One-pot access to 2-naphthols and benzofurans via the aerobic Wacker-type oxidation/intramolecular aldol cyclization

Article abstract of DOI:10.1016/j.tet.2012.12.009

An aerobic Wacker-type oxidation/intramolecular aldol cyclization synthetic route toward two oxygenated 2-naphthols 3 and benzofurans 4 starting with skeleton 2 with good yields is described. The route has been carried by the one-pot transformation of the regioselective PdCl₂/CuCl ₂-mediated Wacker oxidative cyclization of skeleton 2 with molecular oxygen under the alkaline methanolic condition. Skeleton 2 was prepared from skeleton 1 in moderate total yields via the known protocol.

Full text of DOI:10.1016/j.tet.2012.12.009

Tetrahedron 69 (2013) 1532e1538
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Tetrahedron
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One-pot access to 2-naphthols and benzofurans via the aerobic
Wacker-type oxidation/intramolecular aldol cyclization
*
Meng-Yang Chang , Chieh-Kai Chan, Shin-Ying Lin
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
An aerobic Wacker-type oxidation/intramolecular aldol cyclization synthetic route toward two oxygen-
ated 2-naphthols 3 and benzofurans 4 starting with skeleton 2 with good yields is described. The route
has been carried by the one-pot transformation of the regioselective PdCl2/CuCl2-mediated Wacker
oxidative cyclization of skeleton 2 with molecular oxygen under the alkaline methanolic condition.
Skeleton 2 was prepared from skeleton 1 in moderate total yields via the known protocol.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 1 November 2012
Received in revised form 28 November 2012
Accepted 4 December 2012
Available online 10 December 2012
Keywords:
Aerobic Wacker-type oxidation
2-Naphthols
Benzofuran
Isovanillin
1. Introduction
speculate that molecular oxygen may control this reaction to gen-
erate different kinds of products and should provide differences in
During the last decade, Wacker oxidation has become a power-
ful and efficient tool to access a versatile class of functionalized
Markonikov’s adducts that have found use in drug discovery. A
number of review articles have highlighted fascinating de-
velopments based on a Wacker-type reaction.1,2 In particular, the
PdII/CuII system catalyzing an intermolecular or intramolecular
oxidative cyclization of internal or terminal substituted alkenes or
alkynes with different reaction solvents or conditions has been
broadly adopted by synthetic researchers, to the degree that di-
versified alkenes or alkynes are often viewed as various olefinic
compounds, carbocycles or heterocycles.3e16 Bioactive synthesis of
natural products has been directed toward this reaction.17
the assumed catalytic cycles under the Wacker-type oxidative re-
action. In continuation of our recent investigation of skeleton 2
with the o-allyl group (prepared from 1a) for preparing several
oxygenated and benzannulated molecules,21 one-pot PdII/CuII me-
diated the aerobic Wacker-type oxidation/intramolecular aldol
cyclization route for synthesizing two frameworks of 2-naphthols 3
and benzofurans 4 is studied next (Scheme 1).
Me
OMe R
OR
R
O
1
OH
1
2
OH
MeO
MeO
O
MeO
R
1
MeO
O
O
After further investigation, this aerobic PdII/CuII system cata-
lyzed Wacker-type oxidation becomes attractive for the construc-
tion of oxygen- or nitrogen-containing compounds (aza-Wacker-
type) with molecular oxygen (O2) or air as the co-oxidant.18e20
Compared with the impressive examples using PdX2/CuX2 system
catalyzed Wacker-type oxidations of terminal or internal alkynes,
the use of molecular oxygen as the oxidant provides 1,2-diketones
with high yields.20a Without the involvement of molecular oxygen,
two kinds of hexa-substituted benzenes and dihalogenated dienes
have been observed via cyclotrimerization or oligodimerization
under similar conditions.12b,15 From the literature reports, we
R
2
R
R
H
2
2-naphthols (3)
benzofurans (4)
isovanillin (1a)
2
Scheme 1. Skeletons of isovanillin (1a), o-allylbenzaldehyde 2, 2-naphthols 3, and
benzofurans 4.
Most of the related literature on one-pot synthesis of
substituted naphthalenes and benzofurans is focused on transition
metal-catalyzed cyclization.22,23 There have been extensive studies
on the preparation of functionalized 2-naphthols and benzofurans
owing to their prevalence in a variety of derivatives possessing
important physical and biological properities.24,25 However, as yet,
there have been very few efficient syntheses of oxygenated skele-
ton 3 or 4 bearing appropriate functional group of different
positions.
* Corresponding author. Tel.: þ886
7 3121101x2220; e-mail addresses: my-
chang@kmu.edu.tw, mychang624@yahoo.com.tw (M.-Y. Chang).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.12.009

M.-Y. Chang et al. / Tetrahedron 69 (2013) 1532e1538
1533
2. Results and discussion
mixture were isolated at different ratios. From the above results, we
found that the ratios of products 3b and 2b0 were distributed be-
tween 1:5 and 2:5. To our delight, by adjusting the molecular ox-
ygen (by bubbled method) as the oxidant, the isolated yield (84%)
was noticeably enhanced (entry 6). The concise method provides 2-
naphthol 3b with an 84% yield, and presents trace unknown im-
purities or by-products. After the amounts of PdCl2 and CuCl2 were
increased two-fold, 2-naphthol 3b provided similar yields (73e74%,
entries 7e9). Changing the catalyst from PdCl2 to Pd(OAc)2 and
PdCl2(MeCN)2, a similar yield of compound 3a was provided for
entries 10 and 11. When the reaction of compound 2b was treated
with catalytic amounts of RuCl2(PPh3)3, the generated yield of
product 2b0 was higher than the desired product 3b. To change the
oxidant from oxygen to air, product 3b (46%) and starting material
2a (25%) were isolated (entry 13). Without the addition of CuCl2,
compound 2a was recovered as major product (70%, entry 14). We
envisioned the optimized one-pot process for synthesizing com-
pound 3b should involve a combination of PdCl2/CuCl2/O2/NaOH.
How are 2b produced? The initial event may be considered as the
formation of dicarbonyl. Furthermore, intramolecular aldol con-
densation/tautomerization of the resulting enone motif afforded
product 3b.
With our experience in using the o-allyl group for starting
skeleton 2 for the synthesis of functionalized and benzannulated
molecules, we believe that it may be possible to develop this one-
pot methodology for preparing the skeleton of 2-naphthols 3 and
benzofurans 4 via Wacker-type oxidation. As shown in Scheme 2,
a facile five-step known route was employed to create skeleton 2,
starting with isovanillin (1a) and 2-hydroxybenzaldehyde (1b) via
(1) O-allylation with allyl or trans-crotyl bromide (R1¼H/Me), (2)
Claisen rearrangement with decalin, (3) O-alkylation or O-benzy-
lation of skeleton 5 with alkyl or benzyl bromide, (4) Grignard
addition with arylmagnesium bromide and (5) oxidation with
pyridinium chlorochromate (PCC).21
OH
OH
R
1
1) O-allylation
1) O-alkylation
X
X
2) Claisen reaction
2) Grignard addition
3) PCC-oxidation
CHO
CHO
5
1a, X = H
1b, X = OMe
R
1
= H, Me; R = alkyl or benzyl; R = H, aryl
2
Changing the substituents (R or X) of o-allylbenzaldehydes
2ae2h, eight 2-naphthols 3ae3h were isolated in 69e84% yields
via the abovementioned one-pot oxidative protocol (entries 1e8).
When the reaction of o-allylbenzenes 2ie2n (R2¼aryl group,
entries 9e14) was treated with optimal reaction conditions, we
observed that 2-naphthols 3ie3n provided 76e84% yields.
According to the facile one-pot procedure, four 2-naphthols
3oe3r with methyl (R1) and different aryl groups (R2) were
prepared with 83e88% yields (entries 15e18). In comparison
with the isolated yields of products with different aryl sub-
stituents, it was found that compounds 3pe3r (R2, entries 9e14)
were slightly better than the other analogues 3ie3n (entries
16e18). The structures of compounds 3b and 3h are constructed
using single-crystal X-ray analysis.26 Single-crystal X-ray diffrac-
tion analysis was employed to prove the constitution and relative
configuration of the isolated product. Attempts to extend this
one-pot reaction to the skeleton of benzofuran are shown in
entries 19e21. Using a treatment of compounds 5ae5c (R¼H)
with one-pot methodology provided three benzofurans 4ae4c
isolated with 72e76% yield. According to the abovementioned
synthetic procedure, we attempted to construct the bicyclic 2-
naphthols 3 by a combination of PdCl2/CuCl2/O2/NaOH-medi-
ated reaction of skeleton 2 with different substituents as shown
in Table 2. There is only one recent example to describe the one-
pot and direct oxidative cyclization of skeleton 2 with water by
using the combination of PdCl2/CuCl2 system.13
R = Me, R = R = H, X = X = MeO, R = Me, R = H, R =
1 2 1 2
OR
R
1
2a, H
2i, Ph; 2j, 2-Me-Ph
X
X = MeO, R = R = H, R = 2k, 2-MeO-Ph; 2l, 4-F-Ph;
1
2
2b, Me; 2c, n-Bu; 2d, C H 2m, 4-MeO-Ph; 2n, 3,4-CH O -Ph
5
9
2 2
=
O
2e, Bn; 2f, CH -3-F-Ph
X = MeO, R = Me, R = Me, R
1
2
2
2g, CH -3-MeO-Ph
2o, H; 2p, Ph
2q, 4-F-Ph; 2r, 4-MeO-Ph
2
R
2
2h, CH -4-NO -Ph
2
2
Scheme 2. Five-step synthesis of starting skeleton 2.21
Next, an aerobic PdII/CuII system mediated one-pot Wacker-type
oxidative cyclization of skeleton 2 was employed to create two
skeletons of 2-naphthols 3 (RsH) and benzofurans 4 (R¼H) under
an alkaline methanolic condition. After screening different Wacker-
type oxidative conditions (Table 1), we found that PdCl2/CuCl2
system-mediated Wacker-type oxidation of model substrate 2b
with five different oxidants (t-BuO2H, DDQ, CAN, OxoneÒ, and
PhI(OAc)2) provided these lower yields (entries 1e5). In the product
mixture, product 2b0 with olefinic migration and an unknown
Table 1
One-pot Wacker-type cyclization of 2ba,b
OMe
OMe
OH
Me
MeO
MeO
catalyst, CuCl , oxidants
2
2b
+
THF / MeOH (v/v = 9/1),
NaOH (4 equiv), rt
CHO
3b
2b'
Furthermore, when PdCl2/CuCl2-mediated aerobic Wacker oxi-
dationof compound2bwastreated in theabsence ofbasiccondition,
only ketone 6a was isolated at a 90% yield, as shown in Scheme 3.
Following the process, seven compounds 6be6g also provided
86d92% yield though the reaction of compounds 2b, 2c, 2e, 2je2l,
and 2o with the combination of PdCl2/CuCl2/O2. Based on the ex-
perimental results, a possible reaction mechanism is shown in
Scheme 4. Initially, complexation of PdCl2 with terminal olefin of
substrate 2b (R¼Me) or 5b (R¼H) yields the intermediate A1 or A2.
Intermediate B1 or B2 should be afforded via the intermolecular
addition of methanol or intramolecular 5-exo-trig cyclization. Fol-
lowing by the hydride shift on the skeleton of intermediate B1 or B2,
intermediate C1 or C2 is generated. After isomerization of in-
termediate C1 or C2, sequential HCl-mediated olefinic migration
affords compound 6a or 4b. Subsequently, Pd(0) is recycled to PdCl2
by CuCl2 and O2, which is regenerated from forming CuCl and HCl in
situ.13 Finally, compound 3b is provided via the NaOH-mediated
intramolecular aldol cyclization of compound 6a.
Entry
Catalyst (mol %), CuCl2, oxidants (equiv)
3b/2b0 Yield, %
1
2
3
4
5
6
7
8
PdCl2 (5.6), CuCl2 (1.5), t-BuO2H (1)
PdCl2 (5.6), CuCl2 (1.5), DDQ (1)
PdCl2 (5.6), CuCl2 (1.5), CAN (1)
PdCl2 (5.6), CuCl2 (1.5), OxoneÒ (1)
PdCl2 (5.6), CuCl2 (1.5), PhI(OAc)2 (1)
PdCl2 (5.6), CuCl2 (1.5), O2
PdCl2 (11.3), CuCl2 (1.5), O2
PdCl2 (5.6), CuCl2 (3.0), O2
PdCl2 (11.3), CuCl2 (3.0), O2
Pd(OAc)2 (4.5), CuCl2 (1.5), O2
PdCl2(MeCN)2 (3.9), CuCl2 (1.5), O2
RuCl2(PPh3)3 (1.0), CuCl2 (1.5), O2
PdCl2 (5.6), CuCl2 (1.5), air
16/38c
20/50c
w15/31c
<10/47c
26/32c
84/dd
73/dd
75/dd
74/dd
71/dd
70/dd
51/30d
46/de
<10/de
9
10
11
12
13
14
PdCl2 (5.6), CuCl2 (0), air
a
The reactions were run on a 1.0 mmol scale with 2a.
b
c
The products 3b and 2b0 were >95% pure as determined by H NMR analysis.
The unknown products were obtained with different amounts.
d
e
Other trace amounts of unknown products (5e10%) were obtained.
The starting material 2b (25% for entry 13; 70% for entry 14) was recovered.

1534
M.-Y. Chang et al. / Tetrahedron 69 (2013) 1532e1538
Table 2
One-pot aerobic Wacker-type synthetic route toward 2-naphthols 3 and benzofurans 4a,b
Me
OR
R
R
OR
R
O
1
1
PdCl , CuCl , O (balloon)
OH
X
X
X
R
2
2
2
1
+
O
O
THF / MeOH (9/1), then NaOH, rt, 15 h
(X = H, MeO; R = H, Me; R = H, Ar)
1
2
R
R
4
2
2
2
2 / 5
3
Entry
Reactant 2
Product 3
Entry
Reactant 2
Product 3
Entry
15
Reactant 2/5
Product 3/4
NO
OMe
OMe Me
2
OMe Me
NO
OMe
2
MeO
MeO
OH
O
OH
O
MeO
MeO
OH
O
O
H
1
8
O
H
H
3a / 80%
2o
3o / 83%
3h / 73%
2a
2h
OMe
OMe
OMe Me
OMe Me
OMe
OMe
MeO
MeO
OH
MeO
MeO
OH
MeO
MeO
OH
O
O
O
2
9
16
H
3b / 84%
2b
3p / 85%
2i
3i / 82%
2p
OMe Me
OMe Me
OMe
OMe
O
MeO
MeO
OH
MeO
MeO
OH
Me
O
MeO
MeO
OH
O
O
O
Me
3
10
17
H
F
F
3c / 80%
2c
2j
3j / 77%
3q / 86%
2q
OMe Me
OMe Me
OMe
OMe
MeO
MeO
OH
MeO
MeO
OH
O
O
MeO
O
O
MeO
OH
OMe
OMe
4
5
6
O
11
12
13
18
19
20
H
OMe
OMe
3d / 79%
2d
2k
3k / 76%
2r
3r / 88%
OMe
OMe
Me
O
OH
MeO
MeO
OH
O
O
MeO
O
MeO
OH
O
O
O
H
H
H
F
F
3e / 72%
5a
2e
4a / 72%
2l
3l / 84%
OMe
OMe
Me
OH
MeO
MeO
OH
O
O
MeO
O
F
MeO
F
MeO
O
MeO
OH
O
H
O
O
H
H
OMe
OMe
3f / 72%
5b
2f
4b / 76%
2m
3m / 82%
OMe
OMe
Me
OH Me
MeO
MeO
OH
O
MeO
O
O
OMe
MeO
O
Me
O
OMe
OH
MeO
MeO
O
7
14
21
O
H
H
H
O
O
O
O
3g / 69%
5c
4c / 72%
2g
2n
3n / 80%
a
For the optimal reaction conditions: (i) skeleton 2 or 5 (1.0 mmol), PdCl2 (10 mg, 5.6 mol %), CuCl2 (200 mg, 1.5 mmol), O2 (bubbled), THF/MeOH (v/v¼9:1, 20 mL), rt, 10 h,
and then NaOH (160 mg, 4.0 mmol), rt, 5 h.
b
The isolated products were >95% pure as determined by 1H NMR analysis.

M.-Y. Chang et al. / Tetrahedron 69 (2013) 1532e1538
1535
No involvement of NaOH
or without the involvement of molecular oxygen resulting in ac-
ceptable to good yields.
OR
R
OR
R
1
1
Me
MeO
MeO
PdCl , CuCl , O (balloon)
2
2
2
O
O
O
THF / MeOH (9/1), rt, 15 h
4. Experimental section
4.1. General
R
R
2
2
R
2
= H
2b~2c / 2e / 2j~2l / 2o
6a, R = Me, R = H (90%)
1
6b, R = n-Bu, R = H (86%)
1
All other reagents and solvents were obtained from commercial
sources and used without further purification. Reactions were
routinely carried out under an atmosphere of dry nitrogen with
magnetic stirring. Products in organic solvents were dried with
anhydrous MgSO4 before concentration in vacuo. Melting points
were determined with an SMP3 melting apparatus. 1H and 13C NMR
spectra were recorded on a Varian INOVA-400 spectrometer oper-
6c, R = Bn, R = H (88%)
1
6d, R = R = Me (90%)
1
R = Me, R = H
1
6e, R = 2-Me-Ph (86%)
2
2
2
6f, R = 2-MeO-Ph (92%)
6g, R = 4-F-Ph (92%)
Scheme 3. Synthesis of skeleton 6.
ating at 200/400 and at 100 MHz, respectively. Chemical shifts (d)
are reported in parts per million (ppm) and the coupling constants
(J) are given in hertz. High-resolution mass spectra (HRMS) were
measured with a mass spectrometer Finnigan/Thermo Quest MAT
95XL. X-ray crystal structures were obtained with an Enraf-Nonius
FR-590 diffractometer (CAD4, Kappa CCD). Elemental analyses were
carried out with Heraeus Vario III-NCSH, Heraeus CHN-OS-Rapid
Analyzer or Elementar Vario EL III.
2b, R = Me
5b, R = H
5-exo-trig
cyclization
complexation
(for R = H)
2 HCl + 1/2 O
2
RO
PdCl
2
PdCl
2
2 CuCl
MeO
+
δ
H O
2
regeneration
CHO
2 CuCl
2
4.2. A representative synthetic procedure of skeleton 3, 4 or 7
MeOH
A1, R = Me
A2, R = H
Pd(0)
(for R = Me)
addition
A representative synthetic procedure of skeleton 3, 4 or 7 is as
follows: PdCl2 (10 mg, 5.6 mol %) and CuCl2 (200 mg, 1.5 mmol)
were added to a solution of skeleton 2 or 5 (1.0 mmol) in the co-
solvent of THF and methanol (20 mL, v/v¼9:1) at rt. Then oxygen
was bubbled into the mixture for 2 h, and stirred at rt for 8 h. NaOH
(160 mg, 4.0 mmol) was added to a reaction mixture at rt. The re-
action mixture was stirred at rt for 5 h. The residue was diluted with
water (2 mL) and the mixture was extracted with EtOAc (3ꢀ20 mL).
The combined organic layers were washed with brine, dried, fil-
tered, and evaporated to afford crude product. Purification on silica
gel (hexanes/EtOAc¼10:1 to 6:1) afforded skeleton 3, 4 or 7.
reductive
of MeOH
3b
elimination
then NaOH
mediated aldol
cyclization
PdHCl
HCl
H
HCl
MeO
MeO
6a
or
MeO
MeO
PdCl
hydride
shift
OMe
CHO
OMe
CHO
isomerization
C1
B1
4b
or
or
ClPd
O
O
H
MeO
MeO
4.2.1. 3,4-Dimethoxy-2-(prop-1-enyl)benzaldehyde (2b0) Table 1,
entry 1. Yield 38% (78 mg); colorless oil; HRMS (ESI, Mþþ1) calcd
for C12H15O3 207.1021, found 207.1023; 1H NMR (400 MHz, CDCl3):
CHO B2
C2
CHO
Scheme 4. A possible mechanism for synthesizing compound 3b, 4b or 6a from
compound 2b or 5b.
d
10.04 (d, J¼0.8 Hz, 1H), 7.70 (d, J¼8.8 Hz, 1H), 6.91 (d, J¼8.8 Hz,
1H), 6.72 (dq, J¼1.6, 16.0 Hz, 1H), 5.86 (dq, J¼6.4, 16.0 Hz, 1H), 3.93
(s, 3H), 3.78 (s, 3H), 1.98 (dd, J¼1.6, 6.4 Hz, 3H); 13C NMR (100 MHz,
Under the above conditions, reaction for compound 2s was
further studied, as shown in Scheme 5.27 Compound 2s was pre-
pared in 60% yield from Grignard methylation of compound 2b
followed by PCC-mediated oxidation. By changing the R2 group as
methyl group, sole 1-naphthol 7 was isolated with 72% yield via an
intramolecular aldol cyclization. However, the skeleton of 2-
naththol had been not detected. The structure of compound 7
was constructed using single-crystal X-ray analysis.26
CDCl3):
d 191.37, 156.91, 146.15, 136.96, 136.45, 128.24, 125.84,
121.85 110.44, 60.33, 55.88, 19.17.
4.2.2. 8-Methoxynaphthalen-2-ol (3a). Yield 80% (139 mg); color-
less oil; HRMS (ESI, Mþþ1) calcd for C11H11O2 175.0759, found
175.0762; 1H NMR (400 MHz, CDCl3):
d
7.72 (d, J¼8.8 Hz, 1H), 7.57
(d, J¼2.4 Hz, 1H), 7.38 (d, J¼8.0 Hz, 1H), 7.25 (dd, J¼7.6, 8.0 Hz, 1H),
7.13 (dd, J¼2.4, 8.8 Hz, 1H), 6.81 (d, J¼7.6 Hz, 1H), 5.54 (s, 1H), 3.98
(s, 3H); 13C NMR (100 MHz, CDCl3):
d 154.25, 153.17, 129.80, 129.49,
OMe
OMe
Me
MeO
MeO
PdCl , CuCl , O (balloon)
2
2
2
126.58, 123.35, 120.14, 117.98, 104.37, 104.25, 55.48. Anal. Calcd for
C11H10O2: C, 75.84; H, 5.79. Found: C, 75.92; H, 5.96.
O
THF / MeOH (9/1),
then NaOH, rt, 15 h
Me
OH
7 (72%) X-Ray
4.2.3. 7,8-Dimethoxynaphthalen-2-ol (3b). Yield 84% (171 mg);
colorless solid; mp¼125e126 ꢁC (recrystallized from hexanes and
EtOAc); HRMS (ESI, Mþþ1) calcd for C12H13O3 205.0865, found
2s
Scheme 5. Synthesis of compound 7.
205.0872; 1H NMR (400 MHz, CDCl3):
d
7.66 (d, J¼8.4 Hz, 1H), 7.52
(d, J¼8.8 Hz, 1H), 7.45 (d, J¼2.4 Hz, 1H), 7.11 (d, J¼8.8 Hz, 1H), 7.02
(dd, J¼2.4, 8.8 Hz, 1H), 6.76 (s, 1H), 3.97 (s, 3H), 3.91 (s, 3H); 13C
3. Conclusion
NMR (100 MHz, CDCl3):
d 154.49, 148.91, 141.13, 130.24, 129.77,
A synthetic methodology for producing functionalized naph-
thols 3 or 7, benzofurans 4, 1,5-dicarbonyl compounds 6, and iso-
coumarins 7 has been successfully presented from the one-pot
facile PdCl2/CuCl2-mediated reaction of substituted skeleton 2 with
125.15, 124.42, 116.38, 112.09, 102.83, 60.81, 56.63. Anal. Calcd for
C12H12O3: C, 70.57; H, 5.92. Found: C, 70.82; H, 6.21. Single-crystal
X-ray diagram: crystal of compound 3b was grown by slow diffu-
sion of EtOAc into a solution of compound 3b in CH2Cl2 to yield

1536
M.-Y. Chang et al. / Tetrahedron 69 (2013) 1532e1538
colorless prisms. The compound crystallizes in the orthorhombic
129.96, 128.02 (2ꢀ), 125.21, 124.78, 123.60 (2ꢀ), 116.30, 112.07,
102.79, 73.35, 56.62. Anal. Calcd for C18H15NO5: C, 66.46; H, 4.65.
Found: C, 66.70; H, 4.81. Single-crystal X-ray diagram: crystal of
compound 3h was grown by slow diffusion of EtOAc into a solution
of compound 3h in CH2Cl2 to yield colorless prisms. The compound
crystallizes in the monoclinic crystal system, space group P121/c1,
ꢀ
ꢀ
crystal system, space group Pbca, a¼11.5988(5) A, b¼18.2853(7) A,
3
c¼19.0374(7) A, V¼4037.6(3) A , Z¼8, dcalcd¼1.344 g/cm3, F(000)¼
ꢀ
ꢀ
1728, 2
q
range 2.14e26.40ꢁ, R indices (all data) R1¼0.0656,
wR2¼0.0958.
3
ꢀ
ꢀ
ꢀ
ꢀ
4.2.4. 8-Butoxy-7-methoxynaphthalen-2-ol
(3c). Yield
80%
a¼8.6976(7) A, b¼22.816(2) A, c¼7.4313(6) A, V¼1471.4(2) A , Z¼4,
(197 mg); colorless gum; HRMS (ESI, Mþþ1) calcd for C15H19O3
dcalcd¼1.469 g/cm3, F(000)¼680, 2
q
range 1.79e26.38ꢁ, R indices
247.1334, found 247.1339; 1H NMR (400 MHz, CDCl3):
d 7.66 (d,
(all data) R1¼0.0485, wR2¼0.1378.
J¼9.2 Hz, 1H), 7.50 (d, J¼9.2 Hz, 1H), 7.42 (d, J¼2.8 Hz, 1H), 7.11 (d,
J¼9.2 Hz, 1H), 6.97 (dd, J¼2.4, 8.8 Hz, 1H), 5.41 (br s, 1H), 4.09 (t,
J¼6.8 Hz, 2H), 3.96 (s, 3H), 1.89e1.82 (m, 2H), 1.61e1.52 (m, 2H),
4.2.10. 7,8-Dimethoxy-4-phenylnaphthalen-2-ol (3i). Yield 82%
(230 mg); colorless gum; HRMS (ESI, Mþþ1) calcd for C18H17O3
1.00 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d
153.96, 149.04,
281.1178, found 281.1180; 1H NMR (400 MHz, CDCl3):
d 7.54 (d,
140.89, 130.68, 129.74, 125.33, 123.92, 116.06, 112.67, 103.25, 73.29,
56.80, 32.47, 19.33, 13.96.
J¼8.8 Hz, 1H), 7.49e7.40 (m, 6H), 7.05 (d, J¼8.8 Hz, 1H), 6.96 (d,
J¼2.4 Hz, 1H), 5.87 (br s, 1H), 3.98 (s, 3H), 3.96 (s, 3H); 13C NMR
(100 MHz, CDCl3):
d 153.68, 148.78, 142.56, 141.43, 140.22, 130.99,
4.2.5. 8-(Cyclopentyloxy)-7-methoxynaphthalen-2-ol
(3d). Yield
129.80 (2ꢀ), 128.21 (2ꢀ), 127.42, 123.60, 122.85, 117.21, 111.99,
79% (204 mg); colorless solid; mp¼119e121 ꢁC (recrystallized from
102.46, 60.87, 56.58.
hexanes and EtOAc); HRMS (ESI, Mþþ1) calcd for C16H19O3
259.1334, found 259.1339; 1H NMR (400 MHz, CDCl3):
d
7.64 (d,
4.2.11. 7,8-Dimethoxy-4-o-tolylnaphthalen-2-ol (3j). Yield 77%
(226 mg); colorless gum; HRMS (ESI, Mþþ1) calcd for C19H19O3
J¼8.8 Hz, 1H), 7.48 (d, J¼8.8 Hz, 1H), 7.45 (d, J¼2.4 Hz, 1H), 7.11 (d,
J¼9.2 Hz, 1H), 6.96 (dd, J¼2.4, 8.8 Hz, 1H), 5.05e5.00 (m, 1H), 3.95
(s, 3H), 2.01e1.87 (m, 5H), 1.78e1.71 (m, 2H), 1.66e1.57 (m, 2H); 13C
295.1334, found 295.1341; 1H NMR (400 MHz, CDCl3):
d 7.53 (dd,
J¼0.8, 2.8 Hz, 1H), 7.38e7.25 (m, 3H), 7.21 (dd, J¼1.2, 8.4 Hz, 1H),
7.12 (d, J¼8.8 Hz, 1H), 7.00 (d, J¼9.2 Hz, 1H), 6.93 (d, J¼2.0 Hz, 1H),
6.84 (br s, 1H), 3.98 (s, 3H), 3.94 (s, 3H), 2.04 (s, 3H); 13C NMR
NMR (100 MHz, CDCl3):
d 153.93, 148.99, 139.59, 131.51, 129.62,
125.34, 123.72, 116.13, 112.71, 103.73, 84.82, 56.75, 32.81 (2ꢀ), 23.74
(2ꢀ).
(100 MHz, CDCl3):
d 153.99, 148.71, 141.99, 141.20, 139.67, 136.54,
130.62, 130.02, 129.77, 127.58, 125.43, 123.89, 122.89, 117.15, 111.75,
102.25, 60.83, 56.47, 19.88.
4.2.6. 8-(Benzyloxy)-7-methoxynaphthalen-2-ol (3e). Yield 72%
(202 mg); colorless oil; HRMS (ESI, Mþþ1) calcd for C18H17O3
281.1178, found 281.1182; 1H NMR (400 MHz, CDCl3):
d
7.66 (d,
4.2.12. 7,8-Dimethoxy-4-(2-methoxyphenyl)naphthalen-2-ol (3k).
Yield 76% (236 mg); colorless gum; HRMS (ESI, Mþþ1) calcd for
C19H19O4 311.1283, found 311.1288; 1H NMR (400 MHz, CDCl3):
J¼8.8 Hz, 1H), 7.56e7.53 (m, 3H), 7.42e7.33 (m, 4H), 7.14 (d,
J¼8.8 Hz,1H), 6.97 (dd, J¼2.4, 8.8 Hz,1H), 5.98 (br s,1H), 5.13 (s, 2H),
3.98 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
154.19, 149.04, 137.79,
d
7.46 (dd, J¼0.8, 2.8 Hz, 1H), 7.42 (ddd, J¼1.6, 7.2, 9.2 Hz, 1H),
130.56, 129.68, 128.36 (2ꢀ), 128.14 (2ꢀ), 127.92, 127.87, 125.22,
7.25e7.22 (m, 2H), 7.06 (dt, J¼0.8, 8.4 Hz, 1H), 7.04 (d, J¼8.4 Hz, 1H),
7.00 (d, J¼9.2 Hz, 1H), 6.94 (d, J¼2.4 Hz, 1H), 5.96 (br s, 1H), 3.96 (s,
124.32, 116.23, 112.37, 103.21, 75.11, 56.75.
3H), 3.95 (s, 3H), 3.70 (s, 3H); 13C NMR (100 MHz, CDCl3):
d 157.03,
4.2.7. 8-(3-Fluorobenzyloxy)-7-methoxynaphthalen-2-ol (3f). Yield
72% (215 mg); colorless gum; HRMS (ESI, Mþþ1) calcd for
C18H16FO3 299.1084, found 299.1091; 1H NMR (400 MHz, CDCl3):
153.70, 148.63, 141.36, 139.13, 131.70, 130.59, 129.08, 129.00, 124.09,
123.06, 120.49, 117.74, 111.82, 111.06, 102.64, 60.82, 56.58, 55.59.
d
7.68 (d, J¼8.8 Hz, 1H), 7.55 (d, J¼8.4 Hz, 1H), 7.37e7.27 (m, 4H),
4.2.13. 4-(4-Fluorophenyl)-7,8-dimethoxynaphthalen-2-ol (3l). Yield
84% (250 mg); colorless gum; HRMS (ESI, Mþþ1) calcd for
C18H16FO3 299.1084, found 299.1082; 1H NMR (400 MHz, CDCl3):
7.14 (d, J¼9.2 Hz, 1H), 7.05e7.00 (m, 1H), 6.97 (dd, J¼2.4, 8.8 Hz, 1H),
5.43 (br s, 1H), 5.11 (s, 2H), 3.98 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
162.89 (d, J¼244.9 Hz), 154.16, 149.03, 140.52 (d, J¼7.6 Hz), 130.44,
d
7.51 (dd, J¼0.8, 2.8 Hz, 1H), 7.48 (dd, J¼0.8, 9.2 Hz, 1H), 7.40e7.34
129.92, 129.83, 125.26, 124.48, 123.38 (d, J¼3.0 Hz), 116.20, 114.83
(d, J¼21.9 Hz), 114.69 (d, J¼21.2 Hz), 112.32, 112.32, 103.02, 74.10,
56.72.
(m, 2H), 7.17e7.10 (m, 2H), 7.05 (d, J¼8.8 Hz, 1H), 6.94 (d, J¼2.4 Hz,
1H), 6.74 (br s, 1H), 3.96 (s, 3H), 3.95 (s, 3H); 13C NMR (100 MHz,
CDCl3):
d
162.26 (d, J¼244.9 Hz), 153.84, 148.79, 141.36, 141.19,
136.09 (d, J¼3.1 Hz), 131.28 (J¼8.3 Hz, 2ꢀ), 130.96, 123.51, 122.69,
4.2.8. 8-(3-Methoxybenzyloxy)-7-methoxynaphthalen-2-ol(3g). Yield
69% (214 mg); colorless oil; HRMS (ESI, Mþþ1) calcd for C19H19O4
117.46, 115.10 (d, J¼21.3 Hz, 2ꢀ), 111.91, 102.53, 60.85, 56.51.
311.1283, found 311.1290; 1H NMR (400 MHz, CDCl3):
d
7.65 (d,
4.2.14. 7,8-Dimethoxy-4-(4-methoxyphenyl)naphthalen-2-ol (3m).
Yield 82% (254 mg); colorless gum; HRMS (ESI, Mþþ1) calcd for
C19H19O4 311.1283, found 311.1284; 1H NMR (400 MHz, CDCl3):
J¼8.8 Hz, 1H), 7.53 (d, J¼9.2 Hz, 1H), 7.45 (d, J¼2.4 Hz, 1H), 7.27 (t,
J¼7.6 Hz, 1H), 7.17 (t, J¼2.0 Hz, 1H), 7.13 (d, J¼9.2 Hz, 1H), 7.10 (d,
J¼7.2 Hz, 1H), 6.98 (dd, J¼2.8, 8.8 Hz, 1H), 6.87 (dd, J¼0.8, 2.4, 8.4 Hz,
1H), 6.46 (br s, 1H), 5.11 (s, 2H), 3.97 (s, 3H), 3.79 (s, 3H); 13C NMR
d
7.58 (d, J¼9.2 Hz, 1H), 7.49 (d, J¼2.4 Hz, 1H), 7.38e7.34 (m, 2H),
7.04 (d, J¼9.6 Hz, 1H), 7.01e6.98 (m, 2H), 6.97 (d, J¼2.4 Hz, 1H),
(100 MHz, CDCl3):
d
159.47, 154.30, 148.97, 140.42, 139.41, 130.51,
6.88 (br s, 1H), 3.96 (s, 3H), 3.94 (s, 3H), 3.88 (s, 3H); 13C NMR
128.66, 129.38, 125.17, 124.33, 120.50, 116.29, 113.65, 113.49, 112.26,
103.16, 74.94, 56.72, 55.21.
(100 MHz, CDCl3): d 158.88, 153.97, 148.66, 142.10, 141.18, 132.62,
130.99, 130.83 (2ꢀ), 123.66, 122.95, 117.33, 113.62 (2ꢀ), 111.65,
102.10, 60.79, 56.50, 55.28.
4.2.9. 8-(4-Nitrobenzyloxy)-7-methoxynaphthalen-2-ol (3h). Yield
73% (238 mg); colorless solid; mp¼151e152 ꢁC (recrystallized from
hexanes and EtOAc); HRMS (ESI, Mþþ1) calcd for C18H16NO5
4.2.15. 4-(3,4-Dioxymethylenephenyl)-7,8-dimethoxynaphthalen-2-
ol (3n). Yield 80% (259 mg); colorless gum; HRMS (ESI, Mþþ1)
calcd for C19H17O5 325.1076, found 325.1080; 1H NMR (400 MHz,
326.1029, found 326.1021; 1H NMR (400 MHz, CDCl3):
d 8.21 (d,
J¼8.8 Hz, 2H), 7.69 (d, J¼8.4 Hz, 2H), 7.70e7.67 (m, 1H), 7.56 (d,
J¼9.2 Hz, 1H), 7.34 (d, J¼2.4 Hz, 1H), 7.15 (t, J¼8.8 Hz, 1H), 6.98 (dd,
J¼2.4, 8.8 Hz, 1H), 5.52 (br s, 1H), 5.21 (s, 2H), 3.97 (s, 3H); 13C NMR
CDCl3):
d
7.57 (d, J¼9.2 Hz, 1H), 7.45 (dd, J¼0.8, 2.4 Hz, 1H), 7.05 (d,
J¼9.2 Hz, 1H), 6.93 (s, 1H), 6.92 (s, 1H), 6.90 (br s, 2H), 6.19 (br s, 1H),
6.03 (s, 2H), 3.96 (s, 3H), 3.95 (s, 3H); 13C NMR (100 MHz, CDCl3):
(100 MHz, CDCl3):
d
154.30, 148.94, 145.50 (2ꢀ), 139.87, 130.25,
d 153.73, 148.76, 147.39, 146.97, 142.07, 141.36, 134.08, 130.99,

M.-Y. Chang et al. / Tetrahedron 69 (2013) 1532e1538
1537
123.69, 123.23, 122.82, 117.24, 111.91, 110.38, 108.16, 102.35, 101.11,
60.85, 56.57.
The compound crystallizes in the orthorhombic crystal system,
ꢀ
ꢀ
space group P212121, a¼7.0916(5) A, b¼11.5911(8) A,
3
c¼13.4974(10) A, V¼1109.48(14) A , Z¼4, dcalcd¼1.307 g/cm3,
ꢀ
ꢀ
4.2.16. 7,8-Dimethoxy-1-methylnaphthalen-2-ol (3o). Yield 83%
(181 mg); colorless solid; mp¼127e128 ꢁC (recrystallized from
hexanes and EtOAc); HRMS (ESI, Mþþ1) calcd for C13H15O3
F(000)¼464, 2
wR2¼0.1424.
q
range 2.32e26.69ꢁ, R indices (all data) R1¼0.0536,
219.1021, found 219.1022; 1H NMR (400 MHz, CDCl3):
d
9.14 (br s,
4.3. A representative synthetic procedure of skeleton 6
1H), 7.35 (d, J¼10.0 Hz, 1H), 7.08 (d, J¼8.4 Hz, 1H), 6.92 (d, J¼8.0 Hz,
1H), 6.08 (d, J¼10.0 Hz, 1H), 3.99 (s, 3H), 3.93 (s, 3H), 2.61 (s, 3H).
A representative synthetic procedure of skeleton 6 is as follows:
PdCl2 (10 mg, 5.6 mol %) and CuCl2 (200 mg, 1.5 mmol) were added
to a solution of skeleton 2 (1.0 mmol) in the co-solvent of THF and
methanol (20 mL, v/v¼9:1) at rt. Then oxygen was bubbled into the
mixture for 2 h, and stirred at rt for 13 h. The residue was diluted
with water (2 mL) and the mixture was extracted with EtOAc
(3ꢀ20 mL). The combined organic layers were washed with brine,
dried, filtered, and evaporated to afford crude product. Purification
on silica gel (hexanes/EtOAc¼10:1 to 6:1) afforded skeleton 6.
4.2.17. 7,8-Dimethoxy-1-methyl-4-phenylnaphthalen-2-ol (3p). Yield
85% (250 mg); colorless solid; mp¼150e151 ꢁC (recrystallized from
hexanes and EtOAc); HRMS (ESI, Mþþ1) calcd for C19H19O3 295.1334,
found 295.1335; 1H NMR (200 MHz, CDCl3):
d 7.55e7.48 (m, 6H), 7.05
(d, J¼8.4 Hz, 1H), 6.90 (s, 1H), 5.30 (br s, 1H), 3.97 (s, 3H), 3.90 (s, 3H),
2.83 (s, 3H).
4.2.18. 4-(4-Fluorophenyl)-7,8-dimethoxy-1-methylnaphthalen-2-ol
(3q). Yield 86% (268 mg); colorless gum; HRMS (ESI, Mþþ1) calcd
for C19H18FO3 313.1240, found 313.1244; 1H NMR (200 MHz, CDCl3):
4.3.1. 3,4-Dimethoxy-2-(2-oxopropyl)benzaldehyde (6a). Yield 90%
(200 mg); colorless solid; mp¼72e73 ꢁC (recrystallized from hex-
anes and EtOAc); HRMS (ESI, Mþþ1) calcd for C12H15O4 223.0970,
d
7.45 (d, J¼9.2 Hz,1H), 7.33e7.26 (m, 2H), 7.14e7.10 (m, 3H), 6.85 (s,
1H), 5.92 (br s, 1H), 3.93 (s, 3H), 3.87 (s, 3H), 2.82 (s, 3H).
found 223.0977; 1H NMR (400 MHz, CDCl3):
d 9.80 (s, 1H), 7.51 (d,
J¼8.4 Hz, 1H), 6.96 (d, J¼8.4 Hz, 1H), 4.23 (s, 2H), 3.92 (s, 3H), 3.75
4.2.19. 7,8-Dimethoxy-4-(4-methoxyphenyl)-1-methylnaphthalen-2-
ol (3r). Yield 88% (285 mg); colorless gum; HRMS (ESI, Mþþ1)
calcd for C20H21O4 325.1440, found 325.1438; 1H NMR (200 MHz,
(s, 3H), 2.32 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
205.62, 191.87,
157.24, 148.04, 133.27, 130.26, 127.96, 110.08, 60.78, 55.78, 40.49,
30.00.
CDCl3):
d
7.58 (d, J¼9.2 Hz, 1H), 7.32 (d, J¼8.0 Hz, 2H), 7.01e6.96 (m,
3H), 6.88 (s, 1H), 5.40 (br s, 1H), 3.95 (s, 3H), 3.88 (s, 3H), 3.87 (s,
3H), 2.82 (s, 3H).
4.3.2. 3-Butoxy-4-methoxy-2-(2-oxopropyl)benzaldehyde (6b). Yield
86% (227 mg); colorless oil; HRMS (ESI, Mþþ1) calcd for C15H21O4
265.1440, found 265.1446; 1H NMR (400 MHz, CDCl3):
d 9.81 (s, 1H),
4.2.20. 2-Methyl-benzofuran-4-carbaldehyde
(4a). Yield
72%
7.52 (d, J¼8.8 Hz, 1H), 6.96 (d, J¼8.8 Hz, 1H), 4.25 (s, 2H), 3.92 (s, 3H),
(115 mg); colorless oil; HRMS (ESI, Mþþ1) calcd for C10H9O2
3.87 (t, J¼6.8 Hz, 2H), 2.32 (s, 3H), 1.74e1.66 (m, 2H), 1.49e1.43 (m,
161.0603, found 161.0610; 1H NMR (400 MHz, CDCl3):
d
10.17 (s,
2H), 0.95 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 205.68,
1H), 7.66 (dt, J¼0.4, 8.8 Hz, 1H), 7.63 (dt, J¼0.4, 8.8 Hz, 1H), 7.34 (t,
191.98, 157.39, 147.44, 133.17, 130.32, 128.03, 110.02, 73.26, 55.79,
40.73, 32.17, 29.99, 19.08, 13.79.
J¼8.8 Hz, 1H), 7.14 (br t, J¼0.8 Hz, 1H), 2.52 (d, J¼0.8 Hz, 3H); 13C
NMR (100 MHz, CDCl3):
d 192.06, 159.37, 155.26, 128.46, 128.31,
128.20, 122.67, 116.18, 102.97, 14.22.
4.3.3. 3-(Benzyloxy)-4-methoxy-2-(2-oxopropyl)benzaldehyde (6c).
Yield 88% (262 mg); colorless oil; HRMS (ESI, Mþþ1) calcd for
C18H19O4 299.1283, found 299.1285; 1H NMR (400 MHz, CDCl3):
4.2.21. 7-Methoxy-2-methyl-benzofuran-4-carbaldehyde (4b). Yield
76% (144 mg); colorless solid; mp¼67e68 ꢁC (recrystallized from
hexanes and EtOAc); HRMS (ESI, Mþþ1) calcd for C11H11O3
d
9.84 (s, 1H), 7.57 (d, J¼8.8 Hz, 1H), 7.42e7.33 (m, 5H), 7.02 (d,
J¼8.4 Hz, 1H), 4.94 (s, 2H), 4.20 (s, 2H), 3.97 (s, 3H), 2.24 (s, 3H); 13C
191.0708, found 191.0711; 1H NMR (400 MHz, CDCl3):
d
9.96 (s, 1H),
NMR (100 MHz, CDCl3):
133.38, 130.63, 128.45 (2ꢀ), 128.13, 128.10 (2ꢀ), 110.12, 75.21, 55.89,
d
205.63, 191.93, 157.32 (2ꢀ), 147.11, 137.18,
7.56 (d, J¼8.0 Hz, 1H), 7.09 (q, J¼1.2 Hz, 1H), 6.77 (d, J¼8.4 Hz, 1H),
4.03 (s, 3H), 2.47 (d, J¼1.2 Hz, 3H); 13C NMR (100 MHz, CDCl3):
40.81, 30.00.
d
190.53, 158.74, 149.16, 143.63, 131.12, 129.77, 122.41, 104.92,
103.36, 56.16, 14.01.
4.3.4. 3,4-Dimethoxy-2-(3-oxobutan-2-yl)benzaldehyde (6d). Yield
90% (212 mg); colorless solid; mp¼77e78 ꢁC (recrystallized from
hexanes and EtOAc); HRMS (ESI, Mþþ1) calcd for C13H17O4
4.2.22. 7-Methoxy-2,3-dimethyl-benzofuran-4-carbaldehyde (4c).
Yield 72% (147 mg); colorless solid; mp¼74e75 ꢁC (recrystallized
from hexanes and EtOAc); HRMS (ESI, Mþþ1) calcd for C12H13O3
237.1127, found 237.1132; 1H NMR (400 MHz, CDCl3):
d 9.91 (s, 1H),
7.57 (d, J¼8.8 Hz, 1H), 6.98 (d, J¼8.8 Hz, 1H), 4.72 (q, J¼6.8 Hz, 1H),
205.0865, found 205.0871; 1H NMR (400 MHz, CDCl3):
d 10.21 (s,
3.94 (s, 3H), 3.77 (s, 3H), 2.05 (s, 3H),1.38 (d, J¼6.8 Hz, 3H); 13C NMR
1H), 7.70 (d, J¼8.4 Hz, 1H), 6.75 (d, J¼8.4 Hz, 1H), 4.01 (s, 3H), 2.39
(100 MHz, CDCl3): d 207.40, 191.64, 157.39, 147.08, 137.54, 133.03,
(s, 3H), 2.35 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
189.25, 153.82,
127.25, 110.23, 60.77, 55.87, 44.99, 27.85, 16.49.
149.07, 142.96, 131.50, 128.13, 123.88, 111.04, 104.95, 56.07, 12.02,
11.83.
4.3.5. 1-(2,3-Dimethoxy-6-(2-methylbenzoyl)phenyl)propan-2-one
(6e). Yield 86% (268 mg); colorless oil; HRMS (ESI, Mþþ1) calcd for
C19H21O4 313.1440, found 313.1442; 1H NMR (400 MHz, CDCl3):
4.2.23. 5,6-Dimethoxy-3-methylnaphthalen-1-ol (7). Yield 72%
(157 mg); Colorless solid; mp¼171e172 ꢁC (recrystallized from
hexanes and EtOAc); HRMS (ESI, Mþþ1) calcd for C13H15O3
d
7.33 (dt, J¼2.4, 7.2 Hz, 1H), 7.28e7.16 (m, 3H), 7.14 (d, J¼8.4 Hz,
1H), 6.75 (d, J¼8.8 Hz, 1H), 4.24 (s, 2H), 3.88 (s, 3H), 3.81 (s, 3H),
2.33 (s, 3H), 2.28 (s, 3H); 13C NMR (100 MHz, CDCl3):
205.92,
219.1021, found 219.1024; 1H NMR (400 MHz, CDCl3):
d
7.87 (d,
d
J¼9.2 Hz, 1H), 7.28 (s, 1H), 7.12 (d, J¼9.2 Hz, 1H), 6.52 (s, 1H), 3.93 (s,
199.20, 155.93, 148.04, 139.85, 136.63, 130.93, 130.71, 130.29, 130.10,
130.01, 128.71, 125.12, 109.23, 60.80, 55.65, 41.34, 30.00, 19.80.
3H), 3.91 (s, 3H), 3.08 (s, 1H), 2.38 (s, 3H); 13C NMR (100 MHz,
CDCl3):
d 152.59, 148.76, 141.87, 136.69, 130.48, 119.51, 118.55,
112.44, 111.63, 108.48, 60.88, 56.53, 21.97. Single-crystal X-ray dia-
gram: crystal of compound 7 was grown by slow diffusion of EtOAc
into a solution of compound 7 in CH2Cl2 to yield colorless prisms.
4.3.6. 1-(2,3-Dimethoxy-6-(2-methoxybenzoyl)phenyl)propan-2-one
(6f). Yield 92% (302 mg); colorless oil; HRMS (ESI, Mþþ1) calcd for
C19H21O5 329.1389, found 329.1395; 1H NMR (400 MHz, CDCl3):

1538
M.-Y. Chang et al. / Tetrahedron 69 (2013) 1532e1538
13. For isocoumarins, see: Chen, P. Y.; Huang, K. S.; Tsai, C. C.; Wang, T. P.; Wang, E.
d
7.40 (ddd, J¼1.6, 7.6, 7.2, 9.2 Hz, 1H), 7.29 (dd, J¼2.0, 7.6 Hz, 1H),
C. Org. Lett. 2012, 14, 4930.
14. For benzopyrans, see: Asao, N.; Chan, C. S.; Takahashi, K.; Yamamoto, Y. Tetra-
7.19 (d, J¼8.4 Hz, 1H), 6.98e6.92 (m, 2H), 6.73 (d, J¼8.8 Hz, 1H), 4.20
(s, 2H), 3.88 (s, 3H), 3.80 (s, 3H), 3.70 (s, 3H), 2.32 (s, 3H); 13C NMR
hedron 2005, 61, 11322.
15. For arenes, see: Li, J.; Jiang, H.; Chen, M. J. Org. Chem. 2001, 66, 3627.
16. For nitriles, see: Peng, J.; Zhao, J.; Hu, Z.; Liang, D.; Huang, J.; Zhu, Q. Org. Lett.
2012, 4966.
17. For natural products, see: (a) for calvine: Szolcsanyi, P.; Gracza, T.; Spanik, I.
Tetrahedron Lett. 2008, 49, 1357; (b) Kubizna, P.; Spanik, I.; Kozisek, J.; Szolc-
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Lee, K.; Oh, C. Y.; Lee, K. Y. Tetrahedron Lett. 1997, 38, 3247; (d) for marticin:
Pillay, A.; Rousseau, A. L.; Fernandes, M. A.; de Koning, C. B. Tetrahedron 2012,
68, 7116; (e) for varitriol: Palik, M.; Karlubikova, O.; Lackovicova, D.; Lasikova,
A.; Gracza, T. Tetrahedron 2010, 66, 5244.
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19. For aerobic cyclizations, see: (a) Zanoni, G.; Porta, A.; Meriggi, A.; Franzini, M.;
Vidari, G. J. Org. Chem. 2002, 67, 6064; (b) Kawamura, Y.; Kawano, Y.; Matsuda,
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(100 MHz, CDCl3):
130.77, 130.43, 130.02, 129.90, 129.73, 120.19, 111.35, 109.16, 60.79,
55.61, 55.58, 41.54, 29.87.
d 204.65, 196.67, 157.21, 155.78, 147.89, 131.63,
4.3.7. 1-(6-(4-Fluorobenzoyl)-2,3-dimethoxyphenyl)propan-2-one
(6g). Yield 92% (291 mg); colorless solid; mp¼67e68 ꢁC (recrys-
tallized from hexanes and EtOAc); HRMS (ESI, Mþþ1) calcd for
C18H18FO4 317.1189, found 317.1192; 1H NMR (400 MHz, CDCl3):
d
7.80e7.75 (m, 2H), 7.15 (d, J¼8.4 Hz, 1H), 7.12e7.06 (m, 2H), 6.82
(d, J¼8.8 Hz, 1H), 4.07 (s, 2H), 3.91 (s, 3H), 3.81 (s, 3H), 2.32 (s, 3H);
13C NMR (100 MHz, CDCl3):
d
205.75,195.65, 165.28 (d, J¼252.4 Hz),
155.17, 148.01, 134.78 (d, J¼3.0 Hz), 132.67 (d, J¼9.1 Hz, 2ꢀ), 130.49,
130.12, 127.61, 115.19 (d, J¼22.0 Hz, 2ꢀ), 109.22, 60.70, 55.68, 41.15,
29.79.
Acknowledgements
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The authors would like to thank the National Science Council of
the Republic of China for its financial support (NSC 99-2113-M-037-
006-MY3).
Supplementary data
Scanned photocopies of spectral data and crystallographic data
of compounds 3b, 3h, and 7 (CIF) were supported. Supplementary
data associated with this article can be found in the online version,
at http://dx.doi.org/10.1016/j.tet.2012.12.009.
References and notes
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