HETEROCYCLES

Paper | Regular issue | Vol. 78, No. 2, 2009, pp. 397-413
Received, 6th August, 2008, Accepted, 6th October, 2008, Published online, 9th October, 2008.
DOI: 10.3987/COM-08-11515

■ Synthesis of Unusual Naphtho[2,1-b]furans and Novel 1H-Benz[e]indolinones via Selective Intramolecular Cyclization

Zhi-qi Cong and Hiroshi Nishino*

Department of Chemistry, Graduate School of Science and Technology, Kumamoto University, Kurokami 2-39-1, Kumamoto 860-8555, Japan

Abstract

The 2-(2-methoxy-1-naphthyl)-3-oxobutanamides were treated with concentrated hydrochloric acid in acetic acid at room temperature to exclusively give the unusual 5-chloronaphtho[2,1-b]furans in moderate to excellent yields. The same reaction was carried out in ethylene glycol at 80 °C to selectively produce the novel 1H-benz[e]indolinones in good yields. The characterization of the products and the reaction pathway of the selective intramolecular cyclization were discussed.

INTRODUCTION
The furan structure is found in numerous natural products.1 Thus, we have a continuing interest in the synthesis of polyfunctionalized furans via the manganese(III)-based oxidative radical cyclization,2 photo-induced transformations3 and Lewis acid-catalyzed cyclization.4 In recent years, we5 and other groups6 have developed various manganese(III)-mediated aromatic substitutions and additions using active methylene species, and we found that the reaction of methoxynaphthalenes with ethyl 3-oxobutanoate mainly gave the substituted product I together with a small amount of the naphtho[2,1-b]furan II (Scheme 1). 5c Using dimethyl malonate also afforded a similar substituted product III and naphthofuranone IV (Scheme 1).6a Very recently, we reported that the oxidation of 2-methoxynaphthalene with manganese(III) acetate in the presence of N-phenyl-3-oxobutanamide gave the directly 3-oxobutanamide-substituted naphthalene V along with a small amount of the naphtho[2,1-b]furan VI and 1H-benz[e]indolinone VII as by-products (Scheme 1).7 Since the naphtho[2,1-b]furan and benz[e]indolinone frameworks are found in a wide range of natural and synthetic products, which exhibit important biological and pharmacological activities,8,9 a facile and convenient procedure for the synthesis of novel functionalized naphtho[2,1-b]furans and benz[e]indolinones is still necessary from the standpoint of its potential utility, though a significant effort has been directed toward the efficient synthesis of various naphtho[2,1-b]furans and benz[e]indolinones.10,11 We now report the selective one-step route to the novel naphtho[2,1-b]furans and benz[e]indolinones by the intramolecular cyclization of 2-(2-methoxy-1-naphthyl)-3-oxobutanamides 1 such as V.

RESULTS AND DISCUSSION
Synthesis of Naphtho[2,1-b]furan Derivatives 3. The 2-(2-methoxy-1-naphthyl)-3-oxobutanamides 1 were prepared by the manganese(III)-mediated oxidative aromatic substitution of the corresponding 2-methoxynaphthalenes with the N-aryl-3-oxobutanamides.7 When 2-acetoxy-2-(2,7-dimethoxy-1-naphthyl)-N-phenyl-3-oxobutanamide (1a) was treated with acetic acid containing a small amount of concentrated hydrobromic acid at room temperature, one product 2 was isolated from the reaction mixture. The molecular ion peaks of 2 appeared at m/z 441 and 443 (relative intensity ca. 1:1) and the elemental analysis was identical to the molecular formula of C22H20BrNO4. The 1H NMR spectrum of 2 showed two peaks at δ = 3.99 and 3.92 ppm, which were assigned to two methoxyl groups, and two AB spin systems (δA = 7.92, δB = 7.18 ppm, JAB = 9.0 Hz and δA’ = 7.83, δB’ = 7.29 ppm, JA’B’ = 9.0 Hz, respectively) in the aromatic region. Other available information includes a peak at δ = 14.63 ppm due to the intramolecular hydrogen-bonded hydroxyl group and a broad peak at δ = 6.69 ppm assigned to a carbamoyl group which disappeared upon deuteration. These results indicated that the cyclization at the methoxyl group did not occur, but the bromine must be introduced at the peri position of the naphthalene ring (Scheme 2).

Using concentrated hydrochloric acid in place of hydrobromic acid resulted in the expected product 3a containing the naphtho[2,1-b]furan structure such as VI in Scheme 1 in a fairly good yield (Scheme 2). The molecular ion peaks of 3a appeared at m/z 365 and 367 (relative intensity ca. 3:1) and the elemental analysis was identical with the molecular formula of C21H16ClNO3. The product 3a showed an α,β-unsaturated carbonyl absorption band at 1638 and 1624 cm-1 in the IR spectrum. In the 1H NMR spectrum, the characteristic ABX pattern at δA = 8.20 (1H, d, JAB = 9.0 Hz), δB = 7.31 (1H, dd, JAB = 9.0, JBX = 2.7 Hz), and δX = 7.82 (1H, d, JBX = 2.7 Hz) ppm was assigned to H-6, H-7, and a downfield shifted H-9, respectively. The most characteristic singlet aromatic proton appeared at δ = 7.95 ppm due to H-4 adjacent to an electronegative substituent, such as a chlorine. A methoxyl and a methyl proton attached to an sp2 carbon appeared at δ = 3.68 (3H, singlet) and δ = 2.62 (3H, singlet) ppm, respectively. In the DEPT spectrum, seven peaks appeared in the aromatic region. This means that the chloro substituent should be introduced at the naphthalene ring. Accordingly, based on the above information, the structure of 3a was determined to be 5-chloro-8-methoxy-2-methyl-1-phenylcarbamoylnaphtho[2,1-b]furan (Scheme 2). The reaction is in contrast to that using hydrobromic acid. Since the desired cyclization occurred in the presence of hydrochloric acid, the process was then applied to various 2-(2-methoxy-1-naphthyl)-3-oxobutanamides 1b-k, which produced the corresponding 5-chloronaphtho[2,1-b]furans 3b-k in moderate to excellent yields (Scheme 3 and Table 1, Entries 2-11).
Synthesis of 1H-Benz[e]indol-2(3H)-one Derivatives 4. Since the 1H-benz[e]indolinone VII was obtained by the manganese(III) oxidation of N-phenyl-3-oxobutanamide in the presence of 2-methoxynaphthalene (Scheme 1), we next examined the selective synthesis of the corresponding 1H-benz[e]indolinones using the (2-methoxynaphthyl)butanamides 1. In order to selectively cyclize at the

nitrogen atom of the amide group, the protection of the acetyl carbonyl group was needed. Therefore, the reaction of 1a was carried out in ethylene glycol in the presence of a small amount of concentrated hydrochloric acid. Fortunately, (2-metoxynaphthyl)butanamide 1a underwent intramolecular cyclization at the nitrogen atom after the protection of the acetyl group to produce a hydroxylactam 4a in good yield. The IR spectrum of 4a exhibited absorption bands at 1693 cm-1 assigned to a typical lactam carbonyl group and at 3375 cm-1 due to a hydroxyl group. In the 1H NMR spectrum of 4a, characteristic AB and ABX splitting patterns appeared at δA = 7.69 (1H, d) and δB = 7.01 ppm (1H, d) with JAB = 9.0 Hz, and at δA = 7.76 (1H, d), δB = 6.95 (1H, dd), and δX = 6.97 ppm (1H, d) with JAB = 8.7 and JBX = 2.7 Hz, respectively, of the naphthalene ring protons along with a typical 1,3-dioxolane protective group at δ = 4.09 (1H, m), δ = 3.85 (2H, m), and δ = 3.54 (1H, m), one methoxyl group at δ = 3.73 (3H, s), a methyl group at δ = 1.78 (3H, s), and a hydroxyl group at δ = 8.98 ppm which disappeared upon deuteration. The 13C NMR spectrum of 4a also showed an amide carbonyl at δ = 166.9, a quaternary carbon attached a hydroxyl group at δ = 85.8, two methylenes of the 1,3-dioxolane at δ = 58.5 and 57.1, a methoxyl group at δ = 55.1, and a methyl group at δ = 21.9 ppm. Therefore, the structure of 4a was determined to be 1-hydroxy-8-methoxy-1-(2’-methyl-1’,3’-dioxolan-2’-yl)-3-phenyl-1H-benz[e]indol-2(3H)-one (Scheme 4) and the combustion analysis was identical to the structural formula of C23H21NO5. A similar reaction of other (2-metoxynaphthyl)butanamides 1b-h,j,k was carried out and the corresponding benz[e]indolinone derivatives 4b-h,j,k were obtained in 56-88% yields, respectively . Thsee results are listed in Table 2.

Oxidation of 3a with Manganese(III) Acetate in Acetic Acid. In the manganese(III)-mediated oxidation of 2-methoxynaphthalene in the presence of N-phenyl-3-oxobutanamide, the reaction did not afford the 2-methylnaphtho[2,1-b]furan, but the 2-acetoxymethyl-substituted naphthofuran VI (Scheme 1).5c,7 We were interested in the acetoxymethylation and examined the oxidation using the 5-chloro-2-methylnaphthofuran 3a as a model compound in order to confirm the benzyl-type oxidation. The oxidation of naphthofuran 3a with manganese(III) acetate was conducted in acetic acid to give the desired acetoxymethylnaphthofuran 5 in a 70% yield (Scheme 5). The 1H NMR spectrum of 5 revealed a typical acetoxymethyl group instead of the methyl group. As a result, it was found that the methylnaphthofuran 3a was subject to the benzyl-type oxidation as well as the oxidation of methylbenzenes.12a-d

Proposed Mechanism for the Formation of 5-Chloronaphtho[2,1-b]furans 3 and Benz[e]indolinones 4.
The reaction with hydrochloric acid in acetic acid gave the unusual chloro-functionalized naphtho[2,1-b]furans 3. To the best of our knowledge, there have been few related examples reported. Only two similar reactions were found for the cyclization of the naphthoquinones.13 The reaction would start from the deacetoxylation to give the naphthoquinonemethide-type intermediate A, which might be cyclized and then demethanol to produce α-hydroxyhemiacetal intermediate B (Scheme 6). The intermediate B would be successively dehydrated to yield the corresponding cation C, which would be nucleophilically attacked by the chloride ion followed by aromatization via dehydration, and finally the 5-chloronaphtho[2,1-b]furans 3 would be produced. The proposed mechanism is illustrated in Scheme 6. It seemed that the formation of (bromonaphthyl)butanamide 2 in the reaction of 1a with hydrobromic acid in Scheme 2 followed a very different reaction pathway. The bromine formed in situ might possibly electrophilically attack the most electronegative position of 1a.
A similar mechanism for the formation of the 1H-benz[e]indolinones 4 was also proposed in Scheme 7. After protection with ethylene glycol, a similar deacetoxylation, as in the case of acetic acid, would occur to produce a similar naphthoquinonemethide-type intermediate D (Scheme 7). The intermediate D would cyclize at the amide nitrogen followed by demethanol, simultaneous aromatization, and then attack of water to finally furnish the corresponding 1H-benz[e]indolinones 4. It is worth noting that the chlorine atom was not introduced into the benz[e]indolinone skeleton using ethylene glycol as the solvent. The reason for this is not clear at this moment, however, the indolinones 4, which were the equivalents of the α-hydroxyhemiacetal intermediate B in Scheme 6, might be difficult to dehydrate and afford the corresponding cation because of the stability of the indolinones 4.14

CONCLUSION
We achieved the selective intramolecular cyclization of the 2-(2-methoxynaphthyl)butanamides 1. When the reaction using concentrated hydrochloric acid was carried out in acetic acid at room temperature, the 5-chloro-substituted naphtho[2,1-b]furans 3 were exclusively produced in good to excellent yields. When the same reaction was conducted in ethylene glycol at 80 °C, the dioxolane-protected 1H-benz[e]indolinones 4 were selectively obtained in good yields. The unusual hydrochloric acid-mediated selective cyclization could be explained by the reaction pathway during the formation of the naphthoquinonmethide-type intermediate such as A and D in Schemes 6 and 7. The selective intramolecular cyclization would guarantee an efficient access to interesting functionalized heterocyclic compounds.

EXPERIMENTAL
General Information. All of the NMR spectra were recorded by a JNM-AL300 FT-NMR spectrometer at 300 MHz for 1H and at 75 MHz for 13C, with tetramethylsilane as the internal standard. The chemical shifts are given in δ values (ppm) and the coupling constants in Hz. The IR spectra of the neat samples were measured by the KBr disc method using a Shimadzu FTIR-8400 spectrometer and expressed in cm-1. The EI MS spectra were recorded by a Shimadzu GCMS-QP5050A with an ionizing voltage of 70 eV. The elemental analyses were performed at the Instrumental Analysis Center, Kumamoto University, Kumamoto, Japan.
The Reaction of (2-Methoxynaphthyl)butanamide 1a with Hydrobromic Acid. To a solution of naphthylbutanamide 1a (0.2 mmol) in acetic acid (10 mL), a portion of the concentrated hydrobromic acid (47%, 0.28 mL) was slowly dropwise-added using a syringe. The mixture was stirred at rt for 1 h, and then water (50 mL) was added. The aqueous solution was extracted with CHCl3 (30 × 3 mL). The combined extracts were successively washed with a saturated aqueous solution of NaHCO3 (30 × 2 mL) and water (30 × 2 mL), then dried over anhydrous MgSO4, and concentrated to dryness. The residue was separated by TLC (Wakogel B-10) while eluting with EtOAc-hexane (2:5, v/v) to give the 2-(8-bromo-2,7-dimethoxy-1-naphthyl)-N-phenyl-3-oxobutanamide (2) in a 38% yield.
2-(8-Bromo-2,7-dimethoxy-1-naphthyl)-N-phenyl-3-oxobutanamide (2): Colorless microcrystals (from Et2O/hexane); mp 136-137 °C; 1H NMR (300 MHz, CDCl3) δ 14.63 (1H, s, enol H), 7.92 (1H, d, J = 9.0 Hz, Naphthalene H), 7.83 (1H, d, J = 9.0 Hz, Naphthalene H), 7.29 (1H d, J = 9.0 Hz, Naphthalene H), 7.18 (1H, d, J = 9.0 Hz, Naphthalene H), 7.3-7.0 (5H, m, aromatic H), 6.69 (1H, br, s, NH), 3.99 (3H, s, OCH3), 3.92 (3H, s, OCH3), 1.49 (3H, s, CH3); 13C NMR (75 MHz, CDCl3) δ 170.8, 170.7, 158.4, 156.1, 137.5, 132.8, 132.2, 130.4, 128.7, 126.5, 124.1, 120.9, 115.4 111.4, 111.3, 105.4, 100.1, 57.0, 56.6, 19.7; IR (CHCl3) 3404, 1636, 1612 cm-1; MS m/z (rel intensity) 441 (M, 7), 443 (M, 7). Anal. Calcd for C22H20BrNO4: C, 59.74; H, 4.56; N, 3.17. Found: C, 59.42; H, 4.51; N, 3.20.
The Reaction of (2-Methoxynaphthyl)butanamides 1a-k with Hydrochloric Acid. General Procedure for the Synthesis of the 5-Chloronaphtho[2,1-b]furans 3. To a solution of the butanamide 1 (0.2 mmol) in acetic acid (10 mL), a portion of the concentrated hydrochloric acid (36%, 0.34 mL) was slowly dropwise-added using a syringe. The reaction mixture was stirred at rt for 5 h and a precipitate was formed. Water (50 mL) was then added to the reaction mixture, and the produced precipitate was filtered and washed with water. The crude product was dried under vacuum and further purifed by recrystallization from the appropriate solvents.
5-Chloro-8-methoxy-2-methyl-1-phenylcarbamoylnaphtho[2,1-b]furan (3a): Colorless needles (from CHCl3); mp 227-228 °C; 1H NMR (300 MHz, DMSO-d6) δ 10.71 (1H, s, NH), 8.20 (1H, d, J = 9.0 Hz, H-6), 7.95 (1H, s, H-4), 7.82 (1H, d, J = 2.7 Hz, H-9), 7.79 (2H, m, H-2’, 6’), 7.39 (2H, m, H-3’, 5’), 7.31 (1H, dd, J = 9.0, 2.7 Hz, H-7), 7.14 (1H, m, H-4’), 3.68 (3H, s, OCH3), 2.62 (3H, s, CH3); 13C NMR (75 MHz, DMSO-d6) δ 162.7, 158.3, 154.9, 150.0, 138.8, 128.9, 128.5, 127.6, 126.6, 124.1, 122.1, 119.7, 119.3, 117.4, 115.7, 110.4, 104.3, 54.9, 13.3; IR (KBr) 3180-3000, 1638, 1624 cm-1; MS m/z (rel intensity) 365 (M, 81), 367 (M, 27). Anal. Calcd for C21H16ClNO3: C, 68.95; H, 4.41; N, 3.83. Found: C, 68.70; H, 4.38; N, 3.89.
1-(2’-Chlorophenylcarbamoyl)-5-chloro-8-methoxy-2-methylnaphtho[2,1-b]furan (3b): Colorless needles (from EtOAc/hexane); mp 195-196 °C; 1H NMR (300 MHz, CDCl3) δ 8.66 (1H, m, H-6’), 8.26 (1H, d, J = 9.0 Hz, H-6), 8.19 (1H, br, s, NH), 7.89 (1H, d, J = 2.7 Hz, H-9), 7.59 (1H, s, H-4), 7.44 (1H, m, H-3’), 7.38 (1H, m, H-5’), 7.21 (1H, dd, J = 9.0, 2.7 Hz, H-7), 7.13 (1H, m, H-4’), 3.79 (3H, s, OCH3), 2.75 (3H, s, CH3); 13C NMR (75 MHz, CDCl3) δ 163.3, 158.7, 155.8, 151.0, 134.4, 129.6, 129.3, 128.8, 128.0, 127.1, 125.2, 123.0, 122.9, 121.4, 118.7, 117.7, 115.6, 110.0, 103.9, 55.3, 13.9; IR (KBr) 3223, 1647, 1622 cm-1; MS m/z (rel intensity) 399 (M, 61), 401 (M, 20). Anal. Calcd for C21H15Cl2NO3: C, 63.02; H, 3.78; N, 3.50. Found: C, 62.83; H, 3.75; N, 3.42.
1-(4’-Chlorophenylcarbamoyl)-5-chloro-8-methoxy-2-methylnaphtho[2,1-b]furan (3c): Colorless needles (from CHCl3); mp over 300 °C; 1H NMR (300 MHz, DMSO-d6) δ 10.85 (1H, s, NH), 8.22 (1H, d, J = 9.0 Hz, H-6), 7.98 (1H, s, H-4), 7.85 (2H, m, H-2’,6’), 7.82 (1H, d, J = 2.7 Hz, H-9), 7.48 (2H, m, H-3’,5’), 7.33 (1H, dd, J = 9.0, 2.7 Hz, H-7), 3.72 (3H, s, OCH3), 2.64 (3H, s, CH3); 13C NMR (75 MHz, DMSO-d6) δ 162.7, 158.3, 155.2, 149.9, 137.8, 128.9, 128.4, 127.7, 127.6, 126.6, 122.1, 121.3, 119.2, 117.4, 115.5, 110.4, 104.2, 55.0, 13.4; IR (KBr): 3254, 1645, 1624 cm-1; MS: m/z (rel intensity) 400 (M+1, 34), 402 (M+1, 15). Anal. Calcd for C21H15Cl2NO3: C, 63.02; H, 3.78; N, 3.50. Found: C, 62.63; H, 3.72; N, 3.40.
5-Chloro-1-(2’-methoxyphenylcarbamoyl)-8-methoxy-2-methylnaphtho[2,1-b]furan (3d): Colorless microcrystals (from CHCl3/hexane); mp 176.5-177 °C; 1H NMR (300 MHz, CDCl3) δ 8.62 (1H, m, H-6’), 8.29 (1H, br, s, NH), 8.24 (1H, d, J = 9.3 Hz, H-6), 7.91 (1H, br. s, H-4), 7.57 (1H, br. s, H-9), 7.18 (1H, br. d, J = 9.3 Hz, H-7), 7.11 (1H, m, H-4’), 7.07 (1H, m, H-5’), 6.92 (1H, m, H-3’), 3.82 (3H, s, OCH3), 3.75 (3H, s, OCH3), 2.71 (3H, s, CH3); 13C NMR (75 MHz, CDCl3) δ 162.8, 158.6, 155.3, 150.8, 148.0, 129.2, 128.9, 127.4, 127.0, 124.3, 122.9, 121.2, 119.9, 118.9, 117.6, 116.0, 110.0, 103.9, 55.6, 55.2, 13.6; IR (KBr) 3229, 1647, 1624 cm-1; MS m/z (rel intensity) 395 (M, 89), 397 (M, 28). Anal. Calcd for C22H18ClNO4: C, 66.75; H, 4.58; N, 3.54. Found: C, 66.77; H, 4.53; N, 3.63.
5-Chloro-1-(4’-methoxyphenylcarbamoyl)-8-methoxy-2-methylnaphtho[2,1-b]furan (3e): Colorless microcrystals (from CHCl3); mp 269-270 °C; 1H NMR (300 MHz, DMSO-d6) δ 10.56 (1H, s, NH), 8.20 (1H, d, J = 9.3 Hz, H-6), 7.95 (1H, s, H-4), 7.85 (1H, br. s, H-9), 7.70 (2H, m, H-2’,6’), 7.32 (1H, dd, J = 9.3, 2.7 Hz, H-7), 6.97 (2H, m, H-3’,5’), 3.75 (3H, s, OCH3), 3.71 (3H, s, OCH3), 2.62 (3H, s, CH3); 13C NMR (75 MHz, DMSO-d6) δ 162.1, 158.3, 155.8, 154.7, 150.0, 132.0, 128.5, 127.6, 126.6, 122.1, 121.3, 119.4, 117.4, 115.8, 114.1, 110.4, 104.3, 55.3, 55.1, 13.4; IR (KBr) 3271, 1643, 1622 cm-1; MS m/z (rel intensity) 396 (M+1, 87), 398 (M+1, 30). Anal. Calcd for C22H18ClNO4: C, 66.75; H, 4.58; N, 3.54. Found: C, 66.65; H, 4.53; N, 3.51.
5-Chloro-8-methoxy-1-(2’-methylphenylcarbamoyl)-2-methylnaphtho[2,1-b]furan (3f): Colorless microcrystals (from EtOAc/hexane); mp 239-240 °C; 1H NMR (300 MHz, DMSO-d6) δ 10.18 (1H, br. s, NH), 8.20 (1H, d, J = 9.3 Hz, H-6), 7.96 (1H, d, J = 2.7 Hz, H-9), 7.95 (1H, s, H-4), 7.54 (1H, m, H-6’), 7.33 (1H, dd, J = 9.3, 2.7 Hz, H-7), 7.31-7.20 (3H, m, arom H), 3.81 (3H, s, OCH3), 2.72 (3H, s, CH3), 2.33 (3H, s, CH3); 13C NMR (75 MHz, DMSO-d6) δ 163.0, 158.3, 154.7, 150.0, 135.9, 133.1, 130.6, 128.6, 127.6, 126.6, 126.3, 126.0, 122.1, 119.6, 117.4, 115.5, 110.4, 104.5, 55.3, 18.3, 13.6; IR (KBr) 3258, 1643, 1624 cm-1; MS m/z (rel intensity) 379 (M, 15), 381 (M, 8). Anal. Calcd for C22H18ClNO3: C, 69.57; H, 4.78; N, 3.69. Found: C, 69.35; H, 4.71; N, 3.62.
5-Chloro-8-methoxy-1-(4’-methylphenylcarbamoyl)-2-methylnaphtho[2,1-b]furan (3g): Colorless needles (from CHCl3/hexane); mp 248-249 °C; 1H NMR (300 MHz, DMSO-d6) δ 10.61 (1H, s, NH), 8.20 (1H, d, J = 9.0 Hz, H-6), 7.96 (1H, s, H-4), 7.83 (1H, d, J = 2.4 Hz, H-9), 7.67 (2H, m, H-2’,6’), 7.31 (1H, dd, J = 9.0, 2.4 Hz, H-7), 7.19 (2H, m, H-3’, 5’), 3.70 (3H, s, OCH3), 2.61 (3H, s, CH3), 2.29 (3H, s, CH3); 13C NMR (75 MHz, DMSO-d6) δ 162.4, 158.3, 154.8, 149.9, 136.3, 133.1, 129.3, 128.5, 127.6, 126.6, 122.1, 119.8, 119.4, 117.4, 115.8, 110.4, 104.3, 55.0, 20.6, 13.4; IR (KBr) 3254, 1639, 1624 cm-1; MS m/z (rel intensity) 380 (M+1, 78), 381 (M+1, 24). Anal. Calcd for C22H18ClNO3: C, 69.57; H, 4.78; N, 3.69. Found: C, 69.18; H, 4.75; N, 3.65.
5-Chloro-8-methoxy-2-methyl-1-(2’-nitrophenylcarbamoyl)naphtho[2,1-b]furan (3h): Yellow needles (from EtOAc/hexane); mp 239-240 °C; 1H NMR (300 MHz, DMSO-d6) δ 11.12 (1H, s, NH), 8.22 (1H, d, J = 9.3 Hz, H-6), 8.04 (1H, m, H-3’), 7.99 (1H, s, H-4), 7.90 (1H, d, J = 2.7 Hz, H-9), 7.80 (1H, m, H-5’), 7.64 (1H, m, H-6’), 7.50 (1H, m, H-4’), 7.33 (1H, dd, J = 9.3, 2.7 Hz, H-7), 3.81 (3H, s, OCH3), 2.75 (3H, s, CH3); 13C NMR (75 MHz, DMSO-d6) δ 162.9, 158.4, 156.8, 150.2, 143.8, 134.1, 130.2, 128.6, 128.0, 126.5, 126.3, 126.0, 125.0, 122.2, 119.0, 117.6, 114.5, 110.3, 104.9, 55.4, 13.6; IR (KBr) 3233, 1647, 1625, 1526 cm-1; MS m/z (rel intensity) 411 (M+1, 47), 413 (M+1, 29). Anal. Calcd for C21H15ClN2O5: C, 61.40; H, 3.68; N, 6.82. Found: C, 61.42; H, 4.03; N, 6.42.
5-Chloro-1-(4’-fluorophenylcarbamoyl)-8-methoxy-2-methylnaphtho[2,1-b]furan (3i): Colorless needles (from CHCl3); mp 283-283.5 °C; 1H NMR (300 MHz, DMSO-d6) δ 10.76 (1H, s, NH), 8.20 (1H, d, J = 9.3 Hz, H-6), 7.95 (1H, s, H-4), 7.82 (1H, d, J = 2.7 Hz, H-9), 7.80 (2H, m, H-2’,6’), 7.31 (1H, dd, J = 9.3, 2.7 Hz, H-7), 7.25 (2H, m, H-3’,5’), 3.70 (3H, s, OCH3), 2.63 (3H, s, CH3); 13C NMR (75 MHz, DMSO-d6) δ 162.5, 158.3, 155.0, 150.0, 135.2, 135.1, 128.4, 127.7, 126.6, 122.1, 121.6, 121.5, 119.3, 117.4, 115.7, 115.6, 115.4, 110.4, 104.3, 55.0, 20.6, 13.4; IR (KBr) 3250, 1643, 1622 cm-1; MS m/z (rel intensity) 383 (M, 74), 385 (M, 12). Anal. Calcd for C21H15ClFNO3: C, 65.72; H, 3.94; N, 3.65. Found: C, 65.54; H, 4.07; N, 3.53.
5-Chloro-7-methoxy-2-methyl-1-phenylcarbamoylnaphtho[2,1-b]furan (3j): Colorless needles (from CHCl3); mp 275-276 °C; 1H NMR (300 MHz, DMSO-d6) δ 10.63 (1H, s, NH), 8.28 (1H, d, J = 9.3 Hz, H-9), 8.07 (1H, s, H-4), 7.74 (2H, m, H-2’,6’), 7.53 (1H, d, J = 2.4 Hz, H-6), 7.34 (2H, m , H-3’,5’), 7.30 (1H, dd, J = 9.3, 2.4 Hz, H-8), 7.09 (1H, m, H-4’), 3.86 (3H, s, OCH3), 2.57 (3H, s, CH3); 13C NMR (75 MHz, DMSO-d6) δ 162.7, 157.4, 155.3, 148.3, 138.8, 128.9, 128.6, 126.2, 126.1, 124.1, 121.8, 120.3, 119.9, 119.2, 115.5, 113.2, 104.0, 55.3, 13.5; IR (KBr) 3246, 1647, 1625 cm-1; MS m/z (rel intensity) 365 (M, 50), 367 (M, 16). Anal. Calcd for C21H16ClNO3: C, 68.95; H, 4.41; N, 3.83. Found: C, 68.87; H, 4.36; N, 3.80.
5-Chloro-2-methyl-1-phenylcarbamoylnaphtho[2,1-b]furan (3k): Colorless microcrystals (from CHCl3/hexane); mp 268-268.5 °C; 1H NMR (300 MHz, DMSO-d6) δ 10.71 (1H, s, NH), 8.41 (1H, m, H-6), 8.31 (1H, m, H-9), 8.17 (1H, s, H-4), 7.80 (2H, m, H-2’,6’), 7.68 (2H, m, H-7, 8), 7.40 (2H, m, H-3’,5’), 7.16 (1H, m, H-4’), 2.64 (3H, s, CH3); 13C NMR (75 MHz, DMSO-d6) δ 162.6, 155.3, 149.4, 138.8, 128.9, 127.6, 127.1, 127.0, 126.2, 124.8, 124.3, 124.1, 120.1, 119.9, 115.8, 113.0, 13.4; IR (KBr) 3290, 1647 cm-1; MS m/z (rel intensity) 335 (M, 37), 337 (M, 12). Anal. Calcd for C20H14ClNO2: C, 71.54; H, 4.20; N, 4.17. Found: C, 71.26; H, 4.25; N, 4.15.
General Procedure for the Synthesis of 1H-Benz[e]indolinones 4. To a solution of 1 (0.2 mmol) in ethylene glycol (10 mL), a portion of the concentrated hydrochloric acid (36%, 0.34 mL) was slowly dropwise-added using a syringe at rt. The mixture was then heated at 80 °C for 1 h with stirring. After cooling, water (50 mL) was added. The formed precipitates were filtered and dried under vacuum. The crude product was further purified by recrystallization from the appropriate solvents.
1-Hydroxy-8-methoxy-1-(2’-methyl-1’,3’-dioxolan-2’-yl)-3-phenyl-1H-benz[e]indol-2(3H)-one (4a): Colorless microcrystals (from Et2O/hexane); mp 167-168 °C; 1H NMR (300 MHz, CDCl3) δ 8.98 (1H, s, OH), 7.76 (1H, d, J = 8.7 Hz, H-6), 7.69 (1H, d, J = 9.0 Hz, H-5), 7.64 (2H, m, H-2’,6’), 7.34 (2H, m, H-3’,5’), 7.14 (1H, m, H-4’), 7.01 (1H, d, J = 9.0 Hz, H-4), 6.97 (1H, d, J = 2.7 Hz, H-9), 6.95 (1H, dd, J = 8.7, 2.7 Hz, H-7), 4.09 (1H, m, H-CH), 3.85 (2H, m, CH2), 3.73 (3H, s, OCH3), 3.54 (1H, m, H-CH), 1.78 (3H, s, CH3); 13C NMR (75 MHz, CDCl3) δ 166.9, 159.2, 159.0, 137.0, 132.8, 132.0, 130.6, 129.1, 125.1, 124.7, 119.8, 115.8, 113.1 109.1, 108.7, 100.3, 85.8, 58.5, 57.1, 55.1, 21.9; IR (KBr) 3375, 1693 cm-1; MS m/z (rel intensity) 392 (M+1, 19). Anal. Calcd for C23H21NO5: C, 70.58; H, 5.41; N, 3.58. Found: C, 70.47; H, 5.47; N, 3.63.
3-(2’-Chlorophenyl)-1-hydroxy-8-methoxy-1-(2’-methyl-1’,3’-dioxolan-2’-yl)-1H-benz[e]indol-2(3H)-one (4b): Colorless microcrystals (from Et2O/hexane); mp 162-162.5 °C; 1H NMR (300 MHz, CDCl3) δ 9.59 (1H, s, OH), 8.36 (1H, m, H-6’), 7.76 (1H, d, J = 9.0 Hz, H-5), 7.69 (1H, d, J = 9.0 Hz, H-6), 7.41 (1H, m, H-3’), 7.24 (1H, m, H-5’), 7.08 (1H, dd, J = 9.0 Hz, H-4), 7.04 (1H, d, J = 2.7 Hz, H-9), 6.99 (1H, m, H-4’), 6.95 (1H, dd, J = 9.0, 2.7 Hz, H-7), 4.03-4.08 (1H, m, H-CH), 3.84-3.88 (2H, m, CH2), 3.76 (3H, s, OCH3), 3.60-3.66 (1H, m, H-CH), 1.80 (3H, s, CH3); 13C NMR (75 MHz, CDCl3) δ 167.2, 159.3, 159.0, 133.8, 132.8, 131.9, 130.5, 129.1, 127.8, 125.2, 125.1, 123.4, 121.6, 116.1, 113.3 109.1, 108.6, 99.9, 86.1, 59.1, 57.4, 55.1, 21.5; IR (KBr) 3358, 1701 cm-1. Anal. Calcd for C23H20ClNO5: C, 64.87; H, 4.73; N, 3.29. Found: C, 64.82; H, 4.69; N, 3.27.
3-(4’-Chlorophenyl)-1-hydroxy-8-methoxy-1-(2’-methyl-1’,3’-dioxolan-2’-yl)-1H-benz[e]indol-2(3H)-one (4c): Colorless needles (from CHCl3); mp 224-224.5 °C; 1H NMR (300 MHz, CDCl3) δ 8.99 (1H, s, OH), 7.77 (1H, d, J = 9.0 Hz, H-6), 7.71 (1H, d, J = 8.4 Hz, H-5), 7.60 (2H, m, H-2’,6’), 7.31 (2H, m, H-3’,5’), 6.95-7.09 (4H, m, aromatic H), 4.03-4.08 (1H, m, H-CH), 3.84-3.88 (2H, m, CH2), 3.76 (3H, s, OCH3), 3.60-3.66 (1H, m, H-CH), 1.80 (3H, s, CH3); 13C NMR (75 MHz, CDCl3) δ 167.1, 159.2, 159.0, 135.5, 132.9, 131.9, 130.6, 129.7, 129.1, 125.1, 121.0, 115.7, 112.9, 109.1, 108.7 100.3, 85.9, 58.5, 57.1, 55.1, 21.9; IR (KBr) 3387, 1693 cm-1. Anal. Calcd for C23H20ClNO5: C, 64.87; H, 4.73; N, 3.29. Found: C, 64.82; H, 4.69; N, 3.29.
1-Hydroxy-3-(2’-methoxyphenyl)-8-methoxy-1-(2’-methyl-1’,3’-dioxolan-2’-yl)-1H-benz[e]indol-2(3H)-one (4d): Colorless microcrystals (from Et2O/hexane); mp 150.5-151 °C; 1H NMR (300 MHz, CDCl3) δ 9.52 (1H, s, OH), 8.36 (1H, m, H-6’), 7.76 (1H, d, J = 8.7 Hz, H-6), 7.69 (1H, d, J = 9.0 Hz, H-5), 6.90-7.10 (6H, m, aromatic H), 4.01-4.09 (1H, m, H-CH), 3.92 (3H, s, OCH3), 3.81-3.90 (2H, m, CH2), 3.73 (3H, s, OCH3), 3.56-3.62 (1H, m, H-CH), 1.79 (3H, s, CH3); 13C NMR (75 MHz, CDCl3) δ 166.8, 159.2, 159.0, 148.5, 132.6, 132.0, 130.5, 126.7, 125.1, 124.4, 121.0, 120.0, 115.8, 113.7, 110.0, 109.2, 108.8, 100.4, 86.0, 58.9, 57.4, 55.8, 55.0, 21.7; IR (KBr) 3400, 3381, 1692 cm-1. Anal. Calcd for C24H23NO6: C, 68.40; H, 5.50; N, 3.32. Found: C, 68.30; H, 5.48; N, 3.32.
1-Hydroxy-3-(4’-methoxyphenyl)-8-methoxy-1-(2’-methyl-1’,3’-dioxolan-2’-yl)-1H-benz[e]indol-2(3H)-one (4e): Colorless microcrystals (from Et2O/hexane); mp 154-154.5 °C; 1H NMR (300 MHz, CDCl3) δ 8.87 (1H, s, OH), 7.76 (1H, d, J = 8.7 Hz, H-6), 7.70 (1H, d, J = 9.0 Hz, H-5), 7.55 (2H, m, H-2’,6’), 7.00 (1H, d, J = 9.0 Hz, H-4), 6.95 (1H, d, J = 2.7 Hz, H-9), 6.90 (1H, dd, J = 8.7, 2.7 Hz, H-4), 6.87 (2H, m, H-3’,5’), 3.95-4.04 (1H, m, H-CH), 3.83-3.89 (2H, m, CH2), 3.78 (3H, s, OCH3), 3.75 (3H, s, OCH3), 3.51-3.58 (1H, m, H-CH), 1.78 (3H, s, CH3); 13C NMR (75 MHz, CDCl3) δ 166.6, 159.2, 158.9, 156.6, 132.7, 132.0, 130.6, 130.2, 125.1, 121.4, 115.8, 114.2, 113.2, 109.1, 108.8, 100.3, 85.8, 58.5, 57.1, 55.4, 55.1, 21.9; IR (KBr) 3406, 1687 cm-1. Anal. Calcd for C24H23NO6: C, 68.40; H, 5.50; N, 3.32. Found: C, 67.94; H, 5.48; N, 3.19.
1-Hydroxy-8-methoxy-3-(2’-methylphenyl)-1-(2’-methyl-1’,3’-dioxolan-2’-yl)-1H-benz[e]indol-2(3H)-one (4f): Colorless microcrystals (from Et2O/hexane); mp 154-155 °C; 1H NMR (300 MHz, CDCl3) δ 8.85 (1H, s, OH), 7.95 (1H, m, H-6’), 7.77 (1H, d, J = 9.0 Hz, H-6), 7.71 (1H, d, J = 9.0 Hz, H-5), 7.20 (1H, d, J = 9.0 Hz, H-4), 7.06 (1H, d, J = 2.4 Hz, H-9), 7.20-7.02 (3H, m, aromatic H), 6.95 (1H, dd, J = 9.0, 2.4 Hz, H-7), 3.99-4.07 (1H, m, H-CH), 3.82-3.94 (2H, m, CH2), 3.78 (3H, s, OCH3), 3.55-3.62 (1H, m, H-CH), 2.35 (3H, s, CH3), 1.81 (3H, s, CH3); 13C NMR (75 MHz, CDCl3) δ 166.8, 159.2, 159.0, 135.1, 132.8, 132.1, 130.6, 130.5, 128.4, 126.9, 125.3, 125.2, 122.1, 115.9, 113.3, 109.2, 108.8, 100.3, 86.2, 58.9, 57.3, 55.1, 21.8, 17.8; IR (KBr) 3406, 1701 cm-1. Anal. Calcd for C24H23NO5: C, 71.10; H, 5.72; N, 3.45. Found: C, 70.10; H, 5.75; N, 3.47.
1-Hydroxy-8-methoxy-1-(2’-methyl-1’,3’-dioxolan-2’-yl)-3-(4’-methylphenyl)-1H-benz[e]indol-2(3H)-one (4g): Colorless microcrystals (from Et2O/hexane); mp 172-173 °C; 1H NMR (300 MHz, CDCl3) δ 8.91 (1H, s, OH), 7.76 (1H, d, J = 8.7 Hz, H-6), 7.69 (1H, d, J = 8.4 Hz, H-5), 7.52 (2H, m, H-2’,6’), 7.14 (2H, m, H-3’,5’), 7.01 (1H, d, J = 8.4 Hz, H-4), 6.99 (1H, d, J = 2.4 Hz, H-9), 6.90 (1H, dd, J = 8.7, 2.4 Hz, H-7), 3.96-4.04 (1H, m, H-CH), 3.83-3.93 (2H, m, CH2), 3.74 (3H, s, OCH3), 3.51-3.58 (1H, m, H-CH), 2.32 (3H, s, CH3), 1.77 (3H, s, CH3); 13C NMR (75 MHz, CDCl3) δ 166.8, 159.2, 159.0, 134.5, 134.4, 132.8, 132.1, 130.6, 129.6, 125.2, 119.8, 115.9, 113.3, 109.1, 108.8, 100.3, 85.8, 58.6, 57.2, 55.1, 21.9, 20.9; IR (KBr) 3398, 1693 cm-1. Anal. Calcd for C24H23NO5: C, 71.10; H, 5.72; N, 3.45. Found: C, 70.15; H, 5.75; N, 3.47.
1-Hydroxy-8-methoxy-1-(2’-methyl-1’,3’-dioxolan-2’-yl)-3-(2’-nitrophenyl)-1H-benz[e]indol-2(3H)-one (4h): Colorless microcrystals (from Et2O/hexane); mp 152-153 °C; 1H NMR (300 MHz, CDCl3) δ 11.87 (1H, s, OH), 8.77 (1H, m, H-3’), 8.25 (1H, d, J = 8.4 Hz, H-6’), 7.77 (1H, d, J = 8.7 Hz, H-6), 7.70 (1H, d, J = 8.7 Hz, H-5), 7.62 (1H, m, H-5’), 7.22 (1H, m, H-4’), 7.04 (1H, d, J = 2.4 Hz, H-9), 7.01 (1H, d, J = 8.7 Hz, H-4), 6.95 (1H, dd, J = 8.7, 2.4 Hz, H-7), 4.08-4.16 (1H, m, H-CH), 3.81-3.98 (2H, m, CH2), 3.72 (3H, s, OCH3), 3.63-3.69 (1H, m, H-CH), 1.79 (3H, s, CH3); 13C NMR (75 MHz, CDCl3) δ 168.5, 159.3, 159.0, 136.9, 135.9, 133.6, 132.8, 131.9, 130.6, 125.8, 125.1, 123.9, 122.1, 116.0, 113.3, 109.2, 108.3, 99.9, 86.3, 59.3, 57.9, 55.0, 21.2; IR (KBr) 3315, 1705, 1530 cm-1. Anal. Calcd for C23H20N2O7: C, 63.30; H, 4.62; N, 6.42. Found: C, 63.32; H, 4.64; N, 6.46.
1-Hydroxy-7-methoxy-1-(2’-methyl-1’,3’-dioxolan-2’-yl)-3-phenyl-1H-benz[e]indol-2(3H)-one (4j):
Colorless microcrystals (from Et2O/hexane); mp 176-177 °C; 1H NMR (300 MHz, CDCl3) δ 8.95 (1H, s, OH), 7.75 (1H, d, J = 9.0 Hz, H-9), 7.65 (1H, d, J = 9.0 Hz, H-5), 7.64 (2H, m, Ph), 7.34 (2H, m, Ph), 7.16 (1H, d, J = 2.4 Hz, H-6), 7.12 (1H, d, J = 9.0 Hz, H-4), 7.09 (1H, dd, J = 9.0, 2.4 Hz, H-8), 7.10 (1H, m, Ph), 3.84-4.01 (3H, m, H-CHCH2), 3.89 (3H, s, OCH3), 3.51-3.54 (1H, m, H-CH), 1.77 (3H, s, CH3); 13C NMR (75 MHz, CDCl3) δ 166.9, 156.9, 156.1, 137.1, 131.6, 130.8, 129.1, 125.8, 124.7, 122.7, 120.5, 119.7, 114.3, 112.1, 108.5, 107.5, 86.1, 58.7, 57.3, 55.3, 21.7; IR (KBr) 3344, 1688 cm-1. Anal. Calcd for C23H21NO5: C, 70.58; H, 5.41; N, 3.58. Found: C, 70.58; H, 5.40; N, 3.58.
1-Hydroxy-1-(2’-methyl-1’,3’-dioxolan-2’-yl)-3-phenyl-1H-benz[e]indol-2(3H)-one (4k): Colorless needles (from CHCl3/hexane); mp 180-180.5 °C; 1H NMR (300 MHz, CDCl3) δ 8.98 (1H, s, OH), 7.85 (1H, d, J = 9.0 Hz, H-5), 7.81-7.11 (10H, m, aromatic H), 3.91-4.03 (1H, m, H-CH), 3.77-3.90 (2H, m, CH2), 3.48-3.55 (1H, m, H-CH), 1.79 (3H, s, CH3); 13C NMR (75 MHz, CDCl3) δ 166.8, 158.4, 137.1, 133.1, 130.6, 129.8, 129.1, 127.9, 124.9, 123.7, 121.3, 119.7, 114.0, 111.9, 108.8, 85.9, 58.6, 57.2, 21.7; IR (KBr) 3377, 1692 cm-1. Anal. Calcd for C22H19NO4: C, 73.12; H, 5.30; N, 3.88. Found: C, 73.18; H, 5.29; N, 3.86.
Oxidation of 3a with Manganese(III) Acetate in Acetic Acid. To a solution of 3a (73 mg, 0.2 mmol) in AcOH (10 mL) containing acetic anhydride (1 mL) at 70 °C, manganese(III) acetate dihydrate (214mg, 0.8 mmol) was added. The reaction was stopped until the opaque dark-brown mixture changed to a clear reddish-brown solution (within 1 min). After cooling, the solvent was removed in vacuo and the residue was triturated with 2M hydrochloric acid (30 mL). The aqueous solution was extracted with CHCl3 (30 × 3 mL), and the combined extract was successively washed with a saturated aqueous solution of NaHCO3 (30 × 2 mL), water (30 × 2 mL), then dried over anhydrous MgSO4. The solvent was evaporated under reduced pressure, and the crude product was purified by TLC to yield 2-acetoxymethyl-5-chloro-8-methoxy-1-phenylcarbamoylnaphtho[2,1-b]furan (5) (59 mg, 70%).
2-Acetoxymethyl-5-chloro-8-methoxy-1-phenylcarbamoylnaphtho[2,1-b]furan (5): Colorless needles (from MeOH), mp 188-189 °C; 1H NMR (300 MHz, CDCl3) δ 9.99 (1H, s, NH), 8.25 (1H, d, J = 9.0 Hz, H-6), 8.14 (1H, s, H-4), 7.89 (2H, m, H-2’,6’), 7.60 (1H, d, J = 2.7 Hz, H-9), 7.42 (2H, m, H-3’,5’), 7.22 (1H, dd, J = 9.0, 2.7 Hz, H-7), 7.18 (1H, m, H-4’), 5.38 (2H, s, OCH2), 3.91 (3H, s, OCH3), 2.21 (3H, s, Ac); 13C NMR (75 MHz, CDCl3) δ 172.7, 161.7, 159.1, 152.3, 148.4, 138.4, 131.4, 129.7, 129.1, 127.0, 124.7, 123.1, 119.7, 119.5, 118.6, 117.9, 110.0, 104.7, 58.8, 55.5, 20.9; IR (KBr) 3288, 1736, 1645, 1622 cm-1; MS m/z (rel intensity) 423 (M, 44), 425 (M, 15). Anal. Calcd for C23H18ClNO5: C, 65.18; H, 4.28; N, 3.30. Found: C, 65.45; H, 4.35; N, 3.40.

ACKNOWLEDGEMENTS
This research was supported by Grants-in-Aid for Scientific Research (C), No.19550046, from Japan Society for the Promotion of Science.

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14. We appreciate the referees who suggested more reasonable mechanism for the formation of the 5-chloronaphtho[2,1-b]furans 3 and the 1H-benz[e]indolinones 4 than our submitted mechanism.