A synthetic study on bauhinoxepin J: Construction of a dibenzo[bf]oxepin ring system by a DDQ-promoted oxidative dearomatization-cyclization approach

Article abstract of DOI:10.3987/COM-09-S(S)31

Efforts to construct a dibenzo[b,f]oxepin ring system for a synthesis of bauhinoxepin J are described. A DDQ-promoted oxidative dearomatization-cyclization of the 2-phenoxyethyl-substituted tetramethoxybenzene was used to construct a tricyclic quinone mon

Full text of DOI:10.3987/COM-09-S(S)31

HETEROCYCLES, Vol. 80, No. 1, 2010
623
HETEROCYCLES, Vol. 80, No. 1, 2010, pp. 623 - 629. © The Japan Institute of Heterocyclic Chemistry
Received, 3rd June, 2009, Accepted, 6th July, 2009, Published online, 6th July, 2009
DOI: 10.3987/COM-09-S(S)31
A SYNTHETIC STUDY ON BAUHINOXEPIN J: CONSTRUCTION OF A
DIBENZO[b,f]OXEPIN RING SYSTEM BY A DDQ-PROMOTED
OXIDATIVE DEAROMATIZATION–CYCLIZATION APPROACH‡
Masahiro Yoshida,* Yohei Maeyama, and Kozo Shishido
Graduate School of Pharmaceutical Sciences, The University of Tokushima,
1-78-1 Sho-machi, Tokushima 770-8505, Japan.
E-mail: yoshida@ph.tokushima-u.ac.jp
Abstract – Efforts to construct a dibenzo[b,f]oxepin ring system for a synthesis
of bauhinoxepin J are described. A DDQ-promoted oxidative dearomatization–
cyclization of the 2-phenoxyethyl-substituted tetramethoxybenzene was used to
construct a tricyclic quinone monoacetal.
Bauhinoxepin J (1), a secondary metabolite isolated from the root extracts of Bauhinia purpurea (Figure
1),1 is reported to exhibit antimycobacterial and antimalarial activities.1 The dibenzo[b,f]oxepin structure
containing a seven-membered cyclic ether with a functionalized quinone moiety consequently has
attracted considerable synthetic interest. Herein, we describe a synthetic study on bauhinoxepin J (1), in
which the dibenzo[b,f]oxepin ring system was constructed using a DDQ-promoted oxidative
dearomatization–cyclization of the 2-hydroxyphenethyl-substituted tetramethoxybenzene.
O
O
MeO
O
bauhinoxepin J (1)
Figure 1. Structure of bauhinoxepin J (1)
Our synthetic approach for bauhinoxepin J (1) is shown in Scheme 1. We anticipated that the electrophilic
intermediate 3 would be generated when 2-hydroxyphenethyl-substituted tetramethoxybenzene 2 was
‡ This paper is dedicated to Dr. Akira Suzuki on the occasion of his 80th birthday.

624
HETEROCYCLES, Vol. 80, No. 1, 2010
treated with a suitable oxidant.2 Subsequent intramolecular interception of 3 would yield the tricyclic
quinone monoacetal 4, which would be a promising precursor for 1.
OMe
OMe
MeO
MeO
OMe
OMe
OMe
OMe
OH
OH
O
[O]
O
MeO
MeO
MeO
2
3
4
O
O
MeO
O
bauhinoxepin J (1)
Scheme 1. Approach to bauhinoxepin J (1)
O
O
OH
OH
OMe
OMe
NaBH4
Me2SO4, NaHSO3
EtOH, 75%
AcCl, MeOH
79%
EtOH, 82%
HO
MeO
MeO
O
O
OH
6
7
5
HO
OMe
OMe
OMe
OMe
OMe
CHO
BuLi, DMF
THF, 83%
, TiCl4, Zn, pyridine
THF, 41%
OHC
MeO
MeO
OMe
OMe
9
8
OMe
OMe
OMe
OH
OH
Pd-C, H2 (5atm)
AcOEt, 94%
MeO
MeO
OMe
OMe
2
10
Scheme 2. Synthesis of 2-hydroxyphenethyl-substituted tetramethoxybenzene 2
The synthesis of the 2-hydroxyphenethyl-substituted tetramethoxybenzene 2 was conducted as shown in
Scheme 2. Treatment of 2,5-dihydroxy-p-benzoquinone (5) with AcCl in MeOH afforded the
dimethoxyquinone 6 (79% yield), which was reduced with NaBH4 to give the hydroquinone 7 (82%
yield). After methylation with dimethyl sulfate (75% yield), formylation of the resulting

HETEROCYCLES, Vol. 80, No. 1, 2010
625
tetramethoxybenzene 8 with DMF in the presence of n-BuLi gave tetramethoxybenzaldehyde 93 in 83%
yield. McMurry coupling4 of 9 with salicylaldehyde (41% yield) followed by hydrogenation of the
resulting trans-stilbene 10 led to 2 in 94% yield.
With the 2-hydroxyphenethyl-substituted tetramethoxybenzene 2 in hand, we next examined the key
oxidative dearomatization–cyclization (Table 1). When compound 2 was treated with 2 equiv of CAN in
aqueous MeCN, a complex mixture was obtained (entry 1). The reaction with diacetoxyiodobenzene in
aqueous MeOH likewise resulted in the formation of a complex mixture (entry 2). Nevertheless, after
several attempts,5 we were pleased to find that the desired reaction successfully proceeded when carried
out with 5 equiv of DDQ in dioxane to produce the tricyclic quinone monoacetal 4 in 81% yield (entry 3).
The structure of 4 was unambiguously confirmed by an X-ray crystallographic analysis (Figure 2).
Table 1. Oxidative dearomatization cyclizations of 2 with oxidants.
OMe
OMe
OMe
OMe
oxidant
rt
OH
O
O
MeO
OMe
MeO
4
2
Entry
Oxidant
Solvent
Yield (%)
complex mixture
complex mixture
81
1
2
3
CAN (2 equiv)
PhI(OAc)2 (2 equiv)
DDQ (5 equiv)
MeCN/H2O (4/1)
MeOH/H2O (40/1)
dioxane
Figure 2. X-Ray Structure of tricyclic quinone monoacetal 4

626
HETEROCYCLES, Vol. 80, No. 1, 2010
In conclusion, We have succeeded in constructing a dibenzo[b,f]oxepin ring system by a DDQ-promoted
oxidative dearomatization–cyclization of the 2-hydroxyphenethyl-substituted tetramethoxybenzene.
Further studies on the synthesis of bauhinoxepin J are currently underway.
EXPERIMENTAL
Solvents were dried and distilled according to standard protocols. The phrase ‘residue upon workup’
refers to the residue obtained when the organic layer was separated and dried over anhydrous MgSO4 and
the solvent was evaporated under reduced pressure.
2,5-Dimethoxycyclohexa-2,5-diene-1,4-dione (6)
To a stirred suspension of 2,5-dihydroxy-p-benzoquinone (5) (20.0 g, 143 mmol) in MeOH (714 mL) was
added AcCl (3.50 mL, 48.6 mmol) at rt, and the reaction mixture was stirred for 25 h at 80 ºC. The
precipitate was filtered and washed with cold MeOH. The resulting solid was dried in vacuo to give
dimethoxyquinone 6 (18.9 g, 79%) as a yellow solid; mp 202.3–205.7 ºC (AcOEt/hexane); IR (KBr):
1
13
1662, 1599, 1205 cm−1; H-NMR (400 MHz, CDCl3) 3.85 (s, 6H), 5.87 (s, 2H); C-NMR (100 MHz,
CDCl3) 56.6 (CH3), 105.5 (CH), 159.6 (Cq), 181.6 (Cq); HRMS (ESI) m/z calcd for C8H8O4Na
[M++Na+] 191.0320, found 191.0323.
1,4-Dihydroxy-2,5-dimethoxybenzene (7)
To a stirred suspension of dimethoxyquinone 6 (7.70 g, 45.9 mmol) in EtOH (60 mL) was added NaBH4
(4.50 g, 119 mmol) in portions at 0 ºC, and stirring was continued for 3 h at the same temperature. The
reaction mixture was quenched with 1 M HCl and extracted with AcOEt. The combined extracts were
washed with brine, and the residue upon workup gave hydroquinone 7 (6.40 g, 82%) as a yellow solid;
1
mp 181.8–188 ˚C (AcOEt/hexane). IR (KBr): 3406, 1520, 1450, 1240, 1192 cm−1; H-NMR (400 MHz,
CDCl3) 3.82 (s, 6H), 5.23 (s, 2H), 6.58 (s, 2H); 13C-NMR (100 MHz, CDCl3) 56.6 (CH3), 99.8 (CH),
138.6 (Cq), 140.3 (Cq); HRMS (ESI) m/z calcd for C8H10O4Na [M++Na+] 193.0477, found 193.0477.
1,2,4,5-Tetramethoxybenzene (8)
To a stirred suspension of hydroquinone 7 (14.0 g, 82.3 mmol), Me2SO4 (55.0 mL, 370 mmol) and
NaHSO3 (1.37 g, 13.2 mmol) in EtOH (90 mL) was added dropwise 10 N NaOH (47 mL) at 0 ºC. After
stirring for 5.5 h at 80 ºC, the resulting solution was diluted with water and extracted with AcOEt. The
combined extracts were washed with brine, and the residue upon workup gave tetramethoxybenzene 8
(12.3 g, 75%) as colorless needles; mp 99.7–101.8 ˚C (AcOEt/hexane); IR (KBr): 2945, 1525, 1471, 1203
1
13
cm−1; H-NMR (400 MHz, CDCl3) 3.96 (s, 12H), 6.61 (s, 2H); C-NMR (100 MHz, CDCl3) 57.0

HETEROCYCLES, Vol. 80, No. 1, 2010
627
(CH3), 100.7 (CH), 143.2 (Cq); HRMS (ESI) m/z calcd for C10H15O4 [M++H+] 199.0970, found 199.0968.
2,3,5,6-Tetramethoxybenzaldehyde (9)3
To a stirred solution of tetramethoxybenzene 8 (12.3 g, 62.1 mmol) in dry THF (310 mL) was added
dropwise n-BuLi (1.57 M, 47.4 mL, 74.5 mmol) at –78 ºC. The reaction mixture was warmed to –10 ºC
over 1 h and stirred at the same temperature for an additional 1 h. The mixture was then cooled to –78 ºC,
and DMF (24.0 mL, 310 mmol) was added in one portion. The reaction was allowed to warm to 0 ºC over
1 h. The resulting solution was diluted with water and extracted with AcOEt. The combined extracts were
washed with brine. The residue upon workup was chromatographed on silica gel with hexane-AcOEt
(85:15, v/v) as eluent to give tetramethoxybenzaldehyde 9 (11.7 g, 83%) as colorless needles; mp
1
79.5–81.4 ˚C (AcOEt/hexane); IR (KBr): 2995, 1697 cm−1; H-NMR (400 MHz, CDCl3) 3.86 (s, 6H),
13
3.89 (s, 6H), 6.79 (s, 1H), 10.41 (s, 1H); C-NMR (100 MHz, CDCl3) 56.8 (CH3), 62.1 (CH3), 105.1
(CH), 124.3 (Cq), 143.9 (Cq), 149.2 (Cq), 189.9 (CH); HRMS (ESI) m/z calcd for C11H14O5Na [M++Na+]
249.0739, found 249.0739.
(E)-2-(2,3,5,6-Tetramethoxystyryl)phenol (10)
To a stirred solution of activated zinc powder (9.50 g, 146 mmol) and pyridine (11.8 mL, 146 mmol) in
dry THF (180 mL) was added dropwise TiCl4 (8.0 mL, 72.9 mmol) at 0 ºC. The reaction was warmed to
room temperature and stirred for 0.5 h, then heated at reflux for 2.5 h. After cooling to 0 ºC, a solution of
tetramethoxybenzaldehyde 9 (3.00 g, 13.4 mmol) and salicylaldehyde (2.8 mL, 26.5 mmol) in dry THF
(100 mL) was slowly added to the mixture. After refluxing for 17 h, the reaction mixture was quenched
with saturated aqueous NaHCO3. The resulting mixture was filtered through Celite, and extracted with
AcOEt. The combined extracts were washed with brine, and the residue upon workup was
chromatographed on silica gel with hexane-AcOEt (85:15, v/v) as eluent to give the trans-stilbene 10
(1.70 g, 41%) as colorless prisms; mp 145.6–147.2 ˚C (AcOEt/hexane); IR (KBr): 3319, 1587, 1219
cm−1; 1H-NMR (400 MHz, CDCl3) 3.78 (s, 6H), 3.88 (s, 6H), 5.19 (s, 1H), 6.51 (s, 1H), 6.83 (d, 1H, J =
8.0 Hz), 6.96 (t, 1H, J = 8.0 Hz), 7.15 (t, 1H, J = 8.0 Hz), 7.25 (d, 1H, J = 16.8 Hz), 7.55 (d, 1H, J = 8.0
Hz), 7.87 (d, 1H, J = 16.8 Hz); 13C-NMR (100 MHz, CDCl3) 56.5 (CH3), 60.5 (CH3), 98.5 (CH), 116.0
(CH), 120.8 (CH), 121.3 (CH), 125.5 (Cq), 125.8 (Cq), 127.0 (CH), 128.4 (CH), 128.7 (CH), 141.3 (Cq),
149.2 (Cq), 153.4 (Cq); HRMS (ESI) m/z calcd for C18H20O5Na [M++Na+] 339.1208, found 339.1199.
2-(2,3,5,6-Tetramethoxyphenethyl)phenol (2)
To a stirred suspension of Pd-C (197 mg, 20 wt%) in AcOEt (11 mL) was added the trans-stilbene 10
(987 mg, 3.10 mmol) at rt, and stirring was continued for 4.5 h at the same temperature under 5 atm of

628
HETEROCYCLES, Vol. 80, No. 1, 2010
hydrogen gas. The resulting solution was filtered through Celite, and the residue upon evaporation of the
solvent was chromatographed with hexane-AcOEt (85:15, v/v) as eluent to give the
2-hydroxyphenethyl-substituted tetramethoxybenzene 2 (924.7 mg, 94%) as colorless prisms; mp
1
104.9–107.2 ˚C (AcOEt/hexane); IR (KBr): 3357, 1592, 1460, 1226 cm−1; H-NMR (400 MHz, CDCl3)
2.70–2.74 (m, 2H), 2.82–2.86 (m, 2H), 3.86 (s, 6H), 3.88 (s, 6H), 6.47 (s, 1H), 6.58 (s, 1H), 6.85 (dt, J
13
= 1.2, 7.2 Hz, 1H), 6.92 (d, J = 7.2 Hz, 1H), 7.13-7.17 (m, 2H); C-NMR (100 MHz, CDCl3) 25.4
(CH2), 32.3 (CH2), 56.3 (CH3), 61.3 (CH3), 97.2 (CH), 115.8 (CH), 120.1 (CH), 127.1 (Cq), 127.9 (CH),
129.4 (Cq), 129.8 (CH), 140.5 (Cq), 149.0 (Cq), 154.7 (Cq); HRMS (ESI) m/z calcd for C18H22O5Na
[M++Na+] 341.1365, found 341.1356.
1,4,4a-Trimethoxy-10,11-dihydrodibenzo[b,f]oxepin-2(4aH)-one (4)
To a stirred solution of the 2-hydroxyphenethyl-substituted tetramethoxybenzene 2 (50 mg, 0.16 mmol)
in dioxane (4 mL) was added DDQ (178 mg, 0.79 mmol) in portions at rt. After the reaction mixture was
stirred at the same temperature for 10 h, the solvent was evaporated under reduced pressure. The residue
was chromatographed on silica gel with hexane-AcOEt (70:30 v/v) as eluent to give tricyclic quinone
monoacetal 4 (38.5 mg, 81%) as colorless prisms; mp 137.6–138.5 ˚C (AcOEt/hexane); IR (KBr): 3442,
1
2937, 1637, 1458, 1232 cm−1; H-NMR (400 MHz, CDCl3) 2.34–2.42 (m, 1H), 2.73–2.81 (m, 1H),
13
3.11–3.24 (m, 5H), 3.59 (s, 3H), 3.91 (s, 3H), 5.61 (s, 1H), 6.95–7.15 (m, 4H); C-NMR (100 MHz,
CDCl3) 22.2 (CH2), 29.8 (CH2), 51.9 (CH3), 56.4 (CH3), 60.8 (CH3), 98.7 (Cq), 103.1 (CH), 122.7 (CH),
125.1 (CH), 127.5 (CH), 129.0 (CH), 134.4 (Cq), 136.4 (Cq), 150.6 (Cq), 151.9 (Cq), 169.1 (Cq), 182.0
(Cq); HRMS (ESI) m/z calcd for C17H19O5 [M++H+] 303.1232, found 303.1231.
X-Ray crystallographic analysis of compound 4.6 A colorless block crystal having approximate
dimensions of 0.60 x 0.60 x 0.40 mm was mounted on a glass fiber. All measurements were made on a
Rigaku RAXIS RAPID imaging plate area detector with graphite monochromated Mo-K radiation. The
structure was solved by direct methods (SIR97) and expanded using Fourier techniques (DIRDIF99). The
non-hydrogen atoms were refined anisotropically. Hydrogen atoms were refined using the riding model.
The final cycle of full-matrix least-squares refinement on F was based on 13,033 observed reflections (I >
0.00(I)) and 218 variable parameters, and converged (largest parameter shift was 0.54 times its esd) with
unweighted and weighted agreement factors of R = 0.043 and R = 0.110. Crystal data for 4: C17H18O5,
w
M = 302.33, monoclinic, space group P21/n, a = 13.6538(8) Å, b = 8.4884(4) Å, c = 13.9424(9) Å,  =
113.237(2)º, V = 1484.8(1) Å3, Z = 4, Dc = 1.352 g/cm3, F(000) = 640, (MoK) = 0.99 cm–3.

HETEROCYCLES, Vol. 80, No. 1, 2010
629
ACKNOWLEDGEMENT
This study was supported in part by a Grant-in-Aid for the Encouragement of Young Scientists (B) from
the Japan Society for the Promotion of Science (JSPS) and the Program for the Promotion of Basic and
Applied Research for Innovations in the Bio-oriented Industry (BRAIN).
REFERENCES AND NOTES
1. S. Boonphong, P. Puangsombat, A. Baramee, C. Mahidol, S. Ruchirawat, and P. Kittakoop, J. Nat.
Prod., 2007, 70, 795.
2. For representative examples of the oxidative formation of quinone monoacetals, see: (a) K. Miyashita,
T. Sakai, and T. Imanishi, Org. Lett., 2003, 5, 2683; (b) S. Bäsler, A. Brunck, R. Jautelat, and E.
Winterfeldt, Helv. Chim. Acta, 2000, 83, 1854; (c) S. Danishefsky, E. M. Berman, M. Ciufolini, S. J.
Etheredge, and B. E. Segmuller, J. Am. Chem. Soc., 1985, 107, 3891.
3. S. Poigny, M. Guyot, and M. Samad, J. Org. Chem., 1998, 63, 5890.
4. J. E. McMurry and M. P. Fleming, J. Am. Chem. Soc., 1974, 96, 4708.
5. When the DDQ-promoted reaction was carried out under aqueous conditions, the corresponding
2-hydroxyphenethyl-substituted p-quinone was obtained in 31% yield. More than 50% of the starting
material was recovered when 2equiv of DDQ was subjected to the reaction.
6. Crystallographic data (excluding structure factors) for the structures in this paper have been deposited
with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC
733689. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [fax: +44(0) 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk].