Efficient synthesis of diospyrol via Suzuki-Miyaura and modified in situ cross-coupling

Article abstract of DOI:10.1055/s-2005-872176

Tetramethoxydiospyrol was synthesized via Suzuki-Miyaura cross-coupling of the two key intermediates, halonaphthalene and naphthaleneboronic acid derivatives, which were derived from the same naphthol. Moreover, the product could be conveniently obtained

Full text of DOI:10.1055/s-2005-872176

2934
PAPER
Efficient Synthesis of Diospyrol via Suzuki–Miyaura and Modified in situ
Cross-Coupling
Synthesisof
Do
iospyrol olsak Sahakitpichan,a Nopporn Thasana,a Somsak Ruchirawat*a,b
a
Chulabhorn Research Institute, Vipavadee Rangsit Highway, Bangkok 10210, Thailand
Fax +66(2)5742027; E-mail: somsak@cri.or.th
b
Programme on Research and Development of Synthetic Drugs, Institute of Science and Technology for Research and Development,
Mahidol University, Salaya Campus, Nakorn Pathom 73170, Thailand
Received 5 March 2005; revised 18 May 2005
OH OH
OH OH
Abstract: Tetramethoxydiospyrol was synthesized via Suzuki–
Miyaura cross-coupling of the two key intermediates, halonaphtha-
lene and naphthaleneboronic acid derivatives, which were derived
from the same naphthol. Moreover, the product could be conve-
niently obtained by a one-pot modified in situ Suzuki coupling. The
naphthol was synthesized via the cyclization of ortho-allylbenza-
mide intermediate.
Diospyrol 1a
OH
M
R
Key words: biaryls, Suzuki–Miyaura cross-coupling, metalation,
diospyrol
HN
R
OH
OH OMe
Diospyrol1 (1a), a symmetrical dimeric naphthol, was iso-
lated from Diospyros mollis berries widely used in Thai-
land as an anthelmintic.2 Over the years, the synthesis of
this interesting structural motif has challenged many syn-
thetic groups.3,4 The interest in this molecule was intensi-
fied by the recent isolation of the michellamine alkaloids
reported to exhibit potent anti-HIV activity.5 The structure
of michellamine, typified by michellamine B, composed
of two important structural units, i.e. 1,3-dimethyltetrahy-
droisoquinoline and the core binaphthol, which is struc-
turally similar to diospyrol (Figure 1).
o
MeO
OH
P
R
HO
NH
R
OH
Michellamine B
Figure 1 Diospyrol (1a) and michellamine B
OMe OMe
OMe OMe
OMe OMe
Retrosynthetic analysis suggested that breaking the C2
symmetric bond can form two naphthalene units as shown
in Scheme 1. In our approach, we planned to utilize the
Suzuki–Miyaura cross-coupling6 of naphthalene deriva-
tives, i.e. halonaphthalene 2 and naphthaleneboronic acid
3, for the synthesis of this compound. Herein we report
both the classical and modified in situ Suzuki cross-cou-
pling for the synthesis of diospyrol.
X
1b
2a X = Br
2b X = I
+
OMe OMe
(HO2)B
The naphthol precursor 6 was required for the synthesis of
the first key intermediate, halonaphthalene 2. Many syn-
thetic methodologies have been devised for synthesis of
the naphthol derivatives.7 We adopted the procedure de-
veloped by Snieckus et al.7d for the synthesis of our naph-
thol derivative. The naphthol 6 was synthesized in 60%
yield by cyclization of the o-allylbenzamide 5 in the pres-
ence of excess LDA. The use of methyllithium as a base
led also to the cyclized adduct 6 but in lower yield
(27%).7g The precursor allylbenzamide 5 was synthesized
in one pot by selective ortho metalation8 of benzamide 49
3
Scheme 1 Retrosynthetic analysis of tetramethoxydiospyrol (1b)
with t-BuLi followed by transmetalation with MgBr2 and
the resulting organomagnesium intermediate was trapped
with allyl bromide to give the product in 78% yield
(Scheme 2).
The first key intermediate, halonaphthalene 2, could be
synthesized using selective ortho halogenation10 of naph-
thol precursor 6 followed by methylation. The selective
ortho halogenation of naphthol 6 with bromine or iodine
in the presence of tert-butylamine and further methylation
gave bromonaphthalene 2a (37%, two steps) and io-
SYNTHESIS 2005, No. 17, pp 2934–2938
x
x.
x
x
.
2
0
0
5
Advanced online publication: 17.08.2005
DOI: 10.1055/s-2005-872176; Art ID: Z04805SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Diospyrol
2935
OMe O
OMe O
3
OMe OMe
OMe OMe
OMe OMe
1. t-BuLi, THF
Pd(PPh3)3, K2CO3
X
NEt2
NEt2
–78 °C, TMEDA
toluene–EtOH–H2O
reflux
2. MgBr2
3. allyl bromide
78%
4
5
1b
2a X = Br
2b X = I
from 2a 40%, 2b 70%
LDA, THF
–78 °C, 60% –78 °C, 27%
or MeLi, THF
Scheme 3 Classical Suzuki–Miyaura cross-coupling in the synthe-
sis of tetramethoxydiospyrol (1b)
OMe OMe
OMe OH
1. X2, t-BuNH2,
toluene
X
compound in situ from 1.0 equivalent of haloarene fol-
lowed by Suzuki–Miyaura cross-coupling in the same
flask. In the first protocol (Method A)13 arylboronic ester
was prepared by metal–halogen exchange with n-BuLi
followed by quenching with B(OMe)3 whereas in the sec-
ond protocol (Method B)14 the arylboronic ester was pre-
2. MeI, NaH,
DMF
6
2a X = Br, 37% (2 steps via 7a)
2b X = I, 53% (2 steps via 8a)
1. n-BuLi, THF, –78 °C
2. B(OMe)3
pared
by
reacting
haloarene
directly
with
3. 2 N HCl
bis(pinacolato)diboron (9) under palladium catalyst. We
have utilized both protocols for the in situ cross-coupling
of both bromonaphthalene 2a and iodonaphthalene 2b as
shown in Scheme 4. By using method A, the product 1b
was obtained in 21 and 16% yield when bromo compound
and iodo compound were used respectively and the prod-
uct was obtained in 47 and 55% yield when method B was
employed.
OMe OMe
B(OH)2
3 72% from 2b
Scheme 2 Synthesis of key intermediate halonaphthalene 2 and
naphthaleneboronic acid 3
In summary, we have successfully synthesized tetra-
methoxydiospyrol using classical and modified Suzuki–
Miyaura cross-coupling reaction of naphthalene deriva-
tives which were prepared from the same common naph-
thol intermediate. The iodonaphthalene was found to react
more efficiently than bromonaphthalene in the cross-cou-
pling reaction.
donaphthalene 2b (53%, two steps), respectively.11 The
other key intermediate, naphthaleneboronic acid 3, could
be prepared in 72% yield from iodonaphthalene 2b under
metal–halogen exchange condition12 followed by quench-
ing with B(OMe)3 and hydrolysis with 2 N HCl.
With both key intermediates in hand, the Suzuki–Miyaura
cross-coupling was studied.6,13 The classical Suzuki–
Miyaura cross-coupling was carried out by refluxing
naphthaleneboronic acid 3 with both bromonaphthalene
2a and iodonaphthalene 2b in the presence of 3 mol%
Pd(PPh3)4 and K2CO3 in a mixed solvent system (toluene–
EtOH–H2O = 3:3:2) at 115–120 °C for 19 hours to obtain
tetramethoxydiospyrol (1b) in 40 and 70% yield, respec-
tively (Scheme 3). The tetramethoxydiospyrol (1b) could
be converted to the natural diospyrol 1a by a known meth-
od.3a,c
All commercial solvents and reagents were used without purifica-
tion prior to use. THF was distilled from benzophenone ketyl under
argon. Column chromatography purifications were carried out us-
ing silica gel (70–30 mesh).
2-Allyl-N,N-diethyl-6-methoxy-4-methylbenzamide (5)
To a stirred solution of N,N-diethyl-6-methoxy-4-methylbenzamide
(4; 2.0 g, 9.05 mmol) and TMEDA (1.5 mL, 10.0 mmol) in anhyd
THF (50 mL) at –78 °C was slowly added t-BuLi (1.0 M, 10.85 mL,
10.85 mmol) and the mixture was further stirred for 1 h. MgBr2
The modified one-pot, in situ Suzuki cross-coupling was etherate (4 mL) was added and the solution was warmed to r.t. The
developed by Keay13 and Bräse’s14 groups. Both protocols
mixture was recooled to –78 °C and the stirring was continued for
40 min. Allyl bromide (1.5 mL, 17.96 mmol) was then added and
involved the preparation of 0.5 equivalent of arylboronic
the mixture was warmed to r.t. and stirred overnight. Aq sat. NH4Cl
1. n-BuLi, THF, –78 °C
2. B(OMe)3
3. Pd(PPh3)3, K2CO3
toluene–EtOH–H2O,
reflux
from 2a 21%, 2b 16%
OMe OMe
OMe OMe
OMe OMe
X
O
O
1b
2a X = Br
2b X = I
B B
9, PdCl2dppf
O
O
K2CO3, dioxane, 80 °C
from 2a 47%, 2b 55%
Scheme 4 The modified in situ Suzuki cross-coupling for the synthesis of tetramethoxydiospyrol (1b)
Synthesis 2005, No. 17, 2934–2938 © Thieme Stuttgart · New York

2936
P. Sahakitpichan et al.
PAPER
was added and the mixture was extracted with CH2Cl2 (2 × 40 mL).
The combined organic layers were washed with H2O, brine and
dried (Na2SO4). CH2Cl2 was evaporated to dryness to give a crude
viscous oil (2.5 g). Further purification by column chromatography
(SiO2, 25% EtOAc–hexane) gave the required allylamide 5 as a vis-
cous oil (1.85 g, 78%) together with the starting compound (230
mg).
1H NMR (200 MHz, CDCl3): d = 2.42 (s, 3 H, CH3), 4.01 (s, 3 H,
OCH3), 6.62 (s, 1 H, H-7), 6.95 (d, J = 8.8 Hz, 1 H, H-4), 7.14 (s, 1
H, H-5), 7.64 (d, J = 8.8 Hz, 1 H, H-3), 10.16 (s, 1 H, OH).
13C NMR (50 MHz, CDCl3): d = 21.9, 56.3, 107.0, 113.1, 119.7,
120.8, 136.4, 136.5, 153.2, 154.8.
MS (EI, 70 eV): m/z (%) = 172 (34), 188 (26), 299 (34), 314 (100,
[M+]), 315 (12, [M + H+]).
IR (CHCl3): 1631, 1578 cm–1.
HRMS-FAB: m/z [M – H–] calcd for C12H11IO2: 312.9724; found:
312.9726.
1H NMR (200 MHz, CDCl3): d = 1.02 (t, J = 7 Hz, 3 H, CH3), 1.24
(t, J = 7 Hz, 3 H, CH3), 2.32 (s, 3 H, CH3), 3.05 (m, 2 H, NCH2),
3.30 (d, J = 7 Hz, 2 H, CH2), 3.40 (m, 1 H, NCH), 3.77 (m, 1 H,
NCH), 3.77 (s, 3 H, OCH3), 5.07 (m, 2 H, =CH2), 5.93 (m, 1
H, =CH), 6.56 (s, 1 H, H-5), 6.66 (s, 1 H, H-3).
13C NMR (50 MHz, CDCl3): d = 12.7, 13.7, 21.6, 36.9, 38.3, 42.6,
55.4, 109.4, 116.0, 122.3, 123.5, 136.7, 137.6, 139.23, 155.4, 168.2.
8b
Mp 110 °C (dec.) (CH2Cl2–hexane).
IR (KBr): 3266, 1623, 1604, 1557, 1449, 1407, 1355 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.49 (s, 3 H, CH3), 4.05 (s, 3 H,
OCH3), 6.71 (s, 1 H, H-7), 7.43 (s, 1 H, H-5), 8.25 (s, 1 H, H-3),
10.38 (s, 1 H, OH).
MS (EI, 70 eV): m/z (%) = 105 (23), 143 (27), 161 (88), 188 (76),
189 (100), 190 (24), 261 (32, [M+]), 262 (42, [M + H+]).
13C NMR (50 MHz, CDCl3): d = 22.2, 56.7, 85.8, 107.8, 113.4,
125.7, 136.3, 138.2, 146.2, 154.4, 154.8.
HRMS-FAB: m/z [M + H+] calcd for C16H23NO2: 262.1807; found:
262.1806.
MS (EI, 70 eV): m/z (%) = 298 (25), 425 (27), 440 (100, [M+]), 441
(14, [M + H+]).
8-Methoxy-6-methyl-1-naphthol (6)
Diisopropylamine (2.4 mL, 16.86 mmol) was added by syringe to
anhyd THF (50 mL). n-BuLi (1.2 M, 13.4 mL) was added at –78 °C
and the mixture was warmed to 0 °C and further stirred for 20 min.
The mixture was then cooled to –78 °C and a solution of allylamide
5 (2.0 g, 7.66 mmol) in anhyd THF (20 mL) was slowly added. The
mixture was stirred at –78 °C for 3 h and then warmed to r.t. over-
night. Aq sat. NH4Cl was added and the mixture was extracted with
CH2Cl2 (2 × 40 mL). The combined organic layers were washed
with H2O, brine and dried (Na2SO4). Further purification by column
chromatography (SiO2, CH2Cl2) gave the required naphthol 6 as a
pale brown viscous oil (860.0 mg, 60%).15
Anal. Calcd for C12H10I2O2: C, 32.76; H, 2.29. Found: C, 33.01; H,
2.12.
Methylation of 1-Hydroxy-2-iodo-8-methoxy-6-methylnaph-
thalene (8a): 2-Iodo-1,8-dimethoxy-6-methylnaphthalene (2b);
Typical Procedure
To a stirred suspension of NaH (80% in oil, 179 mg, 5.97 mmol) in
DMF (5 mL) was added a solution of iodonaphthol 8a (1.25 g, 3.98
mmol) in DMF (10 mL) at r.t. The mixture was stirred for 1 h and
MeI (0.5 mL, 8 mmol) was then added and the mixture was stirred
overnight. H2O was slowly added and the mixture was extracted
with EtOAc (2 × 25 mL). The combined EtOAc extracts were
washed with H2O, brine and dried (Na2SO4) and evaporated to dry-
ness. The crude product was purified by column chromatography
(SiO2, 2–5% EtOAc–hexane) to obtain 2b as a viscous oil (1.19 g,
91%).
IR (CHCl3): 3404 (s) cm–1.
1H NMR (200 MHz, CDCl3): d = 2.42 (s, 3 H, CH3), 3.99 (s, 3 H,
OCH3), 6.56 (d, J = 1.2 Hz, 1 H, H-7), 6.79 (dd, J = 7.6, 1.2 Hz, 1
H, H-2), 7.16 (s, 1 H, H-5), 7.18 (dd, J = 7.6, 1.2 Hz, 1 H, H-4), 7.30
(t, J = 8 Hz, 1 H, H-3), 9.25 (s, 1 H, OH).
13C NMR (50 MHz, CDCl3): d = 21.8, 56.0, 106.1, 109.5, 113.3,
118.2, 120.8, 127.7, 135.5, 136.9, 154.4, 155.9.
IR (neat): 2929, 1625, 1568, 1454, 1330 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.45 (s, 3 H, CH3), 3.84 (s, 3 H,
OCH3), 3.99 (s, 3 H, OCH3), 6.72 (s, 1 H, H-7), 7.17 (s, 1 H, H-5),
7.20 (d, J = 8.8 Hz, 1 H, H-4), 7.72 (d, J = 8.8 Hz, 1 H, H-3).
13C NMR (50 MHz, CDCl3): d = 21.8, 56.3, 61.7, 88.5, 108.9,
119.0, 120.1, 125.2, 135.9, 136.8, 137.6, 155.0, 155.9.
MS (EI, 70 eV): m/z (%) = 115 (7), 145 (9), 188 (100, [M+]), 189
(16, [M + H+]).
HRMS-FAB: m/z [M – H–] calcd for C12H12O2: 187.0759; found:
187.0753.
MS (EI, 70 eV): m/z (%) = 328 (100, [M+]), 329 (19, [M + H+]).
HRMS-FAB: m/z [M + H+] calcd for C13H13IO2: 329.0037; found:
329.0030.
2-Iodo-8-methoxy-6-methyl-1-naphthol (8a) and 2,4-Diiodo-8-
methoxy-6-methyl-1-naphthol (8b)
To a stirred solution of tert-butylamine (2.14 mL, 20.27 mmol) in
anhyd toluene (20 mL) was added a solution of I2 (2.58 g, 10.16
mmol) in anhyd toluene (35 mL) at r.t. and the mixture was further
stirred for 1 h. The resulting mixture was then transferred to a stirred
solution of naphthol 6 (1.91 g, 10.16 mmol) in anhyd toluene (25
mL) at 0 °C via cannula. After the addition was complete, the reac-
tion was further stirred for 10 min. Aq sat. Na2S2O3 (30 mL) was
added and the mixture was extracted with EtOAc (30 mL), and the
Et2O layer was washed with H2O and brine. The combined extracts
were dried (Na2SO4) and evaporated to dryness. Further purification
was carried out by column chromatography (SiO2, 5% EtOAc–hex-
ane) to obtain o-iodonaphthol 8a (1.87 g, 58%) and o,p-diiodonaph-
thol 8b (603.6 mg, 14%).11
2-Bromo-1,8-dimethoxy-6-methylnaphthalene (2a)
Viscous oil.
IR (neat): 2940, 2840, 1597, 1462, 1355, 1264, 1079, 747 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.39 (s, 3 H, CH3), 3.82 (s, 3 H,
OCH3), 3.93 (s, 3 H, OCH3), 6.67 (s, 1 H, H-7), 7.10 (s, 1 H, H-5),
7.23 (d, J = 8.8 Hz, 1 H, H-4), 7.47 (d, J = 8.8 Hz, 1 H, H-3).
13C NMR (50 MHz, CDCl3): d = 21.8, 56.3, 61.6, 109.1, 113.9,
119.6, 120.1, 124.6, 130.6, 136.6, 136.7, 153.1, 155.3.
MS (GC, 70 eV): m/z (%) = 115 (56), 128 (81), 139 (30), 158 (91),
186 (83), 207 (33), 209 (28), 280 (97, [M+]), 282 (100, [M+ + 2]).
1,8-Dimethoxy-6-methylnaphthalene-2-boronic Acid (3)
To a stirred solution of iodonaphthalene 2b (301.7 mg, 0.92 mmol)
in THF (7 mL) at –78 °C under argon was added n-BuLi (1.12 mL,
1.84 mmol) followed immediately by B(OMe)3 (200 mL, 1.78
8a
Mp 116–116.5 °C (CH2Cl2–hexane).
IR (KBr): 3320, 1626, 1603, 1579, 1495, 1403, 1370 cm–1.
Synthesis 2005, No. 17, 2934–2938 © Thieme Stuttgart · New York

PAPER
Synthesis of Diospyrol
2937
mmol). After stirring at –78 °C for 30 min, the mixture was warmed
to r.t. and stirred for 1 h. The resulting mixture was quenched with
2 N HCl and extracted with CH2Cl2 (2 × 20 mL). The combined ex-
tracts were washed with H2O and brine and dried (Na2SO4). The sol-
vent was removed to obtain the crude boronic acid which was
purified by preparative layer chromatography (PLC) (SiO2, 1%
MeOH–CH2Cl2) to give boronic acid 3 as a white solid (163 mg,
72%); mp 157.5–158 °C (CH2Cl2–hexane).
13C NMR (50 MHz, CDCl3): d = 21.8, 56.1, 61.4, 108.0, 118.6,
120.0, 122.7, 128.5, 130.8, 135.0, 137.2, 153.6, 156.2.
MS (EI, 70 eV): m/z (%) = 298 (8), 341 (25), 357 (21), 402 (100,
[M+]), 403 (29, [M + H+]).
Acknowledgment
We are grateful to the Thailand Research Fund (TRF) for the ge-
nerous support of our research program (TRG468008 to NT) and
for the award of Senior Research Scholar to S.R.
IR (KBr): 2937(br), 1610, 1605, 1572, 1467, 1376 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.49 (s, 3 H, CH3), 3.9 (s, 3 H,
OCH3), 4.04 (s, 3 H, OCH3), 6.71 (s, 2 H, 2 OH), 6.74 (s, 1 H, H-7),
7.24 (s, 1 H, H-5), 7.52 (d, J = 16.4 Hz, 1 H, H-4), 7.83 (d, J = 16.8
Hz, 1 H, H-3).
References
13C NMR (50 MHz, CDCl3): d = 21.9, 56.1, 63.8, 108.4, 117.3,
(1) (a) Loder, J. W.; Mongkolsuk, S.; Robertson, A.; Whalley,
W. B. J. Chem. Soc. 1957, 2233. (b) Mongkolsuk, S.;
Sadarwonvivat, C. J. Chem. Soc. 1965, 1533. (c) Yoshihira,
K.; Natori, S.; Kanchanapee, P. Tetrahedron Lett. 1967,
4857. (d) Yoshihira, K.; Tezuka, M.; Kanchanapee, P.;
Natori, S. Chem. Pharm. Bull. 1971, 19, 2271. (e) Borsub,
L.; Thebtaranonth, Y.; Ruchirawat, S.; Sadavongvivad, C.
Tetrahedron Lett. 1976, 105.
(2) (a) Daengsvang, S.; Mangalasmaya, M. Ann. Trop. Med.
Parasitol. 1941, 35, 43. (b) Sadun, E. H.; Vajrasthira, S. J.
Parasitol. 1954, 40, 49.
(3) (a) Govindachari, T. R.; Viswanathan, N.; Ravindranath, K.
R.; Anjaneyulu, B. Indian J. Chem. 1973, 11, 1081.
(b) Rizzacasa, M. A.; Sargent, M. V. Aust. J. Chem. 1988,
41, 1087. (c) Mahidol, C.; Tarnchompoo, B.;
Thebtaranonth, C.; Thebtaranonth, Y. Tetrahedron Lett.
1989, 30, 3861.
(4) For bromodiospyrol derivative as precursor for the synthesis
of michellamine class alkaloid, see: Bringmann, G.;
Ortmann, T.; Feineis, D.; Peters, E.-M.; Peters, K. Synthesis
2000, 383.
(5) (a) Manfredi, K. P.; Blunt, J. W.; Cardellina, J. H. II;
McMahon, J. B.; Pennell, L. L.; Cragg, G. M.; Boyd, M. R.
J. Med. Chem. 1991, 34, 3402. (b) Boyd, M. R.; Hallock, Y.
F.; Cardellina, J. H.; Manfredi, K. P.; Blunt, J. W.; Buckheit,
R. W. Jr.; Bringmann, G.; Schaffer, M.; Cragg, G. M.;
Thomas, D. W.; Jato, J. G. J. Med. Chem. 1994, 37, 1740.
(c) McMahon, J. B.; Currens, M. J.; Gulakowski, R. J.;
Buckheit, R. W. Jr.; Lackman-Smith, C.; Hallock, Y. F.;
Boyd, M. R. Antimicrob. Agents Chemother. 1995, 39, 484.
(d) Hallock, Y. F.; Manfredi, K. P.; Dai, J.-R.; Cardellina, J.
H. II; Gulakowski, R. J.; McMahon, J. B.; Schaffer, M.;
Stahl, M.; Gulden, K.-P.; Bringmann, G.; Francois, G.;
Boyd, M. R. J. Nat. Prod. 1997, 60, 677.
120.4, 123.9, 132.0, 137.7, 139.9, 155.7, 163.8.
MS (EI, 70 eV): m/z (%) = 191 (22), 201 (22), 202 (15), 204 (75),
231 (14), 245 (27), 246 (100, [M+]), 247 (14, [M + H+]).
Anal. Calcd for C13H15BO4: C, 63.45; H, 6.14. Found: C, 63.32; H,
5.77.
Tetramethoxydiospyrol (1b) by Classical Suzuki–Miyaura
Cross-Coupling Reaction
A mixture of iodonaphthalene 2b (158.5 mg, 0.48 mmol), naphtha-
leneboronic acid 3 (118.9 mg, 0.48 mmol), Pd(PPh3)4 (11 mg, 3
mol%) and K2CO3 (133 mg, 0.96 mmol) in a mixture of toluene–
EtOH–H2O (3:3:2, 8 mL) was refluxed at 115–120 °C for 19 h. Af-
ter cooling the mixture, H2O was added and extracted with EtOAc
(2 × 20 mL). The combined EtOAc extracts were washed with H2O,
brine and dried (Na2SO4). Further purification was carried out by
PLC (SiO2, 0.5% MeOH–CH2Cl2) to give tetramethoxydiospyrol
(1b) which was recrystallized from benzene to afford 1b as white
crystals (136.2 mg, 70%).
Tetramethoxydiospyrol (1b) Modified in situ Suzuki Cross-
Coupling
Method A:13 To a solution of bromonaphthalene (150 mg, 0.5 mmol)
in THF (10 mL) at –78 °C was added 0.5 equiv of 0.77 M of n-BuLi
(0.4 mL) followed by 6 equiv of B(OMe)3 (0.8 mL). The resulting
solution was warmed to r.t. for 4 h and subsequently stirred over-
night under argon. To the solution were then added toluene (6 mL),
EtOH (6 mL), H2O (4 mL), K2CO3 (130 mg, 1.0 mmol), and
Pd(PPh3)4 (2 mg, 10 mol%). The resulting mixture was refluxed un-
der argon for 10 h. The reaction was allowed to warm to r.t. and ex-
tracted with CH2Cl2 (3 × 30 mL). The organic phases were
combined, washed with H2O, dried (Na2SO4), and concentrated un-
der reduced pressure to afford the crude binaphthalene which was
purified on PLC to yield recovered bromonaphthalene 2a (60 mg,
37%), tetramethoxydiospyrol (1b) (40 mg, 21%) and debromonaph-
thalene (30 mg, 26%).16
(6) Kotha, S.; Lahiri, K.; Kashinath, D. Tetrahedron 2002, 58,
9633.
(7) For the synthesis of naphthol derivatives via regiospecific
benzyne annulation, see: (a) Watanabe, M.; Hisamatsu, S.;
Hotokeaka, H.; Furukawa, S. Chem. Pharm. Bull. 1986, 34,
2810. (b) Hoye, T. R.; Chen, M.; Mi, L.; Priest, O. P.
Tetrahedron Lett. 1994, 35, 8747. (c) Hoye, T. R.; Mi, L.
Tetrahedron Lett. 1996, 37, 3097. For intramolecular
cyclization of allylbenzamide derivative, see: (d) Sibi, M.
P.; Dankwardt, J. W.; Snieckus, V. J. Org. Chem. 1986, 51,
271. (e) Hattori, T.; Takeda, A.; Suzuki, K.; Koike, N.;
Koshiishi, E.; Miyano, S. J. Chem. Soc., Perkin Trans. 1
1998, 3661. (f) Namsaaid, A.; Ruchirawat, S. Org. Lett.
2002, 4, 2633. (g) Yu, S.; Rabalakos, C.; Mitchell, W. D.;
Wulff, W. D. Org. Lett. 2005, 7, 367. For thermolysis of
substituted benzocyclobutanol, see: (h) Bungard, C. J.;
Morris, J. C. J. Org. Chem. 2002, 67, 2361. For multistep
Method B:14 A mixture of iodonaphthalene 2b (165.4 mg, 0.5
mmol), bis(pinacolato)diboron (9; 63.5 mg, 0.25 mmol), PdCl2dppf
(14.6 mg, 4 mol%), and K2CO3 (207 mg, 1.5 mmol) in dioxane (5
mL) was heated at 80 °C for 16 h. After cooling the mixture, H2O
was added and extracted with CH2Cl2. The combined CH2Cl2 ex-
tracts were washed with H2O, 20% aq NaOH, and dried (Na2SO4).
Further purification was carried out by column chromatography
(SiO2, 0.5% MeOH–CH2Cl2) to give tetramethoxydiospyrol (1b)
(54.9 mg, 55%) as a white solid; mp (benzene) 239–239.5 °C (Lit.1a
mp 232 °C, Lit.1d mp 243 °C).
IR (KBr): 1625, 1563, 1451, 1338, 1262 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.50 (s, 6 H, 2 CH3), 3.55 (s, 6 H,
2 OCH3), 4.01 (s, 6 H, 2 OCH3), 6.73 (s, 2 H, H-7,7¢), 7.26 (s, 2 H,
H-5,5¢), 7.52 (d, J = 16.4 Hz, 2 H, H-4,4¢), 7.83 (d, J = 16.8 Hz, 2
H, H-3,3¢).
Synthesis 2005, No. 17, 2934–2938 © Thieme Stuttgart · New York

2938
P. Sahakitpichan et al.
PAPER
synthesis, see: (i) Bringmann, G.; Gotz, R.; Kelly, T. R.;
Boyd, M. R. Heterocycles 1994, 39, 503. (j) Hobbs, P. D.;
Upender, V.; Liu, J.; Pollart, D. J.; Thomas, D. W.; Dawson,
M. I. Chem. Commun. 1996, 923. (k) Hoye, T. R.; Mi, L. J.
Org. Chem. 1997, 62, 8586.
(12) Brimble, M. A.; Duncalf, L. J.; Neville, D. J. Chem. Soc.,
Perkin Trans. 1 1998, 4165.
(13) Andersen, N.; Maddaford, S. P.; Keay, B. A. J. Org. Chem.
1996, 61, 9556.
(14) Nising, C. F.; Schmid, U. K.; Nieger, M.; Bräse, S. J. Org.
Chem. 2004, 69, 6830.
(8) Sibi, M. P.; Miah, M. A. J.; Snieckus, V. J. Org. Chem. 1984,
49, 737.
(15) Hobbs, P. D.; Upender, V.; Dawson, M. Synlett 1997, 965.
(16) 1,8-Dimethoxy-3-methylnaphthalene17 obtained as
dehalogenation adduct from half-Suzuki cross-coupling was
a white solid; mp 89–90 °C (MeOH). 1H NMR (200 MHz,
CDCl3): d = 2.47 (s, 3 H, CH3), 3.98 (s, 6 H, 2 OCH3), 6.69
(d, J = 1.0 Hz, 1 H), 6.78 (dd, J = 6.2, 8.4 Hz, 1 H), 7.19 (br
s, 1 H), 7.35 (m, 2 H). 13C NMR (50 MHz, CDCl3): d = 21.7,
56.2, 56.3, 105.2, 108.2, 115.6, 120.0, 120.2, 126.4, 136.1,
137.5, 156.8, 157.0. MS (EI, 70 eV): m/z (%) = 128 (71),
129 (99), 159 (58), 201 (100) 202 (50, [M+]).
(9) Owton, W. M.; Brunavs, M.; Miles, M. V.; Dobson, D. R.;
Steggles, D. J. J. Chem. Soc., Perkin Trans. 1 1995, 931.
(10) Yonezawa, S.; Komurasaki, T.; Kawada, K.; Tsuri, T.; Fuji,
M.; Kugimiya, A.; Haga, N.; Mitsumori, S.; Inagaki, M.;
Nakatani, T.; Tamura, Y.; Takechi, S.; Taishi, T.; Ohtani, M.
J. Org. Chem. 1998, 63, 5831.
(11) The bromination and iodination of naphthol 6 also gave para
halogenated products (Scheme 5). Compounds 7a and 7b
were further methylated without purification.
(17) Bringmann, G.; Jansen, J. R. Tetrahedron Lett. 1984, 25,
2537.
OMe OH
OMe OH
OMe OH
X1
X1
I2, t-BuNH2
toluene
Br2, t-BuNH2
toluene
X2
6
X2
7a X1 = Br, X2 = H
7b X1 = H, X2 = Br
8a X1 = I, X2 = H
8b X1 = X2 = I
Scheme 5
Synthesis 2005, No. 17, 2934–2938 © Thieme Stuttgart · New York