One-Pot Access to 4-Aryl-2-arylacetoxynaphthalenes via Benzannulation of Oxygenated Arylacetic Acids and Alkyl Aryl Ketones

Article abstract of DOI:10.1055/s-0039-1690799

Trifluoroacetic anhydride mediated one-pot intermolecular formal (4+2) benzannulation of oxygenated arylacetic acids with alkyl aryl ketones provides 4-aryl-2-arylacetoxynaphthalenes in moderate to good yields in the presence of H ₃ PO ₄

Full text of DOI:10.1055/s-0039-1690799

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2020, 52, A–L
paper
A
en
M.-Y. Chang et al.
Paper
Synthesis
One-Pot Access to 4-Aryl-2-arylacetoxynaphthalenes via Benz-
annulation of Oxygenated Arylacetic Acids and Alkyl Aryl Ketones
Meng-Yang Chang*a,b
Shin-Mei Chena
Yu-Ting Hsiaoa
0
0
0
0-
0
0
0
2-1
9
8
3-8
5
7
0
O
TFAA, H3PO4
MeCN, 80 °C
O
CO2H
Ar
Ar
R
Ar
+
O
2
R
Ar'
Ar'
>31 examples
a Department of Medicinal and Applied Chemistry, Kaohsiung
Medical University, Kaohsiung 807, Taiwan
mychang@kmu.edu.tw
b Department of Medical Research, Kaohsiung Medical University
Hospital, Kaohsiung 807, Taiwan
51–94% yields
easy-operation
Received: 25.11.2019
Accepted after revision: 23.12.2019
Published online: 27.01.2020
multi-step routes, complex catalytic conditions, lack of
broad substrate generality and the requirement for pre-
functionalized fragments. Therefore, the development of a
one-pot, efficient and straightforward synthetic method to
access substituted -naphthol derivatives is still highly de-
sired.
DOI: 10.1055/s-0039-1690799; Art ID: ss-2019-f0650-op
Abstract Trifluoroacetic anhydride mediated one-pot intermolecular
formal (4+2) benzannulation of oxygenated arylacetic acids with alkyl
aryl ketones provides 4-aryl-2-arylacetoxynaphthalenes in moderate to
good yields in the presence of H3PO4 in an open-vessel in a straightfor-
ward procedure. A plausible mechanism is proposed and discussed. This
protocol provides a highly effective ring-closure via two carbon–carbon
(C–C) and one carbon–oxygen (C–O) bond-formation events.
O
Ar
+
OMe
BPin
α
Ar'
O
o
O
Ar
Ar
Pd(II), Tsukamoto (ref 6a)
Cl
+
Key words trifluoroacetic anhydride, benzannulation, arylacetic acids,
4-aryl-2-arylacetoxynaphthalenes, easy operation
Ar'
2
Ar'
OH
Ar
Al(III), Oh (ref 9a)
Zn(II), Chang (ref 9e)
I2, Larock (ref 7a)
4
Ar'
o
Substituted naphthalenes1 can be utilized as potential
bioactive precursors,2 unique natural products,3 versatile
synthetic blocks or ligands4 and functionalized materials.5
Among these, the synthetic development of -naphthols
has been attracting considerable attention. Traditionally,
the construction of functionalized -naphthols involves
three major routes: (1) transition-metal-catalyzed tandem
benzannulation,6 (2) electrophilic or nucleophilic cyclocon-
densation7 and (3) photo-promoted annulation.8 Other
routes for the formation of substituted -naphthols have
recently been investigated extensively.9 For the preparation
of 4-aryl-substituted -naphthol derivatives, the diverse
range of routes can be divided into three general pathways.
These include an intermolecular formal (4+2) benzannula-
tion of o-boronate arylacetate or arylacetyl chloride with
alkyne,6a,9a,9e an intermolecular formal (4+2) benzannula-
tion of benzyne with aroylacetone,9f an intramolecular ring-
closure of -aryl alkynone7a or o-acetyl arylpropiolate7c and
a direct intermolecular meta-arylation of O--naphthyl car-
bamate with arylboronic acid,9d as shown in Scheme 1. In
spite of these advances, some problems remain, such as
β-Naphthol derivatives
O
O
O
Ar
Ar
OMe
NMe2
O
TMS
m
Ar
+
CO2Me
O
Ar'
Ar'-B(OH)2
Pd(II)/Ag(I), Wang (ref 9d)
OTf
Cu(I), Behar (ref 7c)
Ar'
Cs(I), Okuma (ref 9f)
Scheme 1 Routes to 4-aryl-substituted -naphthol derivatives
We recently explored the synthetic application of oxy-
genated arylacetic acids to establish a polyoxygenated pen-
tacyclic benzo[g]chrysene (BgC) framework using metal tri-
flate promoted domino Friedel–Crafts acylation followed by
photoinduced Scholl annulation strategies (Scheme 2, eq.
1).10 In another approach, TFAA-mediated synthesis of 1-
aryl isochroman-3-ones was developed by using an inter-
molecular (4+2) annulation of oxygenated arylacetic acids
with arylaldehydes (Scheme 2, eq. 2).11 Continuing our re-
search on oxygenated arylacetic acids,10,11 herein, we pres-
ent a TFAA-mediated preparation of an oxygenated O--
naphthyl ester skeleton by a one-pot reaction of oxygenated
arylacetic acids with alkyl aryl ketones in the presence of
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–L
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
M.-Y. Chang et al.
Paper
Synthesis
H3PO4 via two carbon–carbon (C–C) and one carbon–
oxygen (C–O) bond formation events (green marks), as
shown in Scheme 2, eq. 3.
replacing H3PO4 with HOAc, 3a was isolated in a 62% yield
(entry 15). For H2SO4, only unknown products were detect-
ed (40%, entry 16).
O
Table 1 Annulation Conditionsa
Ar
previous work (ref 10)
CO2H
O
Ar
MeO
MeO
O
OMe
OMe
(eq 1)
Sc(OTf)3
Ar
3
+
Ar
O
MeO
Tf2O, MeCN
λ = 254 nm
OMe
Ar'
3a
MeO
Ar
O
3
4
MeO
MeO
previous work (ref 11)
CO2H
O
CO2H
conditions
OMe
O
2
+
O
O
TFAA
MeO
MeO
O
Ar
(eq 2)
(eq 3)
+
1a
2a
MeCN, 25 °C
O
Ar'
O
3a'
this work
CO2H
R
TFAA, H3PO4
MeCN, 80 °C
Entry Anhydride/acid (equiv) Temp (°C) Solvent Time (h) 3a (%)b
Ar
Ar'
Ar
Ar
+
2
O
R
3
c
1
TFAA/H3PO4 (1.1:1.1)
TFAA/H3PO4 (1.1:1.1)
TFAA/H3PO4 (1.1:1.1)
TFAA/H3PO4 (1.1:1.1)
TFAA/H3PO4 (1.1:1.1)
TFAA/H3PO4 (1.1:1.1)
TFAA/H3PO4 (0.5:0.5)
TFAA/H3PO4 (1.5:1.5)
TFAA/H3PO4 (2.0:2.0)
TFAA/H3PO4 (1.1:1.1)
TFAA/H3PO4 (1.1:1.1)
TFAA/H3PO4 (1.1:1.1)
Ac2O/H3PO4 (1.1:1.1)
Tf2O/H3PO4 (1.1:1.1)
TFAA/AcOH (1.1:1.1)
TFAA/H2SO4 (1.1:1.1)
25
25
80
80
80
80
80
80
80
61
80
80
80
80
80
80
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
CHCl3
10
20
5
–
1
2
Ar'
2
17c
35c
61c
80
3
Scheme 2 Our synthetic applications of arylacetic acids
4
10
20
30
20
20
20
20
5
The initial study commenced with treatment of homov-
eratric acid (1a, Ar = 3,4-(MeO)2C6H3, 0.5 mmol) and ace-
tophenone (2a, Ar′ = Ph, R = H, 1.0 mmol) in MeCN (20 mL)
at room temperature (25 °C) for 10 hours using a combina-
tion of TFAA and H3PO4 (1.1 equiv) (Table 1). However, no
desired 3a was detected, and the benzo-fused -lactone 3a′
was obtained in 87% yield (entry 1).11 When the reaction
time was extended to 20 hours, the yield of 3a increased to
17% along with a 68% yield of 3a′ (entry 2). By elevating the
reaction temperature from 25 to 80 °C (r.t. to reflux) and re-
ducing the reaction time (10 to 5 h), the yield of 3a in-
creased to 35% (entry 3). By extending the reaction time (5
to 10, 20 and 30 h), the yields increased to 61, 80, and 73%,
respectively (entries 4–6). From the results, we established
that the application of reflux temperature (80 °C) and ex-
tended reaction time (20 h) could increase the yield of 3a.
Subsequently, the number of equivalents of the combina-
tion of TFAA and H3PO4 was examined. After changing the
number of equivalents of TFAA and H3PO4 from 1.1 to 0.5,
1.5 and 2.0, however, no better yields of 3a were observed.
This showed that when insufficient amounts of TFAA and
H3PO4 were present, the reaction was not triggered com-
pletely (entry 7). Furthermore, the use of excess amounts of
TFAA and H3PO4 provided slightly lower yields (79% and
75%, entries 8 and 9). Solvent screening was then per-
formed. It was found that the reaction gave poorer yields
(42% and 25%) in CHCl3 and MeNO2, respectively (entries 10
and 11), and no desired product was detected in DMF (en-
try 12). When TFAA was changed to Ac2O or Tf2O, different
results were observed: No reaction was detected due to the
poorer reactivity of Ac2O (entry 13), and only 32% yield of
3a was produced with the more reactive Tf2O (entry 14). By
6
73
7
38c
79
8
9
75
10
11
12
13
14
15
16
42c
25c
MeNO2 20
d
DMF
20
20
20
20
20
–
e
MeCN
MeCN
MeCN
MeCN
–
32d
62
d
–
a The reactions were performed on a 1.0 mmol scale with 1a, 2a (0.5
equiv), temp (°C), solvent (20 mL), time (h).
b Isolated yield.
c Compound 3a′ was isolated (entry 1, 87%; entry 2, 68%; entry 3, 35%; en-
try 4, 10%; entry 7, 30%; entry 10, 34%; entry 11, 50%).
d Complex unknown products (entry 12, 75%; entry 14, 30%; entry 16,
40%).
e No reaction.
To study the scope of this approach, the reaction of 1a
with a range of alkyl aryl ketones 2a–z was examined with
the combination of TFAA and H3PO4 to give 4-aryl-2-arylac-
etoxynaphthalenes 3a–x. The products were obtained in a
range of 51–94% under the optimal conditions established
(Table 1, entry 5), as shown in Table 2. By fixing the methyl
group (R = H, entries 1–17) for the reaction of 2a–q with 1a,
stronger electron-withdrawing (Ar′ = 4-F, 4-CF3, 4-NO2) aryl
groups provided rather lower yields (62, 60, and 51%; en-
tries 2, 5, and 6) than other electron-donating and electron-
neutral groups. Changing the R group from H to Me, Et and
Ph, entries 18–21 showed that 3r–u produced 60–81%
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–L

C
M.-Y. Chang et al.
Paper
Synthesis
yields. Since Ar′ has a heterocyclic ring (entries 22–25), 2-
furyl, 3-bromo-2-thienyl and 2-thienyl groups provided
similar yields (74%, 76%, 80%), but no reaction was observed
for Ar′ = 2-pyridyl group because the nitrogen atom trapped
the proton such that the one-pot reaction was inhibited
(entry 25). Furthermore, when the Ar′ group was changed
to n-propyl (an aliphatic group), no desired product 3z was
isolated (entry 26); this result may stem from a cross self-
aldol reaction of 2-pentanone (2z) replacing the desired
one-pot reaction. From the results, we found that Ar′ with
oxygenated groups provided better yields than other sub-
stituents. A possible reason for this is that the oxygenated
group on arene (Ar′) played a key factor in promoting the
tandem benzannulation process.
On the basis of our experimental results, a plausible
mechanism for the formation of 3a is illustrated in Scheme
3. Initially, 1a reacts with protonated TFAA (generated in
situ from protonation of TFAA with H3PO4) to form A and
TFA. By the involvement of 2a, the carbonyl group of 2a at-
tacks the anhydride motif on A to give B. Following this, the
methoxy group on the 3-position of electron-rich arene
promotes an intramolecular ring-closure to yield C with a
-lactone ring. Then, C is converted into 3a′ via a dehydro-
Table 2 Synthesis of 3a–za
O
MeO
MeO
MeO
MeO
O
R
OMe
OMe
R
CO2H
+
TFAA, H3PO4
MeCN, 80 °C
2
O
2
3
Ar'
4
Ar'
1a
2a–z
3a–z
Entry
2
R
Ar′
Ph
3
Yield (%)b
1
2a
2b
2c
2d
2e
2f
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
3a
80
62
76
92
60
51
70
72
86
80
86
80
68
92
92
90
94
81
78
63
60
74
76
80
2
4-FC6H4
3b
3c
3d
3e
3f
3
4-MeC6H4
4
4-MeOC6H4
4-F3CC6H4
4-O2NC6H4
4-PhC6H4
2-naphthyl
3-MeOC6H4
2-BrC6H4
5
6
7
2g
2h
2i
3g
3h
3i
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
2j
3j
2k
2l
2,5-(MeO)2C6H3
4-ClC6H4
3k
3l
2m
2n
2o
2p
2q
2r
3,4-Cl2C6H3
3,4-(MeO)2C6H3
3,4-CH2O2C6H3
2,4-(MeO)2C6H3
3,4,5-(MeO)3C6H2
Ph
3m
3n
3o
3p
3q
3r
Me
2s
2t
Et
Ph
Ph
H
Ph
3s
3t
Ph
2u
2v
2w
2x
2y
2z
4-FC6H4
3u
3v
3w
3x
3y
3z
2-furyl
H
3-Br-2-thienyl
2-thienyl
H
c
H
2-pyridyl
–
c
H
nPr
–
a The reactions were performed using a 1.0 mmol scale with 1a, 2a–z (0.5 equiv), reflux (80 °C), MeCN (20 mL), 20 h.
b Isolated yield.
c No reaction.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–L

D
M.-Y. Chang et al.
Paper
Synthesis
genative aromatization. After -elimination of protonated
3a′ to give D, ring-opening of the benzo-fused -lactone oc-
curs. Subsequently, by treatment of D with the repeated
protonated TFAA, E is generated. Intramolecular cyclization
of E affords F with a dibenzylic tertiary carbocation. Next,
deprotonation of F and tautomerization of G1 furnishes the
construction of G2 with a -naphthol skeleton. Finally, 3a is
formed via intramolecular esterification of G2 with a sec-
ond equivalent of 1a.
O
MeO
MeO
MeO
O
OMe
OMe
CO2H
TFAA, H3PO4
MeCN, 80 °C
2
MeO
O
+
1a
2aa–ad
3aa–ad
MeO
MeO
O
O
OMe
OMe
MeO
MeO
O
OMe
OMe
O
O
( )n
3aa (70%)
3ab, n = 0 (72%)
3ac, n = 1 (73%)
3ad, n = 2 (70%)
O
2a
Ph
O
MeO
MeO
MeO
MeO
O
MeO
O
Scheme 4 Synthesis of 3aa–ad
3
O
O
O
O
O
MeO
O
H
Ph
CF3
+
C
A
B
Ph
With these results in hand, five arylacetic acids 1b–f
were then screened (Scheme 5). By using 3,4-dimethoxyac-
etophenone (2n) as a two-carbon synthon, 3,4-methylene-
dioxyphenylacetic acid (1b) generated 3ae in excellent yield
(93%) under similar conditions. Changing the 3,4-dioxygen-
ated group to a di-n-propyloxy group (for 1c), produced an
isolated yield of 3af of 90%. Compound 1d, with a 3,4,5-tri-
methoxy group, also afforded a high yield (94%) for the for-
mation of 3ag with eight methoxy groups. One plausible
reason to account for the high yields observed with these
substrates is that the electron-donating methoxy group on
arene (for Ar) could provide a driving force to facilitate the
intramolecular ring-closure leading to the formation of the
-naphthol skeleton. However, when phenylacetic acid (1e)
was treated under TFAA/H3PO4-mediated reaction condi-
tions, no desired 3ah with a naphthalene skeleton was ob-
served due to the lack of an electron-rich substituent on the
Ar ring to trigger the reaction process. For 1f, with an elec-
tron-withdrawing 4-fluorophenyl group, no desired prod-
uct 3ai was obtained.
F3C
OH
TFAA
H3PO4
F3C
O
O
H
MeO
MeO
O
MeO
MeO
O
OH
1a
Ph
3a'
TFAA
O
F3C
O
H
H3PO4
MeO
MeO
O
MeO
MeO
O
MeO
OH
O
O
H
MeO
F
E
D
Ph
Ph
O
Ph
1a +
H3PO4
OH
MeO
MeO
O
MeO
MeO
MeO
MeO
OMe
OMe
Ph
Ph
3a
Ph
G1
G2
Scheme 3 Plausible mechanism
From the possible mechanism, we found that the combi-
nation of TFAA and H3PO4 could facilitate a continuous se-
quence of intermolecular Friedel–Crafts type reactions and
intramolecular ring-closures efficiently. Comparing the re-
action systems described in our previous report (TFAA,
25 °C, 10 h)11 and the present work (TFAA, H3PO4, 80 °C, 20
h), we concluded that the addition of H3PO4, the extension
of reaction time (10 to 20 h), and the elevation of the reac-
tion temperature (25 to 80 °C) led to more complete forma-
tion of the arylacetoxynaphthalene skeleton than TFAA
alone, based the plausible reaction pathways (see Scheme
5).
O
O
3
TFAA, H3PO4
MeCN, 80 °C
CO2H
Ar
Ar
Ar
2
+
O
4
5
MeO
1b–f
2n
3ae–ai
OMe
MeO
OMe
O
PrnO
PrnO
O
O
OnPr
OnPr
O
O
O
O
O
As an extension of TFAA/H3PO4-mediated intermolecu-
lar (4+2) annulations of homoveratric acid 1a with alkyl
aryl ketones 2a–z, four cyclic benzoketones 2aa–ad were
studied (Scheme 4). Under the conditions described above,
benzopyrone 2aa produced 3aa in 77% yield, and other ben-
zocycles (n = 1–3, indanone 2ab, tetralone 2ac and benzo-
suberone 2ad) provided 72%, 73% and 70% yields, respec-
tively. The results show that the ring-size did not affect the
isolated yields. The molecular structures of 3t and 3ab were
determined by single-crystal X-ray crystallography.12
3ae (93%)
3af (90%)
MeO
MeO
Ar
OMe
OMe
MeO
MeO
O
OMe
OMe
O
Ar
O
O
MeO
MeO
OMe
3ag (94%)
3ah, Ar = Ph (ND)
3ai, Ar = 4-FC6H4 (ND)
MeO
OMe
OMe
Scheme 5 Reaction of 1b–f with 2n
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–L

E
M.-Y. Chang et al.
Paper
Synthesis
After examining the one-pot synthetic route, a study us-
ing equimolar amounts of model substrates 1a and 2h, 2k,
2o, 2v or 2w was also explored (Scheme 6). Similarly, treat-
ment of 1a (1 equiv) with 2h, 2k, 2o, 2v or 2w (1 equiv) af-
forded -naphthols 3h-1, 3k-1, 3o-1, 3v-1 or 3w-1 in 94,
89, 90, 85 and 86% yields, respectively, in the presence of
TFAA and H3PO4. The results also demonstrated the forma-
tion of intermediate G2 as a plausible reaction mechanism.
Therefore, using equimolar amounts of the two starting
materials could lead to high yields of products. On the basis
of the reaction conditions, the replacement of the side
chain was examined, and acetylation was studied (Scheme
7, eq. 4). After the one-pot reaction of 1a with 2g provided a
-naphthol skeleton, further esterification of -naphthol
formed in situ with the addition of excess amounts Ac2O af-
forded 3g-1, with an acetate arm, in 82% yield. The results
showed that the 2-acyloxy group was installed into the -
naphthol skeleton efficiently by a stepwise addition of an
anhydride reagent. Furthermore, under similar conditions,
3aj was obtained in 71% yield in a one-pot intermolecular
formal (4+2) benzannulation of 1a and 2k, and sequential
esterification of the resulting -naphthol with 1b (eq. 5).
Compared with the formation of 3a, the results showed that
the sequence of addition of arylacetic acids 1a and 1b could
determine the regioselectivity of the generation of 3aj. On
the other hand, by the involvement of TFAA and H3PO4, two
equivalents of 1a were combined to provide 4, with the
benzylidene benzolactone skeleton, under neat conditions
via the cyclodimerization procedure (eq. 6).13 The molecu-
lar structures of 3g-1 and 4 were confirmed by single-
crystal X-ray analysis.12
O
CO2H
+
MeO
MeO
MeO
MeO
O
TFAA, H3PO4
(eq 4)
O
MeCN, 80 °C
then Ac2O
1a
3g-1 (82%)
2g
O
CO2H
MeO
MeO
OMe
MeO
MeO
O
O
O
TFAA, H3PO4
+
O
MeCN, 80 °C
then 1b
MeO
(eq 5)
3aj (71%)
OMe
1a
2k
MeO
CO2H
MeO
MeO
O
TFAA, H3PO4
2
(eq 6)
O
MeO
MeO
80 °C
neat
OMe
OMe
1a
4 (68%)
Scheme 7 Synthesis of 3g-1, 3aj, and 4
discussed related plausible reaction mechanisms. Further
investigations regarding the synthetic application of aryl-
acetic acids are under way in our laboratory.
All reagents and solvents were obtained from commercial sources
and used without further purification. The starting substrates 1 and 2
were purchased commercially and were used without further purifi-
cation. Reactions were routinely carried out under an atmosphere of
dry nitrogen with magnetic stirring. A heating mantle was used to
provide a stable heat source. Products in organic solvents were dried
with anhydrous magnesium sulfate (MgSO4) before concentration in
vacuo. Melting points were determined with an SMP3 melting point
apparatus. 1H and 13C NMR spectra were recorded with a Varian
INOVA-400 spectrometer operating at 400 and at 100 MHz, respec-
tively. Chemical shifts () 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 Finnigan/Thermo Quest MAT
95XL mass spectrometer. X-ray crystal structures were obtained with
an Enraf-Nonius FR-590 diffractometer (CAD4, Kappa CCD).
O
MeO
MeO
MeO
MeO
OH
TFAA, H3PO4
MeCN, 80 °C
CO2H
+
Ar'
1a
Ar'
2h, Ar' = 2-naphthyl
2k, Ar' = 2,5-(MeO)2Ph
2o, Ar' = 3,4-CH2O2Ph
2v, Ar' = 2-furyl
3h-1 (94%)
3k-1 (89%)
3o-1 (90%)
3v-1 (85%)
3w-1 (86%)
2w, Ar' = 3-Br-2-thienyl
Scheme 6 Synthesis of 3h-1, 3k-1, 3o-1, 3v-1 and 3w-1
Synthesis of 3a′, 3a–x and 3aa–ag; General Procedure
In summary, we have herein explored the use of a com-
bination of TFAA and H3PO4 to promote a facile and effi-
cient one-pot synthesis of 4-aryl-2-arylacetoxynaphtha-
lenes via intermolecular formal (4+2) benzannulation of ox-
ygenated arylacetic acids with alkyl aryl ketones. The
reaction is operationally straightforward and proceeds in
MeCN at reflux in moderate to good yields under open-
vessel conditions. To our knowledge, there have been no re-
ports on the use of alkyl aryl ketones as a two-carbon syn-
thon in the formation of substituted naphthalenes. The pro-
cess provides a cascade pathway of carbon–carbon followed
by carbon–oxygen bond formation events. We have also
Trifluoroacetic anhydride (TFAA, 230 mg, 1.1 mmol) and phosphoric
acid (H3PO4, 110 mg, 1.1 mmol) were added to a solution of oxygenat-
ed arylacetic acids 1a–d (1.0 mmol) in MeCN (15 mL) at 25 °C. The re-
action mixture was stirred at 25 °C for 30 min. Ketone 2a–x or 2aa–ad
(0.5 mmol) in MeCN (5 mL) was added to the reaction mixture at
25 °C, and the reaction mixture was stirred at reflux (80 °C) for 20 h.
The solvent of reaction mixture was concentrated, the residue was di-
luted with water (10 mL) and the mixture was extracted with CH2Cl2
(3 × 20 mL). The combined organic layers were washed with brine,
dried, filtered and evaporated to afford the crude product under re-
duced pressure. Purification on silica gel (hexanes/EtOAc = 10:1 to
1:1) afforded compounds 3a′, 3a–x and 3aa–ag.
6,7-Dimethoxy-1-methyl-1-phenylisochroman-3-one (3a′)11
For Table 1, entry 1.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–L

F
M.-Y. Chang et al.
Paper
Synthesis
Yield: 87% (130 mg); colorless solid; mp 159–161 °C (recrystallized
from hexanes and EtOAc).
1H NMR (400 MHz, CDCl3):  = 7.26–7.19 (m, 3 H), 7.15–7.13 (m, 2 H),
6.98 (s, 1 H), 6.65 (s, 1 H), 3.92 (s, 3 H), 3.86 (s, 3 H), 3.44 (d, J =
18.4 Hz, 1 H), 3.07 (dd, J = 0.8, 18.4 Hz, 1 H), 2.00 (s, 3 H).
13C{1H} NMR (100 MHz, CDCl3):  = 171.0, 149.2, 147.9, 143.3, 130.1,
128.3 (2C), 127.8, 125.2 (2C), 123.0, 110.4, 108.5, 85.9, 56.2, 55.9,
36.2, 29.0.
1H NMR (400 MHz, CDCl3):  = 7.41 (d, J = 8.8 Hz, 2 H), 7.37 (d, J =
2.4 Hz, 1 H), 7.19 (s, 1 H), 7.10 (s, 1 H), 7.01 (d, J = 8.8 Hz, 2 H), 6.98–
6.94 (m, 3 H), 6.87 (d, J = 8.4 Hz, 1 H), 3.98 (s, 3 H), 3.90 (s, 3 H), 3.89
(s, 3 H), 3.88 (s, 3 H), 3.84 (s, 2 H), 3.81 (s, 3 H).
13C{1H} NMR (100 MHz, CDCl3):  = 170.5, 159.0, 149.9, 149.2, 149.0,
148.3, 146.8, 140.1, 152.5, 130.7 (2×), 130.1, 125.9, 125.5, 121.5,
119.8, 116.4, 113.8 (2×), 112.4, 111.3, 106.4, 104.9, 55.9 (2×), 55.8,
55.7, 55.3, 41.0.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C29H29O7: 489.1913; found:
489.1920.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C18H19O4: 299.1283; found:
299.1288.
(3,4-Dimethoxyphenyl)acetic Acid 6,7-Dimethoxy-4-(4-trifluoro-
methylphenyl)naphthalen-2-yl Ester (3e)
(3,4-Dimethoxyphenyl)acetic Acid 6,7-dimethoxy-4-phenylnaph-
thalen-2-yl Ester (3a)
Yield: 60% (158 mg); colorless liquid.
Yield: 80% (183 mg); colorless liquid.
1H NMR (400 MHz, CDCl3):  = 7.75 (d, J = 8.4 Hz, 2 H), 7.61 (d, J =
8.0 Hz, 2 H), 7.44 (d, J = 2.0 Hz, 1 H), 7.12 (s, 1 H), 7.06 (s, 1 H), 6.99 (d,
J = 2.4 Hz, 1 H), 6.96 (dd, J = 2.0, 8.0 Hz, 1 H), 6.94 (s, 1 H), 6.87 (d, J =
8.8 Hz, 1 H), 3.99 (s, 3 H), 3.90 (s, 3 H), 3.89 (s, 3 H), 3.85 (s, 2 H), 3.80
(s, 3 H).
13C{1H} NMR (100 MHz, CDCl3):  = 170.5, 150.1, 149.7, 148.4, 146.7,
143.9, 138.7, 130.2, 130.12 (q, J = 37.9 Hz), 130.05 (2×), 130.0, 125.8,
125.4 (q, J = 3.8 Hz, 2×), 125.0, 123.7 (q, J = 270.6 Hz), 121.5, 120.0,
117.5, 112.4, 111.3, 106.6, 104.2, 55.9 (2×), 55.82, 55.76, 41.0.
1H NMR (400 MHz, CDCl3):  = 7.50–7.39 (m, 5 H), 7.40 (d, J = 2.4 Hz,
1 H), 7.17 (s, 1 H), 7.11 (s, 1 H), 7.00 (d, J = 2.4 Hz, 1 H), 6.97–6.94 (m,
2 H), 6.87 (d, J = 8.8 Hz, 1 H), 3.99 (s, 3 H), 3.90 (s, 3 H), 3.89 (s, 3 H),
3.84 (s, 2 H), 3.79 (s, 3 H).
13C{1H} NMR (100 MHz, CDCl3):  = 170.5, 149.9, 149.3, 149.0, 148.3,
146.8, 140.4, 140.2, 130.2, 129.7 (2×), 128.4 (2×), 127.5, 125.9, 125.3,
121.5, 119.9, 116.7, 112.4, 111.3, 106.5, 104.8, 55.91 (2×), 55.87, 55.7,
41.1.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C28H27O6: 459.1808; found:
459.1806.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C29H26F3O6: 527.1682; found:
527.1683.
(3,4-Dimethoxyphenyl)acetic Acid 4-(4-Fluorophenyl)-6,7-dime-
thoxynaphthalen-2-yl Ester (3b)
(3,4-Dimethoxyphenyl)acetic Acid 6,7-Dimethoxy-4-(4-nitrophe-
nyl)naphthalen-2-yl Ester (3f)
Yield: 62% (148 mg); colorless liquid.
Yield: 51% (128 mg); colorless liquid.
1H NMR (400 MHz, CDCl3):  = 7.46–7.43 (m, 2 H), 7.40 (d, J = 2.4 Hz,
1 H), 7.20–7.14 (m, 2 H), 7.11 (s, 1 H), 7.08 (s, 1 H), 6.98 (d, J = 2.4 Hz,
1 H), 6.97–6.94 (m, 2 H), 6.87 (d, J = 9.2 Hz, 1 H), 3.99 (s, 3 H), 3.90 (s,
3 H), 3.89 (s, 3 H), 3.84 (s, 2 H), 3.80 (s, 3 H).
13C{1H} NMR (100 MHz, CDCl3):  = 170.5, 162.3 (d, J = 245.6 Hz),
150.0, 149.4, 149.0, 148.4, 146.8, 139.2, 136.1 (d, J = 3.8 Hz), 131.2 (d,
J = 7.5 Hz, 2×), 130.1, 125.9, 125.4, 121.5, 119.9, 116.9, 115.4 (d, J =
21.3 Hz, 2×), 112.4, 111.3, 106.5, 104.5, 55.89 (2×), 55.86, 55.7, 41.0.
1H NMR (400 MHz, CDCl3):  = 8.36 (d, J = 8.8 Hz, 2 H), 7.67 (d, J =
8.8 Hz, 2 H), 7.46 (d, J = 2.4 Hz, 1 H), 7.13 (s, 1 H), 7.011 (d, J = 2.4 Hz,
1 H), 7.006 (s, 1 H), 6.96 (dd, J = 2.0, 8.0 Hz, 1 H), 6.94 (s, 1 H), 6.87 (d,
J = 8.0 Hz, 1 H), 4.00 (s, 3 H), 3.90 (s, 3 H), 3.89 (s, 3 H), 3.85 (s, 2 H),
3.80 (s, 3 H).
13C{1H} NMR (100 MHz, CDCl3):  = 170.5, 150.3, 149.9, 149.1, 148.4,
147.3, 147.1, 146.7, 137.7, 130.6 (2×), 130.3, 125.7, 124.7, 123.8 (2×),
121.6, 120.0, 118.1, 112.4, 111.3, 106.7, 103.8, 55.9, 55.8, 41.0, 22.7,
14.1.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C28H26FO6: 477.1714; found:
477.1715.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C28H26NO8: 504.1659; found:
504.1658.
(3,4-Dimethoxyphenyl)acetic Acid 6,7-Dimethoxy-4-p-tolylnaph-
thalen-2-yl Ester (3c)
(3,4-Dimethoxyphenyl)acetic acid 4-biphenyl-4-yl-6,7-dimethoxy-
naphthalen-2-yl ester (3g)
Yield: 76% (179 mg); colorless liquid.
1H NMR (400 MHz, CDCl3):  = 7.39–7.37 (m, 3 H), 7.28 (d, J = 7.6 Hz,
2 H), 7.21 (s, 1 H), 7.10 (s, 1 H), 6.99 (d, J = 2.4 Hz, 1 H), 6.97–6.94 (m,
2 H), 6.87 (d, J = 8.8 Hz, 1 H), 3.99 (s, 3 H), 3.90 (s, 3 H), 3.89 (s, 3 H),
3.84 (s, 2 H), 3.80 (s, 3 H), 2.44 (s, 3 H).
13C{1H} NMR (100 MHz, CDCl3):  = 170.5, 149.9, 149.2, 149.0, 148.3,
146.9, 140.4, 137.23, 137.21, 130.2, 129.5 (2×), 129.1 (2×), 126.0,
125.4, 121.5, 119.8, 116.5, 112.4, 111.3, 106.4, 104.9, 55.90 (2×),
55.85, 55.7, 41.1, 21.2.
Yield: 70% (187 mg); colorless liquid.
1H NMR (400 MHz, CDCl3):  = 7.74–7.69 (m, 4 H), 7.58 (d, J = 8.4 Hz,
2 H), 7.52–7.47 (m, 2 H), 7.42 (d, J = 2.0 Hz, 1 H), 7.41–7.37 (m, 1 H),
7.26 (s, 1 H), 7.13 (s, 1 H), 7.06 (d, J = 2.4 Hz, 1 H), 6.98–6.95 (m, 2 H),
6.88 (d, J = 8.8 Hz, 1 H), 4.00 (s, 3 H), 3.91 (s, 3 H), 3.89 (s, 3 H), 3.85 (s,
2 H), 3.83 (s, 3 H).
13C{1H} NMR (100 MHz, CDCl3):  = 170.5, 150.0, 149.4, 149.0, 148.3,
146.9, 140.6, 140.3, 140.0, 139.2, 130.2, 130.1 (2×), 128.9 (2×), 127.5,
127.1 (2×), 127.0 (2×), 125.9, 125.3, 121.5, 119.9, 116.8, 112.4, 111.3,
106.5, 104.8, 55.89 (2×), 55.86, 55.8, 41.0.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C29H29O6: 473.1964; found:
473.1963.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C34H31O6: 535.2121; found:
535.2123.
(3,4-Dimethoxyphenyl)acetic Acid 6,7-Dimethoxy-4-(4-methoxy-
phenyl)naphthalen-2-yl Ester (3d)
Yield: 92% (225 mg); colorless liquid.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–L

G
M.-Y. Chang et al.
Paper
Synthesis
(3,4-Dimethoxyphenyl)acetic Acid 6,7-Dimethoxy[1,2′]binaphtha-
(3,4-Dimethoxyphenyl)acetic Acid 4-(4-Chlorophenyl)-6,7-di-
lenyl-3-yl Ester (3h)
methoxynaphthalen-2-yl Ester (3l)
Yield: 72% (183 mg); colorless liquid.
Yield: 80% (197 mg); colorless liquid.
1H NMR (400 MHz, CDCl3):  = 7.96 (d, J = 0.8 Hz, 1 H), 7.94–7.88 (m,
3 H), 7.63 (dd, J = 2.0, 8.4 Hz, 1 H), 7.57–7.53 (m, 2 H), 7.44 (d, J =
2.4 Hz, 1 H), 7.20 (s, 1 H), 7.14 (s, 1 H), 7.11 (d, J = 2.4 Hz, 1 H), 6.98–
6.95 (m, 2 H), 6.87 (d, J = 8.4 Hz, 1 H), 4.00 (s, 3 H), 3.90 (s, 3 H), 3.88
(s, 3 H), 3.86 (s, 2 H), 3.74 (s, 3 H).
13C{1H} NMR (100 MHz, CDCl3):  = 170.6, 150.0, 149.4, 149.0, 148.3,
146.9, 140.3, 137.8, 133.5, 132.7, 130.2, 128.5, 128.1, 127.9, 127.8,
127.7, 126.4, 126.2, 125.9, 125.5, 121.5, 120.2, 116.9, 112.4, 111.3,
106.5, 104.8, 55.9 (3×), 55.7, 41.1.
1H NMR (400 MHz, CDCl3):  = 7.47–7.40 (m, 5 H), 7.09 (d, J = 8.8 Hz,
2 H), 6.97–6.94 (m, 3 H), 6.87 (d, J = 8.8 Hz, 1 H), 3.99 (s, 3 H), 3.90 (s,
3 H), 3.89 (s, 3 H), 3.84 (s, 2 H), 3.80 (s, 3 H).
13C{1H} NMR (100 MHz, CDCl3):  = 170.5, 150.0, 149.5, 149.0, 148.4,
146.8, 139.0, 138.6, 133.6, 131.0 (2×), 130.2, 128.7 (2×), 125.9, 125.2,
121.5, 119.9, 117.1, 112.4, 111.3, 106.5, 104.4, 55.90 (2×), 55.88, 55.7,
41.0.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C28H26ClO6: 493.1418; found:
493.1420.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C32H29O6: 509.1964; found:
509.1963.
(3,4-Dimethoxyphenyl)acetic Acid 4-(3,4-Dichlorophenyl)-6,7-di-
methoxynaphthalen-2-yl Ester (3m)
(3,4-Dimethoxyphenyl)acetic Acid 6,7-Dimethoxy-4-(3-methoxy-
phenyl)naphthalen-2-yl Ester (3i)
Yield: 68% (179 mg); colorless liquid.
1H NMR (400 MHz, CDCl3):  = 7.59 (d, J = 2.0 Hz, 1 H), 7.55 (d, J =
8.4 Hz, 1 H), 7.42 (d, J = 2.4 Hz, 1 H), 7.33 (dd, J = 2.0, 8.0 Hz, 1 H), 7.11
(s, 1 H), 7.05 (s, 1 H), 6.97 (d, J = 2.4 Hz, 1 H), 6.95 (d, J = 7.6 Hz, 1 H),
6.94 (s, 1 H), 6.87 (d, J = 8.4 Hz, 1 H), 3.99 (s, 3 H), 3.90 (s, 3 H), 3.89 (s,
3 H), 3.84 (s, 2 H), 3.82 (s, 3 H).
Yield: 86% (210 mg); colorless liquid.
1H NMR (400 MHz, CDCl3):  = 7.40–7.37 (m, 2 H), 7.20 (s, 1 H), 7.10
(s, 1 H), 7.08–6.95 (m, 6 H), 6.87 (d, J = 8.8 Hz, 1 H), 3.99 (s, 3 H), 3.90
(s, 3 H), 3.89 (s, 3 H), 3.84 (s, 6 H), 3.80 (s, 2 H).
13C{1H} NMR (100 MHz, CDCl3):  = 170.5, 159.6, 150.0, 149.3, 149.1,
148.4, 146.8, 140.3, 130.2, 129.4, 125.9, 125.3, 124.4, 122.1, 121.5,
119.7, 116.8, 115.1, 113.3, 112.4, 111.3, 106.4, 104.9, 55.91 (2×),
55.87, 55.7, 55.3, 41.1.
13C{1H} NMR (100 MHz, CDCl3):  = 170.5, 150.1, 149.7, 149.1, 148.4,
146.7, 140.2, 137.6, 132.7, 131.8, 131.5, 130.4, 130.2, 129.0, 125.8,
124.9, 121.5, 119.9, 117.6, 112.4, 111.3, 106.6, 104.0, 55.9 (3×), 55.8,
41.0.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C29H29O7: 489.1913; found:
HRMS (ESI-TOF): m/z [M + H]+ calcd for C28H25Cl2O6: 527.1028; found:
489.1919.
527.1030.
(3,4-Dimethoxyphenyl)acetic acid 4-(2-bromophenyl)-6,7-dime-
thoxynaphthalen-2-yl ester (3j)
(3,4-Dimethoxyphenyl)acetic Acid 4-(3,4-Dimethoxyphenyl)-6,7-
dimethoxynaphthalen-2-yl Ester (3n)
Yield: 80% (214 mg); colorless liquid.
Yield: 92% (238 mg); colorless solid; mp 157–159 °C (recrystallized
from hexanes and EtOAc).
1H NMR (400 MHz, CDCl3):  = 7.37 (d, J = 2.4 Hz, 1 H), 7.21 (s, 1 H),
7.10 (s, 1 H), 7.05–6.93 (m, 6 H), 6.86 (d, J = 8.8 Hz, 1 H), 3.98 (s, 3 H),
3.95 (s, 3 H), 3.89 (s, 3 H), 3.882 (s, 3 H), 3.875 (s, 3 H), 3.84 (s, 2 H),
3.80 (s, 3 H).
1H NMR (400 MHz, CDCl3):  = 7.72 (dd, J = 0.8, 8.0 Hz, 1 H), 7.46 (d, J =
2.4 Hz, 1 H), 7.42 (dt, J = 1.2, 7.6 Hz, 1 H), 7.38 (dt, J = 2.0, 8.8 Hz, 1 H),
7.30 (dt, J = 2.4, 8.0 Hz, 1 H), 7.11 (s, 1 H), 6.97 (d, J = 2.4 Hz, 1 H),
6.96–6.93 (m, 2 H), 6.86 (d, J = 8.8 Hz, 1 H), 6.68 (s, 1 H), 3.99 (s, 3 H),
3.90 (s, 3 H), 3.88 (s, 3 H), 3.84 (s, 2 H), 3.75 (s, 3 H).
13C{1H} NMR (100 MHz, CDCl3):  = 170.4, 150.0, 149.4, 149.0, 148.3,
146.6, 140.6, 139.0, 132.8, 131.8, 129.7, 129.3, 127.3, 125.9, 125.3,
123.9, 121.5, 120.0, 117.3, 112.4, 111.3, 106.4, 104.6, 55.9 (2×), 55.8,
55.7, 41.0.
13C{1H} NMR (100 MHz, CDCl3):  = 170.5, 149.8, 149.2, 149.0, 148.6,
148.4, 148.3, 146.7, 140.2, 132.8, 130.1, 125.9, 125.4, 121.9, 121.5,
119.7, 116.5, 112.9, 112.4, 111.2, 111.1, 106.4, 104.8, 55.90, 55.86,
55.82 (2×), 55.79, 55.6, 40.9.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C28H26BrO6: 537.0913; found:
HRMS (ESI-TOF): m/z [M + H]+ calcd for C30H31O8: 519.2019; found:
537.0919.
519.2025.
(3,4-Dimethoxyphenyl)acetic Acid 4-(2,5-Dimethoxyphenyl)-6,7-
dimethoxynaphthalen-2-yl Ester (3k)
(3,4-Dimethoxyphenyl)acetic Acid 4-Benzo[1,3]dioxol-5-yl-6,7-di-
methoxynaphthalen-2-yl Ester (3o)
Yield: 86% (223 mg); colorless liquid.
Yield: 92% (231 mg); colorless liquid.
1H NMR (400 MHz, CDCl3):  = 7.42 (d, J = 2.4 Hz, 1 H), 7.09 (s, 1 H),
7.01 (d, J = 2.4 Hz, 1 H), 6.95–6.84 (m, 7 H), 3.97 (s, 3 H), 3.89 (s, 3 H),
3.87 (s, 3 H), 3.83 (s, 2 H), 3.78 (s, 3 H), 3.77 (s, 3 H), 3.63 (s, 3 H).
1H NMR (400 MHz, CDCl3):  = 7.37 (d, J = 2.4 Hz, 1 H), 7.20 (s, 1 H),
7.09 (s, 1 H), 6.97–6.90 (m, 6 H), 6.86 (d, J = 8.4 Hz, 1 H), 6.03 (s, 2 H),
3.98 (s, 3 H), 3.90 (s, 3 H), 3.88 (s, 3 H), 3.832 (s, 3 H), 3.826 (s, 2 H).
13C{1H} NMR (100 MHz, CDCl3):  = 170.3, 153.5, 151.0, 149.8, 149.0,
148.9, 148.2, 146.7, 136.9, 129.6 (2×), 125.9, 125.7, 121.4, 120.1,
117.1, 116.8, 114.0, 112.33, 112.27, 111.2, 106.2, 105.1, 56.1, 55.8
(2×), 55.7, 55.6, 55.5, 40.9.
13C{1H} NMR (100 MHz, CDCl3):  = 170.5, 149.9, 149.2, 149.0, 148.3,
147.6, 147.0, 146.7, 139.9, 134.0, 130.1, 125.9, 125.4, 123.1, 121.5,
119.8, 116.6, 112.4, 111.2, 110.1, 108.2, 106.4, 104.7, 101.1, 55.83
(2×), 55.79, 55.7, 41.0.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C30H31O8: 519.2019; found:
HRMS (ESI-TOF): m/z [M + H]+ calcd for C29H27O8: 503.1706; found:
519.2023.
503.1708.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–L

H
M.-Y. Chang et al.
Paper
Synthesis
(3,4-Dimethoxyphenyl)acetic Acid 4-(2,4-Dimethoxyphenyl)-6,7-
dimethoxynaphthalen-2-yl Ester (3p)
(3,4-Dimethoxyphenyl)acetic Acid 6,7-Dimethoxy-3,4-diphenyl-
naphthalen-2-yl Ester (3t)
Yield: 90% (233 mg); colorless liquid.
Yield: 63% (168 mg); colorless solid; mp 119–120 °C (recrystallized
from hexanes and EtOAc).
1H NMR (400 MHz, CDCl3):  = 7.45 (s, 1 H), 7.25–7.18 (m, 3 H), 7.13
(s, 1 H), 7.12–7.10 (m, 2 H), 7.13–7.10 (m, 3 H), 7.02–6.98 (m, 2 H),
6.83 (s, 1 H), 6.74 (d, J = 8.4 Hz, 1 H), 6.61–6.58 (m, 2 H), 4.00 (s, 3 H),
3.87 (s, 3 H), 3.81 (s, 3 H), 3.70 (s, 3 H), 3.44 (s, 2 H).
13C{1H} NMR (100 MHz, CDCl3):  = 170.6, 149.9, 149.3, 148.7, 148.1,
145.3, 139.2, 138.6, 136.5, 131.6, 130.8 (2×), 130.6 (2×), 129.1, 127.7
(2×), 127.1 (2×), 126.73, 126.71, 126.3, 125.6, 121.5, 117.7, 112.3,
111.0, 105.9, 105.7, 55.9, 55.8, 55.7, 55.5, 40.5.
1H NMR (400 MHz, CDCl3):  = 7.39 (d, J = 2.4 Hz, 1 H), 7.21 (d, J =
9.2 Hz, 1 H), 7.08 (s, 1 H), 6.98 (d, J = 2.4 Hz, 1 H), 6.95–6.93 (m, 2 H),
6.86–6.84 (m, 2 H), 6.61–6.58 (m, 2 H), 3.97 (s, 3 H), 3.90 (s, 3 H),
3.881 (s, 3 H), 3.878 (s, 3 H), 3.83 (s, 2 H), 3.77 (s, 3 H), 3.68 (s, 3 H).
13C{1H} NMR (100 MHz, CDCl3):  = 170.4, 160.7, 157.8, 149.7, 148.93,
148.90, 148.2, 146.8, 136.9, 132.1, 129.6, 126.2, 126.0, 121.5, 121.4,
120.4, 116.5, 112.4, 111.2, 106.2, 105.3, 104.3, 98.7, 55.81 (2×), 55.75,
55.6, 55.4, 55.3, 41.0.
HRMS (ESI-TOF): m/z: [M + H]+ calcd for C30H31O8: 519.2019; found:
519.2016.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C34H31O6: 535.2121; found:
535.2122.
(3,4-Dimethoxyphenyl)acetic Acid 6,7-Dimethoxy-4-(3,4,5-tri-
methoxyphenyl)naphthalen-2-yl Ester (3q)
Single-crystal X-ray diagram: a crystal of compound 3t was grown by
slow diffusion of EtOAc into a solution of compound 3t in CH2Cl2 to
yield colorless prisms. The compound crystallizes in the monoclinic
crystal system, space group P 21/c, a = 9.9310(3) Å, b = 6.8766(2) Å,
c = 40.3543(11) Å, V = 2751.16(14) Å3, Z = 4, dcalcd = 1.291 g/cm3,
F(000) = 1128, 2θ range 2.022–26.378°, R indices (all data) R1 =
0.0892, wR2 = 0.2254; CCDC 1910997.12
Yield: 94% (258 mg); colorless liquid.
1H NMR (400 MHz, CDCl3):  = 7.39 (d, J = 2.4 Hz, 1 H), 7.23 (s, 1 H),
7.11 (s, 1 H), 7.01 (d, J = 2.4 Hz, 1 H), 6.96–6.95 (m, 2 H), 6.87 (d, J =
8.8 Hz, 1 H), 6.70 (s, 2 H), 3.99 (s, 3 H), 3.93 (s, 3 H), 3.90 (s, 3 H), 3.89
(s, 3 H), 3.86 (s, 6 H), 3.85 (s, 2 H), 3.82 (s, 3 H).
13C{1H} NMR (100 MHz, CDCl3):  = 170.6, 153.1 (2×), 150.0, 149.3,
149.0, 148.3, 146.7, 140.3, 137.4, 135.7, 130.2, 125.9, 125.3, 121.5,
119.6, 116.8, 112.4, 111.3, 106.8 (2×), 106.5, 104.8, 61.0, 56.2 (2×),
55.89 (2×), 55.87, 55.8, 41.0.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C31H33O9: 549.2125; found:
549.2126.
(3,4-Dimethoxyphenyl)acetic Acid 4-(4-Fluorophenyl)-6,7-di-
methoxy-3-phenylnaphthalen-2-yl Ester (3u)
Yield: 60% (166 mg); colorless solid; mp 180–181 °C (recrystallized
from hexanes and EtOAc).
1H NMR (400 MHz, CDCl3):  = 7.45 (s, 1 H), 7.13 (s, 1 H), 7.10–7.05
(m, 5 H), 6.99–6.90 (m, 4 H), 6.78 (s, 1 H), 6.74 (d, J = 8.0 Hz, 1 H),
6.60–6.57 (m, 2 H), 4.00 (s, 3 H), 3.87 (s, 3 H), 3.81 (s, 3 H), 3.72 (s,
3 H), 3.44 (s, 2 H).
13C{1H} NMR (100 MHz, CDCl3):  = 170.6, 161.6 (d, J = 244.1 Hz),
150.0, 149.4, 148.7, 148.1, 145.3, 138.1, 136.3, 134.5 (d, J = 3.8 Hz),
132.4 (d, J = 8.4 Hz, 2×), 131.9, 130.5 (2×), 129.1, 127.3 (2×), 126.7,
126.4, 125.5, 121.5, 118.0, 114.8 (d, J = 21.2 Hz, 2×), 112.3, 111.1,
106.0, 105.4, 55.9, 55.8, 55.7, 55.6, 40.4.
(3,4-Dimethoxyphenyl)acetic Acid 6,7-Dimethoxy-3-methyl-4-
phenylnaphthalen-2-yl Ester (3r)
Yield: 81% (191 mg); colorless liquid.
1H NMR (400 MHz, CDCl3):  = 7.50–7.46 (m, 2 H), 7.44–7.40 (m, 1 H),
7.36 (s, 1 H), 7.26–7.23 (m, 2 H), 7.05 (s, 1 H), 6.99–6.96 (m, 2 H), 6.86
(d, J = 8.8 Hz, 1 H), 6.61 (s, 1 H), 3.96 (s, 3 H), 3.89 (s, 3 H), 3.88 (s, 3 H),
3.87 (s, 2 H), 3.66 (s, 3 H), 1.86 (s, 3 H).
13C{1H} NMR (100 MHz, CDCl3):  = 170.4, 149.3, 149.0, 148.3, 146.6,
139.4, 139.1, 129.9 (2×), 129.5 (2×), 127.8, 127.2, 126.9, 126.0, 125.3,
121.6 (2×), 117.1, 112.4, 111.2, 105.9, 105.3, 55.87, 55.85, 55.8, 55.4,
41.1, 14.2.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C34H30FO6: 553.2027; found:
553.2022.
(3,4-Dimethoxyphenyl)acetic Acid 4-Furan-2-yl-6,7-dimethoxy-
naphthalen-2-yl Ester (3v)
HRMS (ESI): m/z [M+1]+ calcd for C29H29O6: 473.1964; found:
473.1968.
Yield: 74% (166 mg); colorless liquid.
1H NMR (400 MHz, CDCl3):  = 7.72 (s, 1 H), 7.60 (dd, J = 1.2, 2.0 Hz,
1 H), 7.38 (d, J = 2.4 Hz, 1 H), 7.31 (d, J = 2.4 Hz, 1 H), 7.08 (s, 1 H),
6.97–6.95 (m, 2 H), 6.88 (d, J = 8.8 Hz, 1 H), 6.72 (d, J = 3.2 Hz, 1 H),
6.58 (dd, J = 2.0, 3.2 Hz, 1 H), 3.99 (s, 3 H), 3.97 (s, 3 H), 3.92 (s, 3 H),
3.90 (s, 3 H), 3.85 (s, 2 H).
(3,4-Dimethoxyphenyl)acetic Acid 3-Ethyl-6,7-dimethoxy-4-
phenylnaphthalen-2-yl Ester (3s)
Yield: 78% (190 mg); colorless liquid.
1H NMR (400 MHz, CDCl3):  = 7.49–7.42 (m, 3 H), 7.38 (s, 1 H), 7.26–
7.24 (m, 2 H), 7.05 (s, 1 H), 6.99–6.96 (m, 2 H), 6.86 (d, J = 8.8 Hz, 1 H),
6.52 (s, 1 H), 3.96 (s, 3 H), 3.89 (s, 3 H), 3.88 (s, 3 H), 3.87 (s, 2 H), 3.64
(s, 3 H), 2.25 (q, J = 7.6 Hz, 2 H), 0.82 (t, J = 7.6 Hz, 3 H).
13C{1H} NMR (100 MHz, CDCl3):  = 170.6, 149.3, 149.0, 148.9, 148.3,
146.2, 139.1, 138.8, 131.3, 129.9 (2×), 128.3 (2×), 127.8, 127.3, 127.1,
126.0, 121.7, 117.8, 112.5, 111.3, 105.9, 105.6, 55.91, 55.88, 55.8, 55.4,
41.4, 21.7, 14.9.
13C{1H} NMR (100 MHz, CDCl3):  = 170.5, 152.9, 149.9, 149.8, 149.1,
148.4, 146.8, 142.4, 130.5, 128.6, 125.9, 124.1, 121.6, 118.7, 117.7,
112.4, 111.5, 111.3, 109.2, 106.6, 104.5, 55.9 (2×), 55.83, 55.78, 41.0.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C26H25O7: 449.1600; found:
449.1602.
(3,4-Dimethoxyphenyl)acetic Acid 4-(3-Bromothiophen-2-yl)-6,7-
dimethoxynaphthalen-2-yl Ester (3w)
HRMS (ESI-TOF): m/z [M + H]+ calcd for C30H31O6: 487.2121; found:
487.2124.
Yield: 76% (206 mg); colorless liquid.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–L

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M.-Y. Chang et al.
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Synthesis
1H NMR (400 MHz, CDCl3):  = 7.49 (d, J = 2.4 Hz, 1 H), 7.41 (d, J =
5.2 Hz, 1 H), 7.13 (s, 1 H), 7.12 (d, J = 5.2 Hz, 1 H), 7.10 (s, 1 H), 7.01 (s,
1 H), 6.96–6.93 (m, 2 H), 6.86 (d, J = 8.8 Hz, 1 H), 3.98 (s, 3 H), 3.90 (s,
3 H), 3.88 (s, 3 H), 3.86 (s, 3 H), 3.84 (s, 2 H).
c = 14.5717(6) Å, V = 4676.2(3) Å3, Z = 8, dcalcd = 1.337 g/cm3, F(000) =
1984, 2θ range 1.653–26.413°, R indices (all data) R1 = 0.0354, wR2 =
0.0894; CCDC 1910998.12
13C{1H} NMR (100 MHz, CDCl3):  = 170.3, 150.1, 149.7, 148.9, 148.3,
146.2, 135.9, 130.6, 129.9, 129.8, 126.4, 125.74, 125.69, 122.0, 121.5,
118.5, 112.3, 111.2, 110.7, 106.3, 104.9, 55.8 (3×), 57.7, 40.9.
(3,4-Dimethoxyphenyl)acetic Acid 2,3-Dimethoxy-7,8-dihydro-
benzo[c]phenanthren-6-yl Ester (3ac)
Yield: 73% (177 mg); colorless liquid.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C26H24BrO6S: 543.0477;
found: 543.0481.
1H NMR (400 MHz, CDCl3):  = 7.94 (d, J = 7.6 Hz, 1 H), 7.88 (s, 1 H),
7.35 (d, J = 7.6 Hz, 1 H), 7.32–7.25 (m, 3 H), 7.07 (s, 1 H), 7.00–6.97 (m,
2 H), 6.89 (d, J = 8.8 Hz, 1 H), 3.99 (s, 3 H), 3.95 (s, 3 H), 3.910 (s, 3 H),
3.907 (s, 3 H), 3.87 (s, 2 H), 2.73–2.69 (m, 2 H), 2.56–2.52 (m, 2 H).
13C{1H} NMR (100 MHz, CDCl3):  = 170.3, 149.4, 149.2, 149.0, 148.4,
144.9, 139.5, 134.1, 132.7, 129.4, 128.9, 127.9 (2×), 127.1, 126.0,
124.0, 121.6 (2×), 117.3, 112.4, 111.3, 106.6, 105.1, 55.9 (2×), 55.78,
55.77, 41.0, 28.9, 23.1.
(3,4-Dimethoxyphenyl)acetic Acid 6,7-Dimethoxy-4-thiophen-2-
ylnaphthalen-2-yl Ester (3x)
Yield: 80% (186 mg); colorless liquid.
1H NMR (400 MHz, CDCl3):  = 7.55 (s, 1 H), 7.42 (dd, J = 1.2, 5.2 Hz,
1 H), 7.40 (d, J = 2.4 Hz, 1 H), 7.25 (dd, J = 1.2, 3.6 Hz, 1 H), 7.16 (dd, J =
3.2, 5.2 Hz, 1 H), 7.15 (d, J = 2.4 Hz, 1 H), 7.01 (s, 1 H), 6.97–6.94 (m,
2 H), 6.87 (d, J = 8.4 Hz, 1 H), 3.99 (s, 3 H), 3.91 (s, 3 H), 3.889 (s, 3 H),
3.885 (s, 3 H), 3.84 (s, 2 H).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C30H29O6: 485.1964; found:
485.1963.
13C{1H} NMR (100 MHz, CDCl3):  = 170.4, 150.0, 149.6, 149.0, 148.3,
146.5, 141.3, 132.5, 130.2, 127.3, 127.2, 125.9, 125.8, 125.6, 121.5,
120.8, 117.5, 112.4, 111.3, 106.5, 104.7, 55.9 (2×), 55.84, 55.75, 41.0.
(3,4-Dimethoxyphenyl)acetic Acid 2,3-Dimethoxy-8,9-dihydro-
7H-benzo[6,7]cyclohepta[1,2-a]naphthalen-6-yl Ester (3ad)
Yield: 70% (174 mg); colorless liquid.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C26H25O6S: 465.1372; found:
465.1378.
1H NMR (400 MHz, CDCl3):  = 7.49–7.47 (m, 1 H), 7.37–7.29 (m, 5 H),
7.07 (s, 1 H), 7.00–6.98 (m, 2 H), 6.87 (d, J = 8.8 Hz, 1 H), 3.98 (s, 3 H),
3.90 (s, 3 H), 3.89 (s, 3 H), 3.87 (s, 2 H), 3.80 (s, 3 H), 2.53–2.48 (m,
2 H), 2.42–2.34 (m, 1 H), 1.94–1.89 (m, 3 H).
13C{1H} NMR (100 MHz, CDCl3):  = 170.9, 149.3, 149.2, 149.0, 148.4,
145.2, 140.9, 137.8, 137.1, 129.9, 128.9, 128.6, 128.1, 127.8, 126.1,
125.6, 125.3, 121.6, 117.4, 112.3, 111.3, 106.2, 104.9, 55.91, 55.89,
55.8, 55.6, 41.2, 32.3, 30.9, 23.7.
(3,4-Dimethoxyphenyl)acetic Acid 10,11-Dimethoxy-6H-5-oxa-
benzo[c]phenanthren-7-yl Ester (3aa)
Yield: 70% (170 mg); colorless liquid.
1H NMR (400 MHz, CDCl3):  = 8.03 (dd, J = 1.6, 8.0 Hz, 1 H), 7.88 (s,
1 H), 7.37 (s, 1 H), 7.30 (dt, J = 1.6, 7.6 Hz, 1 H), 7.18–7.13 (m, 2 H),
7.08 (s, 1 H), 6.99–6.92 (m, 2 H), 6.90 (d, J = 8.0 Hz, 1 H), 4.81 (s, 2 H),
4.00 (s, 3 H), 3.98 (s, 3 H), 3.92 (s, 3 H), 3.91 (s, 3 H), 3.86 (s, 2 H).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C31H31O6: 499.2121; found:
499.2126.
13C{1H} NMR (100 MHz, CDCl3):  = 170.1, 156.5, 149.9, 149.6, 149.2,
148.5, 142.6, 130.3, 128.9, 127.6, 127.1, 125.6, 124.9, 124.2, 123.0,
121.8, 121.6, 117.9, 117.5, 112.3, 111.4, 106.9, 104.5, 64.4, 55.94,
55.93, 55.8 (2×), 41.0.
Benzo[1,3]dioxol-5-yl-acetic Acid 8-(3,4-Dimethoxyphenyl)naph-
tho[2,3-d][1,3]dioxol-6-yl Ester (3ae)
Yield: 93% (226 mg); colorless liquid.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C29H27O7: 487.1757; found:
487.1762.
1H NMR (400 MHz, CDCl3):  = 7.36 (d, J = 2.0 Hz, 1 H), 7.17 (s, 1 H),
7.10 (s, 1 H), 6.70 (d, J = 2.4 Hz, 1 H), 6.97–6.95 (m, 3 H), 6.91 (d, J =
1.6 Hz, 1 H), 6.84 (d, J = 1.6, 7.6 Hz, 1 H), 6.80 (d, J = 7.6 Hz, 1 H), 6.00
(s, 2 H), 5.96 (s, 2 H), 3.95 (s, 3 H), 3.89 (s, 3 H), 3.80 (s, 2 H).
(3,4-Dimethoxyphenyl)acetic Acid 2,3-Dimethoxy-7H-benzo[c]-
13C{1H} NMR (100 MHz, CDCl3):  = 170.3, 148.7, 148.5, 148.0, 147.9,
147.8, 146.9, 146.8, 140.7, 132.8, 131.4, 127.0, 126.9, 122.5, 122.0,
119.9, 117.3, 113.0, 111.0, 109.7, 108.4, 103.9, 102.5, 101.2, 101.1,
55.9 (2×), 41.0.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C28H23O8: 487.1393; found:
487.1396.
fluoren-6-yl Ester (3ab)
Yield: 72% (169 mg); colorless solid; mp 164–166 °C (recrystallized
from hexanes and EtOAc).
1H NMR (400 MHz, CDCl3):  = 8.20 (d, J = 8.4 Hz, 1 H), 7.94 (s, 1 H),
7.54 (d, J = 7.6 Hz, 1 H), 7.47 (t, J = 7.6 Hz, 1 H), 7.40 (s, 1 H), 7.33 (t, J =
7.6 Hz, 1 H), 7.16 (s, 1 H), 7.04–7.02 (m, 2 H), 6.92 (d, J = 8.8 Hz, 1 H),
4.12 (s, 3 H), 4.00 (s, 3 H), 3.94 (s, 3 H), 3.93 (s, 3 H), 3.91 (s, 2 H), 3.69
(s, 2 H).
13C{1H} NMR (100 MHz, CDCl3):  = 170.1, 149.7, 149.12, 149.08,
148.5, 144.4, 143.8, 142.3, 137.4, 133.3, 130.1, 126.8, 126.1, 125.8,
125.0, 123.4, 122.3, 121.7, 116.9, 112.5, 111.4, 107.3, 102.9, 56.0 (2×),
55.9, 55.8, 41.2, 34.5.
(3,4-Dipropoxyphenyl)acetic Acid 4-(3,4-Dimethoxyphenyl)-6,7-
dipropoxynaphthalen-2-yl Ester (3af)
Yield: 90% (284 mg); colorless liquid.
1H NMR (400 MHz, CDCl3):  = 7.34 (d, J = 2.4 Hz, 1 H), 7.20 (s, 1 H),
7.09 (s, 1 H), 7.04–6.96 (m, 5 H), 6.92 (dd, J = 2.0, 8.0 Hz, 1 H), 6.87 (d,
J = 8.4 Hz, 1 H), 4.07 (t, J = 6.4 Hz, 2 H), 3.99 (t, J = 6.4 Hz, 4 H), 3.96 (s,
3 H), 3.88 (s, 3 H), 3.85 (t, J = 6.4 Hz, 2 H), 3.81 (s, 2 H), 1.94–1.81 (m,
8 H), 1.10–0.99 (m, 12 H).
13C{1H} NMR (100 MHz, CDCl3):  = 170.6, 149.9, 149.20, 149.19,
148.6, 148.5, 148.4, 146.7, 140.0, 133.0, 130.2, 126.1, 125.5, 122.0,
121.7, 119.5, 116.4, 115.0, 114.0, 113.0, 111.1, 107.9, 106.6, 70.81,
70.77, 70.3, 70.2, 55.94, 55.93, 41.0, 22.6 (2×), 22.4, 22.3, 10.5 (4×).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C29H27O6: 471.1808; found:
471.1813.
Single-crystal X-ray structure: Crystals of compound 3ab were grown
by slow diffusion of EtOAc into a solution of compound 3ab in CH2Cl2
to yield colorless prisms. The compound crystallizes in the monoclinic
crystal system, space group C 2/c, a = 23.7585(9) Å, b = 15.1466(6) Å,
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–L

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M.-Y. Chang et al.
Paper
Synthesis
HRMS (ESI-TOF): m/z [M + H]+ calcd for C38H47O8: 631.3271; found:
631.3278.
1H NMR (400 MHz, CDCl3):  = 7.15 (s, 1 H), 7.04 (d, J = 2.4 Hz, 1 H),
7.00 (s, 1 H), 6.96–6.95 (m, 1 H), 6.93–6.92 (m, 2 H), 6.88 (d, J = 2.4 Hz,
1 H), 6.04 (s, 2 H), 5.20 (br s, 1 H), 3.98 (s, 3 H), 3.81 (s, 3 H).
13C{1H} NMR (100 MHz, CDCl3):  = 151.9, 149.9, 147.7, 147.6, 146.9,
140.3, 134.5, 131.1, 123.0, 122.4, 116.6, 110.1, 108.4, 108.3, 105.5,
105.1, 101.1, 55.8, 55.7.
(3,4,5-Trimethoxyphenyl)acetic Acid 4-(3,4-Dimethoxyphenyl)-
5,6,7-trimethoxynaphthalen-2-yl Ester (3ag)
Yield: 94% (272 mg); colorless liquid.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C19H17O5: 325.1076; found:
325.1072.
1H NMR (400 MHz, CDCl3):  = 7.40 (d, J = 2.4 Hz, 1 H), 6.95 (s, 1 H),
6.92–6.86 (m, 3 H), 6.91 (s, 1 H), 6.61 (s, 2 H), 3.95 (s, 3 H), 3.92 (s,
3 H), 3.87 (s, 3 H), 3.86 (s, 6 H), 3.85 (s, 3 H), 3.84 (s, 3 H), 3.81 (s, 3 H),
3.29 (s, 2 H).
4-Furan-2-yl-6,7-dimethoxynaphthalen-2-ol (3v-1)
13C{1H} NMR (100 MHz, CDCl3):  = 170.0, 153.3, 153.2 (3×), 149.7,
147.5, 147.2, 147.0, 142.1, 139.8, 137.2, 136.1, 132.3, 128.8, 121.9,
120.6, 117.0, 112.8, 109.7, 106.3 (2×), 102.9, 61.0, 60.73, 60.70, 56.0
(2×), 55.81, 55.77, 55.7, 41.5.
Yield: 85% (115 mg); colorless liquid.
1H NMR (400 MHz, CDCl3):  = 7.68 (s, 1 H), 7.60 (d, J = 1.2 Hz, 1 H),
7.22 (d, J = 2.4 Hz, 1 H), 7.06 (d, J = 2.4 Hz, 1 H), 7.00 (s, 1 H), 6.71 (d,
J = 3.2 Hz, 1 H), 6.58 (dd, J = 1.6, 3.2 Hz, 1 H), 5.00 (br s, 1 H), 3.99 (s,
3 H), 3.96 (s, 3 H).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C32H35O10: 579.2230; found:
579.2236.
13C{1H} NMR (100 MHz, CDCl3):  = 153.3, 151.8, 150.0, 148.2, 142.3,
131.4, 128.8, 121.2, 115.3, 111.4, 109.7, 108.9, 105.6, 104.8, 55.78,
55.75.
Synthesis of 3h-1, 3k-1, 3o-1, 3v-1 and 3w-1; General Procedure
HRMS (ESI-TOF): m/z [M + H]+ calcd for C16H15O4: 271.0970; found:
271.0964.
Trifluoroacetic anhydride (TFAA, 230 mg, 1.1 mmol) and phosphoric
acid (H3PO4, 110 mg, 1.1 mmol) were added to a solution of homover-
atric acid (1a, 98 mg, 0.5 mmol) in MeCN (15 mL) at 25 °C. The reac-
tion mixture was stirred at 25 °C for 30 min. Ketone 2h, 2k, 2o, 2v or
2w (0.5 mmol) in MeCN (5 mL) was added to the reaction mixture at
25 °C and the reaction mixture was stirred at reflux (80 °C) for 20 h.
The solvent of reaction mixture was concentrated, the residue was di-
luted with water (10 mL) and the mixture was extracted with CH2Cl2
(3 × 20 mL). The combined organic layers were washed with brine,
dried, filtered and evaporated to afford crude product under reduced
pressure. Purification on silica gel (hexanes/EtOAc = 10:1 to 1:1) af-
forded compounds 3h-1, 3k-1, 3o-1, 3v-1 and 3w-1.
4-(3-Bromothiophen-2-yl)-6,7-dimethoxynaphthalen-2-ol (3w-1)
Yield: 86% (157 mg); colorless liquid.
1H NMR (400 MHz, CDCl3):  = 7.40 (d, J = 5.2 Hz, 1 H), 7.14 (d, J =
2.8 Hz, 1 H), 7.12 (d, J = 5.2 Hz, 1 H), 7.02 (d, J = 2.8 Hz, 1 H), 7.00 (s,
1 H), 6.96 (s, 1 H), 5.60 (br s, 1 H), 3.97 (s, 3 H), 3.84 (s, 3 H).
13C{1H} NMR (100 MHz, CDCl3):  = 151.6, 150.1, 148.1, 136.5, 130.8,
130.6, 130.3, 126.2, 122.8, 118.8, 110.52, 110.49, 105.5, 105.3, 55.81,
55.75.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C16H14BrO3S: 364.9847;
found: 364.9853.
6,7-Dimethoxy[1,2′]binaphthalenyl-3-ol (3h-1)
Yield: 94% (155 mg); colorless liquid.
1H NMR (400 MHz, CDCl3):  = 7.94–7.90 (m, 3 H), 7.85–7.82 (m, 1 H),
7.60 (dd, J = 1.2, 8.4 Hz, 1 H), 7.56–7.51 (m, 2 H), 7.18 (s, 1 H), 7.12 (d,
J = 2.4 Hz, 1 H), 7.03 (d, J = 2.4 Hz, 1 H), 7.03 (s, 1 H), 5.99 (br s, 1 H),
3.97 (s, 3 H), 3.73 (s, 3 H).
13C{1H} NMR (100 MHz, CDCl3):  = 152.0, 149.8, 147.7, 140.5, 138.1,
133.4, 132.5, 131.1, 128.3, 128.0, 127.9, 127.70, 127.66, 126.3, 126.1,
122.3, 117.0, 108.7, 105.6, 105.1, 55.7, 55.6.
Acetic Acid 4-Biphenyl-4-yl-6,7-dimethoxynaphthalen-2-yl Ester
(3g-1)
Trifluoroacetic anhydride (TFAA, 230 mg, 1.1 mmol) and phosphoric
acid (H3PO4, 110 mg, 1.1 mmol) were added to a solution of homover-
atric acid 1a (98 mg, 0.5 mmol) in MeCN (15 mL) at 25 °C. The reac-
tion mixture was stirred at 25 °C for 30 min, then ketone 2g (98 mg,
0.5 mmol) in MeCN (5 mL) was added to the reaction mixture at
25 °C. The reaction mixture was stirred at reflux (80 °C) for 20 h, then
cooled to 25 °C. Ac2O (150 mg, 1.5 mmol) was added and the reaction
mixture was stirred at reflux (80 °C) for 1 h. The solvent of reaction
mixture was concentrated, the residue was diluted with water (10
mL) and the mixture was extracted with CH2Cl2 (3 × 20 mL). The com-
bined organic layers were washed with brine, dried, filtered and
evaporated to afford the crude product under reduced pressure. Puri-
fication on silica gel (hexanes/EtOAc = 10:1 to 1:1) afforded com-
pound 3g-1.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C22H19O3: 331.1334; found:
331.1339.
4-(2,5-Dimethoxyphenyl)-6,7-dimethoxynaphthalen-2-ol (3k-1)
Yield: 89% (151 mg); colorless liquid.
1H NMR (400 MHz, CDCl3):  = 6.98 (d, J = 2.8 Hz, 1 H), 6.96–6.93 (m,
3 H), 6.90 (d, J = 2.8 Hz, 1 H), 6.88 (dd, J = 1.2, 2.8 Hz, 1 H), 6.82 (s,
1 H), 4.80 (br s, 1 H), 3.94 (s, 3 H), 3.79 (s, 3 H), 3.75 (s, 3 H), 3.65 (s,
3 H).
13C{1H} NMR (100 MHz, CDCl3):  = 153.5, 151.9, 151.1, 149.8, 147.5,
137.1, 130.6, 130.2, 122.6, 117.2, 117.0, 113.9, 112.4, 108.8, 105.43,
105.39, 56.2, 55.73, 55.69, 55.6.
Yield: 82% (163 mg); colorless solid; mp 166–168 °C (recrystallized
from hexanes and EtOAc).
1H NMR (400 MHz, CDCl3):  = 7.75–7.69 (m, 4 H), 7.60 (d, J = 8.0 Hz,
2 H), 7.51–7.47 (m, 2 H), 7.45 (d, J = 2.4 Hz, 1 H), 7.41–7.37 (m, 1 H),
7.28 (s, 1 H), 7.15 (s, 1 H), 7.09 (d, J = 2.4 Hz, 1 H), 4.02 (s, 3 H), 3.83 (s,
3 H), 2.36 (s, 3 H).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C20H21O5: 341.1389; found:
341.1396.
13C{1H} NMR (100 MHz, CDCl3):  = 169.8, 150.0, 149.4, 146.8, 140.6,
140.3, 140.0, 139.2, 130.3, 130.1 (2×), 128.9 (2×), 127.4, 127.1 (2×),
127.1 (2×), 125.3, 120.1, 116.9, 106.5, 104.8, 55.9, 55.8, 21.2.
4-Benzo[1,3]dioxol-5-yl-6,7-dimethoxynaphthalen-2-ol (3o-1)
Yield: 90% (146 mg); colorless liquid.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–L

K
M.-Y. Chang et al.
Paper
Synthesis
HRMS (ESI-TOF): m/z [M + H]+ calcd for C26H23O4: 399.1596; found:
HRMS (ESI-TOF): m/z [M + H]+ calcd for C20H21O6: 357.1338; found:
399.1598.
357.1345.
Single-crystal X-ray structure: Crystals of compound 3g-1 were
grown by slow diffusion of EtOAc into a solution of compound 3g-1 in
CH2Cl2 to yield colorless prisms. The compound crystallizes in the
monoclinic crystal system, space group P 21/n, a = 14.6778(7) Å, b =
Single-crystal X-ray structure: Crystals of compound 4 were grown by
slow diffusion of EtOAc into a solution of compound 4 in CH2Cl2 to
yield colorless prisms. The compound crystallizes in the monoclinic
crystal system, space group P21/c,
a
=
14.7513(11) Å,
b
=
=
9.3020(5) Å, c = 14.7948(8) Å, V = 2015.60(18) Å3, Z = 4, dcalcd
=
15.0932(10) Å, c = 7.8241(5) Å, V = 1702.9(2) Å3, Z = 4, dcalcd
1.313 g/cm3, F(000) = 840, 2θ range 1.893–26.428°, R indices (all data)
1.390 g/cm3, F(000) = 752, 2θ range 1.412–26.445°, R indices (all data)
R1 = 0.0438, wR2 = 0.0921; CCDC 1910999.12
R1 = 0.0608, wR2 = 0.1163; CCDC 1911000.12
Benzo[1,3]dioxol-5-yl-acetic Acid 4-(2,5-Dimethoxyphenyl)-6,7-
dimethoxynaphthalen-2-yl Ester (3aj)
Funding Information
Trifluoroacetic anhydride (TFAA, 230 mg, 1.1 mmol) and phosphoric
acid (H3PO4, 110 mg, 1.1 mmol) were added to a solution of homover-
atric acid 1a (98 mg, 0.5 mmol) in MeCN (15 mL) at 25 °C. The reac-
tion mixture was stirred at 25 °C for 30 min, then ketone 2k (90 mg,
0.5 mmol) in MeCN (5 mL) was added to the reaction mixture at
25 °C. The reaction mixture was stirred at reflux (80 °C) for 20 h, then
cooled to 25 °C. Compound 1b (90 mg, 0.5 mmol) was added and the
reaction mixture was stirred at reflux (80 °C) for 1 h. The solvent of
reaction mixture was concentrated, the residue was diluted with wa-
ter (10 mL) and the mixture was extracted with CH2Cl2 (3 × 20 mL).
The combined organic layers were washed with brine, dried, filtered
and evaporated to afford crude product under reduced pressure. Puri-
fication on silica gel (hexanes/EtOAc = 10:1 to 1:1) afforded com-
pound 3aj.
The authors would like to thank the Ministry of Science and Technol-
ogy of the Republic of China for its financial support (MOST 106-
2628-M-037-001-MY3).
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690799. Included are scanned cop-
ies of NMR spectral data for all compounds and X-ray analysis data of
3t, 3ab, 3g-1 and 4.
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References
Yield: 71% (178 mg); colorless liquid.
(1) For reviews on the synthesis of naphthalenes, see: (a) de
Koning, C. B.; Rousseau, A. L.; van Otterlo, W. A. L. Tetrahedron
2003, 59, 7. (b) For reviews on the benzannulation of naphtha-
lenes, see: Kotha, S.; Somnath-Halder, S. M. Tetrahedron 2008,
64, 10775.
1H NMR (400 MHz, CDCl3):  = 7.43 (d, J = 2.4 Hz, 1 H), 7.09 (s, 1 H),
7.00 (d, J = 2.4 Hz, 1 H), 6.96 (s, 1 H), 6.95 (d, J = 2.4 Hz, 1 H), 6.91 (d,
J = 1.6 Hz, 1 H), 6.89 (dd, J = 1.2, 2.4 Hz, 1 H), 6.86 (s, 1 H), 6.84 (d, J =
1.6 Hz, 1 H), 6.80 (d, J = 8.0 Hz, 1 H), 5.96 (s, 2 H), 3.98 (s, 3 H), 3.78 (s,
2 H), 3.79 (s, 3 H), 3.77 (s, 3 H), 3.64 (s, 3 H).
(2) For bioactive molecules with the core naphthalene skeleton,
see: (a) Ukita, T.; Nakamura, Y.; Kubo, A.; Yamomoto, Y.;
Takahashi, M.; Kotera, J.; Ikeo, T. J. Med. Chem. 1999, 42, 1293.
(b) Yeo, H.; Li, Y.; Fu, L.; Zhu, J.-L.; Gullen, E. A.; Dutschman, G.
E.; Lee, Y.; Chung, R.; Huang, E.-S.; Austin, D. J.; Cheng, Y.-C.
J. Med. Chem. 2005, 48, 534. (c) Shen, W.; Zou, X.; Chen, M.; Liu,
P.; Shen, Y.; Huang, S.; Guo, H.; Zhang, L. Eur. J. Pharmacol. 2011,
667, 330. (d) Aszno, J.; Chiba, K.; Tada, M.; Yoshii, T. Phytochem-
istry 1996, 42, 713.
(3) For natural products with the core naphthalene skeleton, see:
(a) Ward, R. S. Nat. Prod. Rep. 1999, 16, 75. (b) Apers, S.;
Vlietinck, A.; Pieters, L. Phytochem. Rev. 2003, 2, 201.
(c) Abdissa, N.; Pan, F.; Gruhonjic, A.; Grafenstein, J.; Fitzpatrick,
P. A.; Landberg, G.; Rissanen, K.; Yenesew, A.; Erdelyi, M. J. Nat.
Prod. 2016, 79, 2181.
13C{1H} NMR (100 MHz, CDCl3):  = 170.2, 153.6, 151.2, 149.8, 149.1,
147.8, 146.9, 146.7, 137.0, 129.7, 129.6, 127.1, 125.8, 122.5, 120.1,
117.2, 116.8, 114.2, 112.4, 109.7, 108.4, 106.3, 105.2, 101.0, 56.2,
55.81, 55.77, 55.6, 41.1.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C29H27O8: 503.1706; found:
507.1712.
1-(3,4-Dimethoxybenzylidene)-6,7-dimethoxyisochroman-3-one
(4)
Trifluoroacetic anhydride (TFAA, 230 mg, 1.1 mmol) and phosphoric
acid (H3PO4, 110 mg, 1.1 mmol) were added to a solution of homover-
atric acid (1a, 196 mg, 1.0 mmol) at 25 °C. The reaction mixture was
stirred at 120 °C for 20 h, then cooled to 25 °C. The residue was dilut-
ed with water (10 mL) and the mixture was extracted with CH2Cl2
(3 × 20 mL). The combined organic layers were washed with brine,
dried, filtered and evaporated to afford crude product under reduced
pressure. Purification on silica gel (hexanes/EtOAc = 10:1 to 1:1) af-
forded compound 4.
(4) For synthetic blocks or ligands with core naphthalene skeleton,
see: (a) Ji, N.; Rosen, B. M.; Myers, A. G. Org. Lett. 2004, 6, 4551.
(b) Mulrooney, C. A.; Li, X.; Divirgilio, E. S.; Kozlowski, M. C.
J. Am. Chem. Soc. 2003, 125, 6856.
(5) For functionalized materials with the core naphthalene skele-
ton, see: (a) Lin, K.-T.; Kuo, H.-M.; Sheu, H.-S.; Lai, C.-K. Tetrahe-
dron 2013, 69, 9045. (b) Tanaka, M.; Elias, B.; Barton, J. K. J. Org.
Chem. 2010, 75, 2423. (c) Thalacker, C.; Röger, C.; Würthner, F.
J. Org. Chem. 2006, 71, 8098. (d) Rodriguez, J. G.; Tejedor, J. L.
J. Org. Chem. 2002, 67, 7631. (e) Chowdhury, S.; Georghiou, P. E.
J. Org. Chem. 2002, 67, 6808. (f) Röger, C.; Würthner, F. J. Org.
Chem. 2007, 72, 8070.
Yield: 68% (121 mg); colorless solid; mp 159–160 °C (recrystallized
from hexanes and EtOAc).
1H NMR (400 MHz, CDCl3):  = 7.49 (d, J = 2.0 Hz, 1 H), 7.30 (dd, J = 2.0,
8.4 Hz, 1 H), 7.05 (s, 1 H), 6.88 (d, J = 8.4 Hz, 1 H), 6.61 (s, 1 H), 6.12 (s,
1 H), 3.96 (s, 3 H), 3.95 (s, 3 H), 3.911 (s, 3 H), 3.908 (s, 3 H), 3.81 (s,
2 H).
13C{1H} NMR (100 MHz, CDCl3):  = 165.6, 150.3, 148.8, 148.7, 148.5,
145.4, 127.0, 122.7, 121.0, 120.8, 112.3, 111.0, 109.5, 107.8, 106.4,
56.2, 56.1, 55.8 (2×), 34.5.
(6) For transition-metal-catalyzed tandem benzannulation, see:
(a) Tsukamoto, H.; Kondo, Y. Org. Lett. 2007, 9, 4227. (b) Dai, Y.;
Feng, X.; Liu, H.; Jiang, H.; Bao, M. J. Org. Chem. 2011, 76, 10068.
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L
M.-Y. Chang et al.
Paper
Synthesis
(c) Aiken, S.; Armitage, B.; Gabbutt, C. D.; Heron, B. K. Tetrahe-
dron Lett. 2015, 4840. (d) Collomb, D.; Chantegrel, B.; Deshayes,
C. Tetrahedron 1996, 52, 10455. (e) Jin, T.; Yamamoto, Y. Org.
Lett. 2007, 9, 5259.
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S.; Jiang, P.; Wang, Y.; Luo, S.; Wang, Q. Chem. Commun. 2015,
51, 1297. (e) Peng, C.; Zhang, J.; Xue, J.; Li, S.; Wang, N. A.;
Chang, J. J. Org. Chem. 2018, 83, 9256. (f) Okuma, K.; Itoyama, R.;
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(10) Chang, M.-Y.; Chen, Y.-C.; Chan, C.-K.; Huang, G. G. Tetrahedron
2015, 71, 2095.
(7) For electrophilic or nucleophilic cyclocondensation, see:
(a) Zhang, X.; Sarkar, S.; Larock, R. C. J. Org. Chem. 2006, 71, 236.
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(8) For photo-promoted annulation, see: Padwa, A.; Chiacchio, U.;
Fairfax, D. J.; Kassir, J. M.; Litrico, A.; Semones, M. A.; Xu, S. L.
J. Org. Chem. 1993, 58, 6429.
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(a) Kim, H. Y.; Oh, K. Org. Lett. 2014, 16, 5934. (b) Chen, Z.;
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(12) CCDC 1910997 (3t), 1910998 (3ab), 1910999 (3g-1) and
1911000 (4) contain the supplementary crystallographic
data for this paper. The data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/getstructures.
(13) Marchal, E.; Uriac, P.; Legouin, B.; Toupet, L.; van de Weghe, P.
Tetrahedron 2007, 63, 9979.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–L