熊本大学学術リポジトリ

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Title Synthesis of Dibenz[b,f]oxepins via Manganese(III)-

Based Oxidative 1,2-Aryl Radical Rearrangement

Author(s) Cong, Zhiqi; Miki, Takumi; Urakawa, Osamu; Nishino,

Hiroshi

Citation 熊本大学極低温装置室ユーザー研究報告書 : 熊大極低温

, 19: 9-15

Issue date 2009-03

Type Departmental Bulletin Paper

URL http://hdl.handle.net/2298/12290

Right

Cryogenics Report of Kumamoto University, 2008, 19, 9-15.

Synthesis of Dibenz[b,f]oxepins via Manganese(III)-Based Oxidative

1,2-Aryl Radical Rearrangement

Zhiqi Cong, Takumi Miki, Osamu Urakawa, and Hiroshi Nishino*

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

nishino@sci.kumamoto-u.ac.jp

Abstract—The oxidation of monoalkyl 2-(9H-xanthenyl)malonates 1 with Mn(OAc)3 gave the 9- or 10-dibenz[b,f]oxepincarboxylates 2 in good yields. The reaction proceeds with a high regioselectivity except for the case of (1-methoxyxanthenyl)malonate 1 (R1 = Me, R2 = 1-MeO), that gave two regioisomers. It was proposed that the process for the formation of 2 must include the 1,2-aryl radical rearrangement followed by oxidative decarboxylation.

Manganese(III) acetate, Mn(OAc)3, is a versatile reagent for the C-C bond formation in organic synthesis.1-3 In recent years, we4 and other groups5 have developed various Mn(III)-based oxidations of aromatic compounds in the presence of active methylene species. We previously reported that the oxidation of xanthene in the presence of dimethyl malonate mainly produced 2-(9-xanthenyl)malonate (65%) together with a small amount of 9-dibenz[b,f]oxepincarboxylate (11%) as a by-product.4d Although the naturally occurring dibenz[b,f]oxepin derivatives were only found in the closely related family of the cularine alkaloids,6 many natural products containing the skeleton were recently isolated from the rootbarks of Artocarpus rigida,7 Bauhinia saccocalyx,8 and Cercis chinensis.9 Some of them exhibit excellent biological and pharmaceutical activities10 and their derivatives are widely used in industry.11 The general strategy for the synthesis of dibenz[b,f]oxepin was mainly ascribed to two pathways involving the intramolecular C-O ether bond formation of 2-styrylphenols and the cyclodehydration of preformed diaryl ether intermediates.6 However, both methods are conducted under harsh conditions and also include a multistep reaction process. Xanthene seems to be desirable as a readily available starting material since it only differs in a single carbon atom from dibenz[b,f]oxepin.12 Therefore, we focused on the dibenz[b,f]oxepin isolated from the oxidation of xanthene in the presence of dimethyl malonate,4d because the mechanism for the formation of the dibenz[b,f]oxepin as well as the skeleton was quite interesting to us. The dibenz[b,f]oxepin would probably be formed by the ring-expansion including the oxidative decarboxylation of the monomethyl 2-(9-xanthenyl)malonate intermediate 1. We then examined the reaction using malonates 1a-e in order to establish the synthesis of the dibenz[b,f]oxepincarboxylates 2a-e and elucidate the reaction pathway. We now report our results.

Monomethyl 2-(9-xanthenyl)malonate (1a) was

prepared by the controlled hydrolysis of dimethyl 2-(9-xanthenyl)malonate which was prepared by the oxidation of xanthene with Mn(OAc)3 in the presence of dimethyl malonate.4d The reaction of 1a with Mn(OAc)3 was carried out at the molar ratio of 1:4 in

boiling glacial acetic acid to give methyl 9-dibenz[b,f]oxepincarboxylate (2a) in 52% yield accompanied by an inseparable mixture of 1a unchanged (13% recovered) and the acetoxylated

TABLE 1. Oxidation of 2-(9-Xanthenyl)malonate 1a with Mn(OAc)3

a

O

HO2C CO2Me

O

CO2Me

Mn(OAc)3

AcOH, additivereflux

1a

2a

O

3a

OAc

CO2MeHO2C

entry

1a: Mn(III)

AcOH (mL)

t (min) additives conv

(%) 2a

(%)b 3a

(%)c

1 1:4 20 5 none 87 52 3

2 1:8 20 35 none 100 57 6

3 1:4 20 2.5 TFA (0.2 mL) >99 56 36

4 1:4 20 2 TFA (1 mL) 82 37 12

5 1:4 4.5 4 H2O (0.5 mL) 93 70 12

6 1:4 18 4 H2O (2 mL) 96 72 14

7 1:4 10 120 H2O (5 mL) 84 57

8d 1:4 9 15

H2O (1 mL) Cu(OAc)2 (1eq)

100 69

9e 1:4 9 5

H2O (1 mL) CuBr2 (1eq)

100 49

10f 1:4 9 12

H2O (1 mL) LiBr (2eq)

100 40

a The reaction was carried out at reflux temperature at the molar ratio of 1a (0.5 mmol):Mn(OAc)3. b Isolated yield based on use of 1a. c The acetate 3a was obtained as an inseparable mixtuer of 1a and the yield of 3a was determined by the 1H NMR spectrum. d 9-Xanthenone (4) was also isolated in an 11% yield. e 9-Xanthenone (4) and xanthene (5) were also isolated in 25% and 23% yields, respectively. f 9-Xanthenone (4) was also isolated in a 28% yield.

2

product 3a (3%) (Table 1, entry 1). Using 8 eq. of Mn(OAc)3 led to the complete consumption of 1a and a slight improvement in the yield of 2a (Entry 2). Based on our previous research experience4c,4d,13 and related references,5a,14 the oxidation is sometimes affected by additives, such as sodium acetate, copper(II) acetate, water, or halide ions. Some additives promote the radical reaction in some cases, while others inhibit it. To improve the yield of 2a, the reaction was scrutinized in the presence of various additives. Adding a small amount of trifluoroacetic acid (TFA) (v/v: AcOH/TFA = 100/1) obviously boosted the conversion of 1a, however, a considerable amount of 3a was produced (Entry 3). Adding 1 mL of TFA (v/v: AcOH/TFA = 20/1) decreased both the conversion and the yield of 2a (Entry 4). When water was added (v/v: AcOH/H2O = 9/1), the yield of 2a significantly increased up to 72% (Entry 6). Adding a large amount of water (v/v: AcOH/H2O = 2/1) suppressed the yield of 2a (Entry 7). The combination of water and other additives, such as Cu(OAc)2, CuBr2, and halide ion, showed no effect or decreased the yield of 2a together with the production of 9-xanthenone (4) and/or xanthene (5) (Entries 8-10).

The oxidation of monoethyl 2-(9-

xanthenyl)malonate (1b) and mono-iso-propyl 2-(9-xanthenyl)malonate (1c) instead of 1a was then carried out under the stated conditions (1: Mn(OAc)3 = 1:4; AcOH/H2O = 9/1) to give the corresponding oxepins 2b and 2c in 63% and 68% yields, respectively (Scheme 1). Since the ring-enlargement reaction according to the Wagner-Meerwein rearrangement is subject to an electronic effect,15 the oxidation of (3-methoxyxanthen-9-yl)malonate (1d) and (1-methoxyxanthen-9-yl)malonate (1e) was also examined under the standard reaction conditions (Scheme 1). To our surprise, the reaction gave completely different results. The reaction of 1d was highly regioselective and 3-methoxydibenz[b,f]oxepin-10-carboxylate 2d (81%) was exclusively produced. On the other hand, the reaction of 1e gave both the 1-methoxydibenz[b,f]oxepin-10-carboxylate 2e and 9-carboxylate 2e’ that were obtained in 48% and 37% yields, respectively. The results could probably be explained by the competition of the electronic effect and the steric effect.

The mechanism for the formation of the

dibenz[b,f]oxepins 2 deserves comments. Although the

dibenz[b,f]oxepins 2 must be produced via the 1,2-aryl rearrangement, we were interested in which rearrangement occurred before (route A) or after the decarboxylation (route B) and followed by an ionic or radical process (Scheme 2). When the malonate 1a was heated under reflux in acetic acid in the presence of Mn(OAc)2 or Cu(OAc)2, the decarboxylation did not occur and only 1a was recovered. The results indicate that the decarboxylation should oxidatively proceed and Mn(OAc)3 was essential for the formation of the oxepin 2. In order to examine the rearrangement after the decarboxylation (route A), methyl (9-xanthenylidene)acetate (6), prepared by the Reformatsky reaction of a-bromoacetate in the presence of Zn followed by hydrolysis or the oxidation of 1a with DDQ then by hydrolysis, was treated with perchloric acid (upper reaction in Scheme 3). However, the acid-catalyzed reaction did not give 2a via the

O

HO2C CO2R1

O

CO2R1

R2R2

Mn(OAc)3

AcOH/H2O(v:v = 9:1)

reflux, 5 min1b-e 2b-e

b: R1 = Et, R2 = H

c: R1 = i-Pr, R2 = H

d: R1 = Me, R2 = 3-MeO

e: R1 = Me, R2 = 1-MeO

e': R1 = Me, R2 = 8-MeO

1

3

8

(63%)

(68%)

(81%)

(48%)

(37%)

SCHEME 1 . The Oxidation of 2-(9-Xanthenyl)malonate 1b-e

with Mn(OAc)3

1

or

O

HO2C CO2R1

R2

or

O

H CO2R1

R2

2

-H or -H

-H or -H

-CO2

-CO2

Route A

Route B

A

B

SCHEME 2. The Process for the Formation of Oxepins 2

(The oxidant was omitted in each step.)

O

H CO2Me

6

A 2a

-HHClO4

AcOHreflux

O

H H

(84%)

HClO4

AcOHreflux

10 min

O

CO2Me

7

HCl

A 2a

-HBu3SnH

initiatorbenzene

reflux, argon

O

CO2MeH

H

+ 4 (20-24%)

8 (41-45%)

Bu3SnH

(PhCO2)2 or AIBNbenzene, reflux

48 h, argon

SCHEME 3. Attempt for the Formation of Oxepin 2a

via the Intermediate A

O

O

4 (7%)

+

3

cation equivalent A, but 9-methylenexanthene and 4 in 84% and 7% yields, respectively. In addition, chloro(9-xanthenyl)acetate 7 prepared by the reaction of 9-xanthenol with α-chloromalonate was allowed to react with Bu3SnH in the hope of forming the radical equivalent A which might afford 2a (lower in Scheme 3). However, the reaction only gave the corresponding xanthenylacetate 8 (41-45%) and 4 (20-24%) together with 7 unchanged (25-30%). On the other hand, the oxidative decarboxylation of 2a using Pb(OAc)4 was examined in order to form the intermediate radical A.16 As a result, although the reaction was very complicated, the products 4, 5, 6, 8, and spirolactone 9 were obtained together with only a small amount of the oxepin 2a (Scheme 4).17 These results supported the fact that the 1,2-aryl rearrangement should occur before the decarboxylation (route B), and the rearrangement after the decarboxylation according to route A seemed to be unlikely in the present Mn(OAc)3 oxidation (Scheme 2).

We next explored the rearrangement before the

decarboxylation via route B. Since the intermediate cation B in Scheme 2 seemed to be equivalent to the cation produced by the acid-catalyzed deacetoxylation of the by-product 3a, the reaction of 3a was carried out under acidic conditions (Scheme 5).15 However, the reaction did not give 2a, but 9-xanthenone (4) and xanthene (5) along with 3a unchanged. Therefore, the ionic rearrangement containing the corresponding cation B in Scheme 2 should be ruled out. In order to confirm the formation of the radical intermediate B before the 1,2-aryl rearrangement, we attempted trapping B with an alkene. When the malonate 1a was used under similar reaction conditions in the presence of 1,1-diphenylethene, xanthenylbutanolide 10 (31%; 1:1 stereoisomer) was isolated except for the desired oxepin 2a (Scheme 6). It is obvious that the radical intermediate B must be formed before the 1,2-aryl rearrangement.

It was concluded that the carboxylate C must be formed during the first stage since the Mn(OAc)3 oxidant was essential for the reaction, and then the one-electron oxidation would occur to give the α-carbonylcarbon radical D which should rearrange to form the more stable benzyl-type radical E followed by oxidative decarboxylation to finally produce the corresponding oxepins 2. The reaction pathway is outlined in Scheme 7.

In summary, we have developed a new approach to

the synthesis of the dibenz[b,f]oxepincarboxylates 2a-e during the Mn(OAc)3-mediated oxidative intramolecular rearrangement. We have also proposed the mechanism for the formation of 2 involving the 1,2-arylradical rearrangement and subsequent decarboxylation. Although the 1,2-radical rearrangement has been well-documented for the construction of medium and large rings,18 to the best of our knowledge, the Mn(III)-promoted 1,2-aryl radical rearrangement is little known.19

Experimental Section General Procedure for the Oxidation of

Monomethyl 2-(9-xanthenyl)malonate (1a) with Manganese(III) acetate.

To a heated solution of 1a (149 mg; 0.5 mmol) in glacial acetic acid (10 mL) in the presence and absence of additives, manganese(III) acetate (536 mg; 2 mmol) was added just before refluxing. The reaction was stopped when the dark-brown color of the solution turned clear red. The reaction mixture was then cooled to room temperature, and the solvent was removed in vacuo. The residue was triturated with 2 M (1 M = 1 mol dm−3) hydrochloric acid (15 mL) followed by extraction

SCHEME 4. Oxidation of 1a with Pb(OAc)4

1a 2a (7%) + 4 (7%) + 6 (4%)Pb(OAc)4

AcOHreflux, 24 h

+ 8 (19%) +

O

O

O

CO2Me

9 (19%)

O

5 (13%)

3a B 2a

-CO2H

-AcOH

3a + 4 + 5

1) AcOH/H2O (v:v = 9:1) or 2) HCO2H

(34%)(31%)

(22%)(23%)

(10%)(31%)

reflux, 1 h rec.

SCHEME 5. Reaction of 3a under Acidic Conditions

SCHEME 6. Mn(III)-Based reaction of a mixture of 1a and Alkene

1a +

2a (51%) + 4 (10%) + 5 (5%) +

MnOAc)3

AcOHreflux, 10 min

10 (31%)

Ph

Ph

O

O

CO2Me

OPh

Ph

O

OR2

2

R1O2C

O

O Mn

MnOMn

IIIIII

III

OR2

R1O2CO Mn

Mn

OMn

IIIII

III

O R2

R1O2CO

OMnIII

1,2-arylradicalrearrangement

one-electronoxidation

-CO2

-Mn(II)

1

Mn(OAc)3carboxylateformation

SCHEME 7. Reaction Pathway for the Formation of Oxepins 2

D

E

C

4

with chloroform (10 mL × 3). The combined extracts were washed with a saturated aqueous solution of sodium hydrogencarbonate (15 mL × 2) and water (10 mL × 2). The organic layer was dried over magnesium sulfate, and again concentrated to dryness. The crude products were separated by silica gel TLC (Wako B-10) while eluting with chloroform to give methyl 9-dibenz[b,f]oxepincarboxylate (2a). 9-Xanthenone (4) and xanthene (5) were also isolated in some cases.

The water layer was acidified by concetrated sulfuric acid and then extracted with chloroform (10 mL × 3). The combined extracts were washed with water (20 mL × 2) and dried over magnesium sulfate, and again concentrated to dryness. The crude products were not separated and the yield of 1a and 3a was directly estimated by 1H-NMR spectrum.

Methyl 9-Dibenz[b,f]oxepincarboxylate (2a): colorless needles (from EtOH), mp 91-92 °C (lit.4d mp 91.3-92.0 °C); 1H-NMR (CDCl3) δ 7.91 (1H, s, H-9), 7.51-7.14 (8H, m, arom H), 3.90 (3H, s, OCH3); 13C-NMR (CDCl3) δ 167.4, 159.0, 158.9, 138.1, 131.7, 130.7, 130.4, 130.3, 125.0, 124.7, 52.4.

Ethyl 9-Dibenz[b,f]oxepincarboxylate (2b): colorless needles (from EtOH), mp 66-67 °C (lit.20 colorless oil); IR (KBr): 1710 cm-1 (C=O); 1H-NMR (CDCl3) δ 7.91 (1H, s, H-9), 7.54-7.11 (8H, m, arom H), 4.37 (2H, q, J = 7.2 Hz, OCH2), 1.38 (3H, t, J = 7.2 Hz, CH3); 13C-NMR (CDCl3) δ 166.9, 159.0, 158.8, 137.7, 131.6, 131.5, 130.7, 130.3, 128.8, 127.7, 125.0, 124.6, 121.4, 121.1, 61.4, 14.3.

Isopropyl 9-Dibenz[b,f]oxepincarboxylate (2c): colorless microcrystal (from Et2O-Hexane), mp 74-75 °C; IR (KBr): 1705 cm-1 (C=O); 1H NMR (300 MHz, CDCl3) δ 7.88 (1H, s, H-9), 7.53-7.14 (8H, m, arom H), 5.26 (1H, hept, J = 6.0 Hz, CH) , 1.37 (6H, d, J = 6.0 Hz, CH3 × 2); 13C NMR (75 MHz, CDCl3) δ 166.4, 158.9, 158.7, 137.4, 131.8, 131.5, 130.6, 130.2, 128.8, 127.8, 124.9, 124.5, 121.3, 121.0, 68.9, 21.8; MS: m/z (rel intensity) 280 (M+, 100). Anal. Calcd for C18H16O3: C, 77.12; H, 5.75. Found: C, 77.30; H, 5.64.

Methyl 3-Methoxy-10-dibenz[b,f]oxepin- carboxylate (2d)4d: IR (CHCl3): 1712 cm-1 (C=O); 1H-NMR (CDCl3) δ 7.79 (1H, s, H-9), 7.50-6.60 (7H, m, arom H), 3.88 (3H, s, OCH3), 3.79 (3H, s, OCH3); 13C-NMR (CDCl3) δ 167.6, 161.6, 159.9, 158.6, 136.3, 131.4, 130.8, 130.6, 128.9, 125.0, 121.1, 120.1, 110.9, 55.4, 52.3.

Methyl 1-Methoxy-10-dibenz[b,f]oxepin- carboxylate (2e): colorless plates (from EtOAc-hexane), mp 144-145 °C; IR (KBr): 1707 cm-1 (C=O); 1H-NMR (CDCl3) δ 8.21 (1H, s, H-9), 7.56-7.54 (1H, m, arom H), 7.34-7.7.16 (4H, m, arom H), 6.86-6.83 (1H, m, arom H), 6.67-6.64 (1H, m, arom H), 3.90 (3H, s, OCH3), 3.83 (3H, s, OCH3); 13C-NMR (CDCl3) δ 167.3, 160.7, 158.8, 158.3, 134.0, 132.2, 130.3, 130.1, 130.0, 128.2, 124.7, 121.3, 118.0, 113.2, 106.9, 55.9, 52.3; MS: m/z (rel intensity) 282 (M+, 100). Anal. Calcd for C17H14O4: C, 72.33; H, 5.00. Found: C, 72.11; H, 4.95.

Methyl 1-Methoxy-9-dibenz[b,f]oxepincarboxylate (2e’): colorless microcrystals (from EtOAc-hexane) mp 121-123 °C; IR (CHCl3): 1719 cm-1 (C=O); 1H-NMR (CDCl3) δ 7.58 (1H, s, H-9), 7.35-7.12 (5H, m, arom H), 6.90-6.87 (1H, m, arom H), 6.72-6.69 (1H, m, arom H),

3.82 (3H, s, OCH3), 3.78 (3H, s, OCH3); 13C-NMR (CDCl3) δ 169.1, 161.3, 159.0, 157.5, 135.5, 131.1, 131.0, 130.9, 130.4, 129.0, 125.1, 121.3, 117.6, 113.8, 107.9, 56.1, 52.2; MS: m/z (rel intensity) 282 (M+, 44). Anal. Calcd for C17H14O4: C, 72.33; H, 5.00. Found: C, 72.21; H, 4.89.

Monomethyl 2-Acetoxy-2-(9-xanthenyl)malonate (3a): colorless microcrystals (from methanol) mp 98-101 °C; IR (KBr): 3600-2400(OH), 1740, 1705 cm-1 (C=O); 1H-NMR (CDCl3) δ 10.29 (COOH), 7.46-7.11 (8H, m, arom H), 4.79 (1H, s, H-9’), 3.53 (3H, s, OCH3), 2.15 (3H, s, CH3CO); 13C-NMR (CDCl3) δ 171.3, 170.2, 166.9, 153.8, 153.5, 130.9, 129.9, 129.7, 129.4, 123.7, 123.3, 118.3, 116.8, 116.5, 116.1, 81.8, 54.0, 46.8, 20.1. FAB HRMS (acetone-NBA+NaI) calcd for C19H16O7Na-CO2 335.0895 (M+Na-CO2). Found 335.0899.

Synthesis of Methyl (9-Xanthenylidene)acetate (6). To a solution of zinc and dry diethyl ether (5 mL), a

small portion of a mixture of 9-xanthenone (5 g) and methyl bromoacetate (2 mL) in dry benzene was dropwize added with stirring. When the reaction started, the rest of the mixture was added. After the addition, the reaction mixture was heated under reflux for 30 min. After cooling, 10% aqueous solution of sulfuric acid (50 mL) was added and the aqueous solution was extracted with benzene. The extract was washed with 5% aqueous solution of sulfuric acid, a saturated aqueous solution of sodium hydrogencarbonate, and then water. The crude product was purified by silica gel TLC while eluting with chloroform to give 6 (1.4 g, 22% yield).

Methyl (9-Xanthenylidene)acetate (6): pale yellow needles (from MeOH), mp 86-87 °C (lit.4d mp 87 °C); IR (CHCl3): 1711 cm-1 (C=O); 1H-NMR (CDCl3) δ 8.15-7.05 (8H, m, arom H), 6.20 (1H, s, CH), 3.75 (3H, s, OCH3),; 13C-NMR (CDCl3) δ 167.3, 152.4, 139.7, 131.3, 130.6, 129.7, 123.9, 123.7, 122.8, 122.5, 117.1, 116.8, 119.0, 109.9, 51.4. Anal. Calcd for C16H12O3: C, 76.18; H, 4.79. Found: C, 75.94; H, 4.85.

Alternative Synthesis of 6. A mixture of dimethyl (9-xanthenyl)malonate (217.9 mg) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (320.2 mg) in dry benzene (50 mL) was heated under reflux for 5 h. After cooling, the mixture was filtered and the filtrate was concetrated dryness. The crude product was separated by silica gel TLC which eluting with Et2O-hexane and purified by recrystallization from methanol, giving dimethyl (9-xanthenylidene)malonate (196.8 mg, 91%). The dimethyl (9-xanthenylidene)malonate (1 equiv.) was hydrolyzed with potassium hydroxide (0.5 equiv.) in methanol to give 6 (87%) via decarboxylation.

Reaction of 6 in the Presence of Perchloric Acid. To a solution of 6 (0.2 mmol) in acetic acid (10 mL), a few drops of perchloric acid was added, and the mixture was heated under reflux for 10 min. Atfter cooling, water was added and the aqueous mixture was extracted with chloroform, giving 9-methylenexanthene (84%) and 9-xanthenone (4; 7%).

Synthesis of Methyl Chloro(9-xanthenyl)acetate (7). To a heated solution of 9-xanthenol (1.19 g) and dimethyl chloromalonate (0.92 g) in acetic acid (50 mL), manganese(II) acetate (1.50 g) was added and the mixture was continued to heat under reflux for 5 min. After removal of the solvent in vacuo, the residue was

5

triturated with 2 M (1 M = 1 mol dm−3) hydrochloric acid (50 mL) and the aqueous solution was extracted with chloroform. The extract was washed with a saturated aqueous solution of sodium hydrogencarbonate, water, and then concetrated dryness. The solid residue was purified by recrystallization from methanol, giving dimethyl 2-chloro-(9-xanthenyl)malonate (1.81 g, 88%).4d The dimethyl 2-chloro-(9-xanthenyl)malonate (1.7 g) was hydrolyzed in a mixture of 2 M potassium hydroxide (15 mL) and methanol (15 mL) at room temperature for 30 min. The mixture was acidified with concentrated hydrochloric acid at 0 °C and extracted with ethyl acetate, giving 2-chloro(9-xanthenyl)malonic acid (1.6 g, 88%). The 2-chloro(9-xanthenyl)malonic acid (1.6 g) was heated under reflux in water (20 mL) for 6 h, and the aqueous mixture was extracted with ethyl acetate to give chloro(9-xanthenyl)acetic acid (1.3 g, 90%). The chloro(9-xanthenyl)acetic acid (1.3 g) was methylated by diazomethane in methanol to yield methyl chloro(9-xanthenyl)acetate (7) (1.3 g, 92%).

Methyl Chloro(9-xanthenyl)acetate (7): colorless microcrystals (from methanol); mp 171-173 °C; IR (CHCl3): 1740 cm-1 (C=O); 1H NMR (300 MHz, CDCl3) δ 7.64−7.08 (8H, m, arom H), 4.59 (1H, d, J = 9.0 Hz, >CCl-), 4.30 (1H, d, J = 9.0 Hz, >CH-), 3.65 (3H, s, OMe); 13C NMR (75 MHz, CDCl3) δ 168.2, 122.3, 121.8, 128.8, 128.7, 123.6, 123.4, 116.8,52.5, 40.1.

Reduction of 7 with Tributyltin Hydride. To a heated solution of 7 (145 mg) in benzene (100 mL) at 80 °C, tributyltin hydride (148 mg) in benzene (20 mL) containing benzoyl peroxide (8 mg) was dropwise added, and the mixture was continued to heat for 2 h. After removal of the solvent, the residue was triturated with 2 M (1 M = 1 mol dm−3) hydrochloric acid (50 mL) and the aqueous mixture was extracted with chloroform. The extract was washed with a sturated aqueous solution of sodium hydrogencarbonate, water, and then concentrated to dryness. The crude products were separated by a silica gel flash chromatography while eluting with chloroform, giving methyl (9-xanthenyl)acetate (8) (61 mg, 44%) and 9-xanthenone (4) (29 mg, 20%) together with 7 (32%) unchanged.

Methyl (9-Xanthenyl)acetate (8): colorless microcrystals (from EtOAc-hexane); mp 172-173 °C; IR (KBr): 1738 cm-1 (C=O); 1H NMR (300 MHz, CDCl3) δ 7.26-7.19 (4H, m, arom H), 7.11-7.02 (4H, m, arom H), 4.51 (1H, t, J = 7.2 Hz, CH), 2.66 (2H, d, J = 7.2 Hz, CH2); 13C NMR (75 MHz, CDCl3) δ 171.6, 152.1, 128.3, 128.0, 124.3, 123.3, 116.6, 51.5, 45.3, 35.7; MS: m/z (rel intensity) 254 (M+, 23); Anal. Calcd for C16H14O3: C, 75.57; H, 5.55. Found: C, 75.41; H, 5.46.

Oxidation of Monomethyl 2-(9-Xanthenyl)malonate (1a) with Lead(IV) Acetate.

The malonate 1a (298 mg; 1 mmol) was dissolved in glacial acetic acid (10 mL), and lead(IV) acetate (487 mg (90%), 1 mmol) was added to the mixture. The mixture was heated under reflux for 24 h and then cooled to room temperature. The solvent was removed in vacuo and the residue was treated with 2 M (1 M = 1 mol dm−3) sulfuric acid (5 mL) followed by extraction with chloroform (5 mL × 3). The combined extracts were washed with a saturated aqueous solution of sodium hydrogencarbonate (5 mL × 2), water (5 mL × 2),

dried over magnesium sulfate, and then concentrated to dryness. The crude products were separated by silica gel TLC (Wako gel B-10) while eluting with chloroform, giving 2a (18 mg, 7%), 9-xanthenone (4) (13 mg, 7%), xanthene (5 ) (24 mg, 13%), methyl (9-xanthenylidene)acetate 6 (10 mg, 4%), methyl (9-xanthenyl)acetate (8) (43 mg, 17%), and spirolactone 9 (59 mg, 19%), respectively.

4-Methoxycarbonylspiro[2(3H)-oxoduhydrofuran-5,9’-xanthene] (9): colorless microcrystals (from EtOAc-hexane); mp 127-128 °C; IR (KBr): 1792, 1738 cm-1 (C=O); 1H NMR (300 MHz, CDCl3) δ 7.50-7.15 (8H, m, arom H), 3.58 (1H, t, J = 9.2 Hz, >CH-), 3.41 (1H, dd, J = 18.3, 9.2 Hz, CH-H), 3.23 (3H, s, OCH3), 2.95 (1H, dd, J = 18.3, 9.2 Hz, CH-H); 13C NMR (75 MHz, CDCl3) δ 174.5, 169.1, 150.4, 150.1, 130.4, 130.0, 125.5, 124.9, 124.1, 123.5, 123.4, 119.2, 116.8, 116.6, 80.3, 56.7, 52.2, 30.8; MS: m/z (rel intensity) 310 (M+, 43); Anal. Calcd for C18H14O5: C, 69.67; H, 4.55. Found: C, 69.52; H, 4.46.

The combined aqueous layers were acidified and then treated with the same procedure of the oxidation of 1a with manganese(III) acetate, giving 1a unchanged (39 mg, 13%).

Reaction of Monomethyl 2-Acetoxy-2-(9-xanthenyl)malonate (3a) under Acidic Conditions.

The xanthenylmalonate 3a (160 mg; 0.45 mmol) was heated under reflux for 1 h in acetic acid containing water (2.5 mL; v:v = 9:1). The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was triturated with 2 M (1 M = 1 mol dm−3) hydrochloric acid (10 mL) followed by extraction with chloroform (8 mL × 3). The combined extracts were washed with a saturated aqueous solution of sodium hydrogencarbonate (8 mL × 2), water (8 mL × 2), and dried over magnesium sulfate, and then concentrated to dryness. The crude products were separated by silica gel TLC (Wako gel B-10) while eluting with chloroform, giving 9-xanthenone (4) (19 mg, 22%) and xanthene (5) (19 mg, 23%). The combined aqueous layer was acidified by concentrated sulfuric acid and then extracted with ethyl acetate (8 mL × 3). The combined extract was washed with water (8 mL × 2), dried over magnesium sulfate, and then concentrated to dryness, which gave the starting material 3a unchanged (55 mg, 34%).

A similar reaction of 3a (128 mg, 0.36 mmol) was carried out in formic acid (2 mL) instead of acetic acid at reflux temperature to give 3a unchanged (40 mg, 31%), 4 (4 mg, 10%), and 5 (11 mg, 31%).

Oxidation of Monomethyl 2-(9-Xanthenyl)malonate (1a) with Manganese(III) Acetate in the Presence of 1,1-Diphenylethene.

To a mixture of 1a (290 mg; 0.97 mmol) and 1,1-diphenylethene (350 mg; 1.94 mmol) in glacial acetic acid (20 mL), manganese(III) acetate (1043 mg; 3.88 mmol) was added just before refluxing. The reaction was heated under reflux until the dark-brown color of the solution turned clear red (ca. 10 min). The reaction mixture was cooled to room temperature, and the solvent was removed in vacuo. The residue was triturated with 2 M (1 M = 1 mol dm−3) hydrochloric acid (25 mL) followed by extraction with chloroform (20 mL × 3).

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The combined extracts were washed with a saturated aqueous solution of sodium hydrogencarbonate (20 mL × 2), water (20 mL × 2), dried over magnesium sulfate, and then concentrated to dryness. The crude products were separated by silica gel TLC (Wako gel B-10) while eluting with chloroform, giving the oxepin 2a (128 mg; 51%), 9-xanthenone 4 (24 mg; 12%), xanthene 5 (9 mg; 5%), and a 1:1 stereoisomeric mixture of 10 (143 mg; 31%). The stereoisomeric mixture of 10 was separated by silica gel TLC (Wako gel B-10) while eluting with Et2O-hexane (2:5), however, the exact stereochemistry of each isomer 10 was not assigned.

2-Methoxycarbonyl-4,4-diphenyl-2-(9-xanthenyl)-4-butanolide (10): colorless microcrystals (from EtOAc-hexane); mp 140-141 °C; IR (KBr): 1782, 1740 cm-1 (C=O); 1H NMR (300 MHz, CDCl3) δ 7.39−7.05 (18H, m, arom H), 6.26 (1H, s, CH), 3.35 (1H, d, J = 13.8 Hz, CH-H), 3.23 (3H, s, OCH3), 2.76 (1H, d, J = 13.8 Hz, CH-H); 13C NMR (75 MHz, CDCl3) δ 172.7, 168.8, 146.3, 143.5, 142.1, 142.0, 138.3, 130.2, 128.5, 128.3, 128.1, 128.0, 127.9, 127.8, 127.7, 127.6, 125.3, 125.0, 124.9, 123.6, 57.9, 53.0, 45.4; MS: m/z (rel intensity) 476 (M+, 14). Anal. Calcd for C31H24O5: C, 78.14; H, 5.08. Found: C, 77.96; H, 5.04.

2-Methoxycarbonyl-4,4-diphenyl-2-(9-xanthenyl)-4-butanolide (10’): colorless microcrystals (from EtOAc-hexane); mp 64-65 °C; IR (KBr): 1774, 1724 cm-

1 (C=O); 1H NMR (300 MHz, CDCl3) δ 7.56-7.00 (18H, m, arom H), 6.62 (2H, m, arom H), 5.16 (1H, s, CH), 3.43 (1H, d, J = 14.1 Hz, CH-H), 3.34 (3H, s, OCH3), 2.71 (1H, d, J = 14.1 Hz, CH-H); 13C NMR (75 MHz, CDCl3) δ 171.8, 167.0, 153.9, 143.3, 141.3, 130.2, 129.3, 129.0, 128.6, 128.2, 128.0, 127.8, 127.7, 126.1, 125.7, 124.4, 123.5, 120.3, 120.2, 116.9, 116.8, 87.7, 65.1, 52.8, 44.6, 39.4; MS: m/z (rel intensity) 477 (M+1, 11). Anal. Calcd for C31H24O5: C, 78.14; H, 5.08. Found: C, 78.09; H, 5.13.

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

References (1) For review, see: (a) Demir, A.S.; Emrullahoglu, M. Current Organic Synthesis 2007, 4, 321-351. (b) Nishino, H. In Bioactive Heterocycles I; Eguchi, S. (Eds.); Springer: Berlin, 2006, 39-76. (c) Melikyan, G. G. Aldrichimica Acta 1998, 31, 50-98. (d) Melikyan, G. G. Org. React. 1997, 49, 427-675. (e) Snider, B. B. Chem. Rev. 1996, 96, 339-363. (f) Iqbal, J.; Bhatia, B.; Nayyar, N. K. Chem. Rev. 1994, 94, 519-564. (2) (a) Wang, Y.-F.; Toh, K. K.; Chiba, S.; Narasaka, K. Org. Lett. 2008, 10, 5019-5022. (b) Wang, G.-W.; Dong, Y.-W.; Wu, P.; Yuan, T.-T.; Shen, Y.-B. J. Org. Chem. 2008, 73, 7088-7095. (c) Powell, L. H.; Docherty, P. H.; Hulcoopa, D. G.; Kemmitt, P. D.; Burton, J. W. Chem. Commun. 2008, 2559-2561. (d) Demir, A. S.; Findik, H. Tetrahedron 2008, 64, 6196-6201. (e) Shu. C.; Cai, T. Xu, L.; Zuo, T. Reid, J. Harich, K. Dorn, H. C. Gibson, H. W. J. Am. Chem. Soc. 2007, 129, 15710-15717. (f) Chuang, C.-P.; Tsai, A.-I. Tetrahedron 2007, 63, 11911-11919. (g) Elkaim, L. Grimaud, L.; Vieu, E. Org. Lett. 2007, 9, 4171-4173. (h) Chuang, C.-P.; Tsai, A.-I. Tetrahedron 2007, 63, 9712-9717. (i) Shanmugam, P.; Kumar, K. H.; Perumal, P. T. J. Heterocycl. Chem. 2007, 44, 827-830. (j) Burgaz, E. V.; Yilmaz, M.; Pekel, A. T.;

Oektemer, A. Tetrahedron 2007, 63, 7229-7239. (k) Wu, Z.; Huang, X. Synthesis 2007, 45-50. (l) Fu, W.-J.; Huang, X. J. Organomet. Chem. 2007, 692, 740-745. (m) Çaliskan, R.; Ali, M. F.; Sahin, E.; Watson, W. H.; Balci, M. J. Org. Chem. 2007, 72, 3353-3359. (3) (a) Asahi, K.; Nishino, H. Tetrahedron 2008, 64, 1620-1634. (b) Asahi, K.; Nishino, H. Eur. J. Org. Chem. 2008, 2404-2416. (c) Asahi, K.; Nishino, H. Tetrahedron Lett. 2006, 47, 7259-7263. (d) Asahi, K.; Nishino, H. Tetrahedron 2005, 61, 11107-11124. (e) Fujino, R.; Nishino, H. Synthesis 2005, 731-740. (f) Kumabe, R.; Nishino, H. Heterocycl. Commun. 2004, 10, 135-138. (g) Kumabe, R.; Nishino, H. Tetrahedron Lett. 2004, 45, 703-706. (h) Rahman, M. T.; Nishino, H. Tetrahedron 2003, 59, 8383-8392. (i) Rahman, M. T.; Nishino, H. Org. Lett. 2003, 5, 2887-2890. (j) Rahman, M. T.; Nishino, H.; Qian, C.-Y. Tetrahedron Lett. 2003, 44, 5225-5228. (k) Jogo, S.; Nishino, H.; Yasutake, M.; Shinmyozu, T. Tetrahedron Lett. 2002, 43, 9031-9034. (l) Kumabe, R.; Nishino, H.; Yasutake, M.; Nguyen, V.-H.; Kurosawa, K.Tetrahedron Lett. 2001, 42, 69-72. (4) (a) Nishino, H. Bull. Chem. Soc. Jpn. 1986, 59, 1733-1739. (b) Nishino, H.; Tsunoda, K.; Kurosawa, K. Bull. Chem. Soc. Jpn. 1989, 62, 545-550. (c) Tsunoda, K.; Yamane, M.; Nishino, H.; Kurosawa, K. Bull. Chem. Soc. Jpn. 1991, 64, 851-856. (d) Nishino, H.; Kamachi, H.; Baba, H; Kurosawa, K. J. Org. Chem. 1992, 57, 3551-3557. (e) Cong, Z.-Q.; Nishino, H. Synthesis 2008, 2686-2694. (5) (a) Citterio, A.; Santi, R.; Fiorani, T.; Strologo, S. J. Org. Chem. 1989, 54, 2703-2712. (b) Citterio, A.; Fancelli, D.; Finzi, C.; Pesce, L.; Santi, R. J. Org. Chem. 1989, 54, 2713-2718. (c) Citterio, A.; Sebastiano, R.; Marion, A.; Santi, R. J. Org. Chem. 1991, 56, 5328-5335. (d) Baciocchi, E.; Muraglia, E. J. Org. Chem. 1993, 58, 7610-7612. (e) Jiang, M.-C.; Chuang, C.-P. J. Org. Chem. 2000, 65, 5409-5412. (f) Wu, Y.-L; Chuang, C.-P.; Lin, P.-Y. Tetrahedron 2001, 57, 5543-5549. (g) Tsai, A.-I.; Wu, Y.-L.; Chuang, C.-P. Tetrahedron 2001, 57, 7829-7837. (h) Im, Y. J.; Lee, K. Y.; Kim, T. H.; Kim, J. N. Tetrahedron Lett. 2002, 43, 4675-4678. (6) For review, see: (a) Olivera, R.; SanMartin, R.; Churruca, F.; Domínguez, E. Org. Prep. Proc. Int. 2004, 36, 297-330 and references cited therein. (7) (a) Ko, H.-H.; Yang, S.-Z.; Lin, C.-N. Tetrahedron. Lett. 2001, 5269-5270. (b) Lu, Y.-H.; Lin, C.-N.; Ko, H.-H.; Yang, S.-Z.; Tsao, L.-T.; Wang, J.-P. Helv. Chem. Acta 2003, 86, 2566-2572. (c) Paduraru, M. P.; Wilson, P. D. Org. Lett. 2003, 5, 4911-4913. (8) (a) Kittakoop, P.; Nopichai, S.; Thongon, N.; Charoenchai, P.; Thebtaranonth, Y. Helv. Chem. Acta 2004, 87, 175-179. (b) Pettit, G. R.; Numata, A.; Iwamoto, C.; Usami, Y.; Yamada, T.; Ohishi, H.; Cragg, G. M. J. Nat, Prod. 2006, 69, 323-327. (9) Mu, L.-H.; Li, J.-B.; Yang, J.-Z.; Zhang, D.-M. J. Asian Nat. Prod. Res. 2007, 9, 649-653. (10) (a) Trabanco, A. A.; Alonso, J. M.; Andrés, J. I.; Cid, J. M.; Fernández, J.; Iturrino, L.; Megens, A. Chem. Pham. Bull. 2004, 52, 262-265. (b) Fernández, J.; Alonso, J. M.; Andrés, J. I.; Cid, J. M.; Díaz, A.; Iturrino, L.; Gil, P.; Megens, A.; Sipido, V. K.; Trabanco, A. A. J. Med. Chem. 2005, 48, 1709-1712. (c) Tra banco, A. A.; Alonso, J. M.; Cid, J. M.; Font, L. M.; Megens, A. Il Farmaco 2005, 60, 241-248. (c) Zimmermann, K.; Waldmeier, P. C.; Tatton, W. G.; Pure Appl. Chem. 1999, 71, 2039-2046. (d) Waldmeier, P. C.; Boulton, A. A.; Cools, A. R.; Kato, A. C.; Tatton, W. G. Adv. Res. Neurodegen. 2000, 8, 197-214. (11) (a) Cloos, P. A. C.; Jensen F. R.; Boissy, P.; Stahlhut, M. PCT Int. Appl. 2004, 61, WO 2004039773; Chem.

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Abstr. 2004, 140, 406751. (b) Lambrou, G. N.; Latour, E.; Waldmeier, P. PCT Int. Appl. 2004, 27, WO 2004066993; Chem. Abstr. 2004, 141, 167848. (12) (a) Whitlock, H. W. Tetrahedron Lett. 1961, 593-595. (b) Kasmai, H. S.; Whitlock, Jr., H. W. J. Org. Chem. 1972, 37, 2161-2165. (c) Anet, F. A. L.; Bavin, P. M. G. Can. J. Chem. 1957, 35, 1084-1087. (d) Hess, Jr., B. A.; Bailey, A. S.; Boekelheide, V. J. Am. Chem. Soc. 1967, 89, 2746-2747. (e) Hess, Jr., B. A.; Bailey, A. S.; Bartusek, B.; Boekelheide, V. J. Am. Chem. Soc. 1969, 91, 1665-1672. (f) Storz, T.; Vangrevelinghe, E.; Dittmar, P. Synthesis 2005, 2562-2570. (13) (a) Futami, Y.; Nishino, H.; Kurosawa, K. Bull. Chem. Soc. Jpn. 1989, 62, 3567-3571. (b) Yonemura, H.; Nishino, H.; Kurosawa, K. Bull. Chem. Soc. Jpn. 1987, 62, 809-811. (c) Yonemura, H.; Nishino, H.; Kurosawa, K. Bull. Chem. Soc. Jpn. 1986, 59, 3153-3159. (14) (a) Kochi, J. K.; Subramanian, R. V. J. Am. Chem. Soc. 1965, 87, 4855-4866. (b) Fristad, W. E.; Peterson, J. R. J. Org. Chem. 1985, 50, 10-18. (c) Heiba, E. I.; Dessau, R. M.; Koehl, Jr.,W. J. J. Am. Chem. Soc. 1969, 91, 138-145. (15) (a) Anet, F. A. L.; Bavin, P. M. G. Can. J. Chem. 1957, 35, 1084-1087. (b) Hess, Jr., B. A.; Bailey, A. S.; Boekelheide, V. J. Am. Chem. Soc. 1967, 89, 2746-2747.

(16) (c) Hess, Jr., B. A.; Bailey, A. S.; Bartusek, B.; Boekelheide, V. J. Am. Chem. Soc. 1969, 91, 1665-1672. (d) Storz, T.; Vangrevelinghe, E.; Dittmar, P., Synthesis 2005, 2562-2570. (e) Bergmann, E. D.; Rabinovitz, M. Israel J. Chem. 1963, 1, 125-128. (17) (a) Kochi, J. K. J. Am. Chem. Soc. 1965, 87, 1811-1812. (b) Bacha, J. D.; Kochi, J. K. Tetrahedron 1968, 24, 2215-2216. (c) Kochi, J. K. Bacha, J. D.; Bethea, T. W. J. Am. Chem. Soc. 1967, 89, 6538-6547. (d) Sheldon, R. A.; Kochi, J. K. Org. React. 1972, 19, 279-421. (e) Chottard, J. C.; Julia, M.; Salard, J. M. Tetrahedron 1969, 25, 4967-4983. (18) Incidentally, the xanthenylidenemalonate 6 and xanthenylacetate 8 would be produced by the dehydrogenation and the hydrogen-abstraction of the intermediate radical A, and the spirolactone 9 would be obtained by the coupling of A with the carboxymethyl radical, •CH2CO2H, followed by oxidative lactonization since the a carbonyl carbon radicals, such as A, could not be oxidized by Pb(OAc)4, but the benzyl-type radicals, such as the 9-xanthenyl radical, could be easily oxidized.16d,e (19) Zhang, W. In Radicals in Organic Synthesis, Vol. 2, eds. By Renaud, P., Sibi, M. P. Wiley-VCH: 2001, 234-245, and references cited therein. (20) Tsai, A.-I.; Chuang, C.-P. Tetrahedron 2008, 64, 5098-5102.