Microwave-promoted syntheses of fluoren-9-ones and benzisoxazoles

Abstract

Synthesis of some new fluoren-9-ones and benzisoxazoles under both thermal and microwave conditions is reported. The prepared products under microwave conditions are obtained with high yields and within shorter reaction times. Reaction of lithiated bromobenzene with aromatic aldehydes 2a,b delivered diarylmethanols 3a,b that were oxidized to 4a,b. Compound 4a was cyclized to give methoxyfluoren-9-one 5, which was demethylated affording hydroxyfluoren-9-one 6. Compound 4b was reacted with triethyl phosphite to produce benzisoxazole 10. On the other hand, reaction of triethyl phosphite with 13a,b afforded a mixture of phosphoramidates 14a,b and benzisoxazoles 15a,b. The structures of the synthesized compounds have been elucidated unambiguously by NMR-spectroscopic methods including HH COSY, HSQC, and HMBC experiments.

Introduction

Fluorenes and related compounds have broad-spectrum biological activities. The biologically active fluoren-9-ones such as dendroflorin, denchrysan A, and 1,4,5-trihydroxy-7-methoxyfluoren-9-one, which have been isolated from plants, are used as health foods [1]. In the last decade, hipposudoric and norhipposudoric acids, two natural dyes with a fluorene framework, have been isolated from the red sweat of Hippopotamus amphibius by Hashimoto, see Nakata et al. [2–4]. It has been reported that hipposudoric acid exhibits antibiotic activity while the two natural dyes may act as sunscreens. Various methods have been developed to synthesize fluorenes and their related compounds. For example, one approach involves the intramolecular Friedel–Crafts acylation of biaryls [5]. Using an alternative directed metallation methodologies, Snieckus and coworkers have prepared a range of substituted fluoren-9-ones [6]. Langer et al. have recently reported the synthesis of fluoren-9-one using a [3 + 3] cyclization/Suzuki cross-coupling/Friedel–Crafts acylation route starting from a 1,3-bis-silyl enol ether and a silyloxypentenone [7]. Over the past years, notable progress has been achieved in the field of Cu(I)-catalyzed C-, N-, O-, and S-arylations [8, 9]. Depending on the substrate ratio and the reaction conditions, 4H-chromenes or naphthalenes were synthesized via Cu(I)-catalyzed domino reactions [10]. Haggam reported a novel and simple intramolecular Cu(I)-catalyzed cyclization of substituted 2-iodobenzophenones under both thermal and microwave conditions to build methoxy-substituted fluoren-9-ones [11].

Results and discussion

We report on the synthesis of some novel fluoren-9-one, benzisoxazole and phosphoramidate derivatives utilizing aryl bromides and aromatic aldehydes as commercial starting materials. The ether cleavage of methoxy-substituted fluoren-9-ones was carried out via a demethylating agent 48 % HBr/AcOH. The substituted diarylmethanols 3a,b were prepared by reaction of the lithiated bromobenzene with the methoxy-substituted aromatic aldehydes 2a,b according to the method described by Qabaja and Jones [12]. The reactions among the methoxy-substituted 2-bromobenzene 1, t-butyllithium, and the aldehydes 2a,b were performed at −78 °C. After quenching with ammonium chloride solution, the crude products were purified by column chromatography to produce 3a in 72 % and 3b in 88 % yields [4, 13]. Oxidation of the secondary alcohols 3a,b to the corresponding ketones 4a in 89 % and 4b [4, 13] in 85 % yields was performed using potassium dichromate depending on the procedure of Fieser and Williamson [14, 15] (Scheme 1).

Scheme 1

Synthesis of the starting materials 4a,b

Several attempts were made to cyclize bis-(2,5-dimethoxyphenyl)methanone (4a) using different reagents such as Pd(OAC)₂ or/and Cu(OAC)₂ under different reaction conditions. Unfortunately, all of these trials failed to achieve our goal. We found that heating of 4a with a mixture of Pd(OAc)₂ and heteropolymolybdovanadic acid (HPMV) [16] in acetic acid within a stream of oxygen at 120 °C for 16 h resulted in the formation of the methoxyfluoren-9-one 5 in 89 % yield (Scheme 2). After the successful cyclization of 4a, the methoxy substituents in the cyclization product 5 had to be transformed into the free hydroxyl groups. For this purpose, a mixture of compound 5, acetic acid, and 48 % HBr was refluxed for 8 h according to the method of Ciske and Jones [17]. After work-up and purification of the resulting crude product by column chromatography, the hydroxy-substituted fluoren-9-one 6 was obtained in 87 % yield. Other trials were undertaken to realize the oxidation of methoxyfluoren-9-one 5 to the corresponding tricyclic quinone 8 [18, 19]. Compound 5 was treated with cerium ammonium nitrate (CAN) in acetonitrile as a solvent under reflux at 80 °C for 30 min. However, the formation of compound 8 could not be achieved (Scheme 2). Instead, the unexpected anhydride 7 (48 %) was obtained. The reaction was repeated by adding a solution of CAN in water to a stirred solution of tetramethoxyfluoren-9-one 5 in acetonitrile for 4 h. The crude product was purified to give the anhydride 7 in (64 %) yield but no appearance for the quinone 8. In accordance with the condensation reactions of fluoren-9-one 5, the chalkone 9 could not be observed via TLC when compound 5 was refluxed with malononitrile under various reaction conditions (Scheme 2).

Scheme 2

Reaction of fluoren-9-one 5 with different reagents under various reaction conditions

The substituted 2-nitrobenzophenone 4b was treated with triethyl phosphite under reflux at 157 °C for 13 h to produce the 3-aryl 2,1-benzisoxazole 10 in 63 % yield [20]. On the other hand, performing the reaction under microwave conditions (300 W, 20 bar) at 200 °C in toluene for 40 min the 3-aryl 2,1-benzisoxazole 10 was also obtained but with higher yield (71 %). However, the synthesis of acridin-9-one 11 or diethyl N-arylphosphoramidate 12 could not be realized on treatment compounds 4b or 10 with triethyl phosphite under thermal or microwave conditions at all (Scheme 3).

Scheme 3

Synthesis of 3-aryl 2,1-benzisoxazole 10 with yield (71 %) under microwave conditions

Regarding the proposal for the reaction mechanism of the cyclization of nitroaromatic 4b to give benzisoxazole 10, it is assumed that the reduction of 4b takes place via the following steps [21–23]. The first step is the reduction of the nitro group to a nitroso compound B and triethyl phosphate through electrophilic attack of the phosphorous atom at the nucleophilic oxygen atom of 4b via the intermediate A. The second step is the deoxygenation of B to give the arylnitrene D through the intermediate C. Lastly, compound D underwent intramolecular nucleophilic cyclization to deliver 3-aryl 2,1-benzisoxazole 10 (Scheme 4).

Scheme 4

Proposal for the reaction mechanism of the cyclization of nitroaromatic 4b with triethyl phosphite

The chemical structure of compound 10 was elucidated by the analysis of its ¹H NMR and the ¹H,¹H-COSY spectra (Fig. 1), which displayed the presence of two doublets at δ = 6.05 and 6.42 ppm with coupling constant ³J = 7.9 Hz for 5-H and 6-H protons. We deduce that both 5-H and 6-H protons are ortho to each other. In the same manner, both 3′-H and 4′-H protons are adjacent to each other.

Fig. 1

Section of the ¹H,¹H-COSY spectrum of 10

The HSQC spectrum of 10 (Fig. 2) could be used to identify the carbon atoms that are directly attached to hydrogen atoms. The HSQC spectrum revealed the carbons C-5, C-6, C-3′, C-6′, and C-4′ at δ = 99.1, 106.3, 113.1, 117.2, and 117.9 ppm, respectively.

Fig. 2

Section of the HSQC spectrum of 10

The HMBC spectrum of compound 10 is used to determine the correlation between the carbons and the hydrogen atoms. From the ¹³C NMR and HMBC (Fig. 3) spectra the proton 5-H showed strong ³J_CH-correlations with C-3a at δ = 112.3 ppm and C-7 at δ = 147.4 ppm. On the other hand, the proton 6-H exhibited strong ³J_CH-correlation with C-4 at δ = 142.3 ppm. This means that both 5-H and 6-H protons are attached with the same benzene ring. In addition, there are strong ³J_CH-correlations with 6′-H and both C-4′ at δ = 117.9 ppm and C-3 at δ = 164.1 ppm, respectively. The proton 3′-H displayed strong ³J_CH-correlation with C-3 at δ = 164.1 ppm (Fig. 3).

Fig. 3

Section of the HMBC spectrum of 10

By repeating the reaction using the 2-nitrobenzophenone 13a as a monomethoxy substituent with triethyl phosphite at (300 W, 20 bar), 200 °C for 35 min the reaction gave two products, methoxyphosphoramidate 14a and 3-methoxyphenyl 2,1-benzisoxazole 15a in 55 and 34 % yields (Table 1, entry 1), respectively. Further experiments were carried out utilizing trimethoxy substituents 13b for 25 min. In this case, the reaction also resulted in a mixture of trimethoxyphosphoramidate 14b and 3-aryl 2,1-benzisoxazole 15b with 58 and 35 % yields (Table 1, entry 2), respectively.

Table 1 Reaction of 2-nitrobenzophenone 13 with triethyl phosphite under microwave conditions

As another example, the discussion of the spectral data of 3-methoxyphenyl 2,1-benzisoxazole 15a is given. The ¹H NMR and ¹H,¹H-COSY spectra of 15a (Fig. 4) showed that two doublets of doublets at δ = 6.97 and 7.30 ppm with two coupling constants ³J = 6.4 Hz and ³J = 8.8 Hz for 5′-H and 4′-H protons, respectively. Also, there is a doublet at δ = 7.74 ppm with ³J = 8.8 Hz for 6′-H. This indicates that 5′-H proton is ortho to both 4′-H and 6′-H protons. On the other hand 4-H and 5-H as well as 5-H and 6-H protons are adjacent to each other.

Fig. 4

Section of the ¹H,¹H-COSY spectrum of 15a

The HSQC spectrum of 15a showed the carbons C-7, C-5, C-4, C-6 appear at δ = 111.9, 121.4, 130.7, and 132.1 ppm, respectively. In addition, the HSQC spectrum revealed the carbons C-3′, C-6′, C-5′, and C-5′ at δ = 115.3, 122.8, 123.5 and 130.8 ppm, respectively (Fig. 5).

Fig. 5

Section of the HSQC spectrum of 15a

The ¹³C NMR and HMBC spectra of compound 15a showed that the proton 6′-H exhibited strong ³J_CH-correlations with C-4′ at δ = 130.8 ppm, C-2′ at δ = 158.0 ppm and C-3 at δ = 163.6 ppm, respectively. The proton 4-H showed strong ³J_CH-correlations with both C-6 at δ = 132.1 ppm and C-3 at δ = 163.6 ppm as shown in (Fig. 6).

Fig. 6

The HMBC spectrum of 15a

Experimental

Melting points were measured on a Büchi melting point apparatus B-545 with open capillary tubes and are uncorrected. IR spectra were recorded on a Perkin–Elmer Spectrum One (FT-IR- Spectrometer). UV–VIS spectra were measured with a Varian Cary 50. ¹H and ¹³C NMR spectra were recorded at 300 (75) MHz on a Varian^Inova Spectrometer with CDCl₃ or DMSO as solvent and TMS as internal standard. The ¹H and ¹³C chemical shifts were referenced to residual solvent signals at δH/C 7.26/77.00 (CDCl₃) and at δH/C 2.49/39.50 (DMSO). HSQC-, HMBC-, and COSY spectra were recorded on a Varian^Inova at 300 MHz. Coupling constants J [Hz] were directly taken from the spectra and are averaged. Low-resolution electron impact mass spectra (MS) and exact mass electron impact mass spectra (HRMS) were recorded on a Finnigan MAT 90 spectrometer operating at an ionization potential of 70 eV. Elemental analyses were carried out at the Institute of Organic and Biomolecular Chemistry, Göttingen University, Germany. Temperatures are reported as inner temperatures. Solvents used in extraction and purification were distilled prior to use. Thin-layer chromatography (TLC) was performed on Alugram SIL G/UV 254 (Macherey and Nagel). Compounds were visualized with UV light (λ = 254 nm) and/or by immersion in an ethanolic vanillin solution followed by heating. Products were purified by flash chromatography on silica gel 60 M, 230–400 mesh (Macherey and Nagel).

Bis-(2,5-dimethoxyphenyl)methanol (3a)

A mixture of tert-butyllithium 1.5 M in pentane (30.0 mmol) in dry THF (25 ml) was added dropwise over 30 min to a magnetically stirred solution of a 2-bromo-1,4-dimethoxybenzene (1) (20.0 mmol) in dry THF (25 ml) at −78 °C and under argon. After stirring for 30 min a solution of 1,4-dimethoxybenzaldehyde (2a) (16.0 mmol) in dry THF (25 ml) was added dropwise and the reaction mixture was stirred for 20 min at −78 °C and then allowed to warm up to room temperature with stirring for 3 h. After quenching with ammonium chloride solution (80 ml), the reaction mixture was extracted with tert-butylmethyl ether (4 × 80 ml). The combined organic layers were washed with brine (1 × 50 ml), dried over anhydrous MgSO₄ and concentrated in vacuo. The crude products were purified by column chromatography (SiO₂; cyclohexane/EtOAc = 2:1) to give compound 3a in 72 % yield as pale yellow crystals. R _f (cyclohexane/EtOAc = 1:1) 0.62. Mp. 89–90 °C, IR (ATR): 3,528 cm⁻¹ (OH), 1,228 cm⁻¹ (C–O). λ _max (MeCN) (log ε) 208 (4.22), 293 (3.70) nm. ¹H NMR (300 MHz, CDC1₃): δ = 3.61 (br, 1H, OH), 3.76 (s, 6H, 5-OCH₃, 5′-OCH₃), 3.82 (s, 6H, 2-OCH₃, 2′-OCH₃), 6.27 (d, 1H, ³ J _HH = 1.9 Hz, CH-OH), 6.77 (dd, 2H, ³ J _HH = 8.8 Hz, ⁴ J _HH = 2.8 Hz, 4-H, 4′-H), 6.81 (d, 2H, ³ J _HH = 8.8 Hz, 3-H, 3′-H), 6.84 (d, 2H, ⁴ J _HH = 2.8 Hz, 6-H, 6′-H). ¹³C NMR (300 MHz, CDC1₃): δ = 55.9 (5-OCH₃, 5′-OCH₃), 56.3 (2-OCH₃, 2′-OCH₃), 67.7 (CH-OH), 111.8 (C-3, C-3′), 113.1 (C-4, C-4′), 114.4 (C-6, C-6′), 132.3 (C-1, C-1′), 151.4 (C-2, C-2′), 153.9 (C-5, C-5′). m/z (EI, 70 eV) 304 (100, M⁺), 165 (85), 139 (35), 138 (25 %). Anal. Calcd for C₁₇H₂₀O₅ (304.1305): C, 66.79; H, 6.52. Found: C, 66.89; H, 6.41.

Bis-(2,5-dimethoxyphenyl)methanone (4a)

Potassium dichromate (4.13 mmol) was dissolved in glacial acetic acid (20 ml). A solution of bis-(2,5-dimethoxyphenyl)methanol (3a) (8.22 mmol) in toluene (40 ml) was added dropwise at room temperature. The reaction mixture was heated for 3 h at 85 °C. After cooling to room temperature, the reaction mixture was filtered off and extracted with water (3 × 100 ml) to remove the acetic acid and the chromium salts. Then the mixture was extracted with ethyl acetate (3 × 60 ml). The combined organic layers were washed with 10 % NaOH solution (1 × 50 ml), dried over anhydrous MgSO₄ and concentrated in vacuo. The crude products were purified by column chromatography (SiO₂; cyclohexane/EtOAc = 3:1) to give compound 4a in 89 % yield as yellow crystals. R _f (cyclohexane/EtOAc = 2:1) 0.46. Mp. 86–87 °C, IR (ATR): 1,640 cm⁻¹ (C = O), 1,290 cm⁻¹ (C–O). λ _max (MeCN) (log ε) 225 (3.73), 341 (2.94) nm. ¹H NMR (300 MHz, CDC1₃): δ = 3.64 (s, 6H, 5-OCH₃, 5′-OCH₃), 3.84 (s, 6H, 2-OCH₃, 2′-OCH₃), 6.85 (d, 2H, ³ J _HH = 8.9 Hz, 3-H, 3′-H), 6.99 (dd, 2H, ³ J _HH = 8.9 Hz, ⁴ J _HH = 3.2 Hz, 4-H, 4′-H), 7.08 (d, 2H, ⁴ J _HH = 3.2 Hz, 6-H, 6′-H). ¹³C NMR (300 MHz, CDC1₃): δ = 56.1 (2-OCH₃, 2′-OCH₃), 56.8 (5-OCH₃, 5′-OCH₃), 113.5 (C-3, C-3′), 114.8 (C-6, C-6′), 118.8 (C-4, C-4′), 131.1 (C-1, C-1′), 152.9 (C-5, C-5′), 153.7 (C-2, C-2′), 195.1 (C = O). m/z (EI, 70 eV) 302 (100, M⁺), 165 (85), 151 (65 %). Anal. Calcd for C₁₇H₁₈O₅ (302.1149): C, 67.54; H, 6.00. Found: C, 67.35; H, 5.86.

1,4,5,8-Tetramethoxyfluoren-9-one (5)

Bis-(2,5-dimethoxyphenyl)methanone (4a) (0.60 mmol), Pd(OAc)₂ (0.06 mmol), and HPMV [16] (0.06 mmol) were added to a two-necked flask that contained acetic acid (6 ml). The reaction mixture was purged with a stream of oxygen for approximately 5 min. Subsequently, the reaction was then stirred at 120 °C in an oil bath for 16 h. The reaction mixture was diluted with water (50 ml) and extracted with tert-butyl methyl ether (4 × 40 ml). The combined organic layers were washed with water (2 × 50 ml) and potassium carbonate (1 × 50 ml), dried over anhydrous MgSO₄ and concentrated in vacuo. The crude product was purified by column chromatography (SiO₂; cyclohexane/EtOAc = 1:1) to give compound 5 in 89 % yield as orange crystals. R _f (CH₂Cl₂/EtOAc = 1:1) 0.29. Mp. 133–134 °C, IR (ATR): 1,692 cm⁻¹ (C = O), 1,265 cm⁻¹ (C–O). λ _max (MeCN) (log ε) 443 (3.83), 360 (3.53), 245 (3.82), 214 (3.80) nm. ¹H NMR (300 MHz, CDC1₃): δ = 3.91 (s, 6H, 1-OCH₃, 8-OCH₃), 3.96 (s, 6H, 4-OCH₃, 5-OCH₃), 6.86 (d, 2H, ³ J _HH = 8.9 Hz, 2-H, 7-H), 7.10 (d, 2H, ³ J _HH = 8.9 Hz, 3-H, 6-H). ¹³C NMR (300 MHz, CDC1₃): δ = 56.8 (1-OCH₃, 8-OCH₃), 58.8 (4-OCH₃, 5-OCH₃), 115.3 (C-2, C-7), 122.0 (C-8a, C-9a), 124.0 (C-3, C-6′), 131.8 (C-4a, C-4b), 149.3 (C-1, C-8), 153.7 (C-4, C-5), 189.9 (C = O). m/z (EI, 70 eV) 300 (60, M⁺), 285 (M⁺-CH₃, 100), 242 (16 %). HRMS (EI, 70 eV): (M⁺) C₁₇H₁₆O₅ found 300.0996 requires 300.0998.

1,4,5,8-Tetrahydroxyfluoren-9-one (6) [13]

A mixture of 1,4,5,8-tetramethoxyfluoren-9-one (5) (0.90 mmol), acetic acid (3 ml) and 48 % HBr (9 ml) was heated under reflux for 8 h. After cooling, the dark reaction mixture was poured into water (100 ml) and filtered off. The filtrate was extracted with tert-butyl methyl ether (4 × 30 ml), The ethereal extracts were dried over anhydrous MgSO₄ and concentrated in vacuo. The crude product was purified by column chromatography (SiO₂; cyclohexane/EtOAc = 1:3) to give compound 6 in 87 % yield as red crystals. R _f (cyclohexane/EtOAc = 2:3) 0.62. Mp. 238–239 °C, IR (ATR): 3,300–2,980 cm⁻¹ (OH), 1,696 cm⁻¹ (C = O), 1,259 cm⁻¹ (C–O). λ _max (MeCN) (log ε) 474 (3.22), 364 (2.95), 243 (3.98), 217 (3.72) nm. ¹H NMR (300 MHz, CDC1₃): δ = 6.68 (d, 2H, ³ J _HH = 8.9 Hz, 2-H and 7-H), 6.89 (d, 2H, ³ J _HH = 8.9 Hz, 3-H and 6-H), 9.62 (s, 2H, 4-OH and 5-OH), 10.69 (s, 2H, 1-OH and 8-OH). ¹³C NMR (300 MHz, CDC1₃): δ = 118.2 (C-8a and C-9a), 120.6 (C-2 and C-7), 126.0 (C-4a and C-4b), 126.3 (C-3 and C-6), 143.8 (C-4 and C-5), 151.3 (C-1 and C-8), 191.2 (C = O). m/z (EI, 70 eV) 244 (100, M⁺), 222 (75), 177 (18), 150 (15), 28 (M⁺-C₁₂H₈O₄, 100 %). HRMS (EI, 70 eV): (M⁺) C₁₃H₈O₅ found 244.0331 requires 244.0339.

3,6-Dimethoxyphthalic anhydride (7)

Method A

A mixture of 1,4,5,8-tetramethoxyfluoren-9-one (5) (0.44 mmol) in acetonitrile (30 ml) was heated at 80 °C. CAN [18] (5.33 mmol) dissolved in water (4 ml) was added. The reaction mixture was kept under reflux for 30 min. After cooling, the dark-blood mixture was poured over ethylacetate/water (80:150). The combined organic layers were washed with water (5 × 50 ml), dried over anhydrous MgSO₄ and concentrated in vacuo. The crude product was purified by column chromatography (SiO₂; cyclohexane/EtOAc = 1:2) to give compound 7 in 48 % yield as yellow crystals.

Method B

A solution of CAN [19] (11.8 mmol) in water (7 ml) was added to a stirred solution of 1,4,5,8-tetramethoxyfluoren-9-one (5) (0.99 mmol) in acetonitrile (15 ml). After 4 h, the thin-layer chromatography showed complete consumption of the starting materials. Water (100 ml) was added to the red solution and extracted with dichloromethane (3 × 50 ml). The combined organic layers were washed with water (5 × 50 ml), dried over anhydrous MgSO₄ and concentrated in vacuo. The crude product was purified by column chromatography (SiO₂; cyclohexane/EtOAc = 1:2) to give compound 7 in 64 % yield as yellow crystals. R _f (cyclohexane/EtOAc = 1:3) 0.41. Mp. 252–253 °C, IR (ATR): 1,769, 1,729 cm⁻¹ (2 C = O), 1,276 cm⁻¹ (C–O). λ _max (MeCN) (log ε) 317 (3.17) nm. ¹H NMR (300 MHz, CDC1₃): δ = 3.96 (s, 6H, 3-OCH₃, 5-OCH₃), 7.63 (s, 2H, 4-H, 5-H). ¹³C NMR (300 MHz, CDC1₃): δ = 57.4 (3-OCH₃, 6-OCH₃), 117.5 (C-2a, C-6a), 123.3 (C-4, C-5), 151.9 (C-3, C-6), 161.2 (C-2, C-7). m/z (EI, 70 eV) 208 (100, M⁺), 179 (24), 163 (M⁺-COOH, 62), 162 (64), 134 (49 %). HRMS (EI, 70 eV): (M⁺) C₁₀H₈O₅ found 208.0359 requires 208.0369.

General synthetic procedure under microwave conditions of compounds (10, 14a,b and 15a,b)

A mixture of (3,6-dimethoxy-2-nitrophenyl)(2′,5′-dimethoxyphenyl)methanone (4b) (1 mmol) or (2,5-dimethoxyphenyl)(2′-nitrophenyl)methanone (13a,b) (1 mmol), triethyl phosphite (6 mmol) and/or without toluene (3 ml) was sealed in a 10-ml septum vial and irradiated with microwaves (Discover by CEM, 2,450 MHz, 300 W, 20 bar, 200 °C). After removal of triethyl phosphite and triethyl phosphate at reduced pressure (10⁻¹ mbar) and temperatures between 65 and 80 °C, the residue was diluted with EtOAc (45 ml), washed with water (2 × 50 ml) and brine (3 × 20 ml), dried over anhydrous MgSO₄, and concentrated in vacuo. The remaining residue was purified by column chromatography over silica gel.

3-(2′,5′-Dimethoxyphenyl)-4,7-dimethoxybenzo[c]-2,1-isoxazole (10)

The crude product was purified by column chromatography (SiO₂; petroleum ether/EtOAc = 2:1) to give compound 10 in 71 % yield as yellow crystals. R _f (petroleum ether/EtOAc = 1:1) 0.35. Mp. 150–151 °C, IR (ATR): 1,640, 1,556, 1,503 cm⁻¹ (C = C arom.), 1,266 cm⁻¹ (C–O). λ _max (MeCN) (log ε) 367 (3.49), 334 (3.46), 247 (3.74), 222 (3.77) nm. ¹H NMR (300 MHz, CDC1₃): δ = 3.78 (s, 3H, 7-OCH₃), 3.82 (s, 3H, 5′-OCH₃), 3.84 (s, 3H, 2′-OCH₃), 3.99 (s, 3H, 4-OCH₃), 6.05 (d, 1H, ³ J _HH = 7.9 Hz, 5-H), 6.42 (d, 1H, ³ J _HH = 7.9 Hz, 6-H), 6.99 (1H, d, ³ J _HH = 9.1 Hz, 3′-H), 7.06 (dd, 1H, ³ J _HH = 9.1 Hz, ⁴ J _HH = 2.9 Hz, 4′-H), 7.14 (d, 1H, ⁴ J _HH = 2.9 Hz, 6′-H). ¹³C NMR (300 MHz, CDC1₃): δ = 55.7 (7-OCH₃), 56.2 (4-OCH₃ and 5′-OCH₃), 56.7 (2′-OCH₃), 99.1 (C-5), 106.3 (C-6), 112.3 (C-3a), 113.1 (C-3′), 117.2 (C-6′), 117.9 (C-4′), 118.1 (C-1′), 142.3 (C-4), 147.4 (C-7), 152.5 (C-5′), 153.2 (C-2′), 153.6 (C-7a), 164.1 (C-3). m/z (EI, 70 eV) 315 (100, M⁺), 284 (M⁺-OCH₃, 20), 165 (15 %). HRMS (EI, 70 eV): (M⁺) C₁₇H₁₇NO₅ found 315.1128 requires 315.1100. Anal. Calcd for C₁₇H₁₇NO₅ (315.1100): 64.74; H, 5.44; N, 4.44. Found: C, 64.65; H, 5.15; N, 4.73.

Diethyl N-2-(2′-methoxybenzoyl)phenylphosphoramidate (14a)

The crude product of 14a was purified by column chromatography (SiO₂; cyclohexane/EtOAc = 1:1) to give compound 14a in 55 % yield as pale yellow crystals. R _f (cyclohexane/EtOAc = 1:1) 0.27. Mp. 105–106 °C, IR (ATR): 1,633, 1,618, 1,577 cm⁻¹ (C = C arom.), 1,252 cm⁻¹ (C–O). λ _max (MeCN) (log ε) 336 (3.31), 262 (3.53), 223 (3.99) nm. ¹H NMR (300 MHz, CDC1₃): δ = 1.36 (t, 6H, ³ J _HH = 7.1 Hz, 2 × CH₃), 3.74 (s, 3H, 2′-OCH₃), 4.17–4.23 (m, 4H, 2 × OCH₂), 6.84 (t, 1H, ³ J _HH = 7.4 Hz, 5-H), 6.98 (d, 1H, ³ J _HH = 8.5 Hz, 4′-H), 7.04 (d, 1H, ³ J _HH = 8.5 Hz, 5′-H), 7.23 (d, 1H, ⁴ J _HH = 1.5 Hz, 6′-H), 7.39 (d, 1H, ³ J _HH = 8.5 Hz, 3′-H), 7.42–7.48 (m, 1H, 3-H, 4-H), 7.52 (d, 1H, ³ J _HH = 7.4 Hz, 6-H), 10.0 (d, 1H, ² J _PH = 10.9 Hz, NH). ¹³C NMR (300 MHz, CDC1₃): δ = 16.4 (d, ³ J _PC = 6.9 Hz, 2 × CH₃), 55.9 (2′-OCH₃), 63.5 (² J _PC = 5.4 Hz, 2 × OCH₂), 111.6 (C-4′), 118.4 (d, ³ J _PC = 2.4 Hz, C-6), 119.9 (C-5), 120.7 (C-5′), 121.8 (d, ³ J _PC = 2.4 Hz, C-1), 129.0 (C-6′), 129.6 (C-1′), 131.8 (C-3′), 135.2 (C-2), 135.3 (C-4), 144.4 (d, ³ J _PC = 2.4 Hz, C-2), 156.8 (C-2′), 200.4 (C = O). Anal. Calcd for C₁₈H₂₂NO₅P (363.3400): C, 59.50; H, 6.10; N, 3.85. Found: C, 59.36; H, 6.02; N, 3.68.

Diethyl N-2-(2′-methoxybenzoyl)-4,5-dimethoxyphenylphosphoramidate (14b)

The crude product of 14b was purified by column chromatography (SiO₂; cyclohexane/EtOAc = 1:2) to give compound 14b in 58 % yield as yellow oil. R _f (cyclohexane/EtOAc = 1:2) 0.24. IR (ATR): 1,627, 1,578 1,507 cm⁻¹ (C = C arom.), 1,276 cm⁻¹ (C–O). λ _max (MeCN) (log ε) 339 (3.52), 262 (3.53) nm. ¹H NMR (300 MHz, CDC1₃): δ = 1.42 (t, 6H, ³ J _HH = 7.2 Hz, 2 × CH₃), 3.76 (s, 3H, 2′-OCH₃), 3.83 (s, 3H, 5-OCH₃), 3.95 (s, 3H, 4-OCH₃), 4.16–4.22 (m, 4H, 2 × OCH₂), 6.80 (s, 1H, 3-H), 6.83 (d, 1H, ³ J _HH = 8.9 Hz, 3′-H), 6.91 (d, 1H, ³ J _HH = 8.9 Hz, 6′-H), 6.94 (s, 1H, 6-H), 7.00 (m, 1H, 5′-H), 7.20 (dd, 1H, ³ J _HH = 8.9 Hz, ⁴ J _HH = 1.8 Hz, 4′-H), 10.24 (d, 1H, ² J _PH = 10.5 Hz, NH). ¹³C NMR (300 MHz, CDC1₃): δ = 16.5 (d, ³ J _PC = 6.9 Hz, 2 × CH₃), 56.3 (2′-OCH₃), 56.4 (4-OCH₃), 56.5 (5-OCH₃), 63.5 (d, ² J _PC = 5.6 Hz, 2 × OCH₂), 101.3 (d, ³ J _PC = 2.1 Hz, C-6), 113.4 (C-3′), 114.1 (d, ² J _PC = 2.3 Hz, C-2), 114.6 (C-6′), 117.1 (C-3), 117.2 (C-4′), 123.2 (C-5′), 131.3 (C-1′), 141.6 (d, ³ J _PC = 2.1 Hz, C-1), 143.0 (C-5), 155.2 (C-2′), 156.7 (C-4), 197.3 (C = O). m/z (EI, 70 eV) 423 (100, M⁺), 392 (55 %). HRMS (EI, 70 eV): (M⁺) C₂₀H₂₆NO₇P found 423.1439 requires 423.1447.

3-(2′-Methoxyphenyl)benzo[c]-2,1-isoxazole (15a)

The crude product of 15a was purified by column chromatography (SiO₂; cyclohexane/EtOAc = 8:1) to give compound 15a in 34 % yield as yellow oil. R _f (cyclohexane/EtOAc = 4:1) 0.44. IR (ATR): 1,632, 1,600, 1,581 cm⁻¹ (C = C arom.), 1,250 cm⁻¹ (C–O). λ _max (MeCN) (log ε) 344 (3.06), 252 (3.93) nm. ¹H NMR (300 MHz, CDC1₃): δ = 3.94 (s, 3H, 2′-OCH₃), 6.97 (dd, 1H, ³ J _HH = 6.4 Hz, ³ J _HH = 8.8 Hz, 2′-H), 7.08 (dd, 1H, ³ J _HH = 8.4 Hz, ⁴ J _HH = 1.6 Hz, 7-H), 7.13 (t, 1H, ³ J _HH = 7.7 Hz, 5-H), 7.30 (dd, 1H, ³ J _HH = 6.3 Hz, ³ J _HH = 8.8 Hz, 5′-H), 7.49 (dt, 1H, ³ J _HH = 7.8 Hz, ⁴ J _HH = 1.6 Hz, 6-H), 7.58 (d, 1H, ³ J _HH = 9.1 Hz, 3′-H), 7.74 (d, 1H, ³ J _HH = 8.9 Hz, 6′-H), 7.83 (dd, 1H, ³ J _HH = 7.8 Hz, ⁴ J _HH = 1.6 Hz, 4-H). 10.30 (d, 1H, ² J _PH = 10.6 Hz, NH). ¹³C NMR (300 MHz, CDC1₃): δ = 55.8 (2′-OCH₃), 111.9 (C-7), 115.3 (C-3′), 116.2 (C-1′), 117.9 (C-3a), 121.4 (C-5), 122.8 (C-6′), 123.5 (C-5′), 130.75 (C-4), 130.77 (C-4′), 132.1 (C-6), 156.6 (C-7a), 158.0 (C-2′), 163.6 (C-3). m/z (EI, 70 eV) 255 (100, M⁺), 196 (23 %). HRMS (EI, 70 eV): (M⁺) C₁₄H₁₁NO₂ found 225.0776 requires 225.0787.

3-(2′-Methoxyphenyl)-5,6-dimethoxybenzo[c]-2,1-isoxazole (15b)

The crude product of 15b was purified by column chromatography (SiO₂; cyclohexane/EtOAc = 2:1) to give compound 15b in 35 % yield as yellow oil. R _f (cyclohexane/EtOAc = 4:1) 0.25. IR (ATR): 1,635, 1,616, 152 cm⁻¹ (C = C arom.), 1,272 cm⁻¹ (C–O). λ _max (MeCN) (log ε) 364 (3.48), 253 (3.75) nm. ¹H NMR (300 MHz, CDC1₃): δ = 3.87 (s, 3H, 2′-OCH₃), 3.93 (s, 3H, 5-OCH₃), 3.98 (s, 3H, 6-OCH₃), 6.88 (s, 1H, 7-H), 6.91 (dd, 1H, ³ J _HH = 9.0 Hz, ³ J _HH = 6.5 Hz, 5′-H), 7.03 (s, 1H, 4-H), 7.52 (d, 1H, ³ J _HH = 9.0 Hz, 3′-H), 7.61 (dd, 1H, ³ J _HH = 9.0 Hz, ³ J _HH = 6.5 Hz, 4′-H). ¹³C NMR (300 MHz, CDC1₃): δ = 55.4 (6-OCH₃), 55.6 (5-OCH₃), 65.2 (2′-OCH₃), 113.7 (C-7), 111.4 (C-4), 115.3 (C-1′), 116.2 (C-3′), 118.2 (C-3a), 123.1 (C-6′), 124.2 (C-5′),144.1 (C-6), 148.3 (C-5), 157.0 (C-7a), 158.4 (C-2′). m/z (EI, 70 eV) 285 (100, M⁺), 254 (M⁺-OCH₃, 65 %). HRMS (EI, 70 eV): (M⁺) C₁₆H₁₅NO₄ found 285.1011 requires 285.1001.