheme 5 Conversion of acetophenones 8 and 9 into benzofuran 4a

Scheme 6 Proposed mechanism for the formation of benzofuran

Zusatzmaterial

Supporting Information