Synthesis of dibenz[b,f]oxepins via manganese(III)-based oxidative 1,2-radical rearrangement

Article abstract of DOI:10.1021/jo9002773

(Chemical Equation Presented) 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 high regioselectivity except for the case of (1-meth

Full text of DOI:10.1021/jo9002773

byproduct.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 activities,10
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 cyclodehydra-
tion 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 malonate4d 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
Synthesis of Dibenz[b,f]oxepins via
Manganese(III)-Based Oxidative 1,2-Radical
Rearrangement
Zhiqi Cong, Takumi Miki, Osamu Urakawa, and
Hiroshi Nishino*
Department of Chemistry, Graduate School of Science and
Technology, Kumamoto UniVersity, Kurokami 2-39-1,
Kumamoto 860-8555, Japan
nishino@sci.kumamoto-u.ac.jp
ReceiVed February 11, 2009
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The oxidation of monoalkyl 2-(9H-xanthenyl)malonates 1
with Mn(OAc)3 gave the 9- or 10-dibenz[b,f]oxepincarboxy-
lates 2 in good yields. The reaction proceeds with high
regioselectivity except for the case of (1-methoxyxanthe-
nyl)malonate 1 (R1 ) Me, R2 ) 1-MeO), which gave two
regioisomers. It was proposed that the process for the
formation of 2 must include the 1,2-aryl radical rearrange-
ment 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
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amount of 9-dibenz[b,f]oxepincarboxylate (11%) as
a
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Springer: Berlin, 2006; pp 39-76. (c) Melikyan, G. G. Aldrichim. 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.
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Hulcoopa, D. G.; Kemmitt, P. D.; Burton, J. W. Chem. Commun. 2008, 2559,
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3978 J. Org. Chem. 2009, 74, 3978–3981
10.1021/jo9002773 CCC: $40.75 2009 American Chemical Society
Published on Web 04/22/2009

a
TABLE 1. Oxidation of 2-(9-Xanthenyl)malonate 1a with Mn(OAc)3
entry
1a/Mn(III)
AcOH (mL)
time (min)
additives
conv (%)
2ab (%)
3ac (%)
1
2
3
4
5
1:4
1:8
1:4
1:4
1:4
1:4
1:4
1:4
1:4
1:4
20
20
20
20
4.5
18
10
9
5
35
2.5
2
4
4
120
15
5
none
none
TFA (0.2 mL)
TFA (1 mL)
H2O (0.5 mL)
H2O (2 mL)
H2O (5 mL)
H2O (1 mL) Cu(OAc)2 (1 equiv)
H2O (1 mL) CuBr2 (1 equiv)
H2O (1 mL) LiBr (2 equiv)
87
100
>99
82
93
96
52
57
56
37
70
72
57
69
49
40
3
6
36
12
12
14
6
7
84
8d
9e
10f
100
100
100
9
9
12
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 H NMR spectrum. d 9-Xanthenone (4) was also isolated in
1
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.
SCHEME 1. Oxidation of 2-(9-Xanthenyl)malonate 1b-e
with Mn(OAc)3
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 a molar ratio of 1:4 in
boiling glacial acetic acid to give methyl 9-dibenz[b,f]oxepin-
carboxylate (2a) in 52% yield accompanied by an inseparable
mixture of 1a unchanged (13% recovered) and the acetoxylated
suppressed the yield of 2a (entry 7). The combination of water
and other additives, such as Cu(OAc)2, CuBr2, and halide ion,
product 3a (3%) (Table 1, entry 1). Using 8 equiv of Mn(OAc)3
led to the complete consumption of 1a and a slight improvement
showed no effect or decreased the yield of 2a together with the
in the yield of 2a (entry 2). Based on our previous research
production of 9-xanthenone (4) and/or xanthene (5) (entries
experience4c,d,13 and related references,5a,14 the oxidation is
8-10).
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
The oxidation of monoethyl 2-(9-xanthenyl)malonate (1b) and
monoisopropyl 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
presence of various additives. Adding a small amount of
and 2c in 63% and 68% yields, respectively (Scheme 1). Since
trifluoroacetic acid (TFA) (V/V: AcOH/TFA ) 100/1) obviously
the ring-enlargement reaction according to the Wagner-Meerwein
boosted the conversion of 1a; however, a considerable amount
rearrangement is subject to an electronic effect,15 the oxidation
of 3a was produced (entry 3). Adding 1 mL of TFA (v/v: AcOH/
of (3-methoxyxanthen-9-yl)malonate (1d) and (1-methoxyxan-
TFA ) 20/1) decreased both the conversion and the yield of
then-9-yl)malonate (1e) was also examined under the standard
2a (entry 4). When water was added (v/v: AcOH/H2O ) 9/1),
reaction conditions (Scheme 1). To our surprise, the reaction
the yield of 2a significantly increased up to 72% (entry 6).
gave completely different results. The reaction of 1d was highly
Adding a large amount of water (v/v: AcOH/H2O ) 2/1)
regioselective and 3-methoxydibenz[b,f]oxepin-10-carboxylate
2d (81%) was exclusively produced. On the other hand, the
(12) (a) Whitlock, H. W. Tetrahedron Lett. 1961, 593, 595. (b) Kasmai, H. S.;
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.
Whitlock, H. W., Jr. 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, B. A., Jr.; Bailey,
A. S.; Boekelheide, V. J. Am. Chem. Soc. 1967, 89, 2746–2747. (e) Hess, B. A.,
Jr.; 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, B. A., Jr.; Bailey, A. S.; Boekelheide, V. J. Am. Chem. Soc.
1967, 89, 2746–2747. (c) Hess, B. A., Jr.; 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. Isr. J. Chem. 1963, 1, 125–128.
J. Org. Chem. Vol. 74, No. 10, 2009 3979

SCHEME 2. Process for the Formation of Oxepins 2 (the
Oxidant Was Omitted in Each Step)
SCHEME 4. Oxidation of 1a with Pb(OAc)4
SCHEME 5. Reaction of 3a under Acidic Conditions
SCHEME 3. Attempt for the Formation of Oxepin 2a via
the Intermediate A
tively. In addition, chloro(9-xanthenyl)acetate 7 prepared by the
reaction of 9-xanthenol with R-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.17 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).18 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 decarboxy-
lation 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 byproduct 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 stereo-
isomer) 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 since it is well-known that
the malonic acid radical such as B adds alkene.1
The mechanism for the formation of the dibenz[b,f]oxepins
2 deserves comment. 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 R-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 cation equivalent A, but
9-methylenexanthene16 and 4 in 84% and 7% yields, respec-
(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 R 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.17d,e
(16) 9-Methylenexanthene decomposed during the separation procedure to
afford 4.
3980 J. Org. Chem. Vol. 74, No. 10, 2009

SCHEME 6. Mn(III)-Based Reaction of a Mixture of 1a
and Alkene
Experimental Section
General Procedure for the Oxidation of 2-(9-Xanthenyl)-
malonates 1 with Mn(OAc)3. To a heated solution of 1 (0.5 mmol)
in glacial acetic acid (10 mL) in the presence and absence of an
additive was added Mn(OAc)3 (2 mmol) 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) HCl (15 mL) followed
by extraction with CHCl3 (10 mL × 3). The combined extracts
were washed with a saturated aqueous solution of NaHCO3 (15
mL × 2) and water (10 mL × 2). The organic layer was dried
over MgSO4 and again concentrated to dryness. The crude products
were separated by silica gel TLC (Wako B-10) while eluting with
CHCl3 to give dibenz[b,f]oxepincarboxylate 2. 9-Xanthenone (4)
and xanthene (5) were also isolated in some cases. For the reaction
of 1a, the water layer was acidified with concd H2SO4 and then
extracted with CHCl3 (10 mL × 3). The extract was washed with
water (20 mL × 2), dried over MgSO4, and again concentrated to
dryness. The crude products were not separated and the yields of
SCHEME 7. Reaction Pathway for the Formation of
Oxepins 2
1
1a and 3a were directly estimated by the H NMR spectrum.
Isopropyl 9-dibenz[b,f]oxepincarboxylate (2c): colorless mi-
crocrystal (from Et2O-hexane); mp 74-75 °C; IR (KBr) 1705 cm-1
1
(CdO); H NMR (300 MHz, CDCl3) δ 7.88 (1H, s), 7.53-7.14
(8H, m), 5.26 (1H, hept, J ) 6.0 Hz), 1.37 (6H, d, J ) 6.0 Hz);
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.
2-Methoxycarbonyl-4,4-diphenyl-2-(9-xanthenyl)-4-butano-
lide (10): one of the stereoisomers; colorless microcrystals (from
EtOAc-hexane); mp 140-141 °C; IR (KBr) 1782, 1740 cm-1
(CdO); 1H NMR (300 MHz, CDCl3) δ 7.39-7.05 (18H, m), 6.26
(1H, s), 3.35 (1H, d, J ) 13.8 Hz), 3.23 (3H, s), 2.76 (1H, d, J )
13.8 Hz); 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.
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 R-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,19 to the best of our knowledge, the Mn(III)-promoted 1,2-
aryl radical rearrangement is little known.20
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.
Supporting Information Available: Experimental proce-
dures and characterization of the products 2a-e, 3a, and 6-10′
1
as well as copies of the H NMR,13C NMR, and IR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(19) Zhang, W. In Radicals in Organic Synthesis; Renaud, P., Sibi, M. P.,
Eds.; Wiley-VCH: New York, 2001; Vol. 2, pp 234-245, and references cited
therein.
(20) Tsai, A.-I.; Chuang, C.-P. Tetrahedron 2008, 64, 5098–5102.
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