Trifluoroacetic Anhydride Mediated One-Pot Synthesis of 1-Aryl Isochroman-3-ones via the Carboxy-Pictet-Spengler Reaction

Article abstract of DOI:10.1021/acs.joc.9b01605

In this paper, a novel and open-vessel route for the facile-operational synthesis of 1-aryl isochroman-3-ones is described via (CF₃CO)₂O (trifluoroacetic anhydride, TFAA)-mediated intermolecular (4 + 2) annulation of oxygenated arylacetic acids with arylaldehydes or ketones under mild reaction conditions. A plausible mechanism is proposed and discussed herein. Various reaction conditions are investigated for efficient transformation under an environmentally friendly one-pot carboxy-Pictet-Spengler reaction.

Full text of DOI:10.1021/acs.joc.9b01605

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Article
Trifluoroacetic Anhydride-Mediated One-Pot Synthesis of 1-Aryl
Isochroman-3-ones via the Carboxy-Pictet-Spengler Reaction
Meng-Yang Chang, Shin-Mei Chen, and Yu-Ting Hsiao
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01605 • Publication Date (Web): 29 Aug 2019
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Trifluoroacetic Anhydride-Mediated One-Pot Synthesis of 1-Aryl
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Isochroman-3-ones via the Carboxy-Pictet-Spengler Reaction
Meng-Yang Chang,*a,b Shin-Mei Chena and Yu-Ting Hsiaoa
aDepartment of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan bDepartment of
Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
*Email: mychang@kmu.edu.tw
Supporting Information Placeholder
O
O
(CF CO) O
O
3
2
(MeO)
Ar
Ar'
> 50 examples
2 CF CO H
+
n
+
O
3
2
(MeO)
Ar
n
Ar'
H / R
OH
MeCN
H / R
one-pot synthesis
easy-operational
mild condition
open-vessel
high yields
environmentally friendly
inexpensive reagents
ABSTRACT: In this paper, a novel and open-vessel route for the facile-operational synthesis of 1-aryl isochroman-3-ones is de-
scribed via (CF3CO)2O (trifluoroacetic anhydride, TFAA)-mediated intermolecular (4+2) annulation of oxygenated arylacetic acids
with arylaldehydes or ketones under mild reaction conditions. A plausible mechanism is proposed and discussed herein. Various
reaction conditions are investigated for efficient transformation under an environmentally friendly one-pot carboxy-Pictet-Spengler
reaction.
Introduction
Among these synthetic variations towards heteroatom-
Pictet-Spengler type reactions, to the best of our knowledge,
only a few early examples on the generation of 1-substituted
isochromans via the synthetic route have been reported.16-18 On
the basis of the above recorded observations for Pictet-
Spengler type reactions and the ongoing effort to emphasize
the synthesis of oxygen-containing benzocycles,19-23 herein,
we present an efficient, one-step synthetic route towards 1-aryl
isochroman-3-ones 3 via a carboxy-Pictet-Spengler reaction of
oxygenated arylacetic acids 1 with arylaldehydes or ketones 2
in the presence of inexpensive commercially available
(CF3CO)2O (trifluoroacetic anhydride, TFAA) via intermolec-
ular (4+2) annulation. In equation 2, only 2 equivalents of
trifluoroacetic acid (TFA, a byproduct) are generated from the
hydrolysis of TFAA with the in situ-formed H2O. This is im-
portant from a facile-operational point of view because a
TFAA-mediated reaction possesses excellent selectivity and
activity, and it produces high-yield products.24-25
The Pictet-Spengler reaction is an important tool for prepar-
ing isoquinoline and β-carboline derivatives via
cyclocondensation of β-arylethylamines with carbonyl com-
pounds.1 On the basis of the Pictet-Spengler type reactions
(Scheme 1, eq 1, X = NH), many review articles have docu-
mented synthetic applications for diversified natural products,
bioactive molecules, functionalized materials and synthetic
blocks.2-4 After ca. ninety years, an oxa-Pictet-Spengler reac-
tion (X = O) was developed by Wunsch and Zott to construct
the core skeleton of substituted isochroman with modest to
good yields by the combination of ZnCl2, pTsOH and HCl(g) or
Lewis acid (e.g., TiCl4, AlCl3, and SnCl2)-mediated intermo-
lecular annulation of 2-arylethanol with aldehydes or ke-
tones.5-12 In recent years, the evaluated scope has been extend-
ed to a thia-Pictet-Spengler reaction (X = S) in the formation
of a thiaisochroman skeleton.13-15 Overall, the facile intermo-
lecular annulation of 2-arylethyl amines, alcohols and thiols
with a variety of carbonyl synthons has seen growing interest
with Brønsted acids or Lewis acids-promoted routes.
For preparation of the skeleton of 1-substituted isochroman,
many efforts using synthetic routes have also been well-
documented.26-32 Regarding the installation of 1-substituent
into a key core skeleton of 1-substituted isochroman, the syn-
thetic route has long held a respected position in a number of
reports in the synthetic and pharmaceutic fields due to its spe-
cific chemoselectivity and diversified bioactivity.33-37 These
major significant efforts focus on transition metal (e.g., Mn4+,
Cu2+, and Fe3+)-catalysed or oxidant (e.g., DDQ, PIFA, and
TBHP)-mediated C(sp3)-H bond functionization of
isochromans with activated carbon nucleophiles (e.g., ketones,
Scheme 1. Heteroatom-Pictet-Spengler Type Reactions
O
acids
Ar
Ar
H O
(eq 1)
+
+
2
XH
X
Ar'
solvents
X = NH, O, S
Ar'
O
O
(CF CO) O
O
3
2
Ar
+
2 CF CO H (eq 2)
Ar
+
3
2
O
R
Ar'
R
OH
MeCN
Ar'
1
2
3
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β-dicarbonyls, and oxygenated arenes) under a direct cross-
dehydrogenative-coupling (CDC) procedure.
and Tf2O, however, neither of them obtained higher yields of
3a. In entry 10, only a 10% yield of 3a was isolated along with
the recovered amount (35%) of 1a since the reactivity of Ac2O
was lower than TFAA. Tf2O might possess a higher reactivity
than TFAA such that a low yield (25%) of 3a was obtained
(entry 11). Subsequently, three Brønsted acids, AcOH, TFA,
and TfOH, were studied. However, trace amounts (<5%) of 3a
were provided for AcOH (entry 12). For TFA and TfOH, no
better yields of 3a were observed than for TFAA (entries 13-
14). These results from acid-mediated reactions were similar
to those for anhydride. Finally, catalytic amounts of TFAA
were tested. The amounts of TFAA were decreased to 0.5
equivalent, and a lower yield (52%) was provided (entry 15).
From these observations, we concluded that entry 5 provided
optimal conditions for the formation of 3a (90%) via an
intramolecular annulation of 1a with 2a. Generally, we found
that conditions of TFAA (1.0 equiv), MeCN (10 mL), and
Results and discussion
The initial study commenced with the treatment of model
substrate 1a (Ar = 3,4-(MeO)2C6H3; Ar’ = Ph, 1.0 mmol) with
benzaldehyde (2a, 1.0 equiv). First, by the addition of TFAA
(1.0 equiv), 3a was obtained in an 80% yield in MeCN (10 mL)
o
9
at 25 C for 5 h via intramolecular annulation (Table 1, entry
1). With these results in mind, the optimal annulation condi-
tion was examined next. Controlling TFAA as the promoter,
we surveyed the factors of solvent, time and reaction tempera-
ture on the ring-closure process. However, a lower yield (63%)
of 3a was observed for MeNO2 (entry 2), and THF provided a
low yield (28%) along with other major complex mixtures
(entry 3).
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Table 1. Reaction Conditionsa
o
reaction time of 10 h at room temperature (25 C) efficiently
3
MeO
O
O
MeO
MeO
O
promoters
conditions
+
obtained higher yields of 3a.
OH
Ph
O
4
MeO
Ph
Scheme 2. Plausible Mechanism
1a
2a
3a
MeO
O
MeO
MeO
O
O
TFAA
time (h) temp (oC) 3a (%)b
+
entry promoters solvent
OH
O
O
Ph
MeO
O
H
CF
1
2
TFAA
TFAA
TFAA
TFAA
TFAA
TFAA
TFAA
TFAA
TFAA
Ac2O
MeCN
MeNO2
THF
5
5
25
25
25
25
25
25
25
50
82
25
25
25
25
25
25
80
63
3
1a
2a
2a Ph
A
3
5
28c
MeO
MeO
O
MeO
MeO
O
MeO
MeO
O
O
O
4
CH2Cl2
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
5
70
O
H
TFA
+
Ph
Ph
3a
Ph
5
10
20
40
10
10
5
90
C
B
6
87
On the basis of our experimental results, a plausible mecha-
nism for the formation of 3a is illustrated in Scheme 2. Initial-
ly, coupling 1a with TFAA yields A via intermolecular acyla-
tion. With the involvement of 2a, carbonyl-mediated acylation
of A leads to B and TFA. Following the Pictet-Spengler type
annulation, an oxygenated group on the benzene ring promot-
ed the intramolecular ring-closure of B generating C. Finally,
after dehydrogenative aromatization, 3a could be formed
spontaneously.
7
88
8
78
9
69
10
11
12
13
14
15
10d
25c
<5e
72
Tf2O
5
AcOH
TFA
5
5
18c
To investigate the substrate scope and limitations of this
one-pot approach, homoveratric acid 1a and its derivatives of
1b-1e were reacted with substituted arylbenzaldehydes 2a-2an
to afford diversified 1-aryl isochroman-3-ones 3a-3ai in the
presence of TFAA, as shown in Table 2. With optimal condi-
tions established (Table 1, entry 5) and a plausible mechanism
proposed (Scheme 2), we found that this route allowed a direct
one-pot reduction under mild conditions in the range of mod-
erate to good yields (52%-94%). Among entries 1-16, efficient
formations of 3a-3p showed that the Ar’ group with mono-
substituent halogen, oxygenated groups, nitro group, etc. did
not affect the isolated yields. In entries 17-18, bicyclic 2-
naphthyl and tricyclic 9-anthryl groups provided 3q and 3r in
87% and 72% yields, respectively. For the Ar’ group with di-
substituent halogen and oxygenated groups, entries 19-24
showed that yields of 3s-3x were provided in a range of 72%-
89%. The tri-substituted oxygenated Ar’ group produced 3y
and 3z at good yields (86% and 85%, entries 25 and 26, re-
TfOH
TFAAf
5
5
52
aReactions were run on a 1.0 mmol scale with 1a, 2a (106 mg,
1.0 equiv), solvent (10 mL), and promoter (1.0 equiv).
bIsolated yields. cMajor complex mixture was isolated. d2a
(35%) was recovered. eMajor 1a was isolated. f0.5 equivalent.
By changing the solvent to CH2Cl2, a better yield of 3a was
obtained in 70% (entry 4). To increase the yield, elongated
times (10, 20 and 40 h) were investigated. In entries 5-7, the
three reaction times provided yields of nearly 90%, 87% and
88%, respectively, under TFAA/MeCN conditions. From the
results, we found that longer reaction times (20 or 40 h) did
not enhance the yield. Furthermore, reaction temperature
o
screening (50 and 82 C) was performed. By elevating the
temperature to 50 oC, a 78% yield of 3a was isolated (entry 8),
but when the reaction was treated at a reflux temperature (82
oC), the yield of 3a was decreased to 69% (entry 9). It is obvi-
ous that the reaction was highly temperature-dependent with
higher yields obtained at 25 oC. On the basis of the abovemen-
tioned experimental data, different anhydrides were investi-
gated next. After changing the promoters from TFAA to Ac2O
spectively).
By
changing
1a
to
2,3-
dioxymethylenephenylacetic acid (1b), 3aa-3ad were obtained
in similar yields (83%-88%, entries 27-30). After elongating
the carbon chain from methoxy to propoxy on the Ar’ group
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(for 1c), however, the yield of 3ae was decreased to 65% (en-
Then, 2ab with a heterocyclic 2-thienyl group provided 3ai
2
try 31), and 2,3-dimethoxyphenylacetic acid (1d) provided 3af
in an 80% yield (entry 32). For 1e with the trimethoxy Ar’
group, 3ag was afforded in a 78% yield (entry 33). Further-
more, when the treatment of 1a was reacted with 1,4-
diformylbenzene (2aa), 3ah with a 1,4-benzo conjugated bis-
isochroman-3-one was isolated in a 72% yield. This was a
facile route to obtain the dimeric isochroman-3-one skeleton.
in a fairly low yield (60%). However, for treatment of 1a with
furfural, no desired product was isolated, and only a complex
unknown mixture was detected due to the low aromaticity of
the furan ring. For the treatment of 1a with 3- or 4-
picolinaldehydes, no reactions were observed. A possible rea-
son could be that the lone-pair of nitrogen atoms trapped the
TFAA such that the reaction could not be initiated. To obtain
the desired 1-pyridyl isochroman-3-one, excess amounts of
TFAA (2.0 or 3.0 equivs) were added to compensate for the
potential nitrogen-trapped intermediate. However, attempts to
increase additional equivalents of TFAA failed, and only 1a
was recovered. From these results, we understood that the
electronic nature of aryl substituent (Ar’) of 2 was appropriate
for different electron-neutral, electron-donating and electron-
withdrawing groups. The molecular structures of 3j, 3p, 3s, 3z,
3af and 3ag were determined by single-crystal X-ray crystal-
lography.38
3
4
5
6
7
8
9
Table 2. Synthesis of 3a-3aia
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2
O
O
O
TFAA
MeCN
3
4
Ar
Ar
+
O
Ar'
H
OH
5
Ar'
H
1a-1e
2a-2an
3a-3ai
entry 1a, Ar =
2, Ar’ =, R =
3 (%)b
3a, 90
3b, 94
3c, 83
3d, 82
3e, 60
3f, 83
3g, 82
3h, 93
3i, 87
3j, 90
3k, 84
3l, 90
3m, 90
3n, 84
3o, 52
3p, 87
3q, 87
3r, 72
3s, 80
3t, 80
3u, 78
3v, 73
1
2
3
4
5
6
7
8
9
1a, 3,4-(MeO)2C6H3 2a, Ph, H
1a, 3,4-(MeO)2C6H3 2b, 2-FC6H4, H
1a, 3,4-(MeO)2C6H3 2c, 4-BrC6H4, H
Table 3. Synthesis of 3aj-3aza
1a, 3,4-(MeO)2C6H3 2d, 2-HOC6H4, H
MeO
MeO
O
1a, 3,4-(MeO)2C6H3 2e, 2-NO2C6H4, H
1a, 3,4-(MeO)2C6H3 2f, 3-MeOC6H4, H
1a, 3,4-(MeO)2C6H3 2g, 3-NO2C6H4, H
1a, 3,4-(MeO)2C6H3 2h, 4-MeC6H4, H
1a, 3,4-(MeO)2C6H3 2i, 4-ClC6H4, H
O
MeO
O
TFAA
MeCN
+
O
R
Ar'
R
OH
MeO
Ar'
1a
2ac-2as
3aj-3az
entry 2, Ar =
3 (%)b
1
2
3
4
5
6
7
8
9
2ac, Ph, Me
3aj, 74
3ak, 73
3al, 72
3am, 72
3an, 80
3ao, 73
3ap, 74
3aq, 70
3ar, 62
3as, 70
3at, 67
3au, 70
3av, 80
3aw, 66
3ax, 67
3ay, 63
3az, 47
10 1a, 3,4-(MeO)2C6H3 2j, 4-FC6H4, H
11 1a, 3,4-(MeO)2C6H3 2k, 4-CF3C6H4, H
12 1a, 3,4-(MeO)2C6H3 2l, 4-MeOC6H4, H
2ad, 3-MeOC6H4, Me
2ae, 3-FC6H4, Me
2af, 4-ClC6H4, Me
2ag, 4-FC6H4, Me
2ah, 4-MeC6H4, Me
2ai, 4-MeOC6H4, Me
2aj, 4-FC6H4, Me
13 1a, 3,4-(MeO)2C6H3 2m, 4-MeSC6H4, H
14 1a, 3,4-(MeO)2C6H3 2n, 4-NCC6H4, H
15 1a, 3,4-(MeO)2C6H3 2o, 4-NO2C6H4, H
16 1a, 3,4-(MeO)2C6H3 2p, 4-PhC6H4, H
17 1a, 3,4-(MeO)2C6H3 2q, 2-naphthyl, H
18 1a, 3,4-(MeO)2C6H3 2r, 9-anthryl, H
19 1a, 3,4-(MeO)2C6H3 2s, 3,4-Cl2C6H3, H
20 1a, 3,4-(MeO)2C6H3 2t, 3,4-CH2O2C6H3, H
21 1a, 3,4-(MeO)2C6H3 2u, 2-F-6-ClC6H3, H
22 1a, 3,4-(MeO)2C6H3 2v, 3,4-F2C6H 3, H
2ak, 4-NO2C6H4, Me
10 2al, 2-naphthyl, Me
11 2am, 4-PhC6H4, Me
12 2an, 3,4-Cl2C6H4, Me
13 2ao, 5-F-2,4-Cl2C6H2, Me
14 2ap, 3,4,5-(MeO)3C6H2, Me
15 2aq, Ph, nPr
23 1a, 3,4-(MeO)2C6H3 2w, 3,4-(MeO)2C6H3, H 3w, 89
24 1a, 3,4-(MeO)2C6H3 2x, 3-HO-4-MeOC6H3, H 3x, 74
25 1a, 3,4-(MeO)2C6H3 2y, 3,4,5-(MeO)3C6H2, H 3y, 86
26 1a, 3,4-(MeO)2C6H3 2z, 2,3,4-(MeO)3C6H2, H 3z, 85
16 2ar, 4-FC6H4, Bn
17 2as, Ph, Ph
aReactions were run on a 1.0 mmol scale with 1a, 2ac-2as (1.0
equiv), TFAA (210 mg, 1.0 equiv), MeCN (10 mL), 10 h, 25
oC. bIsolated yields.
27 1b, 3,4-CH2O2C6H3 2t, 3,4-CH2O2C6H3, H
3aa, 83
28 1b, 3,4-CH2O2C6H3 2w, 3,4-(MeO)2C6H3, H 3ab, 85
29 1b, 3,4-CH2O2C6H3 2y, 3,4,5-(MeO)3C6H2, H 3ac, 88
30 1b, 3,4-CH2O2C6H3 2z, 2,3,4-(MeO)3C6H2, H 3ad, 84
31 1c, 3,4-nBuO2C6H3 2w, 3,4-(MeO)2C6H3, H 3ae, 65
By using 1a as the carboxy source, different arylketones
2ac-2as were screened next (Table 3). However, controlling
the R as a methyl group (for 2ac-2ap) diversified the Ar’
substituent, so that the electron-neutral, electron-donating and
electron-withdrawing groups were tolerated, and the isolated
yields of 3aj-3aw were distributed in a range of 62%-80%.
When R was adjusted to the propyl and benzyl groups, 3ax
and 3ay were produced in 67% and 63% yields, respectively.
However, after choosing benzophenone (2as) as the carbonyl
synthon, only a 47% yield of 3az was obtained. Compared
with the isolated yields for 3a-3ai and 3aj-3az overall, we
32 1d, 2,3-(MeO)2C6H3 2f, 3-MeOC6H4, H
3af, 80
33 1e, 3,4,5-(MeO)3C6H2 2w, 3,4-(MeO)2C6H3, H 3ag, 78
34 1a, 3,4-(MeO)2C6H3 2aa, 1,4-(CHO)2C6H4, H 3ah, 72
35 1a, 3,4-(MeO)2C6H3 2ab, 2-thienyl, H
3ai, 60
aReactions were run on a 1.0 mmol scale with 1a-1e, 2a-2ab
(1.0 equiv), TFAA (210 mg, 1.0 equiv), MeCN (10 mL), 10 h,
25 oC. bIsolated yields.
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found that arylaldehydes provided better results than
Encouraged by the above experimental results, synthesis of
arylketones due to the slightly higher reactivities of the
carbonyl group’s intermolecular (4+2) annulation. The
structures of 3aj and 3at were determined by single-crystal X-
ray analysis.38
the skeletons of dibenzosuberanone and isochroman were
studied next (Scheme 4). By involvement of Me3SiH/BF3·OEt2,
3w was converted into 5a with an o-benzylphenylacetic acid
skeleton in an 88% yield. By intramolecular Friedel-Crafts
annulation, treatment of 5a with TFAA produced tricyclic 6a
in an 87% yield. Changing Nu from a hydride to cyano group,
5b and 6b were obtained in 89% and 86% yields, respectively,
by similar annulation conditions. After adjusting Nu to an allyl
group, 5c was isolated in an 82% yield. However, attempts to
annulate 5c failed. Only complex unknown products were
detected. The reason could be the competition among the
olefinic moiety, carboxylic acid and the two oxygenated aryl
rings in the presence of TFAA. Herein, we developed a novel,
concise two-step synthetic transformation from a 1-aryl
isochroman-3-one to a dibenzosuberanone skeleton via one
carbon-oxygen bond cleavage and one carbon-carbon bond
formation. By the combination of NaBH4 and BF3·OEt2, a one-
pot conversion from isochroman-3-one to isochroman was
examined. The first reduction of 3w provided BF3-chelated
lactol intermediate I. After the lone-pair of oxygen atoms
promoted the removal of OBF3, NaBH4 mediated a second
reduction of the resulting intermediate II with the
oxocarbenium ion produced 7 in a 90% yield. This was an
efficient transformation for the preparation of an isochroman.
For the combination of BF3·OEt2 and nucleophile (Nu)-
mediated ring opening and addition/reduction, this strategy
was reported by Kishi et al. in the 1980s,39 investigated by
Woerpel,40 and expanded in the area of natural product total
synthesis by Jennings.41
3
4
5
6
7
8
9
In addition to the carboxy-Pictet-Spengler reaction, TFAA
was also a good promoter for O-acylation of carboxylic acids
with phenols. To compare the reactivity, the competitive re-
sults between O-acylation and the carboxy-Pictet-Spengler
reaction were examined (Scheme 3). Using 2 equivalents of
TFAA, the treatment of isovanillin (2x) with 2 equivalents of
phenylacetic acid (1f) afforded 4a in an 83% yield via the O-
acylation process, and no desired 1-aryl isochroman-3-one
skeleton was detected (eq 3). The results showed that TFAA
was a more specific protomer for O-acylation. To understand
the electronic influences of substituents on the aromatic (Ar)
ring, the electron-rich Ar group was examined for the O-
acylation and the carboxy-Pictet-Spengler reaction. When 1f
was displaced as 1b, the reaction of 1b (2 equiv) with 2x
produced 4b in a 73% yield via the intermolecular annulation
and then the O-acylation procedure. From this phenomenon,
we envisioned that the oxygenated group could enrich the
electron density of the Ar ring such that a carboxy-Pictet-
Spengler reaction would be triggered (eq 4). By the removal of
the phenol moiety (Ar’) and oxygenated group of Ar, no reac-
tion was observed, and the desired product could not be isolat-
ed via the treatment of 1f with 2w (eq 5). Although substrate 1
was limited to the oxygenated aryl group, it still provided a
novel and efficient synthesis of the 1-aryl isochroman-3-one
skeleton.
10
11
12
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Scheme 5. Synthesis of 8
Scheme 3. Synthesis of 4a-4c
H
O
OnPr
O
TFAA
nPrO
nPrO
O
O
HO
O
(2 equiv)
OnPr
MeO
MeO
(eq 3)
tBuOK, dioxane
+
2
O
OH
O
MeO
O
MeCN
MeO
O
then 6N H SO
2
4
OMe
1f
2x
4a (83%)
nPrO
nPrO
OMe
OMe
O
O
O
3ae
tBuOK
8 (52%)
O
TFAA
(2 equiv)
OMe
O
HO
O
O
(eq 4)
6N H SO
2
4
+
2
OH
OnPr
OnPr
MeCN
O
O
OnPr
MeO
O
MeO
MeO
OnPr
MeO
O
O
O
O
1b
2x
3ae
4b (73%)
O
O
O
O
MeO
OMe
O
O
O
O
OMe
OMe
OMe
O
TFAA
(1 equiv)
nPrO
nPrO
nPrO
OMe
O
MeO
MeO
+
(eq 5)
nPrO
III
VI
OH
MeCN
OnPr
OnPr
OnPr
1f
2w
OMe
OnPr
MeO
MeO
MeO
4c (NR)
OMe
tBuOK
O
O
MeO
O
O
Scheme 4. Synthesis of 5a-5c, 6a-6b and 7
O
O
OMe
OMe
OMe
O
O
O
O
nPrO
nPrO
nPrO
OMe
MeO
O
MeO
MeO
TMS-Nu
OH TFAA
OMe
IV
nPrO
V
O
MeO
o
BF OEt
3
2MeO
MeO
OMe
OMe
After changing the Lewis acid (BF3·OEt2)-mediated
conditions to a bulky base, treatment of 3ae with excess
amounts (3 equiv) of tBuOK was examined, as shown in
Scheme 5. In particular, dimeric dibenzosuberanone 8 was
obtained in a 52% yield. After deprotonation of 3ae,
intermediate III with a α-carbanion ion was formed. Then, an
intermolecular self-dimerization of 3ae and in situ-formed III
provided IV. By another equivalent of tBuOK, deprotonation
of IV, V was generated. The intramolecular annulation of V
provided VI. Following the acidic process (6N H2SO4), the
carboxylate ion on VI was protonated and then cyclized to
Nu
Nu
6a, Nu = H (87%)
OMe
OMe
3w
NaBH
5a, Nu = H (88%)
5b, Nu = CN (89%)
5c, Nu = allyl (82%)
OMe
6b, Nu = CN (86%)
6c, Nu = allyl (ND)
4
BF OEt
3
2
BF
3
H
O
H
H
MeO
MeO
O
MeO
MeO
MeO
MeO
O
O
OMe
OMe
OMe
7 (90%)
I
OMe
II
OMe
OMe
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afford 8 under a one-pot process. The transformation was a
In summary, we have developed a facile, environmentally
2
facile and efficient route to establish the novel tricyclic dimer
molecule with a head-to-tail conjugation. The structural
characterization of 8 were supported by 2D NMR experiments
(gCOSY and gHSQC) as well (see Supporting Information).
In addition to 2D-NMR techniques, the stereochemical
structure of 8 was determined by single-crystal X-ray
analysis.38
friendly, one-step carboxy-Pictet-Spengler route for the
synthesis of 1-aryl isochroman-3-ones via TFAA-mediated
intermolecular (4+2) annulation of oxygenated arylacetic acids
with arylaldehydes or ketones. Related plausible mechanisms
have been proposed. The structures of the key products were
confirmed by X-ray crystallography. The uses of various reac-
tion conditions were investigated for efficient transformation.
Further investigations regarding the TFAA-mediated synthetic
application will be conducted and published in due course.
3
4
5
6
7
8
9
By adjusting the Ar group on arylacetic acid from a di- or
tri- to a mono-oxygenated group, 4-methoxyphenylacetic acid
(1g) and 3-methoxyphenylacetic acid (1h) were involved in
the above TFAA-mediated condition (Scheme 6). When 1g
was reacted with veratraldehyde (2w), however, only 9 was
isolated in a 57% yield under the dehydration process (eq 6).
One possible reason could be that the C4-methoxy group on
the Ar group of 1g could not promote the electron density
efficiently to the meta-position such that dehydration occurred
more easily than a ring-closure. As expected, reaction of 1h
with a C3-methoxy group provided 10 in an 85% yield under
the TFAA-mediated condition (eq 7). On the basis of the
electronic influences of substituents on aromatic ring, 3-
methoxy group (for 1h) showed better reactivity than 4-
methoxy group (for 1g) because aromatic ring position para to
a 3-methoxy substituent would be involved in nucleophilic
attack on aldehydic carbon of 2w (also see Scheme 2). By
changing arylacetic acid to arylpropionic acid (one-carbon
elongation), 11, with an indenone skeleton, was generated in
an 80% yield via an intramolecular annulation (eq 8). Under
the TFAA-mediated conditions, no desired benzo-fused
oxepinone skeleton was detected. On the basis of the ring-
formation efficacy, a five-membered ring was preferred to
cyclize rather than the seven-membered ring. By changing
arylacetic acid to benzoic acid (one-carbon diminishing), no
reaction was observed. The desired product, 12, with an
isobenzofuranone skeleton could not be yielded, and only two
starting materials were recovered (eq 9). Compared with the
reactivity of the carboxylic group between 1i and 1j, benzoic
acid with a stable conjugated system possessed a low
reactivity such that the formyl group of 3w could not react
with the in situ-formed anhydride moiety (Scheme 3,
intermediate A).
10
11
12
13
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15
16
17
18
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Experimental Section
General. All reagents and solvents were obtained from
commercial sources and used without further purification.
Reactions were routinely carried out under an atmosphere of
dry air with magnetic stirring. Products in organic solvents
were dried with anhydrous magnesium sulfate before concen-
tration in vacuo. Melting points were determined with a SMP3
1
melting apparatus. H and 13C NMR spectra were recorded on
a Varian INOVA-400 spectrometer operating at 400 and at
100 MHz, respectively. Chemical shifts (δ) are reported in
parts per million (ppm) and the coupling constants (J) are giv-
en 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).
For the starting substrates 1 and 2, these materials were pur-
chased commercially and were used without further purifica-
tion.
General Procedure for Synthesis of Compounds 3a-3az: A
100 mL dry two-necked round-shaped flask equipped with a
magnetic stirrer was charged with arylacetic acids 1a-1e (1.0
o
mmol) and MeCN (8 mL) at 25 C. Trifluoroacetic anhydride
(TFAA, 210 mg, 1.0 mmol) was added in one portion to the
solution at 25 oC. The reaction mixture was stirred at 25 oC for
10 min. Then, aldehydes 2a-2ab or ketones 2ac-2as (1.0 mmol)
in MeCN (2 mL) was added to the reaction mixture at 25 C.
The reaction mixture was stirred at 25 C for 10 h. The crude
solution was evaporated by rotavapor, diluted with water (10
mL), and 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 = 15/1~1/1) afford-
ed compounds 3a-3az.
o
o
Scheme 6. Synthesis of 9-12
OMe
OMe
O
O
MeO
MeO
TFAA
MeCN
6,7-Dimethoxy-1-phenylisochroman-3-one (3a). Yield =
90% (256 mg); Colorless liquid; HRMS (ESI-TOF) m/z: [M +
(eq 6)
+
+
O
OH
m
MeO
MeO
H]+ calcd for C17H17O4 285.1127, found 285.1130; H NMR
1
OH
1g
2w
MeO
9 (57%)
O
(400 MHz, CDCl3): δ 7.37-7.32 (m, 3H), 7.26-7.24 (m, 2H),
6.71 (s, 1H), 6.46 (s, 1H), 6.32 (s, 1H), 3.86 (s, 3H), 3.72 (s,
3H), 3.64 (d, J = 18.4 Hz, 1H), 3.51 (d, J = 18.4 Hz, 1H);
13C{1H} NMR (100 MHz, CDCl3): δ 170.5, 149.3, 148.0,
137.2, 128.7, 128.6 (2C), 127.3 (2C), 126.1, 122.9, 110.1,
109.2, 81.9, 55.94, 55.90, 35.6.
MeO
O
O
MeO
MeO
TFAA
MeCN
O
(eq 7)
(eq 8)
(eq 9)
p
OH
1h
2w
2w
OMe
10 (85%)
OMe
O
O
MeO
MeO
MeO
MeO
TFAA
MeCN
MeO
MeO
O
+
1-(2-Fluorophenyl)-6,7-dimethoxyisochroman-3-one (3b).
Yield = 94% (284 mg); Colorless liquid; HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C17H16FO4 303.1033, found 303.1035;
1H NMR (400 MHz, CDCl3): δ 7.37-7.31 (m, 1H), 7.19-7.07
(m, 3H), 6.72 (s, 1H), 6.61 (s, 1H), 6.34 (s, 1H), 3.84 (s, 3H),
3.71 (d, J = 18.0 Hz, 1H), 3.69 (d, J = 18.0 Hz, 1H), 3.66 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3): δ 170.0, 160.3 (d, J =
OH
O
O
1i
11 (80%)
O
MeO
MeO
MeO
MeO
MeO
MeO
TFAA
MeCN
O
OH
+
OMe
OMe
1j
2w
12 (ND)
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8
247.1 Hz), 149.4, 148.1, 130.7 (d, J = 7.6 Hz), 128.8 (d, J =
3.1 Hz), 125.0, 124.4 (d, J = 3.8 Hz), 124.3, 122.9, 115.6 (d, J
= 21.2 Hz), 109.9, 108.5, 76.1 (d, J = 3.8 Hz), 55.9, 55.8, 35.4.
129.1 (2C), 127.2 (2C), 126.1, 122.8, 109.9, 109.1, 81.7, 55.78,
55.76, 35.5, 20.9.
1-(4-Chlorophenyl)-6,7-dimethoxyisochroman-3-one (3i).
Yield = 87% (277 mg); Colorless solid; mp = 127-129 oC (re-
crystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z:
1-(2-Bromophenyl)-6,7-dimethoxyisochroman-3-one (3c).
Yield = 83% (300 mg); Colorless liquid; HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C17H16BrO4 363.0232, found 363.0236;
1H NMR (400 MHz, CDCl3): δ 7.65 (dd, J = 1.2, 8.0 Hz, 1H),
7.38-7.24 (m, 3H), 6.76 (s, 1H), 6.70 (s, 1H), 6.20 (s, 1H),
3.88 (s, 3H), 3.81 (d, J = 18.4 Hz, 1H), 3.73 (d, J = 18.4 Hz,
1H), 3.65 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 170.1,
149.6, 148.2, 136.2, 132.9, 130.4, 129.6, 128.0, 125.4, 123.4,
123.2, 110.0, 109.0, 80.5, 56.03, 55.96, 35.9.
1
[M + H]+ calcd for C17H16ClO4 319.0737, found 319.0742; H
NMR (400 MHz, CDCl3): δ 7.38-7.35 (m, 2H), 7.24-7.21 (m,
2H), 6.74 (s, 1H), 6.45 (s, 1H), 6.31 (s, 1H), 3.90 (s, 3H), 3.76
(s, 3H), 3.67 (d, J = 18.4 Hz, 1H), 3.53 (d, J = 18.4 Hz, 1H);
13C{1H} NMR (100 MHz, CDCl3): δ 170.3, 149.7, 148.3,
135.9, 134.9, 129.99 (2C), 128.96 (2C), 125.7, 123.0, 110.3,
109.2, 81.3, 56.1 (2C), 35.7; Anal. Calcd for C17H15ClO4: C,
64.06; H, 4.74. Found: C, 64.28; H, 4.55.
9
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15
16
17
18
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23
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26
27
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29
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32
33
34
35
36
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1-(2-Hydroxyphenyl)-6,7-dimethoxyisochroman-3-one (3d).
Yield = 82% (246 mg); Colorless liquid; HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C17H17O5 301.1076, found 301.1077;
1H NMR (400 MHz, CDCl3): δ 7.28-7.24 (m, 1H), 6.95 (d, J =
8.0 Hz, 1H), 6.90-6.85 (m, 2H), 6.75 (s, 1H), 6.65 (s, 1H),
6.52 (s, 1H), 6.30 (br s, 1H), 3.91 (s, 3H), 3.75 (s, 3H), 3.70 (d,
J = 18.8 Hz, 1H), 3.66 (d, J = 18.8 Hz, 1H); 13C{1H} NMR
(100 MHz, CDCl3): δ 170.7, 154.7, 149.6, 148.4, 130.7, 128.4,
124.9, 123.2, 123.0, 120.7, 117.0, 110.2, 109.1, 79.4, 56.12,
56.07, 35.6.
1-(4-Fluorphenyl)-6,7-dimethoxyisochroman-3-one
(3j).
Yield = 90% (272 mg); Colorless solid; mp = 125-127 oC (re-
crystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z:
1
[M + H]+ calcd for C17H16FO4 303.1033, found 303.1038; H
NMR (400 MHz, CDCl3): δ 7.27-7.23 (m, 2H), 7.08-7.03 (m,
2H), 6.73 (s, 1H), 6.42 (s, 1H), 6.31 (s, 1H), 3.88 (s, 3H), 3.73
(s, 3H), 3.66 (d, J = 18.8 Hz, 1H), 3.53 (d, J = 18.4 Hz, 1H);
13C{1H} NMR (100 MHz, CDCl3): δ 170.4, 162.8 (d, J =
247.1 Hz), 149.5, 148.2, 133.2 (d, J = 3.8 Hz), 129.5 (d, J =
8.4 Hz, 2C), 125.9, 122.9, 115.7 (d, J = 21.2 Hz, 2C), 110.2,
109.1, 81.3, 56.03, 56.00, 35.7; Anal. Calcd for C17H15FO4: C,
67.54; H, 5.00. Found: C, 67.78; H, 5.27. Single-crystal X-Ray
diagram: crystal of compound 3j was grown by slow diffusion
of EtOAc into a solution of compound 3j in CH2Cl2 to yield
colorless prisms. The compound crystallizes in the monoclinic
crystal system, space group P 21/n, a = 10.6600(12) Å , b =
8.2642(9) Å , c = 16.2137(17) Å , V = 1420.5(3) Å 3, Z = 4, dcalcd
= 1.414 g/cm3, F(000) = 632, 2θ range 2.185~26.592o, R indi-
ces (all data) R1 = 0.0460, wR2 = 0.1030.
6,7-Dimethoxy-1-(2-nitrophenyl)isochroman-3-one
(3e).
Yield = 60% (197 mg); Colorless liquid; HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C17H16NO6 330.0978, found 330.0979;
1H NMR (400 MHz, CDCl3): δ 8.08 (dd, J = 1.2, 8.4 Hz, 1H),
7.70 (dt, J = 1.2, 7.6 Hz, 1H), 7.60 (dt, J = 1.6, 8.0 Hz, 1H),
7.57 (dd, J = 1.2, 7.6 Hz, 1H), 6.99 (s, 1H), 6.77 (s, 1H), 6.18
(s, 1H), 3.90 (s, 3H), 3.81 (d, J = 18.4 Hz, 1H), 3.70 (d, J =
18.4 Hz, 1H), 3.64 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3):
δ 169.8, 149.9, 148.7, 148.3, 133.9, 132.1, 130.0, 129.9, 125.7,
124.5, 123.4, 110.1, 109.2, 76.8, 56.1 (2C), 36.1.
6,7-Dimethoxy-1-(4-trifluoromethylphenyl)isochroman-3-
one (3k). Yield = 84% (296 mg); Colorless solid; mp = 124-
126 oC (recrystallized from hexanes and EtOAc); HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C18H16F3O4 353.1001, found
6,7-Dimethoxy-1-(3-methoxyphenyl)isochroman-3-one (3f).
Yield = 83% (261 mg); Colorless liquid; HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C18H19O5 315.1233, found 315.1235;
1H NMR (400 MHz, CDCl3): δ 7.23 (dt, J = 1.6, 8.8 Hz, 1H),
6.84 (dd, J = 2.4, 8.0 Hz, 1H), 6.80-6.78 (m, 2H), 6.69 (s, 1H),
6.47 (s, 1H), 6.26 (s, 1H), 3.84 (s, 3H), 3.72 (s, 3H), 3.71 (s,
3H), 3.61 (d, J = 18.8 Hz, 1H), 3.50 (d, J = 18.8 Hz, 1H);
13C{1H} NMR (100 MHz, CDCl3): δ 170.5, 159.6, 149.3,
147.9, 138.7, 129.5, 125.9, 122.8, 119.5, 114.1, 112.9, 110.1,
109.2, 81.6, 55.9 (2C), 55.0, 35.5.
1
353.1002; H NMR (400 MHz, CDCl3): δ 7.65 (d, J = 8.4 Hz,
2H), 7.42 (d, J = 8.0 Hz, 2H), 6.75 (s, 1H), 6.46 (s, 1H), 6.38
(s, 1H), 3.90 (s, 3H), 3.77 (s, 3H), 3.68 (d, J = 18.8 Hz, 1H),
3.52 (d, J = 18.8 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3):
δ 170.0, 149.8, 148.4, 141.3, 131.1 (q, J = 32.6 Hz), 127.8
(2C), 125.8 (q, J = 3.8 Hz, 2C), 125.3, 123.0, 122.9 (q, J =
89.4 Hz), 110.4, 109.2, 81.1, 56.15, 56.12, 35.7; Anal. Calcd
for C18H15F3O4: C, 61.37; H, 4.29. Found: C, 61.59; H, 4.01.
6,7-Dimethoxy-1-(3-nitrophenyl)isochroman-3-one
(3g).
Yield = 82% (270 mg); Colorless liquid; HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C17H16NO6 330.0978, found 330.0979;
1H NMR (400 MHz, CDCl3): δ 8.23 (ddd, J = 1.2, 2.4, 8.0 Hz,
1H), 8.12 (t, J = 2.0 Hz, 1H), 7.67 (dt, J = 1.2, 8.0 Hz, 1H),
7.60 (t, J = 8.0 Hz, 1H), 6.76 (s, 1H), 6.42 (s, 2H), 3.90 (s, 3H),
3.74 (s, 3H), 3.70 (d, J = 18.4 Hz, 1H), 3.54 (d, J = 18.8 Hz,
1H); 13C{1H} NMR (100 MHz, CDCl3): δ 169.7, 149.9, 148.4,
139.6, 133.5, 129.9, 124.7, 123.9, 122.9, 122.5, 122.3, 110.5,
109.0, 80.7, 56.12, 56.09, 35.6.
6,7-Dimethoxy-1-(4-methoxyphenyl)isochroman-3-one (3l).
Yield = 90% (283 mg); Colorless liquid; HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C18H19O5 315.1233, found 315.1234;
1H NMR (400 MHz, CDCl3): δ 7.18 (d, J = 8.4 Hz, 2H), 6.88
(d, J = 8.8 Hz, 2H), 6.72 (s, 1H), 6.46 (s, 1H), 6.29 (s, 1H),
3.88 (s, 3H), 3.80 (s, 3H), 3.74 (s, 3H), 3.64 (d, J = 18.4 Hz,
1H), 3.54 (d, J = 18.4 Hz, 1H); 13C{1H} NMR (100 MHz,
CDCl3): δ 170.7, 159.9, 149.3, 148.1, 129.3, 129.0 (2C), 126.4,
123.0, 114.0 (2C), 110.1, 109.3, 81.9, 56.03, 56.00, 55.2, 35.7.
6,7-Dimethoxy-1-p-tolylisochroman-3-one (3h). Yield =
93% (277 mg); Colorless liquid; HRMS (ESI-TOF) m/z: [M +
6,7-Dimethoxy-1-(4-methylsulfanylphenyl)isochroman-3-
one (3m). Yield = 90% (297 mg); Colorless liquid; HRMS
(ESI, M++1) calcd for C18H19O4S 331.1004, found 331.1005;
1H NMR (400 MHz, CDCl3): δ 7.18 (d, J = 8.8 Hz, 2H), 7.13
(d, J = 8.4 Hz, 2H), 6.70 (s, 1H), 6.44 (s, 1H), 6.26 (s, 1H),
3.84 (s, 3H), 3.71 (s, 3H), 3.61 (d, J = 18.8 Hz, 1H), 3.49 (d, J
1
H]+ calcd for C18H19O4 299.1283, found 299.1286; H NMR
(400 MHz, CDCl3): δ 7.11-7.10 (br s, 4H), 6.69 (s, 1H), 6.44
(s, 1H), 6.26 (s, 1H), 3.83 (s, 3H), 3.69 (s, 3H), 3.60 (d, J =
18.4 Hz, 1H), 3.49 (d, J = 18.4 Hz, 1H), 2.29 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3): δ 170.5, 149.1, 147.8, 138.4, 134.1,
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= 18.4 Hz, 1H), 2.42 (s, 3H); 13C{1H} NMR (100 MHz,
2H), 7.99 (br s, 2H), 7.81 (s, 1H), 7.48-7.40 (m, 4H), 6.88 (s,
2
3
4
CDCl3): δ 170.4, 149.3, 147.9, 139.5, 133.7, 127.8 (2C), 126.0
(2C), 125.8, 122.8, 110.0, 109.1, 81.5, 55.9 (2C), 35.5, 15.1.
1H), 5.91 (s, 1H), 4.04 (d, J = 18.0 Hz, 1H), 3.98 (d, J = 18.0
Hz, 1H), 3.91 (s, 3H), 3.23 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 170.6, 149.7, 148.4, 130.5, 130.2 (4C), 129.3 (2C),
127.6, 126.4 (2C), 125.5, 125.0 (4C), 122.9, 110.1, 109.4, 77.3,
56.1, 55.9, 36.7; Anal. Calcd for C25H20O4: C, 78.11; H, 5.24.
Found: C, 78.38; H, 5.40.
5
6
7
8
4-(6,7-Dimethoxy-3-oxoisochroman-1-yl)benzonitrile (3n).
Yield = 84% (260 mg); Colorless solid; mp = 172-174 oC (re-
crystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z:
[M + H]+ calcd for C18H16NO4 310.1079, found 310.1077; H
1
NMR (400 MHz, CDCl3): δ 7.69 (d, J = 8.0 Hz, 2H), 7.42 (d,
J = 8.0 Hz, 2H), 6.74 (s, 1H), 6.42 (s, 1H), 6.37 (s, 1H), 3.90
(s, 3H), 3.76 (s, 3H), 3.68 (d, J = 18.8 Hz, 1H), 3.50 (d, J =
18.4 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 169.8,
149.9, 148.4, 142.4, 132.6 (2C), 128.1 (3C), 124.8, 122.9,
118.2, 112.8, 110.4, 109.0, 80.9, 56.1, 35.6; Anal. Calcd for
C18H15NO4: C, 69.89; H, 4.89; N, 4.53. Found: C, 69.72; H,
4.78; N, 4.28.
1-(3,4-Dichlorophenyl)-6,7-dimethoxyisochroman-3-one
(3s). Yield = 80% (282 mg); Colorless solid; mp = 129-131 oC
(recrystallized from hexanes and EtOAc); HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C17H15Cl2O4 353.0347, found
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10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
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43
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46
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49
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52
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56
57
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353.0345; H NMR (400 MHz, CDCl3): δ 7.41 (d, J = 8.8 Hz,
1H), 7.32 (d, J = 2.0 Hz, 1H), 7.10 (ddd, J = 0.8, 2.0, 8.4 Hz,
1H), 6.71 (s, 1H), 6.43 (s, 1H), 6.25 (s, 1H), 3.86 (s, 3H), 3.74
(s, 3H), 3.63 (d, J = 18.8 Hz, 1H), 3.48 (d, J = 18.4 Hz, 1H);
13C{1H} NMR (100 MHz, CDCl3): δ 169.8, 149.6, 148.2,
137.6, 132.9, 132.8, 130.6, 129.3, 126.7, 124.8, 122.8, 110.3,
109.0, 80.4, 56.03, 56.96, 35.5; Anal. Calcd for C17H14Cl2O4:
C, 57.81; H, 4.00. Found: C, 57.68; H, 4.18. Single-crystal X-
Ray diagram: crystal of compound 3s was grown by slow dif-
fusion of EtOAc into a solution of compound 3s in CH2Cl2 to
yield colorless prisms. The compound crystallizes in the mon-
oclinic crystal system, space group C 2/c, a = 20.246(2) Å , b =
6,7-Dimethoxy-1-(4-nitrophenyl)isochroman-3-one
(3o).
Yield = 52% (171 mg); Colorless liquid; HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C17H16NO6 330.0978, found 330.0982;
1H NMR (400 MHz, CDCl3): δ 8.12 (d, J = 8.8 Hz, 2H), 7.42
(d, J = 8.8 Hz, 2H), 6.70 (s, 1H), 6.38 (s, 1H), 6.37 (s, 1H),
3.81 (s, 3H), 3.67 (s, 3H), 3.63 (d, J = 18.8 Hz, 1H), 3.47 (d, J
= 18.4 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 169.7,
149.6, 148.1, 147.7, 144.1, 128.1 (2C), 124.6, 123.6 (2C),
122.6, 110.2, 108.7, 80.4, 55.83, 55.81, 35.3.
4.8365(5) Å , c = 31.055(3) Å , V = 3040.7(6) Å 3, Z = 8, dcalcd
=
1.543 g/cm3, F(000) = 1456, 2θ range 2.012~26.462o, R indi-
1-Biphenyl-4-yl-6,7-dimethoxyisochroman-3-one
(3p).
ces (all data) R1 = 0.0348, wR2 = 0.0738.
Yield = 87% (313 mg); Colorless solid; mp = 132-134 oC (re-
1-Benzo[1,3]dioxol-5-yl-6,7-dimethoxyisochroman-3-one
(3t). Yield = 80% (262 mg); Colorless liquid; HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C18H17O6 329.1025, found
crystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z:
1
[M + H]+ calcd for C23H21O4 361.1440, found 361.1442; H
NMR (400 MHz, CDCl3): δ 7.63-7.58 (m, 4H), 7.47-7.43 (m,
2H), 7.39-7.34 (m, 3H), 6.76 (s, 1H), 6.57 (s, 1H), 6.40 (s, 1H),
3.91 (s, 3H), 3.79 (s, 3H), 3.69 (d, J = 18.4 Hz, 1H), 3.58 (d, J
= 18.4 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 170.6,
149.5, 148.2, 141.7, 140.2, 136.3, 128.8 (2C), 127.9 (2C),
127.6, 127.4 (2C), 127.0 (2C), 126.0, 123.0, 110.2, 109.3, 81.9,
56.1 (2C), 35.8; Anal. Calcd for C23H20O4: C, 76.65; H, 5.59.
Found: C, 76.90; H, 5.38. Single-crystal X-Ray diagram: crys-
tal of compound 3p was grown by slow diffusion of EtOAc
into a solution of compound 3p in CH2Cl2 to yield colorless
prisms. The compound crystallizes in the monoclinic crystal
system, space group P 21/c, a = 8.203(2) Å , b = 21.807(7) Å , c
= 10.328(3) Å , V = 1779.9(9) Å 3, Z = 4, dcalcd = 1.345 g/cm3,
F(000) = 760, 2θ range 1.868~26.786o, R indices (all data) R1
= 0.1267, wR2 = 0.1826.
1
329.1028; H NMR (400 MHz, CDCl3): δ 6.77 (d, J = 8.0 Hz,
1H), 6.75 (d, J = 2.0 Hz, 1H), 6.72 (s, 1H), 6.71-6.69 (m, 1H),
6.49 (s, 1H), 6.24 (s, 1H), 5.97 (d, J = 1.2 Hz, 1H), 5.96 (d, J =
1.6 Hz, 1H), 3.89 (s, 3H), 3.77 (s, 3H), 3.64 (d, J = 18.8 Hz,
1H), 3.54 (d, J = 18.4 Hz, 1H); 13C{1H} NMR (100 MHz,
CDCl3): δ 170.5, 159.5, 148.2, 148.1, 148.0, 131.2, 126.1,
123.0, 121.4, 110.2, 109.3, 108.11, 108.07, 101.3, 82.0, 56.09,
56.06, 36.7.
1-(2-Chloro-6-fluorophenyl)-6,7-dimethoxyisochroman-3-
one (3u). Yield = 78% (262 mg); Colorless solid; mp = 116-
118 oC (recrystallized from hexanes and EtOAc); HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C17H15ClFO4 337.0643, found
1
337.0649; H NMR (400 MHz, CDCl3): δ 7.37-7.27 (m, 2H),
7.04 (dt, J = 1.2, 8.0 Hz, 1H), 7.01 (s, 1H), 6.69 (s, 1H), 6.29
(s, 1H), 3.88 (s, 3H), 3.82 (d, J = 18.8 Hz, 1H), 3.80 (d, J =
18.4 Hz, 1H), 3.68 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3):
δ 169.1, 161.5 (d, J = 252.4 Hz), 149.5, 148.4, 134.8 (d, J =
5.3 Hz), 131.2 (d, J = 9.9 Hz), 126.0 (d, J = 3.8 Hz), 123.6 (d,
J = 22.7 Hz), 123.5, 121.9, 115.2 (d, J = 21.9 Hz), 109.9,
107.3, 76.1, 56.02, 55.99, 34.4 (d, J = 2.3 Hz); Anal. Calcd for
C17H14ClFO4: C, 60.63; H, 4.19. Found: C, 60.48; H, 4.40.
6,7-Dimethoxy-1-naphthalen-2-ylisochroman-3-one
(3q).
Yield = 87% (291 mg); Colorless liquid; HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C21H19O4 335.1283, found 335.1287;
1H NMR (400 MHz, CDCl3): δ 7.88 (d, J = 8.8 Hz, 1H), 7.86-
7.84 (m, 1H), 7.80-7.79 (m, 1H), 7.65 (s, 1H), 7.54-7.47 (m,
2H), 7.46 (dd, J = 2.0, 8.8 Hz, 1H), 6.76 (s, 1H), 6.52 (s, 1H),
6.51 (s, 1H), 3.92 (s, 3H), 3.73 (s, 3H), 3.70 (d, J = 18.8 Hz,
1H), 3.58 (d, J = 18.8 Hz, 1H); 13C{1H} NMR (100 MHz,
CDCl3): δ 170.6, 149.5, 148.2, 134.6, 133.3, 132.9, 128.8,
128.2, 127.7, 126.70, 126.65, 126.5, 126.1, 125.0, 123.1,
110.2, 109.4, 82.2, 56.1 (2C), 35.8.
1-(3,4-Difluorophenyl)-6,7-dimethoxyisochroman-3-one
(3v). Yield = 73% (234 mg); Colorless solid; mp = 127-129 oC
(recrystallized from hexanes and EtOAc); HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C17H15F2O4 321.0939, found 321.0945;
1H NMR (400 MHz, CDCl3): δ 7.11-6.93 (m, 3H), 6.68 (s, 1H),
6.39 (s, 1H), 6.22 (s, 1H), 3.80 (s, 3H), 3.67 (s, 3H), 3.58 (d, J
= 18.4 Hz, 1H), 3.44 (d, J = 18.4 Hz, 1H); 13C{1H} NMR (100
MHz, CDCl3): δ 169.8, 150.1 (ddd, J = 8.3, 12.1, 248.6 Hz),
149.9 (ddd, J = 7.6, 12.2, 247.9 Hz), 149.4, 148.0, 134.4 (t, J =
5.4 Hz), 125.0, 123.6 (dd, J = 3.8, 6.8 Hz), 122.7, 117.3 (d, J =
1-Anthracen-9-yl-6,7-dimethoxyisochroman-3-one
(3r).
Yield = 72% (276 mg); Colorless solid; mp = 172-174 oC (re-
crystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z:
1
[M + H]+ calcd for C25H21O4 385.1440, found 385.1438; H
NMR (400 MHz, CDCl3): δ 8.59 (s, 1H), 8.06 (d, J = 8.4 Hz,
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17.4 Hz), 116.5 (d, J = 17.4 Hz), 110.1, 108.8, 80.4, 55.8, 55.7,
35.2; Anal. Calcd for C17H14F2O4: C, 63.75; H, 4.41. Found: C,
63.50; H, 4.26.
(m, 1H), 6.67 (s, 1H), 6.39 (s, 1H), 6.17 (s, 1H), 5.961 (d, J =
1.6 Hz, 1H), 5.957 (d, J = 1.6 Hz, 1H), 5.951 (d, J = 2.0 Hz,
1H), 5.948 (d, J = 2.0 Hz, 1H), 3.62 (d, J = 18.0 Hz, 1H), 3.53
(dd, J = 2.0, 18.4 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3):
δ 170.7, 148.1, 148.04, 147.99, 146.9, 130.6, 127.8, 124.3,
121.3, 108.1, 107.9, 107.5, 106.6, 101.4, 101.3, 81.7, 36.1.
1-(3,4-Dimethoxyphenyl)-6,7-dimethoxyisochroman-3-one
(3w). Yield = 89% (306 mg); Colorless solid; mp = 118-120
oC (recrystallized from hexanes and EtOAc); HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C19H21O6 345.1338, found
5-(3,4-Dimethoxyphenyl)-5,8-dihydro[1,3]dioxolo[4,5-
g]isochromen-7-one (3ab). Yield = 85% (279 mg); Colorless
solid; mp = 156-158 oC (recrystallized from hexanes and
EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H17O6
1
345.1336; H NMR (400 MHz, CDCl3): δ 6.77 (d, J = 2.0 Hz,
9
1H), 6.73 (d, J = 8.4 Hz, 1H), 6.65 (s, 1H), 6.63 (dd, J = 2.0,
8.4 Hz, 1H), 6.36 (s, 1H), 6.18 (s, 1H), 3.77 (s, 3H), 3.76 (s,
3H), 3.71 (s, 3H), 3.62 (s, 3H), 3.56 (d, J = 18.8 Hz, 1H), 3.46
(d, J = 18.4 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ
170.4, 149.1, 149.0, 148.9, 147.7, 129.3, 126.1, 122.8, 119.9,
110.4 (2C), 109.8, 109.0, 81.6, 55.7 (2C), 55.5, 55.4, 35.4;
Anal. Calcd for C19H20O6: C, 66.27; H, 5.85. Found: C, 66.52;
H, 6.07.
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23
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26
27
28
29
30
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32
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35
36
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56
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329.1025, found 329.1028; H NMR (400 MHz, CDCl3): δ
6.87 (d, J = 1.6 Hz, 1H), 6.83 (d, J = 8.0 Hz, 1H), 6.75 (dd, J =
2.4, 8.4 Hz, 1H), 6.70 (s, 1H), 6.38 (s, 1H), 6.21 (s, 1H), 5.97
(d, J = 1.6 Hz, 1H), 5.96 (d, J = 1.2 Hz, 1H), 3.88 (s, 3H), 3.84
(s, 3H), 3.64 (d, J = 18.4 Hz, 1H), 3.55 (d, J = 18.4 Hz, 1H);
13C{1H} NMR (100 MHz, CDCl3): δ 170.6, 149.5, 149.3,
148.0, 146.9, 129.2, 128.2, 124.5, 120.1, 110.7, 110.5, 107.5,
106.8, 101.4, 81.8, 55.91, 55.87, 36.4; Anal. Calcd for
C18H16O6: C, 65.85; H, 4.91. Found: C, 66.08; H, 5.23.
1-(3-Hydroxy-4-methoxyphenyl)-6,7-dimethoxyisochroman-
3-one (3x). Yield = 74% (244 mg); Colorless liquid; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C18H19O6 331.1182, found
1
331.1184; H NMR (400 MHz, CDCl3): δ 6.82 (d, J = 8.4 Hz,
5-(3,4,5-Trimethoxyphenyl)-5,8-dihydro[1,3]dioxolo[4,5-
g]isochromen-7-one (3ac). Yield = 88% (315 mg); Colorless
liquid; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H19O7
1H), 6.79-6.74 (m, 2H), 6.70 (s, 1H), 6.51 (s, 1H), 6.25 (s, 1H),
3.88 (s, 3H), 3.86 (s, 3H), 3.76 (s, 3H), 3.62 (d, J = 18.4 Hz,
1H), 3.53 (d, J = 18.8 Hz, 1H), 2.53 (br s, 1H); 13C{1H} NMR
(100 MHz, CDCl3): δ 170.8, 149.3, 148.1, 146.9, 145.7, 130.5,
126.1, 122.9, 119.5, 113.9, 110.5, 110.1, 109.3, 81.9, 56.0
(2C), 55.9, 35.6.
1
359.1131, found 359.1135; H NMR (400 MHz, CDCl3): δ
6.70 (s, 1H), 6.51 (s, 2H), 6.38 (s, 1H), 6.18 (s, 1H), 5.97 (d, J
= 1.2 Hz, 1H), 5.96 (d, J = 1.2 Hz, 1H), 3.85 (s, 3H), 3.81 (s,
6H), 3.65 (d, J = 18.4 Hz, 1H), 3.57 (d, J = 18.0 Hz, 1H);
13C{1H} NMR (100 MHz, CDCl3): δ 170.5, 143.4 (2C), 148.1,
146.9, 138.3, 132.2, 128.1, 124.5, 107.5, 106.7, 104.6 (2C),
101.5, 81.7, 60.8, 56.1 (2C), 36.4.
6,7-Dimethoxy-1-(3,4,5-trimethoxyphenyl)isochroman-3-
one (3y). Yield = 86% (322 mg); Colorless liquid; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C20H23O7 375.1444, found
1
375.1443; H NMR (400 MHz, CDCl3): δ 6.68 (s, 1H), 6.433
5-(2,3,4-Trimethoxyphenyl)-5,8-dihydro[1,3]dioxolo[4,5-
g]isochromen-7-one (3ad). Yield = 84% (301 mg); Colorless
solid; mp = 149-150 oC (recrystallized from hexanes and
EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H19O7
(s, 2H), 6.426 (s, 1H), 6.20 (s, 1H), 3.82 (s, 3H), 3.77 (s, 3H),
3.73 (s, 6H), 3.68 (s, 3H), 3.59 (d, J = 18.0 Hz, 1H), 3.51 (d, J
= 18.4 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 170.3,
153.1 (2C), 149.3, 147.9, 138.0, 132.5, 125.9, 122.9, 109.9,
109.2, 104.6 (2C), 81.8, 60.5, 55.90, 55.87 (2C), 55.8, 35.5.
1
359.1131, found 359.1125; H NMR (400 MHz, CDCl3): δ
6.72 (d, J = 8.4 Hz, 1H), 6.57 (d, J = 8.8 Hz, 1H), 6.52 (s, 1H),
6.44 (s, 1H), 6.18 (s, 1H), 5.79 (d, J = 1.2 Hz, 2H), 3.78 (s,
3H), 3.77 (s, 3H), 3.74 (s, 3H), 3.61 (d, J = 18.4 Hz, 1H), 3.54
(d, J = 18.4 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ
170.1, 154.0, 151.6, 147.4, 146.5, 141.6, 127.6, 124.1, 122.8,
122.4, 107.0, 106.8, 105.7, 101.0, 76.8, 61.0, 60.3, 55.5, 35.6;
Anal. Calcd for C19H18O7: C, 63.68; H, 5.06. Found: C, 63.57;
H, 5.33.
6,7-Dimethoxy-1-(2,3,4-trimethoxyphenyl)isochroman-3-
one (3z). Yield = 85% (318 mg); Colorless solid; mp = 136-
138 oC (recrystallized from hexanes and EtOAc); HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C20H23O7 375.1444, found
1
375.1443; H NMR (400 MHz, CDCl3): δ 6.72 (d, J = 9.2 Hz,
1H), 6.70 (s, 1H), 6.61 (d, J = 8.8 Hz, 1H), 6.60 (s, 1H), 6.37
(s, 1H), 3.89 (s, 3H), 3.86 (s, 6H), 3.83 (s, 3H), 3.69 (s, 3H),
3.68 (br s, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 170.5,
154.4, 152.2, 149.2, 148.1, 142.1, 126.1, 123.2, 123.1, 122.9,
109.8, 108.8, 107.1, 77.6, 61.4, 60.6, 56.0, 55.9, 55.8, 35.4;
Anal. Calcd for C20H22O7: C, 64.16; H, 5.92. Found: C, 64.37;
H, 6.22. Single-crystal X-Ray diagram: crystal of compound
3z was grown by slow diffusion of EtOAc into a solution of
compound 3z in CH2Cl2 to yield colorless prisms. The com-
pound crystallizes in the monoclinic crystal system, space
group P21/c, a = 11.8572(4) Å , b = 21.4415(7) Å , c = 7.3083(3)
Å , V = 1768.69(11) Å 3, Z = 4, dcalcd = 1.406 g/cm3, F(000) =
792, 2θ range 1.804~26.437o, R indices (all data) R1 = 0.0457,
wR2 = 0.0916.
1-(3,4-Dimethoxyphenyl)-6,7-dipropoxyisochroman-3-one
(3ae). Yield = 65% (260 mg); Colorless solid; mp = 127-129
oC (recrystallized from hexanes and EtOAc); HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C23H29O6 401.1964, found
1
401.1963; H NMR (400 MHz, CDCl3): δ 6.86 (d, J = 2.0 Hz,
1H), 6.82 (d, J = 8.4 Hz, 1H), 6.74-6.71 (m, 2H), 6.47 (s, 1H),
6.26 (s, 1H), 3.96 (t, J = 6.4 Hz, 2H), 3.88 (s, 3H), 3.83 (s, 3H),
3.80-3.78 (m, 2H), 3.63 (d, J = 18.4 Hz, 1H), 3.53 (d, J = 18.4
Hz, 1H), 1.87-1.81 (m, 2H), 1.78-1.73 (m, 2H), 1.04 (t, J = 7.2
Hz, 3H), 0.98 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 170.9, 149.7, 149.4, 149.2, 148.1, 129.7, 126.5,
123.3, 120.2, 112.4, 112.1, 110.7, 110.6, 82.0, 71.0, 70.8, 55.9,
55.8, 55.9, 22.5, 22.4, 10.4, 10.3; Anal. Calcd for C23H28O6: C,
68.98; H, 7.05. Found: C, 68.67; H, 7.32.
5-Benzo[1,3]dioxol-5-yl-5,8-dihydro[1,3]dioxolo[4,5-
g]isochromen-7-one (3aa). Yield = 83% (259 mg); Colorless
liquid; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H13O6
5,6-Dimethoxy-1-(4-methoxyphenyl)-isochroman-3-one
(3af). Yield = 80% (251 mg); Colorless solid; mp = 138-140
oC (recrystallized from hexanes and EtOAc); HRMS (ESI-
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313.0712, found 313.0718; H NMR (400 MHz, CDCl3): δ
6.77 (d, J = 8.0 Hz, 1H), 6.76 (d, J = 2.0 Hz, 1H), 6.75-6.70
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TOF) m/z: [M + H]+ calcd for C18H19O5 315.1233, found
2H), 6.98 (s, 1H), 6.65 (s, 1H), 3.92 (s, 3H), 3.86 (s, 3H), 3.44
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315.1239; H NMR (400 MHz): δ 7.22-7.19 (m, 2H), 6.92-
(d, J = 18.4 Hz, 1H), 3.07 (dd, J = 0.8, 18.4 Hz, 1H), 2.00 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3): δ 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; Anal. Calcd for C18H18O4:
C, 72.47; H, 6.08. Found: C, 72.75; H, 6.30. Single-crystal X-
Ray diagram: crystal of compound 3aj was grown by slow
diffusion of EtOAc into a solution of compound 3aj in CH2Cl2
to yield colorless prisms. The compound crystallizes in the
monoclinic crystal system, space group P21/c, a = 9.7914(3) Å ,
b = 11.0553(4) Å , c = 14.4153(5) Å , V = 1506.22(9) Å 3, Z = 4,
dcalcd = 1.316 g/cm3, F(000) = 632, 2θ range 2.155~26.402o, R
indices (all data) R1 = 0.0386, wR2 = 0.0900.
6.89 (m, 2H), 6.80 (d, J = 8.4 Hz, 1H), 6.64 (d, J = 8.4 Hz,
1H), 6.29 (s, 1H), 3.87 (s, 3H), 3.86 (s, 3H), 3.82 (s, 3H), 3.72
(s, 2H); 13C NMR (100 MHz): δ170.7, 159.9, 152.6, 145.6,
129.4, 129.0 (2C), 127.7, 124.7, 121.6, 114.0 (2C), 110.7, 81.6,
60.9, 55.9, 55.3, 30.6; Anal. Calcd for C18H18O5: C, 68.78; H,
5.77. Found: C, 69.05; H, 6.06. Single-crystal X-Ray diagram:
crystal of compound 3af was grown by slow diffusion of
EtOAc into a solution of compound 3af in CH2Cl2 to yield
colorless prisms. The compound crystallizes in the monoclinic
crystal system, space group P 1 21/c 1, a = 12.6139(9) Å , b =
14.2691(10) Å , c = 9.0436(7) Å , V = 1579.1(2) Å 3, Z = 4, dcalcd
= 1.322 g/cm3, F(000) = 664, 2θ range 1.66~26.39o, R indices
(all data) R1 = 0.1402, wR2 = 0.1211.
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6,7-Dimethoxy-1-(3-methoxyphenyl)-1-methylisochroman-
3-one (3ak). Yield = 73% (239 mg); Colorless liquid; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C19H21O5 329.1389, found
1-(3,4-Dimethoxyphenyl)-6,7,8-trimethoxyisochroman-3-
one (3ag). Yield = 78% (292 mg); Colorless solid; mp = 131-
133 oC (recrystallized from hexanes and EtOAc); HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C20H23O7 375.1444, found
1
329.1383; H NMR (400 MHz, CDCl3): δ 7.18 (t, J = 8.0 Hz,
1H), 6.98 (s, 1H), 6.79-6.71 (m, 3H), 6.66 (s, 1H), 3.94 (s, 3H),
3.88 (s, 3H), 3.73 (s, 3H), 3.47 (d, J = 18.4 Hz, 1H), 3.14 (dd,
J = 0.8, 18.4 Hz, 1H), 2.01 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 171.2, 159.5, 149.3, 148.0, 145.2, 130.2, 129.5,
123.2, 117.7, 112.8, 111.6, 110.5, 108.6, 85.9, 56.3, 56.0, 55.2,
36.4, 29.0.
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375.1446; H NMR (400 MHz, CDCl3): δ 6.90 (d, J = 2.4 Hz,
1H), 6.72 (d, J = 8.4 Hz, 1H), 6.67 (s, 1H), 6.52 (dd, J = 1.2,
8.4 Hz, 1H), 6.51 (d, J = 2.4 Hz, 1H), 3.88 (s, 3H), 3.87 (s,
3H), 3.85 (s, 3H), 3.83 (s, 3H), 3.82 (s, 3H), 3.52 (d, J = 19.2
Hz, 1H), 3.37 (dd, J = 0.8, 18.8 Hz, 1H); 13C{1H} NMR (100
MHz, CDCl3): δ 170.8, 154.2, 149.8, 149.21, 149.17, 140.7,
130.5, 126.3, 119.1, 118.5, 110.6, 110.5, 106.0, 77.6, 61.1,
60.9, 56.1, 55.83, 55.79, 35.6; Anal. Calcd for C20H22O7: C,
64.16; H, 5.92. Found: C, 64.47; H, 6.24. Single-crystal X-Ray
diagram: crystal of compound 3ag was grown by slow diffu-
sion of EtOAc into a solution of compound 3ag in CH2Cl2 to
yield colorless prisms. The compound crystallizes in the mon-
oclinic crystal system, space group P 21/n, a = 8.2452(3) Å , b
= 7.9051(3) Å , c = 27.3274(10) Å , V = 1781.17(11) Å 3, Z = 4,
dcalcd = 1.396 g/cm3, F(000) = 792, 2θ range 1.490~26.414o, R
indices (all data) R1 = 0.0444, wR2 = 0.0928.
1-(3-Fluorophenyl)-6,7-dimethoxy-1-methylisochroman-3-
one (3al). Yield = 72% (228 mg); Colorless liquid; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C18H18FO4 317.1189,
found 317.1193; 1H NMR (400 MHz, CDCl3): δ 7.28-7.23 (m,
1H), 7.01-6.93 (m, 2H), 6.97 (s, 1H), 6.87-6.84 (m, 1H), 6.67
(s, 1H), 3.95 (s, 3H), 3.90 (s, 3H), 3.50 (d, J = 18.4 Hz, 1H),
3.13 (dd, J = 1.2, 18.4 Hz, 1H), 2.02 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3): δ 170.8, 162.7 (d, J = 245.6 Hz), 149.6,
148.2, 146.3 (d, J = 6.1 Hz), 130.2 (d, J = 8.4 Hz), 129.6,
123.2, 121.1 (d, J = 3.1 Hz), 115.0 (d, J = 21.2 Hz), 112.8 (d, J
= 22.8 Hz), 110.6, 108.6, 85.4, 56.3, 56.1, 36.3, 29.0.
1-(4-Chlorophenyl)-6,7-dimethoxy-1-methylisochroman-3-
one (3am). Yield = 72% (239 mg); Colorless liquid; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C18H18ClO4 333.0894,
1,1'-(1,4-phenylene)bis(6,7-dimethoxyisochroman-3-one)
(3ah). Rotamer; Ratio = 2:1; Yield = 72% (353 mg); Colorless
solid; mp = 174-176 oC (recrystallized from hexanes and
EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C28H27O8
1
found 333.0896; H NMR (400 MHz, CDCl3): δ 7.23 (d, J =
8.4 Hz, 2H), 7.10 (d, J = 8.8 Hz, 2H), 6.95 (s, 1H), 6.66 (s,
1H), 3.93 (s, 3H), 3.88 (s, 3H), 3.49 (d, J = 18.4 Hz, 1H), 3.10
(dd, J = 0.8, 18.4 Hz, 1H), 2.00 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3): δ 170.7, 149.5, 148.1, 142.1, 133.9, 129.6,
128.6 (2C), 126.8 (2C), 123.0, 110.5, 108.5, 85.5, 56.3, 56.0,
36.2, 29.0.
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491.1706, found 491.1708; For major comformation; H NMR
(400 MHz, CDCl3): δ 7.32 (s, 4H), 6.73 (s, 2H), 6.48 (s, 2H),
6.36 (s, 2H), 3.90 (s, 6H), 3.77 (s, 6H), 3.68 (d, J = 18.8 Hz,
2H), 3.54 (d, J = 18.4 Hz, 2H); 13C{1H} NMR (100 MHz,
CDCl3): δ 170.4 (2C), 149.7 (2C), 148.3 (2C), 138.24, 138.19,
128.0 (4C), 125.6 (2C), 123.0 (2C), 110.3 (2C), 109.3 (2C),
81.6 (2C), 56.2 (2C), 56.1 (2C), 35.73, 35.70.
1-(4-Fluorophenyl)-6,7-dimethoxy-1-methylisochroman-3-
one (3an). Yield = 80% (253 mg); Colorless liquid; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C18H18FO4 317.1189,
found 317.1184; 1H NMR (400 MHz, CDCl3): δ 7.16-7.13 (m,
2H), 6.97-6.93 (m, 2H), 6.95 (s, 1H), 6.67 (s, 1H), 3.94 (s, 3H),
3.90 (s, 3H), 3.50 (d, J = 18.4 Hz, 1H), 3.11 (dd, J = 0.8, 18.4
Hz, 1H), 2.01 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ
170.9, 162.2 (d, J = 245.6 Hz), 149.5, 148.2, 139.4 (d, J = 3.0
Hz), 129.9, 127.3 (d, J = 8.4 Hz, 2C), 123.1, 115.4 (d, J = 21.2
Hz, 2C), 110.6, 108.5, 85.6, 56.3, 56.1, 36.3, 29.2.
6,7-Dimethoxy-1-thiophen-2-ylisochroman-3-one
(3ai).
Yield = 60% (174 mg); Colorless liquid; HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C15H15O4S 291.0691, found 291.0696;
1H NMR (400 MHz, CDCl3): δ 7.35 (dd, J = 1.2, 4.8 Hz, 1H),
6.97 (dd, J = 3.6, 4.8 Hz, 1H), 6.87 (dd, J = 1.2, 3.6 Hz, 1H),
6.71 (s, 2H), 6.56 (s, 1H), 3.91 (s, 3H), 3.84 (s, 3H), 3.63 (s,
2H); 13C{1H} NMR (100 MHz, CDCl3): δ 170.1, 149.7, 148.3,
141.4, 127.3, 127.1, 126.8, 125.5, 122.6, 110.2, 108.8, 78.1,
56.12, 56.09, 35.3.
6,7-Dimethoxy-1-(4-methylphenyl)-1-methylisochroman-3-
one (3ao). Yield = 73% (228 mg); Colorless liquid; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C19H21O4 313.1440, found
6,7-Dimethoxy-1-methyl-1-phenylisochroman-3-one (3aj).
Yield = 74% (221 mg); Colorless solid; mp = 159-161 oC (re-
crystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z:
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313.1442; H NMR (400 MHz, CDCl3): δ 7.09-7.03 (m, 4H),
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[M + H]+ calcd for C18H19O4 299.1283, found 299.1288; H
6.98 (s, 1H), 6.66 (s, 1H), 3.95 (s, 3H), 3.90 (s, 3H), 3.47 (d, J
NMR (400 MHz, CDCl3): δ 7.26-7.19 (m, 3H), 7.15-7.13 (m,
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= 18.4 Hz, 1H), 3.13 (dd, J = 0.8, 18.4 Hz, 1H), 2.30 (s, 3H),
142.4, 140.9, 140.1, 130.2, 128.8 (2C), 127.5, 127.1 (2C),
2.02 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 171.3,
149.3, 148.0, 140.5, 137.8, 130.4, 129.1 (2C), 125.3 (2C),
123.3, 110.5, 108.6, 86.1, 56.3, 56.1, 36.4, 29.2, 20.9.
127.0 (2C), 125.8 (2C), 123.3, 110.6, 108.6, 85.9, 56.3, 56.1,
36.4, 29.1; Anal. Calcd for C24H22O4: C, 76.99; H, 5.92. Found:
C, 77.28; H, 6.20. Single-crystal X-Ray diagram: crystal of
compound 3at was grown by slow diffusion of EtOAc into a
solution of compound 3at in CH2Cl2 to yield colorless prisms.
The compound crystallizes in the monoclinic crystal system,
space group P 21/c, a = 16.0440(14) Å , b = 11.1195(9) Å , c =
10.6719(8) Å , V = 1900.2(3) Å 3, Z = 4, dcalcd = 1.309 g/cm3,
F(000) = 792, 2θ range 2.230~26.434o, R indices (all data) R1
= 0.0585, wR2 = 0.1043.
6,7-Dimethoxy-1-(4-methoxyphenyl)-1-methylisochroman-
3-one (3ap). Yield = 74% (243 mg); Colorless liquid; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C19H21O5 329.1389, found
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329.1386; H NMR (400 MHz, CDCl3): δ 7.08 (d, J = 8.8 Hz,
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2H), 6.96 (s, 1H), 6.80 (d, J = 9.2 Hz, 2H), 6.67 (s, 1H), 3.94
(s, 3H), 3.90 (s, 3H), 3.77 (s, 3H), 3.48 (d, J = 18.0 Hz, 1H),
3.15 (dd, J = 0.8, 18.0 Hz, 1H), 2.02 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3): δ 171.3, 159.2, 149.3, 148.1, 135.6, 130.4,
126.8 (2C), 123.3, 113.7 (2C), 110.5, 108.6, 86.0, 56.3, 56.1,
55.3, 36.4, 29.2.
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1-(3,4-Dichlorophenyl)-6,7-dimethoxy-1-
methylisochroman-3-one (3au). Yield = 70% (256 mg); Color-
less liquid; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
1
C18H17Cl2O4 367.0504, found 367.0506; H NMR (400 MHz,
6,7-Dimethoxy-1-methyl-1-(4-
CDCl3): δ 7.32 (d, J = 8.4 Hz, 1H), 7.20 (d, J = 2.4 Hz, 1H),
7.02 (dd, J = 2.4, 8.4 Hz, 1H), 6.92 (s, 1H), 6.67 (s, 1H), 3.92
(s, 3H), 3.87 (s, 3H), 3.47 (d, J = 18.8 Hz, 1H), 3.11 (d, J =
18.4 Hz, 1H), 1.97 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3):
δ 170.3, 149.6, 148.2, 143.9, 132.7, 132.2, 130.4, 128.9, 127.5,
124.8, 122.9, 110.6, 108.4, 84.9, 56.3, 56.0, 36.1, 28.9.
trifluoromethylphenyl)isochroman-3-one (3aq). Yield = 70%
o
(256 mg); Colorless solid; mp = 125-127 C (recrystallized
from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+
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calcd for C19H18F3O4 367.1157, found 367.1152; H NMR
(400 MHz, CDCl3): δ 7.52 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.0
Hz, 2H), 6.99 (s, 1H), 6.67 (s, 1H), 3.94 (s, 3H), 3.88 (s, 3H),
3.50 (d, J = 18.4 Hz, 1H), 3.06 (dd, J = 0.8, 18.4 Hz, 1H), 2.02
(s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 170.5, 149.7,
148.2, 147.5, 130.2 (q, J = 32.6 Hz), 129.3, 125.8 (2C), 125.5
(q, J = 3.8 Hz, 2C), 123.7 (q, J = 270.6 Hz), 123.0, 110.6,
108.5, 85.4, 56.3, 56.0, 36.2, 29.0; Anal. Calcd for C19H17F3O4:
C, 62.29; H, 4.68. Found: C, 62.44; H, 4.93.
1-(2,4-Dichloro-5-fluorophenyl)-6,7-dimethoxy-1-
methylisochroman-3-one (3av). Yield = 80% (307 mg); Color-
less liquid; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C18H16Cl2FO4 385.0410, found 385.0418; 1H NMR (400 MHz,
CDCl3): δ 7.45 (d, J = 6.8 Hz, 1H), 7.04 (d, J = 10.0 Hz, 1H),
6.66 (s, 1H), 6.54 (s, 1H), 3.90 (s, 3H), 3.80 (s, 3H), 3.68 (d, J
= 19.6 Hz, 1H), 3.47 (d, J = 19.6 Hz, 1H), 2.11 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3): δ 169.3, 156.2 (d, J = 247.9 Hz),
149.6, 148.4, 139.6 (d, J = 5.3 Hz), 133.7, 129.2 (d, J = 3.8
Hz), 128.6, 122.1, 121.9 (d, J = 18.2 Hz), 116.3 (d, J = 24.3
Hz), 110.4, 108.4, 85.3, 56.3, 56.1, 35.0, 27.1.
6,7-Dimethoxy-1-methyl-1-(4-nitrophenyl)isochroman-3-
one (3ar). Yield = 62% (213 mg); Colorless solid; mp = 159-
161 oC (recrystallized from hexanes and EtOAc); HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C18H18NO6 344.1134, found
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344.1138; H NMR (400 MHz, CDCl3): δ 8.15 (d, J = 9.2 Hz,
2H), 7.40 (d, J = 8.8 Hz, 2H), 6.98 (s, 1H), 6.69 (s, 1H), 3.96
(s, 3H), 3.91 (s, 3H), 3.54 (d, J = 18.8 Hz, 1H), 3.07 (dd, J =
0.8, 18.4 Hz, 1H), 2.05 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 170.2, 150.6, 149.9, 148.5, 147.5, 128.9, 126.5 (2C),
123.8 (2C), 123.0, 110.7, 108.5, 85.2, 56.4, 56.1, 36.2, 29.0;
Anal. Calcd for C18H17NO6: C, 62.97; H, 4.99; N, 4.08. Found:
C, 63.30; H, 5.30; N, 4.32.
6,7-Dimethoxy-1-methyl-1-(3,4,5-
trimethoxyphenyl)isochroman-3-one (3aw). Yield = 66% (256
o
mg); Colorless solid; mp = 153-155 C (recrystallized from
hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd
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for C21H25O7 389.1600, found 389.1602; H NMR (400 MHz,
CDCl3): δ 6.98 (s, 1H), 6.67 (s, 1H), 6.35 (s, 2H), 3.93 (s, 3H),
3.89 (s, 3H), 3.79 (s, 3H), 3.71 (s, 6H), 3.49 (d, J = 18.0 Hz,
1H), 3.19 (dd, J = 0.8, 18.4 Hz, 1H), 2.01 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3): δ 171.2, 153.0 (2C), 149.4, 148.0,
139.3, 137.6, 130.1, 123.5, 110.5, 108.6, 102.9 (2C), 86.0,
60.7, 56.4, 56.1 (2C), 56.0, 36.4, 29.1; Anal. Calcd for
C21H24O7: C, 64.94; H, 6.23. Found: C, 65.28; H, 6.00.
6,7-Dimethoxy-1-methyl-1-naphthalen-2-ylisochroman-3-
one (3as). Yield = 70% (244 mg); Colorless liquid; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C22H21O4 349.1440, found
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349.1437; H NMR (400 MHz, CDCl3): δ 7.82-7.78 (m, 2H),
7.74-7.71 (m, 1H), 7.50-7.46 (m, 3H), 7.42 (dd, J = 2.0, 8.8
Hz, 1H), 7.07 (s, 1H), 6.69 (s, 1H), 3.99 (s, 3H), 3.92 (s, 3H),
3.50 (d, J = 18.0 Hz, 1H), 3.16 (dd, J = 0.8, 18.4 Hz, 1H), 2.12
(s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 171.2, 149.5,
148.1, 140.8, 132.8, 132.7, 130.2, 128.6, 128.2, 127.5, 126.6,
126.5, 124.1, 123.5, 123.4, 110.6, 108.8, 86.2, 56.4, 56.1, 36.4,
29.1.
6,7-Dimethoxy-1-phenyl-1-propylisochroman-3-one (3ax).
Yield = 67% (218 mg); Colorless solid; mp = 109-111 oC (re-
crystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z:
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[M + H]+ calcd for C20H23O4 327.1596, found 327.1598; H
NMR (400 MHz, CDCl3): δ 7.27-7.21 (m, 3H), 7.16-7.14 (m,
2H), 6.97 (s, 1H), 6.63 (s, 1H), 3.95 (s, 3H), 3.86 (s, 3H), 3.46
(d, J = 18.8 Hz, 1H), 3.09 (d, J = 18.8 Hz, 1H), 2.23 (t, J = 7.6
Hz, 2H), 1.56-1.42 (m, 2H), 0.93 (t, J = 7.6 Hz, 3H); 13C{1H}
NMR (100 MHz, CDCl3): δ 171.2, 149.2, 147.9, 142.9, 128.7,
128.3 (2C), 127.6, 125.5 (2C), 123.6, 110.6, 109.0, 88.5, 56.3,
55.9, 43.5, 36.0, 17.1, 14.1; Anal. Calcd for C20H22O4: C,
73.60; H, 6.79. Found: C, 73.81; H, 6.90.
1-Biphenyl-4-yl-6,7-dimethoxy-1-methylisochroman-3-one
(3at). Yield = 67% (251 mg); Colorless solid; mp = 172-174
oC (recrystallized from hexanes and EtOAc); HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C24H23O4 375.1596, found
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375.1599; H NMR (400 MHz, CDCl3): δ 7.55-7.48 (m, 4H),
7.44-7.40 (m, 2H), 7.36-7.32 (m, 1H), 7.27-7.23 (m, 2H), 7.03
(s, 1H), 6.69 (s, 1H), 3.97 (s, 3H), 3.91 (s, 3H), 3.52 (d, J =
18.8 Hz, 1H), 3.20 (dd, J = 0.8, 18.4 Hz, 1H), 2.08 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 171.1, 149.4, 148.1,
1-Benzyl-1-(4-fluorophenyl)-6,7-dimethoxyisochroman-3-
one (3ay). Yield = 63% (247 mg); Colorless liquid; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C24H22FO4 393.1502,
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found 393.1508; 1H NMR (400 MHz, CDCl3): δ 7.21-7.11 (m,
oC. The reaction mixture was stirred at 25 oC for 10 min. Then,
BF3·OEt2 (210 mg, 1.5 mmol) was added to the reaction mix-
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5H), 7.01-6.91 (m, 4H), 6.86 (s, 1H), 6.50 (s, 1H), 3.851 (s,
3H), 3.846 (s, 3H), 3.66 (d, J = 14.0 Hz, 1H), 3.57 (d, J = 14.0
Hz, 1H), 3.08 (d, J = 19.6 Hz, 1H), 2.92 (d, J = 19.6 Hz, 1H);
13C{1H} NMR (100 MHz, CDCl3): δ 170.0, 162.2 (d, J =
246.3 Hz), 149.2, 147.8, 138.3 (d, J = 3.0 Hz), 134.6, 131.1
(2C), 128.2 (d, J = 8.4 Hz, 2C), 128.1, 127.9 (2C), 126.9,
123.3, 115.0 (d, J = 21.2 Hz, 2C), 110.0, 109.1, 87.9, 56.2,
55.9, 47.1, 34.9.
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6
7
8
9
o
o
ture at 25 C. The reaction mixture was stirred at 25 C for 10
h. The crude solution was evaporated by rotavapor, diluted
with water (10 mL), and extracted with EtOAc (3 x 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 = 15/1~1/1)
afforded compounds 5a-5c.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6,7-Dimethoxy-1,1-diphenylisochroman-3-one (3az). Yield
[2-(3,4-Dimethoxybenzyl)-4,5-dimethoxyphenyl]acetic acid
(5a). Yield = 88% (304 mg); Colorless solid; mp = 111-113 oC
(recrystallized from hexanes and EtOAc); HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C19H23O6 347.1495, found 347.1496;
1H NMR (400 MHz, CDCl3): δ 10.14 (br s, 1H), 6.76 (d, J =
7.6 Hz, 1H), 6.75 (s, 1H), 6.65 (s, 1H), 6.63 (d, J = 2.0 Hz,
1H), 6.61 (dd, J = 2.0, 8.4 Hz, 1H), 3.92 (s, 2H), 3.86 (s, 3H),
3.83 (s, 3H), 3.79 (s, 3H), 3.78 (s, 3H), 3.56 (s, 2H); 13C{1H}
NMR (100 MHz, CDCl3): δ 177.4, 148.9, 148.2, 147.4, 147.3,
132.8, 131.8, 124.1, 120.5, 113.9, 113.7, 111.9, 111.2, 55.9,
55.84, 55.82, 55.7, 38.1, 37.9; Anal. Calcd for C19H22O6: C,
65.88; H, 6.40. Found: C, 65.62; H, 6.68. Single-crystal X-Ray
diagram: crystal of compound 5a was grown by slow diffusion
of EtOAc into a solution of compound 5a in CH2Cl2 to yield
colorless prisms. The compound crystallizes in the triclinic
crystal system, space group P -1, a = 11.4341(7) Å , b =
12.3823(8) Å , c = 13.3138(7) Å , V = 1839.91(19) Å 3, Z = 4,
dcalcd = 1.315 g/cm3, F(000) = 776, 2θ range 1.566~26.422o, R
indices (all data) R1 = 0.0641, wR2 = 0.1691.
= 47% (169 mg); Colorless liquid; HRMS (ESI, M++1) calcd
1
for C23H21O4 361.1440, found 361.1445; H NMR (400 MHz,
CDCl3): δ 7.35-7.30 (m, 6H), 7.16-7.12 (m, 4H), 6.71 (s, 1H),
6.19 (s, 1H), 3.90 (s, 3H), 3.60 (s, 3H), 3.38 (s, 2H); 13C{1H}
NMR (100 MHz, CDCl3): δ 171.0, 149.4, 147.6, 141.7 (2C),
130.8, 128.4 (2C), 128.1 (8C), 123.4, 111.4, 110.2, 90.8, 56.1,
55.9, 36.6.
General Procedure for Synthesis of Compounds 4a-4b: A
100 mL dry two-necked round-shaped flask equipped with a
magnetic stirrer was charged with arylacetic acids 1f or 1b
o
(2.0 mmol) in MeCN (8 mL) at 25 C. Trifluoroacetic anhy-
dride (TFAA, 420 mg, 2.0 mmol) was added in one portion to
the solution at 25 oC. The reaction mixture was stirred at 25 oC
for 10 min. Then, isovanillin (2x, 152 mg, 1.0 mmol) in
o
MeCN (2 mL) was added to the reaction mixture at 25 C. The
reaction mixture was stirred at 25 oC for 10 h. The crude solu-
tion was evaporated by rotavapor, diluted with water (10 mL),
and 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 = 15/1~1/1) afforded compounds
4a-4b.
{2-[Cyano-(3,4-dimethoxyphenyl)methyl]-4,5-
dimethoxyphenyl}acetic acid (5b). Yield = 89% (330 mg);
o
Colorless solid; mp = 87-89 C (recrystallized from hexanes
and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd for
1
C20H22NO6 372.1447, found 372.1443; H NMR (400 MHz,
Phenylacetic acid 5-formyl-2-methoxyphenyl ester (4a).
Yield = 83% (224 mg); Colorless liquid; HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C16H15O4 271.0970, found 271.0974;
1H NMR (400 MHz, CDCl3): δ 9.82 (s, 1H), 7.71 (dd, J = 2.0,
8.4 Hz, 1H), 7.55 (d, J = 2.0 Hz, 1H), 7.42-7.29 (m, 5H), 7.01
(d, J = 8.4 Hz, 1H), 3.90 (s, 2H), 3.80 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3): δ 189.9, 169.1, 156.1, 140.1, 133.1, 130.1,
129.7, 129.2 (2C), 128.5 (2C), 127.2, 123.0, 111.9, 55.9, 40.7.
CDCl3): δ 10.08 (br s, 1H), 6.91 (br s, 1H), 6.81 (d, J = 0.8 Hz,
2H), 6.75 (s, 2H), 5.39 (s, 1H), 3.88 (s, 3H), 3.844 (s, 3H),
3.841 (s, 3H), 3.79 (s, 3H), 3.59 (d, J = 16.0 Hz, 1H), 3.54 (d,
J = 16.0 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 176.5,
149.4, 148.93, 148.92, 148.8, 127.3, 126.4, 123.8, 120.0,
119.7, 114.4, 112.0, 111.3, 110.8, 56.04, 55.98, 55.9 (2C),
38.6, 37.8; Anal. Calcd for C20H21NO6: C, 64.68; H, 5.70; N,
3.77. Found: C, 64.90; H, 5.98; N, 4.01.
Benzo[1,3]dioxol-5-ylacetic acid 2-methoxy-5-(7-oxo-7,8-
dihydro-5H-[1,3]dioxolo[4,5-g]isochromen-5-yl)phenyl ester
(4b). Yield = 73% (348 mg); Colorless liquid; HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C26H21O9 477.1186, found
{2-[1-(3,4-Dimethoxyphenyl)but-3-enyl]-4,5-
dimethoxyphenyl}acetic acid (5c). Yield = 82% (317 mg);
Colorless liquid; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
1
1
C22H27O6 387.1808, found 387.1809; H NMR (400 MHz,
477.1194; H NMR (400 MHz, CDCl3): δ 7.11 (dd, J = 2.4,
CDCl3): δ 9.50 (br s, 1H), 6.80 (s, 1H), 6.77-6.73 (m, 3H),
6.70 (s, 2H), 5.77-5.66 (m, 1H), 5.04 (dq, J = 1.6, 16.8 Hz,
1H), 4.96 (dq, J = 1.6, 10.0 Hz, 1H), 4.16 (t, J = 7.6 Hz, 1H),
3.84 (s, 2H), 3.822 (s, 3H), 3.819 (s, 3H), 3.76 (s, 3H), 3.62 (d,
J = 16.4 Hz, 1H), 3.58 (d, J = 16.4 Hz, 1H), 2.79-2.66 (m, 2H);
13C{1H} NMR (100 MHz, CDCl3): δ 178.0, 148.7, 148.2,
147.3, 147.1, 136.52, 136.49, 135.2, 123.8, 119.5, 116.4,
113.9, 111.6, 111.1, 110.9, 55.9, 55.74, 55.71, 55.6, 45.6, 40.5,
37.9.
8.4 Hz, 1H), 6.94 (d, J = 8.8 Hz, 1H), 6.93 (d, J = 2.4 Hz, 1H),
6.88 (d, J = 1.2 Hz, 1H), 6.81 (dd, J = 2.0, 8.4 Hz, 1H), 6.78 (d,
J = 7.6 Hz, 1H), 6.69 (s, 1H), 6.45 (s, 1H), 6.21 (s, 1H), 6.98
(d, J = 1.2 Hz, 1H), 6.97 (d, J = 1.2 Hz, 1H), 5.95 (s, 2H), 3.80
(s, 3H), 3.78 (s, 2H), 3.60 (d, J = 18.4 Hz, 1H), 3.50 (d, J =
18.4 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 170.4,
169.4, 151.5, 148.2, 147.8, 147.0, 146.8, 140.0, 129.5, 127.6,
126.9, 126.1, 124.4, 122.6, 122.1, 112.4, 109.8, 108.3, 107.7,
106.8, 101.5, 101.0, 81.1, 55.9, 40.5, 36.3.
General Procedure for Synthesis of Compounds 6a-6b: A
100 mL dry two-necked round-shaped flask equipped with a
magnetic stirrer was charged with 5a or 5b (1.0 mmol) in
General Procedure for Synthesis of Compounds 5a-5c: A
100 mL dry two-necked round-shaped flask equipped with a
magnetic stirrer was charged with 3w (344 mg, 1.0 mmol) in
CH2Cl2 (20 mL) at 25 oC. TMSNu (Me3SiH, Me3SiCN, Me3Si-
allyl, 2.0 mmol) was added in one portion to the solution at 25
o
MeCN (10 mL) at 25 C. Trifluoroacetic anhydride (TFAA,
420 mg, 2.0 mmol) was added in one portion to the solution at
o
25 oC. The reaction mixture was stirred at 25 C for 10 h. The
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crude solution was evaporated by rotavapor, diluted with wa-
ter (10 mL), and extracted with CH2Cl2 (3 × 20 mL). The
combined organic layers were washed with brine, dried, fil-
tered and evaporated to afford crude product under reduced
pressure. Purification on silica gel (hexanes/EtOAc = 15/1~1/1)
afforded compounds 6a-6b.
mixture was stirred at reflux for 10 h. The reaction mixture
was cooled to 25 C. Aqueous H2SO4 solution (6N, 10 mL)
o
was added to the reaction mixture, and the mixture was stirred
at reflux for 10 h. The solvent of reaction mixture was cooled
to 25 oC, evaporated by rotavapor, diluted with water (10 mL),
and extracted with EtOAc (3 x 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 = 15/1~1/1) afforded compound
2,3,7,8-Tetramethoxy-5,11-
dihydrodibenzo[a,d]cyclohepten-10-one (6a). Yield = 87%
9
o
(285 mg); Colorless solid; mp = 191-193 C (recrystallized
o
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+
8. Yield = 52% (200 mg); Colorless solid; mp > 250 C
1
(recrystallized from hexanes and EtOAc); HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C46H53O10 765.3639, found 765.3645;
1H NMR (400 MHz, CDCl3): δ 7.43 (s, 2H), 6.66 (s, 2H), 6.61
(s, 2H), 6.14 (s, 2H), 4.75 (d, J = 11.2 Hz, 2H), 4.50 (d, J =
11.2 Hz, 2H), 3.96-3.79 (m, 4H), 3.94 (s, 6H), 3.79 (s, 6H),
3.75-3.63 (m, 4H), 1.80-1.71 (m, 4H), 1.62-1.52 (m, 4H), 0.98
(t, J = 7.2 Hz, 6H), 0.89 (t, J = 7.2 Hz, 6H); 13C{1H} NMR
(100 MHz, CDCl3): δ 195.7 (2C), 152.5 (2C), 147.8 (2C),
147.71 (2C), 147.68 (2C), 136.8 (2C), 131.8 (2C), 127.8 (2C),
127.3 (2C), 118.4 (2C), 117.0 (2C), 112.9 (2C), 112.2 (2C),
71.0 (2C), 70.8 (2C), 66.3 (2C), 56.8 (2C), 56.1 (2C), 55.8
(2C), 22.4 (2C), 22.2 (2C), 10.4 (2C), 10.2 (2C); Anal. Calcd
for C46H52O10: C, 72.23; H, 6.85. Found: C, 72.50; H, 6.67.
Single-crystal X-Ray diagram: crystal of compound 8 was
grown by slow diffusion of EtOAc into a solution of com-
pound 8 in CH2Cl2 to yield colorless prisms. The compound
crystallizes in the monoclinic crystal system, space group P
21/n, a = 16.1741(16) Å , b = 8.5137(8) Å , c = 28.773(3) Å , V
= 3930.5(7) Å 3, Z = 4, dcalcd = 1.293 g/cm3, F(000) = 1632, 2θ
range 1.375~26.776o, R indices (all data) R1 = 0.1227, wR2 =
0.1502.
calcd for C19H21O5 329.1389, found 329.1393; H NMR (400
MHz, CDCl3): δ 7.60 (s, 1H), 6.79 (s, 1H), 6.78 (s, 1H), 6.74
(s, 1H), 4.07 (s, 2H), 4.00 (s, 2H), 3.92 (s, 3H), 3.82 (s, 3H),
3.81 (s, 3H), 3.80 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3):
δ 193.2, 152.4, 147.6, 147.5, 147.4, 137.6, 132.1, 127.1, 124.7,
112.5, 112.1, 111.7, 111.4, 55.89, 55.86 (2C), 55.8, 50.1, 41.6;
Anal. Calcd for C19H20O5: C, 69.50; H, 6.14. Found: C, 69.83;
H, 6.45.
2,3,7,8-Tetramethoxy-10-oxo-10,11-dihydro-5H-
dibenzo[a,d]cycloheptene-5-carbonitrile (6b). Yield = 86%
o
(304 mg); Colorless solid; mp = 215-217 C (recrystallized
from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+
calcd for C20H20NO5 354.1342, found 354.1344; 1H NMR (400
MHz, CDCl3): δ 7.66 (s, 1H), 7.17 (s, 1H), 7.09 (s, 1H), 6.82
(s, 1H), 5.57 (s, 1H), 4.23 (d, J = 18.0 Hz, 1H), 4.13 (d, J =
18.0 Hz, 1H), 4.03 (s, 3H), 3.91 (s, 3H), 3.89 (s, 3H), 3.86 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3): δ 191.7, 152.9, 149.1,
148.9, 148.2, 130.5, 126.5, 126.4, 124.0, 117.9, 113.3, 113.2,
109.8, 109.5, 56.3 (2C), 56.2, 56.1, 49.6, 40.9; Anal. Calcd for
C20H19NO5: C, 67.98; H, 5.42; N, 3.96. Found: C, 68.25; H,
5.67; N, 4.23.
General Procedure for Synthesis of Compounds 9-11: A
100 mL dry two-necked round-shaped flask equipped with a
magnetic stirrer was charged with arylacetic acids 1g-1i (1.0
1-(3,4-Dimethoxyphenyl)-6,7-dimethoxyisochroman (7). A
100 mL dry two-necked round-shaped flask equipped with a
magnetic stirrer was charged with 3w (344 mg, 1.0 mmol) in
o
mmol) in MeCN (8 mL) at 25 C. Trifluoroacetic anhydride
o
MeOH (10 mL) at 25 C. NaBH4 (70 mg, 2.0 mmol) was add-
(TFAA, 210 mg, 1.0 mmol) was added in one portion to the
solution at 25 oC. The reaction mixture was stirred at 25 oC for
10 min. Then, veratraldehyde (2w, 166 mg, 1.0 mmol) in
MeCN (2 mL) was added to the reaction mixture at 25 oC. The
ed in one portion to the solution at 25 oC. The reaction mixture
o
was stirred at 25 C for 10 min. Then, BF3·OEt2o(210 mg, 1.5
mmol) was added to the reaction mixture at 25 C. The reac-
o
o
tion mixture was stirred at 25 C for 10 h. The crude solution
reaction mixture was stirred at 25 C for 10 h. The crude solu-
was evaporated by rotavapor, diluted with water (10 mL), and
extracted with EtOAc (3 x 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 = 15/1~1/1) afforded compound
7. Yield = 90% (297 mg); Colorless liquid; HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C19H23O5 331.1546, found 331.1548;
1H NMR (400 MHz, CDCl3): δ 6.82 (br s, 3H), 6.64 (s, 1H),
6.25 (s, 1H), 5.61 (s, 1H), 4.13 (dt, J = 4.4, 11.6 Hz, 1H), 3.90-
3.84 (m, 1H), 3.867 (s, 3H), 3.865 (s, 3H), 3.82 (s, 3H), 3.66 (s,
3H), 3.02 (ddd, J = 5.6, 8.8, 15.2 Hz, 1H), 2.71 (dt, J = 4.0,
16.0 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 149.0,
148.8, 147.8, 147.1, 134.7, 129.0, 126.0, 121.4, 111.7, 111.1,
110.6, 109.7, 79.0, 63.5, 55.84, 55.81, 55.78 (2C), 28.3.
tion was evaporated by rotavapor, diluted with water (10 mL),
and 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 = 15/1~1/1) afforded compounds
9-11.
3-(3,4-Dimethoxyphenyl)-2-(4-methoxyphenyl)acrylic acid
o
(9). Yield = 57% (179 mg); Colorless solid; mp = 208-210 C
(recrystallized from hexanes and EtOAc); HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C18H19O5 315.1233, found 315.1239;
1H NMR (400 MHz, CDCl3): δ 8.90 (brs, 1H), 7.86 (s, 1H),
7.21 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 6.86 (dd, J =
2.0, 8.4 Hz, 1H), 6.74 (d, J = 8.4 Hz, 1H), 6.52 (d, J = 2.0 Hz,
1H), 3.85 (s, 3H), 3.82 (s, 3H), 3.46 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3): δ 172.9, 159.3, 150.3, 148.2, 142.2, 131.2
(2C), 128.7, 128.0, 127.3, 125.8, 114.4 (2C), 112.5, 110.5,
55.8, 55.3, 55.2; Anal. Calcd for C18H18O5: C, 68.78; H, 5.77.
Found: C, 68.93; H, 5.52.
2,3,9,10-Tetramethoxy-18,19,24,25-tetra-n-propoxy-
5,6,12,13-tetrahydro-5,13:6,12-
bis([1,2]benzeno)dibenzo[a,f][10]annulene-7,14-dione (8). A
100 mL dry two-necked round-shaped flask equipped with a
magnetic stirrer was charged with 3ae (400 mg, 1.0 mmol) in
o
1-(3,4-Dimethoxyphenyl)-6-methoxyisochroman-3-one (10).
Yield = 85% (267 mg); Colorless liquid; HRMS (ESI-TOF)
dioxane (10 mL) at 25 C. tBuOK (330 mg, 3.0 mmol) was
o
added in one portion to the solution at 25 C. The reaction
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The Journal of Organic Chemistry
m/z: [M + H]+ calcd for C18H19O5 315.1233, found 315.1241;
a Catalytic Asymmetric Oxa-Pictet-Spengler Reaction. J. Am.
Chem. Soc. 2016, 138, 9429-9432.
2
3
4
5
6
7
8
9
1H NMR (400 MHz, CDCl3): δ 6.85 (d, J = 2.0 Hz, 1H), 6.81
(d, J = 8.4 Hz, 1H), 6.80 (s, 1H), 6.75 (s, 1H), 6.75-6.72 (m,
2H), 6.26 (s, 1H), 3.85 (s, 3H), 3.80 (s, 3H), 3.78 (s, 3H), 3.69
(d, J = 18.0 Hz, 1H), 3.60 (d, J = 18.0 Hz, 1H); 13C{1H} NMR
(100 MHz, CDCl3): δ 170.5, 159.9, 149.3, 149.2, 132.5, 129.5,
127.1, 126.9, 120.0, 112.5, 112.4, 110.60, 110.55, 81.7, 55.78,
55.77, 55.3, 36.7.
(7) Zhao, C.; Chen, S. B.; Seidel, D. Direct Formation of
Oxocarbenium Ions under Weakly Acidic Conditions: Catalytic
Enantioselective Oxa-Pictet-Spengler Reactions. J. Am. Chem.
Soc. 2016, 138, 9053-9056.
(8) Eid, C. N.; Shim, J.; Bikker, J.; Lin, M. Direct Oxa-Pictet-
Spengler Cyclization to the Natural (3a,5)-trans-Stereochemistry
in the Syntheses of (+)-7-Deoxyfrenolicin
B and (+)-7-
Deoxykalafungin. J. Org. Chem., 2009, 74, 423-426.
5,6-dimethoxy-2,3-dihydro-1H-inden-1-one (11). Yield =
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(9) Fan, W.-T.; Li, N.-K.; Xu, L.; Qiao, C.; Wang, X.-W. Organo-
Catalyzed Asymmetric Michael-Hemiketalization-Oxa-Pictet-
Spengler Cyclization for Bridged and Spiro Heterocyclic Skele-
tons: Oxocarbenium Ion as a Key Intermediate. Org. Lett. 2017,
19, 6626-6629.
o
80% (154 mg); Colorless solid; mp = 119-121 C (recrystal-
lized from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C11H13O3 193.0865, found 193.0863; H NMR
1
(400 MHz, CDCl3): δ 7.08 (s, 1H), 6.81 (s, 1H), 3.89 (s, 3H),
3.82 (s, 3H), 2.98-2.95 (m, 2H), 2.59-2.57 (m, 2H); 13C{1H}
NMR (100 MHz, CDCl3): δ 205.5, 155.2, 150.2, 149.2, 129.7,
107.3, 103.9, 56.0, 55.9, 36.3, 25.4; Anal. Calcd for C11H12O3:
C, 68.74; H, 6.29. Found: C, 68.90; H, 6.47.
(10) Zhang, Y.; Wang, X.; Sunkara, M.; Ye, Q.; Ponomereva, L. V.;
She, Q.-B.; Morris, A. J.; Thorson, J. S. A Diastereoselective
Oxa-Pictet-Spengler-Based Strategy for (+)-Frenolicin B and
epi-(+)-Frenolicin B Synthesis. Org. Lett. 2013, 15, 5566-5569.
(11) Zhang, X.; Li, X.; Lanter, J. C.; Sui, Z. Silicon-Directed Oxa-
Pictet-Spengler Cyclization and an Unusual Dimerization of 2-
Trimethylsilanyl Tryptophols. Org. Lett. 2005, 7, 2043-2046.
(12) Hegedus, A.; Hell, Z. Zeolite-Catalyzed Simple Synthesis of
Isochromans via the Oxa-Pictet-Spengler Reaction. Org. Biomol.
Chem. 2006, 4, 1220-1222.
(13) Gharpure, S. J.; Nanda, S. K. Stereoselective Synthesis of
Thiazino[4,3-a]indoles Using the Thia-Pictet-Spengler Reaction
of Indoles Bearing N-Tethered Thiols and Vinylogous
Thiocarbonates. Org. Biomol. Chem. 2016, 14, 5586-5590.
(14) Saeed, A. Oxa-Pictet-Spengler Reaction in Water. Synthesis of
Some (+/-)-1-Aryl-6,7-dimethoxyisochromans. Chin. Chem. Lett.
2010, 21, 261-264.
ASSOCIATED CONTENT
Supporting Information
Scanned photocopies of NMR spectral data for all compounds and
X-ray analysis data of 3j, 3p, 3s, 3z, 3af, 3ag, 3aj, 3at, 5a and 8.
This information is available free of charge via the Internet at http:
//pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Email: mychang@kmu.edu.tw
ORCID
(15) Lherbet, C.; Soupaya, D.; Baudoin-Dehoux, C.; Andre, C.;
Blonski, C.; Hoffmann, P. Bismuth Triflate-Catalyzed Oxa- and
Thia-Pictet-Spengler Reactions: Access to Iso- and Isothio-
Chroman Compounds. Tetrahedron Lett. 2008, 49, 5449-5451.
Meng-Yang Chang: 0000-0002-1983-8570
Notes
(16) Finkelstein,
J.;
Brossi,
A.
The
Synthesis
of
Tetrahydroisoquinolines from 1,4-Dihydro-3-(2H)-isoquinolones.
J. Heterocycl. Chem. 1967, 4, 315-318.
The authors declare no competing financial interest.
(17) Finkelstein, J. 1,4-Dihydro-3(2H)-Isoquinolinones. US 3480634
Hoffmann-La Roche Inc. Nov. 25, 1969.
ACKNOWLEDGMENT
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densation of Phenyl Ethers with Aliphatic Aldehydes. XXII. Re-
action of Bis(3,4-Dimethoxyphenyl)Acetic Acid with Chlorinat-
ed Aldehydes. Ann. Chim. (Rome) 1968, 58, 298-313.
(19) Chang, M.-Y.; Wu, Y.-S.; Chen, H.-Y. CuI Mediated Synthesis
of Sulfonyl Benzofuran-3-ones and Chroman-4-ones. Org. Lett.
2018, 20, 1824-1827.
(20) Chang, M.-Y.; Chen, Y.-H.; Wang, H.-S. Cu(OAc)2 Mediated
Synthesis of 3-Sulfonyl Chromen-4-ones. J. Org. Chem. 2018,
83, 2361-2368.
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Sulfonyl Chroman-4-ols. J. Org. Chem. 2018, 83, 6798-6804.
(22) Chan, C.-K.; Tsai, Y.-L.; Chang, M.-Y. Construction of Nitrated
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The authors would like to thank the Ministry of Science and
Technology of the Republic of China for financial support
(MOST 106-2628-M-037-001-MY3).
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