MCPBA-Mediated Intramolecular Oxidative Annulation of ortho-Crotyl or Cinnamyl Arylaldehydes: Synthesis of Benzofused Five-, Six-, and Seven-Membered Oxacycles

Article abstract of DOI:10.1021/acs.joc.8b02146

mCPBA-mediated intramolecular oxidative annulation of ortho-crotyl or cinnamyl arylaldehydes provides chroman, coumaran, isochroman, and tetrahydrobenzo[c]oxepine under different reaction conditions. This research investigates the reaction conditions for facile and efficient transformation.

Full text of DOI:10.1021/acs.joc.8b02146

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Note
mCPBA-Mediated Intramolecular Oxidative Annulation
of ortho-Crotyl or Cinnamyl Arylaldehydes. Synthesis of
Benzofused Five-, Six- and Seven-Membered Oxacycles
Meng-Yang Chang, Yu-Ting Hsiao, and Kai-Hsiang Lai
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02146 • Publication Date (Web): 23 Oct 2018
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mCPBA-Mediated Intramolecular Oxidative Annulation of ortho-
Crotyl or Cinnamyl Arylaldehydes. Synthesis of Benzofused Five-,
Six- and Seven-Membered Oxacycles
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Meng-Yang Chang,*a,b Yu-Ting Hsiaoa and Kai-Hsiang Laia
aDepartment of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan bDepartment of
Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
Supporting Information Placeholder
OH
OH
Ph
Ar
Ar
Ph P=CH
K CO
2 3
3
2
O
O
Ph
OH
Me
R
Ar
Ar
O
then mCPBA
mCPBA
O
O
R = Ph, Me
O
Cl mCPBA then
NaBH then
4
Jones ox.
mCPBA, K CO
2
3
O
R
OH
OH
Ph
Me
Ar
O
Ar
Ar
O
O
R = Ph
R = Me
O
ABSTRACT: mCPBA-mediated intramolecular oxidative annulation of ortho-crotyl or cinnamyl arylaldehydes provides chroman,
coumaran, isochroman, and tetrahydrobenzo[c]oxepine under different reaction conditions. This research investigates the reaction
conditions for facile and efficient transformation.
ortho-Carbonyl allylarenes are the key synthetic intermedi-
ates for diversified structural transformations, and they are
also used as building blocks to prepare many bioactive mole-
cules.1-2 For this core structure along with its related deriva-
tives, many synthetic applications on the construction of dif-
ferent benzofused five-membered carbocycles (indene,3 1-
indanol,4 1-indanone5), six-membered carbocycles (dialin,6 1-
tetralone,7 dihydroisoquinoline nitrone8), and heterocycles
(dioxacycle,9 isoquinoline10) have been reported via transition
metal-catalyzed and base or acid-promoted intramolecular
annulation. Intramolecular annulations of ortho-carbonyl vi-
nylarenes are also popular approaches.11
still a continuing need in the organic synthetic field. Among
the present scaffolds in the benzofused oxacyclic family, the
core structures of chroman, coumaran, isochroman, and tetra-
hydrobenzo[c]oxepine having five-, six-, or seven-membered
ring systems are relatively well-studied, especially elegant
synthetic methods13 and biological activities (Scheme 1).14
However, the involvement of
a direct mCPBA (m-
chloroperoxybenzoic acid)-mediated intramolecular annula-
tion route into different ring-size oxacyclic skeletons has not
been reported until recently. Based on the recent findings and
studies, facile and efficient methods for their preparation are
needed.
We recently explored synthetic applications of ortho-
methylallyl (crotyl) and phenylallyl (cinnamyl) arylaldehydes
for establishing some significant frameworks using facile con-
densation and cyclization strategies, including benzoazaho-
moisotwistane,12a tetrahydrocyclobuta[a]naphthalene,12b aryl-
dihydronaphthalene,12c benzobicycle.12d-f and vinylindane.12g
Although many synthetic protocols have been extensively
investigated in the formation of multiple unique skeletons via
functionalization of ortho-carbonyl allylarenes, few reports
focus on the synthesis of oxygen-containing cyclic frame-
works.9,11a Therefore, the development of an easy, one-pot
route for the simultaneous carbon-oxygen (C-O) bond for-
mation and ring-construction of diversified oxa-benzocycles
from readily available starting ortho-carbonyl allylarenes is
Scheme 1. Structures of ortho-Crotyl or Cinnamyl Arylalde-
hyde, Chroman, Coumaran, Isochroman, and Tetrahydroben-
zo[c]oxepine
OH
OH
Ph / Me
Ar
Ar
Ar
coumaran
O
Me
O
O
Ph
o-crotyl or o-cinnamyl
chroman
arylaldehyde
O
OH
Me
OH
Ph
OH
Ph
Ph / Me
Ar
Ar
Ar
Ar
O
O
O
O
O
O
O
isochroman
tetrahydrobenzo[c]oxepine
Cl
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Continuing our research on the synthetic applications of o-
To study the scope of this route, o-cinnamyl arylaldehydes
cinnamyl arylaldehydes,12 herein, we present the peroxide
reagents-mediated preparation of chroman skeleton via one-
pot synthetic sequence of epoxidation, Dakin reaction, de-
formylation and intramolecular annulation (Table 1). The ini-
tial study commenced with treatment of model substrate 1a
(1.0 mmol) with 2.2 equivalents of mCPBA in CH2Cl2 (10 mL)
1b-1e (R1 = benzyl, cyclopentyl, n-butyl and isopropyl) were
reacted with the combination of mCPBA and K2CO3 to afford
diversified 2b-2e with the dihydrobenzopyran skeleton at
80%-84% based on the optimal conditions established (Table
1, entry 4), as shown in Table 2, entries-2-5. For treatment of
o-crotyl arylaldehydes 1f-1j (R1 = methyl, benzyl, cyclopentyl,
n-butyl and isopropyl), only coumaran 3a-3e with dihydroben-
zofuran skeleton were isolated at 76%-84% yields (entries 6-
10). One possible reason could be the cinnamyl arm provided
a more reactive epoxide center than the crotyl arm such that
in-situ generated phenoxide (for intermediate A1) that could
attack this benzylic center to form 2a-2e with a six-membered
ring via the intramolecular annulation. According to the effi-
ciency of ring-formation, the five-membered ring was pre-
ferred to cyclize versus the six-membered ring by intramolecu-
lar annulation of in-situ generated phenoxide (for intermediate
A2) and crotyl epoxide arm. On the basis of the results, we
understood that the substituent of the cinnamyl (R = Ph) and
crotyl (R = Me) could control the generation of two key ben-
zofused oxacycles, chroman and coumaran, via the combina-
tion of mCPBA and K2CO3. The stereochemical structures of
2a and 3b were determined by single-crystal X-ray crystallog-
raphy.15
o
at 25 C for 3 h. However, the complex mixture was isolated
9
as major products and only trace 2a (5% yield) were detected
(entry 1). By the addition of K2CO3 (2.2 equiv), the yield of 2a
was increased to 57% along with 30% yield of the complex
mixture (entry 2). Elongating the reaction time (3  15, 30
and 45 h), the yield increased to 70%, 90%, and 89%, respec-
tively (entries 3-5). In entry 4, 2a was isolated as a sole trans-
isomer, and cis-form diastereomer was not detected. However,
when the reaction temperature was elevated to reflux (~40 oC),
the yield of 2a decreased to 65% (entry 6). From the results,
we envisioned that the elongated reaction time could increase
the yield of 2a. Subsequently, two peroxides were examined,
such as t-butyl hydroperoxide (tBuO2H) and H2O2. However,
no isolation of the desired 2a was observed (entries 7-8). After
changing K2CO3 to Na2CO3 and Li2CO3, 2a was produced at
only 32% and 22% yields, respectively, due to weaker basicity
inhibiting the intramolecular annulation (entries 9-10). By
controlling mCPBA and K2CO3 (2.2 equiv) as the combination,
other equivalents (1.1 and 3.3 equiv) were examined; however,
1.1 equivalents provided complex products and 3.3 equiva-
lents afforded a similar yield (85%, entries 11-12). Solvent
screening was performed next. It was found that the reaction
had poorer yields (70% and 52%) obtained in DMF and
MeCN, respectively (entries 13-14), while no desired product
was detected in toluene (entry 15).
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Table 2. Synthesis of 2 and 3a
MeO
MeO
OH
Ph
O
1
1
R O
O
R O
O
Ph
MeO
K CO
3
R
2
A1
2a-2e
O
1
R O
mCPBA
O
MeO
OH
Me
MeO
1a-1e, 1f-1j
1
1
Me
O
R O
R O
O
Table 1. Intramolecular Annulation Conditionsa
A2
3a-3e
MeO
intramolecular
annulation
MeO
OH
Ph
Ph
entry
1, R =, R1 =
1a, Ph, Me
2 / 3 (%)b
2a, 90
2b, 82
2c, 80
2d, 81
2e, 84
3a, 84
3b, 83
3c, 78
3d, 76
3e, 78
O
MeO
MeO
O
conditions
1
2
1a
2a
1b, Ph, Bn
entry peroxide base
solvent time (h) 2a (%)b
3
4
1c, Ph, c-C5H9
1d, Ph, n-C4H9
1e, Ph, i-C3H7
1f, Me, Me
1
2
mCPBA
mCPBA
mCPBA
mCPBA
mCPBA
mCPBA
tBuO2H
H2O2
–
CH2Cl2
CH2Cl2
3
3
5c
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
57
70
90
89
65
5
6
3
CH2Cl2 15
CH2Cl2 30
CH2Cl2 45
CH2Cl2 30
CH2Cl2 30
CH2Cl2 30
4
5
6d
7
7
8
1g, Me, Bn
1h, Me, c-C5H9
1i, Me, n-C4H9
1j, Me, i-C3H7
9
10
e
–
e
aThe reactions were run on a 1.0 mmol scale with 1a-1j,
8
–
32c
22c
K2CO3 (2.2 equiv), mCPBA (70%, 2.2 equiv), CH2Cl2 (10 mL),
9
mCPBA
Na2CO3 CH2Cl2 30
25 oC, 30 h. bIsolated yields.
10 mCPBA
Li2CO3
CH2Cl2 30
CH2Cl2 30
CH2Cl2 30
11 mCPBAf K2CO3
12 mCPBAg K2CO3
–
f
e
As an extension of mCPBA-mediated intramolecular annu-
lations o-cinnamyl and o-crotyl arylaldehydes, the synthetic
application on the skeleton of tetrahydrobenzo[c]oxepine was
investigated (Table 3). By reduction of substrates 1a-1j with
g
85
70
52
13 mCPBA
14 mCPBA
15 mCPBA
K2CO3
K2CO3
K2CO3
DMF
30
30
MeCN
toluene 30
o
NaBH4 in MeOH at 25 C, the primary alcohols were generat-
e
–
ed in quantitative amounts. Without purification, reaction of
the resulting products with the combination of mCPBA and
K2CO3 at 25 oC for 30 h produced tetrahydrobenzo[c]oxepines
4a-4e (for R = Ph) and isochromans 5a-5d (for R = Me) at
80%-88% yields. Among entries 1-9, efficient formation of
4a-4e and 5a-5d showed that the R1 substituent did not affect
aThe reactions were run on a 1.0 mmol scale with 1a, perox-
o
ide (2.2 equiv), base (2.2 equiv), solvent (10 mL), 25 C, time
(h). bIsolated yields. cComplex products were isolated as major
products. dReflux. eNo detection. f1.1 equivalents. g3.3 equiva-
lents.
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the yield. However, when R1 is an isopropyl group (entry 10),
a bulkier steric hindrance provided more repulsion such that
2
only de-isopropyl 5e (R1 = H) was obtained at a 67% yield.
Attempts to afford isopropyl-5e failed. For the intramolecular
ring-closure of in-situ formed benzyloxide (for intermediate
B1), the reactive benzylic position on the cinnamyl epoxide
arm of 1a-1e could be attacked to yield 4a-4e with a seven-
membered ring specifically. In contrast to the generation of
4a-4e, the situation for the formation of 5a-5e was similar to
3a-3e. The intramolecular ring-closure from benzyloxide to
the crotyl epoxide arm (for intermediate B2) still obeyed the
ring-formation principal to generate a six-membered ring ra-
ther than a seven-membered ring. The stereochemical struc-
tures of 4a, 4d, and 5b were determined by single-crystal X-
ray crystallography.15
the carboxylate attacked another carbon. A similar phenome-
non was observed in the formation of 7a-7e (R = Me) via in-
tramolecular annulation of chromium benzoate with a crotyl
epoxide chain (for 1f-1j). To demonstrate reproducibility,
different aryl (Ar) groups were tested (Table 4, entries 11-18).
For the electronic nature of the Ar group, the electron-neutral
group (1k) and electron-withdrawing (1m-1n) and electron-
donating groups (1l, 1o-1r) were appropriate and well-
tolerated.
3
4
5
6
7
8
9
10
11
12
13
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Table 4. Synthesis of 6 and 7a
O
3
4
mCPBA then Jones ox.
R
R
Ar
Ar
O
O
5
Table 3. Synthesis of 4 and 5a
O
6, R = Ph
7, R = Me
1
mCPBA
OH
O
more repulsion
H
H
MeO
O
MeO
Ph
Me
R
R
Ph
Jones
H CrO
R
Ar
Ar
D
Ar
O
O
1
O
1
O
O
R O
O
R O
2
4
Cr
MeO
Cr
O
OH
O
O
HO
R
B1
B2
4a-4e
5a-5e
NaBH
then
O
4
O
OH
HO
C
E
OH
Me
O
1
O
O
R O
MeO
MeO
entry 1, R =, Ar =
6 / 7 (%)b
6a, 93
6b, 94
6c, 90
6d, 91
6e, 89
7a, 94
7b, 96
7c, 96
7d, 95
7e, 94
6f, 93
6g, 93
6h, 94
6i, 93
mCPBA
1a-1e, 1f-1j
O
K CO
1
2
3
1
R O
R O
1
2
3
1a, Ph, 4,5-(MeO)2C6H2
1b, Ph, 4-MeO-5-BnOC6H2
1c, Ph, 4-MeO-5-c-C5H9OC6H2
1d, Ph, 4-MeO-5-n-C4H9OC6H2
1e, Ph, 4-MeO-5-i-C3H7OC6H2
1f, Me, 4,5-(MeO)2C6H2
1g, Me, 4-MeO-5-BnOC6H2
1h, Me, 4-MeO-5-c-C5H9OC6H2
1i, Me, 4-MeO-5-n-C4H9OC6H2
1j, Me, 4-MeO-5-i-C3H7OC6H2
1k, Ph, Ph
entry
1, R =, R1 =
1a, Ph, Me
4 / 5 (%)b
4a, 86
4b, 88
4c, 83
4d, 84
4e, 80
5a, 80
5b, 84
5c, 80
5d, 84
5e,c 67
1
2
3
4
5
1b, Ph, Bn
1c, Ph, c-C5H9
1d, Ph, n-C4H9
1e, Ph, i-C3H7
1f, Me, Me
6
7
4
5
8
9
6
7
1g, Me, Bn
10
11
12
13
14
15
16
17
18
8
9
1h, Me, c-C5H9
1i, Me, n-C4H9
1j, Me, i-C3H7
1l, Ph, 4-MeO-5-allylOC6H2
1m, Ph, 4-FC6H3
10
aThe reactions were run on a 1.0 mmol scale with 1a-1j,
1n, Ph, 5-FC6H3
1o, Ph, 5-MeOC6H3
NaBH4 (1.0 equiv), MeOH (10 mL), 25 oC, 30 min; mCPBA
6j, 90
6k, 89
6l, 84
(70%, 1.1 equiv), then K2CO3 (1.1 equiv), CH2Cl2 (10 mL), 25
oC, 30 h. bIsolated yields. cR1 = H.
1p, Ph, 3,5-(MeO)2C6H2
1q, Ph, 3-MeO-5-BnOC6H2
1r, Ph, 3-MeO-5-n-C4H9OC6H2
After examining the phenoxide and benzyloxide-mediated
intramolecular annulations, this study also explored how ben-
zoate promoted ring-closure. Similarly, o-cinnamyl and o-
crotyl arylaldehydes 1a-1e and 1f-1j (1.0 mmol) were reacted
with 1.1 equivalents of mCPBA in the absence of K2CO3 in
CH2Cl2 at 25 oC for 30 min to give an epoxide intermediate C.
Subsequently, the resulting intermediate was oxidized by an
6m, 88
aThe reactions were run on a 1.0 mmol scale with 1a-1r,
mCPBA (70%, 1.1 equiv), CH2Cl2 (10 mL), 25 oC, 30 min;
Jones reagent (2 mL), 25 oC, 3 h. bIsolated yields.
After investigating how the oxygen-atom (phenoxide, ben-
zyloxide and benzoate) mediated the carbon-oxygen bond
formation, this study then examined mCPBA-promoted car-
bon-carbon formation. First, Wittig olefination of the formyl
group of 1a-1e (R = Ph, 1.0 mmol) with in-situ generated ex-
cess Ph3P=CH2 (prepared from 2.0 equivalents of Ph3CH3I and
1.8 equivalents tBuOK) in THF (Table 5). Without further
purification, the double expoxdation of the resulting olefin
with 2.2 equivalents of mCPBA provided 8a-8e as a mixture
of two isomers (ratio ~ 1:1) in modest yields (60%-73%) via
the release of m-chlorobenzoic acid mediating two epoxide
ring-openings of intermediate F and a seven-membered ring
formation (entries 1-5). However, after treatment of 1k with
the combination of Ph3P=CH2 and mCPBA, only di-epoxide
product 9a with a mixture of two isomers (ratio ~ 1:1) was
o
excess Jones reagent (2 mL) at 25 C for 3 h to afford iso-
chroman-1-ones 6a-6e (R = Ph) and 7a-7e (R = Me) in good to
excellent yields (89%-94% and 94%-96%) via intramolecular
annulation of in-situ formed chromium benzoate intermediate
D with cinnamyl epoxide chain followed by further oxidation
of intermediate E with the resulting secondary alcohols (Table
4, entries 1-10). The structure of 6a was determined by single-
crystal X-ray crystallography.15 Compared with the formation
of 2a-2e and 4a-4e, the motif of carboxylate on the chromium-
cheated complex favored to attack the less-reactive benzylic
position of 1a-1e to construct a six-membered ring system
under the acidic conditions. According to our experimental
results, one plausible reason is that the benzylic position with
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generated at a 78% yield, while no desired product conjugated
Reactions were routinely carried out under an atmosphere of
m-chlorobenzoic acid was observed (Scheme 2). The possible
reason should be that the oxygenated group on arene (Ar)
played a key factor at promoting epoxide ring-opening such
that in-situ generated alkoxy group could attack the benzylic
position of another epoxide ring to produce polysubstituted
oxygenated tetrahydrobenzo[c]oxepine skeleton via an intra-
molecular tandem process.
dry nitrogen with magnetic stirring. Products in organic sol-
vents were dried with anhydrous magnesium sulfate before
concentration in vacuo. Melting points were determined with a
1
SMP3 melting apparatus. H and 13C NMR spectra were rec-
orded 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
given in Hertz. High resolution mass spectra (HRMS) were
measured with a mass spectrometer Finnigan/Thermo Quest
MAT 95XL by electrospray ionization (ESI-TOF) method. X-
ray crystal structures were obtained with an Enraf-Nonius FR-
590 diffractometer (CAD4, Kappa CCD).
9
Table 5. Synthesis of 8a
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
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OH
O
MeO
Ph P=CH
3 2
MeO
MeO
Ph
Ph
Ph
O
then
1
1
1
O
R O
O
R O
R O
mCPBA
O
O
1
F
8
O
Representative synthetic procedure of compounds 1a-1j, 1l
and 1p-1r is as follows: K2CO3 (2.7 g, 20.0 mmol) was added
to a stirred solution of isovanillin (1.52 g, 10.0 mmol) or 3-
hydroxy-5-methoxy-benzaldehyde (1.52 g, 10.0 mmol) in
HO
Cl
Cl
o
MeCN (100 mL) at 25 C. The reaction mixture was stirred at
entry
1, R =, R1 =
1a, Ph, Me
1b, Ph, Bn
8 (%)b
8a, 73
8b, 70
8c, 66
8d, 60
8e, 67
25 oC for 10 min. Trans-cinnamyl bromide (2.1 g, 11.0 mmol)
or crotyl bromide (1.5 g, 11.0 mmol) was added to the reaction
mixture at 25 oC. The reaction mixture was stirred at reflux for
8 h. The reaction was traced by TLC until isovanillin was con-
sumed. The reaction mixture was cooled to 25 oC, concentrat-
ed, and extracted with EtOAc (3 x 60 mL). The combined
organic layers were washed with brine, dried, filtered and
evaporated to afford crude product under reduced pressure.
Without further purification, decalin (15 mL) was added to a
solution of the resulting products. The reaction mixture was
stirred at reflux for 8 h. The reaction was traced by TLC until
the resulting product was consumed. The reaction mixture was
cooled to 25 oC. Decalin was evaporated to afford crude prod-
uct under reduced pressure. Without further purification,
K2CO3 (2.7 g, 20.0 mmol) was added to a solution of the re-
1
2
3
4
5
1c, Ph, c-C5H9
1d, Ph, n-C4H9
1e, Ph, i-C3H7
aThe reactions were run on a 1.0 mmol scale with 1a-1e,
Ph3P=CHI (excess, in-situ formed from 2.0 equiv of PPh3-
CH3I and 1.8 equiv of tBuOK), THF (10 mL), 25 C, 30 min;
o
o
b
mCPBA (70%, 1.1 equiv), CH2Cl2 (10 mL), 25 C, 30 h. I-
solated yields.
Scheme 2. Synthesis of 9a
OH
O
Ph P=CH
Ph
3
2
Ph
Ph
o
O
sulting product in THF (100 mL) at 25 C. The reaction mix-
O
then
mCPBA
O
O
ture was stirred at 25 oC for 10 min. Methyl iodide (1.6 g, 11.0
mmol, for 1a, 1f 1p), benzyl bromide (1.9 g, 11.0 mmol, for
1b, 1g, 1q), cyclopentyl bromide (1.6 g, 11.0 mmol for 1c, 1h),
n-butyl bromide (1.5 g, 11.0 mmol for 1d, 1i, 1r), isopropyl
bromide (1.36 g, 11.0 mmol for 1e, 1j) or allyl bromide (1.3 g,
11.0 mmol, for 1l) was added to the reaction mixture at 25 oC.
The reaction mixture was stirred at reflux for 8 h (the reaction
was traced by TLC). The reaction mixture was cooled to 25 oC,
concentrated, and extracted with EtOAc (3 x 60 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 = 10/1~2/1)
afforded 1a-1j, 1l and 1p-1r. Compounds 1a-1j, 1l and 1p-1r
are known compounds and the analytical data are consistent
with those in the references 12a-12g.
O
1k
9a (78%)
not detected
Cl
In summary, we have herein developed mCPBA promoted
facile and the efficient synthesis of benzofused oxacycles,
including chroman, coumaran, isochroman, and tetrahydro-
benzo[c]oxepine via intramolecular oxidative annulation of o-
crotyl or o-cinnamyl arylaldehydes under different reaction
combinations (e.g. K2CO3, NaBH4, Jones reagent, and
o
Ph3P=CH2) at 25 C in moderate to good yields. The protocol
provided products 2-3 and 4-5 as sole trans-isomers diastere-
oselectively. As far as we know, there have been no reports on
the use of o-crotyl or o-cinnamyl arylaldehydes serving as the
starting materials in the formation of benzofused oxacycles by
the mCPBA-mediated one-pot synthetic route. The process
provides a cascade pathway of carbon-oxygen and then car-
bon-carbon bond formations. We have also discussed the re-
lated plausible reaction mechanisms. The structures of the key
products were confirmed by X-ray crystallography. Further
investigations regarding the synthetic application of o-crotyl
or o-cinnamyl arylaldehydes will be conducted and published
in due course.
Representative synthetic procedure of compounds 1k and
1m-1o is as follows: Pd(OAc)2 (5.6 mg, 2.5 mol %) and PPh3
(13 mg, 5.0 mol %) were added to a solution of cinnamyl
bromide (200 mg, 1.0 mmol) in a cosolvent of DME and
EtOH (v/v = 9/1, 10 mL) at 25 oC. Then, Na2CO3 (159 mg, 1.5
mmol) and arylboronic acid (1.1 mmol) were added to the
solution directly. The reaction mixture was stirred at reflux for
o
18 h. The reaction mixture was cooled to 25 C, and the sol-
Experimental Section
vent was concentrated, 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 = 10/1~6/1)
General. All reagents and solvents were obtained from
commercial sources and used without further purification.
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The Journal of Organic Chemistry
afforded compounds 1k and 1m-1o. Compounds 1k and 1m-
6.8 Hz, 2H), 3.82 (s, 3H), 2.99 (dd, J = 5.2, 16.0 Hz, 1H), 2.83
2
3
4
1o are known compounds and the analytical data are con-
sistent with those in the reference 12g.
(dd, J = 8.4, 16.0 Hz, 1H), 1.88 (br s, 1H), 1.85-1.76 (m, 2H),
1.52-1.43 (m, 2H), 0.96 (t, J = 7.2 Hz, 3H); 13C{1H} NMR
(100 MHz, CDCl3): δ 148.2, 147.8, 144.0, 138.1, 128.7 (2C),
128.6, 127.1 (2C), 112.9, 110.3, 101.8, 81.7, 68.6, 68.3, 56.7,
32.4, 31.0, 19.1, 13.8.
5
6
7
8
Representative synthetic procedure of compounds 2a-2e and
3a-3e is as follows: mCPBA (70%, 550 mg, 2.2 mmol) was
added to a solution of 1a-1j (1.0 mmol) in CH2Cl2 (10 mL) at
25 C. The reaction mixture was stirred at 25 C for 30 min.
Then, K2CO3 (300 mg, 2.2 mmol) was added to reaction mix-
ture at 25 C. The reaction mixture was stirred at 25 C for 30
h. The reaction mixture was diluted with water (10 mL) and
the mixture was extracted with CH2Cl2 (2 x 20 mL). The com-
bined organic layers were washed with saturated NaHCO3(aq)
(3 x 20 mL), dried, filtered and evaporated to afford crude
product under reduced pressure. Purification on silica gel
(hexanes/EtOAc = 8/1~4/1) afforded compounds 2a-2e and
3a-3e.
o
o
7-Isopropoxy-6-methoxy-2-phenylchroman-3-ol (2e). Yield
= 84% (264 mg); Colorless oil; HRMS (ESI-TOF) m/z: [M +
9
o
o
1
H]+ calcd for C19H23O4 315.1596, found 315.1598; H NMR
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
(400 MHz, CDCl3): δ 7.43-7.37 (m, 5H), 6.59 (s, 1H), 6.53 (s,
1H), 4.74 (d, J = 8.0 Hz, 1H), 4.49-4.43 (m, 1H), 4.13-4.09 (m,
1H), 3.81 (s, 3H), 3.00 (dd, J = 5.2, 16.0 Hz, 1H), 2.84 (dd, J =
8.8, 16.0 Hz, 1H), 1.85 (br s, 1H), 1.37 (d, J = 5.6 Hz, 3H),
1.36 (d, J = 5.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ
147.7, 146.9, 144.8, 138.1, 128.8 (2C), 128.6, 127.1 (2C),
113.0, 110.7, 103.9, 81.8, 71.1, 68.3, 56.6, 32.5, 22.0, 21.9.
3-Hydroxy-6,7-dimethoxy-2-phenylchroman (2a). Yield =
90% (257 mg); Colorless solid; mp = 128-130 C (recrystal-
1-(5,6-Dimethoxy-2,3-dihydrobenzofuran-2-yl)ethanol (3a).
Yield = 84% (188 mg); Colorless oil; HRMS (ESI-TOF) m/z:
o
1
lized from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M +
[M + H]+ calcd for C12H17O4 225.1127, found 225.1125; H
1
H]+ calcd for C17H19O4 287.1283, found 287.1286; H NMR
NMR (400 MHz, CDCl3): δ 6.60 (s, 1H), 6.26 (s, 1H), 4.51 (dt,
J = 4.0, 12.4 Hz, 1H), 3.95-3.89 (m, 1H), 3.66 (s, 3H), 3.65 (s,
3H), 3.52 (dd, J = 8.0, 15.2 Hz, 1H), 2.97 (br s, 1H), 2.92 (dd,
J = 9.6, 15.2 Hz, 1H), 1.08 (d, J = 6.4 Hz, 3H); 13C{1H} NMR
(100 MHz, CDCl3): δ 153.3, 148.7, 142.8, 116.2, 109.0, 94.3,
86.7, 67.8, 56.5, 55.5, 29.5, 17.5.
(400 MHz, CDCl3): δ 7.43-7.31 (m, 5H), 6.56 (s, 1H), 6.50 (s,
1H), 4.73 (d, J = 8.4 Hz, 1H), 4.11-4.06 (m, 1H), 3.82 (s, 3H),
3.80 (s, 3H), 2.96 (dd, J = 5.6, 16.0 Hz, 1H), 2.81 (dd, J = 8.8,
16.0 Hz, 1H), 2.01 (br s, 1H); 13C{1H} NMR (100 MHz,
CDCl3): δ 148.4, 147.7, 143.5, 138.1, 128.6 (2C), 128.5, 127.0
(2C), 112.2, 110.2, 100.5, 81.7, 68.1, 56.3, 55.7, 32.3. Single-
crystal X-Ray diagram: crystal of compound 2a was grown by
slow diffusion of EtOAc into a solution of compound 2a in
CH2Cl2 to yield colorless prisms. The compound crystallizes
in the triclinic crystal system, space group P - 1, a = 8.0587(6)
Å , b = 8.8690(7) Å , c = 10.2746(8) Å , V = 705.26(9) Å 3, Z = 2,
dcalcd = 1.348 g/cm3, F(000) = 304, 2θ range 2.063~26.410o, R
indices (all data) R1 = 0.0405, wR2 = 0.0928.
1-(6-Benzyloxy-5-methoxy-2,3-dihydrobenzofuran-2-
yl)ethanol (3b). Yield = 83% (249 mg); Colorless solid; mp =
o
88-90 C (recrystallized from hexanes and EtOAc); HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C18H21O4 301.1440, found
1
301.1442; H NMR (400 MHz, CDCl3): δ 7.43-7.26 (m, 5H),
6.76 (s, 1H), 6.42 (s, 1H), 5.06 (s, 2H), 4.62 (dt, J = 4.0, 12.4
Hz, 1H), 4.06-4.03 (m, 1H), 3.80 (s, 3H), 3.14 (dd, J = 8.4,
15.2 Hz, 1H), 3.01 (dd, J = 9.6, 15.2 Hz, 1H), 2.38 (br s, 1H),
1.17 (d, J = 6.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ
153.4, 148.2, 143.9, 136.9, 128.3 (2C), 127.6, 127.1 (2C),
117.4, 110.1, 97.1, 87.0, 71.1, 68.0, 57.1, 29.5, 17.6. Single-
crystal X-Ray diagram: crystal of compound 3b was grown by
slow diffusion of EtOAc into a solution of compound 3b in
CH2Cl2 to yield colorless prisms. The compound crystallizes
in the monoclinic crystal system, space group C 2/c, a =
22.457(3) Å , b = 5.2177(7) Å , c = 25.976(3) Å , V = 3028.0(7)
Å 3, Z = 8, dcalcd = 1.318 g/cm3, F(000) = 1280, 2θ range
1.576~26.616o, R indices (all data) R1 = 0.0983, wR2 =
0.1661.
7-Benzyloxy-6-methoxy-2-phenylchroman-3-ol (2b). Yield =
82% (297 mg); Colorless oil; HRMS (ESI-TOF) m/z: [M +
1
H]+ calcd for C23H23O4 363.1596, found 363.1599; H NMR
(400 MHz, CDCl3): δ 7.44-7.28 (m, 10H), 6.61 (s, 1H), 6.54 (s,
1H), 5.12 (d, J = 12.8 Hz, 1H), 5.09 (d, J = 12.8 Hz, 1H), 4.73
(d, J = 8.0 Hz, 1H), 4.13-4.08 (m, 1H), 3.85 (s, 3H), 2.99 (dd,
J = 5.6, 16.0 Hz, 1H), 2.84 (dd, J = 8.8, 16.0 Hz, 1H), 1.80 (br
s, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 147.8, 147.7,
144.2, 138.1, 136.9, 128.8 (2C), 128.6, 128.5 (2C), 127.8,
127.2 (2C), 127.1 (2C), 113.1, 111.1, 102.8, 81.7, 70.8, 68.3,
56.7, 32.4.
7-Cyclopentyloxy-6-methoxy-2-phenylchroman-3-ol
(2c).
1-(6-Cyclopentyloxy-5-methoxy-2,3-dihydrobenzofuran-2-
yl)ethanol (3c). Yield = 78% (217 mg); Colorless oil; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C16H23O4 279.1596, found
279.1598; 1H NMR (400 MHz, CDCl3): δ 6.68 (s, 1H), 6.35 (s,
1H), 4.63-4.56 (m, 2H), 4.04-3.98 (m, 1H), 3.71 (s, 3H), 3.09
(dd, J = 8.4, 15.2 Hz, 1H), 2.97 (dd, J = 9.2, 15.2 Hz, 1H),
2.66 (br s, 1H), 1.84-1.71 (m, 6H), 1.56-1.49 (m, 2H), 1.15 (d,
J = 6.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 153.5,
147.7, 144.1, 116.6, 110.5, 97.6, 86.9, 80.3, 68.0, 57.2, 32.50,
32.47, 29.6, 23.7 (2C), 17.7.
Yield = 80% (272 mg); Colorless oil; HRMS (ESI-TOF) m/z:
[M + H]+ calcd for C21H25O4 341.1753, found 341.1753; H
1
NMR (400 MHz, CDCl3): δ 7.46-7.34 (m, 5H), 6.58 (s, 1H),
6.51 (s, 1H), 4.75 (d, J = 7.6 Hz, 1H), 4.71-4.67 (m, 1H), 4.15-
4.09 (m, 1H), 3.80 (s, 3H), 3.00 (dd, J = 5.6, 15.6 Hz, 1H),
2.84 (dd, J = 8.8, 15.6 Hz, 1H), 1.94-1.76 (m, 7H), 1.63-1.55
(m, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 147.8, 147.4,
144.6, 138.1, 128.8 (2C), 128.6, 127.2 (2C), 113.3, 110.3,
103.5, 81.8, 80.3, 68.4, 56.8, 32.8, 32.7, 32.4, 24.0 (2C).
7-n-Butoxy-6-methoxy-2-phenyl-chroman-3-ol (2d). Yield =
81% (266 mg); Colorless oil; HRMS (ESI-TOF) m/z: [M +
1-(6-n-Butoxy-5-methoxy-2,3-dihydrobenzofuran-2-
yl)ethanol (3d). Yield = 76% (202 mg); Colorless solid; mp =
1
o
H]+ calcd for C20H25O4 329.1753, found 329.1756; H NMR
56-58 C (recrystallized from hexanes and EtOAc); HRMS
(400 MHz, CDCl3): δ 7.46-7.35 (m, 5H), 6.58 (s, 1H), 6.52 (s,
1H), 4.74 (d, J = 7.6 Hz, 1H), 4.13-4.08 (m, 1H), 3.96 (t, J =
(ESI-TOF) m/z: [M + H]+ calcd for C15H23O4 267.1596, found
267.1596; 1H NMR (400 MHz, CDCl3): δ 6.65 (s, 1H), 6.32 (s,
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The Journal of Organic Chemistry
Page 6 of 11
1
2
3
4
5
6
7
8
o
1H), 4.54 (dt, J = 4.0, 12.4 Hz, 1H), 3.98-3.94 (m, 1H), 3.83 (t,
J = 6.8 Hz, 2H), 3.69 (s, 3H), 3.05 (dd, J = 8.4, 15.2 Hz, 1H),
2.94 (dd, J = 9.6, 15.2 Hz, 1H), 2.84 (br s, 1H), 1.74-1.66 (m,
2H), 1.44-1.35 (m, 2H), 1.12 (d, J = 6.4 Hz, 3H), 0.88 (t, J =
7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 153.5, 148.5,
143.4, 116.4, 110.1, 95.9, 86.8, 68.5, 67.9, 57.0, 30.8, 29.6,
18.8, 17.6, 13.5.
Colorless solid; mp = 78-80 C (recrystallized from hexanes
and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C24H25O4 377.1753, found 377.1754; H NMR (400 MHz,
1
CDCl3): δ 7.46-7.29 (m, 10H), 6.86 (s, 1H), 6.78 (s, 1H), 5.14
(s, 2H), 4.68 (d, J = 12.8 Hz, 1H), 4.66 (d, J = 12.8 Hz, 1H),
4.41 (d, J = 8.4 Hz, 1H), 3.91 (s, 3H), 3.71 (dt, J = 2.4, 8.8 Hz,
1H), 3.28 (dd, J = 10.4, 14.4 Hz, 1H), 3.12 (dd, J = 2.4, 14.4
Hz, 1H), 1.95 (br s, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ
149.1, 146.4, 140.0, 137.1, 133.6, 132.4, 128.8 (2C), 128.6
(2C), 128.5 (2C), 127.8, 127.6 (2C), 127.3, 115.0, 114.5, 91.6,
73.7, 72.2, 71.3, 56.2, 42.1.
1-(6-Isopropoxy-5-methoxy-2,3-dihydrobenzofuran-2-
yl)ethanol (3e). Yield = 78% (197 mg); Colorless oil; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C14H21O4 253.1440, found
253.1441; 1H NMR (400 MHz, CDCl3): δ 6.69 (s, 1H), 6.36 (s,
1H), 4.58 (dt, J = 4.0, 8.8 Hz, 1H), 4.38-4.32 (m, 1H), 4.04-
3.98 (m, 1H), 3.71 (s, 3H), 3.09 (dd, J = 8.4, 15.2 Hz, 1H),
2.98 (dd, J = 9.2, 15.2 Hz, 1H), 2.58 (br s, 1H), 1.28 (d, J =
6.0 Hz, 6H), 1.15 (d, J = 6.8 Hz, 3H); 13C{1H} NMR (100
MHz, CDCl3): δ 153.5, 147.2, 144.6, 117.4, 110.2, 98.6, 86.9,
71.5, 68.0, 57.0, 29.6, 21.84, 21.80, 17.7.
9
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
8-Cyclopentyloxy-7-methoxy-3-phenyl-1,3,4,5-
tetrahydrobenzo[c]oxepin-4-ol (4c). Yield = 83% (294 mg);
Colorless solid; mp = 115-117 oC (recrystallized from hexanes
and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd for
1
C22H27O4 355.1909, found 355.1912; H NMR (400 MHz,
CDCl3): δ 7.41-7.29 (m, 5H), 6.82 (s, 1H), 6.74 (s, 1H), 4.79-
4.74 (m, 1H), 4.70 (s, 2H), 4.40 (d, J = 8.8 Hz, 1H), 3.86 (s,
3H), 3.69 (dt, J = 2.0, 8.4 Hz, 1H), 3.26 (dd, J = 10.0, 14.0 Hz,
1H), 3.08 (dd, J = 2.4, 14.4 Hz, 1H), 2.20 (br s, 1H), 1.95-1.79
(m, 6H), 1.64-1.57 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3):
δ 149.3, 145.7, 140.1, 132.3, 129.2, 128.6 (2C), 128.4, 127.5
(2C), 115.8, 114.6, 91.5, 80.6, 73.7, 72.1, 56.2, 42.1, 32.8,
32.7, 23.9 (2C).
A representative synthetic procedure of compounds 4a-4e
and 5a-5e is as follows: NaBH4 (38 mg, 1.0 mmol) was added
o
to a solution of 1a-1j (1.0 mmol) in MeOH (10 mL) at 25 C.
o
The reaction mixture was stirred at 25 C for 30 min. Then,
o
water (1 mL) was added to the reaction mixture at 25 C and
the reaction mixture was concentrated. Then, the residue was
diluted with water (10 mL) and the mixture was extracted with
CH2Cl2 (3 x 20 mL). The combined organic layers were
washed with brine, dried, filtered and evaporated to afford
crude product under reduced pressure. Without further purifi-
cation, mCPBA (70%, 270 mg, 1.1 mmol) was added to a so-
lution of the resulting crude product in CH2Cl2 (10 mL) at 25
oC. The reaction mixture was stirred at 25 oC for 30 min. Then,
K2CO3 (150 mg, 1.1 mmol) was added to the reaction mixture
8-Butoxy-7-methoxy-3-phenyl-1,3,4,5-
tetrahydrobenzo[c]oxepin-4-ol (4d). Yield = 84% (287 mg);
o
Colorless solid; mp = 70-72 C (recrystallized from hexanes
and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd for
1
C21H27O4 343.1909, found 343.1912; H NMR (400 MHz,
CDCl3): δ 7.40-7.34 (m, 5H), 6.83 (s, 1H), 6.75 (s, 1H), 4.71
(s, 2H), 4.41 (d, J = 8.4 Hz, 1H), 4.02 (dt, J = 2.4, 5.2 Hz, 2H),
3.88 (s, 3H), 3.70 (dt, J = 2.4, 8.8 Hz, 1H), 3.28 (dd, J = 10.4,
14.4 Hz, 1H), 3.10 (dd, J = 2.4, 14.4 Hz, 1H), 1.86-1.79 (m,
2H), 1.54-1.45 (m, 2H), 1.60 (br s, 1H), 0.98 (t, J = 7.2 Hz,
3H); 13C{1H} NMR (100 MHz, CDCl3): δ 148.7, 146.7, 140.1,
132.4, 129.2, 128.7 (2C), 128.5, 127.6 (2C), 114.4, 113.9, 91.6,
73.8, 72.2, 68.9, 56.2, 42.1, 31.3, 19.2, 13.8. Single-crystal X-
Ray diagram: crystal of compound 4d was grown by slow
diffusion of EtOAc into a solution of compound 4d in CH2Cl2
to yield colorless prisms. The compound crystallizes in the
monoclinic crystal system, space group P 21/n, a = 12.0101(14)
Å , b = 10.6094(13) Å , c = 15.9081(19) Å , V = 1883.8(4) Å 3, Z
= 4, dcalcd = 1.207 g/cm3, F(000) = 736, 2θ range
2.363~26.438o, R indices (all data) R1 = 0.0542, wR2 =
0.1079.
o
o
at 25 C. The reaction mixture was stirred at 25 C for 30 h.
The reaction mixture was diluted with water (10 mL) and the
mixture was extracted with CH2Cl2 (2 x 20 mL). The com-
bined organic layers were washed with saturated NaHCO3(aq)
(3 x 20 mL), dried, filtered and evaporated to afford crude
product under reduced pressure. Purification on silica gel
(hexanes/EtOAc = 8/1~4/1) afforded compounds 4a-4e and
5a-5e.
7,8-Dimethoxy-3-phenyl-1,3,4,5-tetrahydrobenzo[c]oxepin-
4-ol (4a). Yield = 86% (258 mg); Colorless solid; mp = 145-
147 oC (recrystallized from hexanes and EtOAc); HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C18H21O4 301.1440, found
1
301.1442; H NMR (400 MHz, CDCl3): δ 7.41-7.31 (m, 5H),
6.83 (s, 1H), 6.75 (s, 1H), 4.73 (s, 2H), 4.42 (d, J = 8.8 Hz,
1H), 3.90 (s, 3H), 3.88 (s, 3H), 3.71 (dt, J = 2.4, 8.8 Hz, 1H),
3.29 (dd, J = 10.4, 14.4 Hz, 1H), 3.11 (dd, J = 2.4, 14.4 Hz,
1H), 2.00 (br s, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ
148.3, 147.1, 140.0, 132.4, 129.3, 128.7 (2C), 128.5, 127.6
(2C), 113.9, 112.2, 91.6, 73.7, 72.2, 56.02, 56.00, 42.1. Single-
crystal X-Ray diagram: crystal of compound 4a was grown by
slow diffusion of EtOAc into a solution of compound 4a in
CH2Cl2 to yield colorless prisms. The compound crystallizes
in the monoclinic crystal system, space group P 21/n, a =
6.8432(2) Å , b = 18.7402(7) Å , c = 11.7029(4) Å , V =
1500.39(9) Å 3, Z = 4, dcalcd = 1.330 g/cm3, F(000) = 640, 2θ
range 2.052~26.409o, R indices (all data) R1 = 0.0542, wR2 =
0.1116.
8-Isopropoxy-7-methoxy-3-phenyl-1,3,4,5-
tetrahydrobenzo[c]oxepin-4-ol (4e). Yield = 80% (262 mg);
Colorless oil; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
1
C20H25O4 329.1753, found 329.1754; H NMR (400 MHz,
CDCl3): δ 7.40-7.31 (m, 5H), 6.83 (s, 1H), 6.76 (s, 1H), 4.69
(s, 2H), 4.54-4.48 (m, 1H), 4.40 (d, J = 8.8 Hz, 1H), 3.87 (s,
3H), 3.70 (dt, J = 2.4, 8.8 Hz, 1H), 3.27 (dd, J = 10.4, 14.4 Hz,
1H), 3.09 (dd, J = 2.4, 14.4 Hz, 1H), 1.98 (br s, 1H), 1.38 (d, J
= 5.6 Hz, 3H), 1.36 (d, J = 6.4 Hz, 3H); 13C{1H} NMR (100
MHz, CDCl3): δ 149.7, 145.3, 140.1, 132.4, 129.8, 128.6 (2C),
128.4, 127.5 (2C), 116.8, 114.6, 91.5, 73.7, 72.1, 71.7, 56.1,
42.2, 22.13, 22.08.
1-(6,7-Dimethoxyisochroman-3-yl)ethanol (5a). Yield =
80% (190 mg); Colorless oil; HRMS (ESI-TOF) m/z: [M +
8-Benzyloxy-7-methoxy-3-phenyl-1,3,4,5-
tetrahydrobenzo[c]oxepin-4-ol (4b). Yield = 88% (331 mg);
H]+ calcd for C13H19O4 239.1283, found 239.1282; H NMR
1
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The Journal of Organic Chemistry
(400 MHz, CDCl3): δ 6.63 (s, 1H), 6.48 (s, 1H), 4.78 (s, 2H),
was added to a solution of 1a-1r (1.0 mmol) in CH2Cl2 (10 mL)
2
3
4
5
6
7
o
4.06-4.01 (m, 1H), 3.85 (s, 3H), 3.83 (s, 3H), 3.61 (dt, J = 3.2,
11.2 Hz, 1H), 2.90 (dd, J = 11.2, 16.0 Hz, 1H), 2.55 (dd, J =
3.2, 16.0 Hz, 1H), 2.17 (br s, 1H), 1.24 (d, J = 6.8 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 147.8, 147.5, 126.2,
124.8, 111.9, 107.0, 77.9, 69.2, 68.1, 55.9 (2C), 26.7, 17.7.
at 25 oC. The reaction mixture was stirred at 25 C for 30 min.
Excess Jones reagent (1 mL) was added to the reaction mix-
ture at 25 oC. The reaction mixture was stirred at 25 oC for 3 h.
Then, isopropanol (1 mL) was added to the reaction mixture at
o
25 C and the reaction mixture was concentrated. Then, the
residue was diluted with water (10 mL) and the mixture was
extracted with CH2Cl2 (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 = 8/1~2/1) afforded compounds
6a-6m and 7a-7e.
1-(7-Benzyloxy-6-methoxyisochroman-3-yl)ethanol
(5b).
8
9
Yield = 84% (264 mg); Colorless solid; mp = 113-115 oC (re-
crystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z:
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
[M + H]+ calcd for C19H23O4 315.1596, found 315.1598; H
1
NMR (400 MHz, CDCl3): δ 7.44-7.42 (m, 2H), 7.37-7.27 (m,
3H), 6.65 (s, 1H), 6.51 (s, 1H), 5.09 (s, 2H), 4.78 (s, 2H),
4.04-3.99 (m, 1H), 3.85 (s, 3H), 3.56 (dt, J = 3.2, 11.2 Hz, 1H),
2.89 (dd, J = 11.2, 16.0 Hz, 1H), 2.55 (dd, J = 3.2, 16.0 Hz,
1H), 2.50 (br s, 1H), 1.23 (d, J = 6.8 Hz, 3H); 13C{1H} NMR
(100 MHz, CDCl3): δ 148.4, 146.5, 137.0, 128.4 (2C), 127.7,
127.2 (2C), 126.1, 125.9, 112.4, 109.9, 77.9, 71.1, 69.1, 67.9,
56.0, 26.7, 17.6. Single-crystal X-Ray diagram: crystal of
compound 5b was grown by slow diffusion of EtOAc into a
solution of compound 5b in CH2Cl2 to yield colorless prisms.
The compound crystallizes in the monoclinic crystal system,
space group C 2/c, a = 35.856(6) Å , b = 5.1944(10) Å , c =
19.808(3) Å , V = 3252.1(10) Å 3, Z = 8, dcalcd = 1.321 g/cm3,
F(000) = 1384, 2θ range 1.288~25.3316o, R indices (all data)
R1 = 0.1516, wR2 = 0.2804.
3-Benzoyl-6,7-dimethoxyisochroman-1-one (6a). Yield =
o
93% (290 mg); Colorless solid; mp = 132-134 C (recrystal-
lized from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M +
1
H]+ calcd for C18H17O5 313.1076, found 313.1077; H NMR
(400 MHz, CDCl3): δ 7.99-7.97 (m, 2H), 7.64-7.60 (m, 1H),
7.55 (s, 1H), 7.52-7.47 (m, 2H), 6.63 (s, 1H), 5.92 (dd, J = 5.6,
6.8 Hz, 1H), 3.91 (s, 3H), 3.90 (s, 3H), 3.40 (dd, J = 5.6, 16.8
Hz, 1H), 3.33 (dd, J = 6.8, 16.8 Hz, 1H); 13C{1H} NMR (100
MHz, CDCl3): δ 194.1, 163.9, 153.9, 148.7, 134.0, 133.8,
130.9, 129.0 (2C), 128.9 (2C), 117.0, 111.6, 109.4, 78.0, 56.2,
56.1, 29.3. Single-crystal X-Ray diagram: crystal of com-
pound 6a was grown by slow diffusion of EtOAc into a solu-
tion of compound 6a in CH2Cl2 to yield colorless prisms. The
compound crystallizes in the triclinic crystal system, space
group P-1, a = 27.5282(6) Å , b = 8.2601(7) Å , c = 13.8286(12)
Å , V = 731.54(11) Å 3, Z = 2, dcalcd = 1.418 g/cm3, F(000) =
328, 2θ range 2.810~26.406o, R indices (all data) R1 =
0.04273, wR2 = 0.1079.
1-(7-Cyclopentyloxy-6-methoxyisochroman-3-yl)ethanol
(5c). Yield = 80% (234 mg); Colorless oil; HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C17H25O4 293.1753, found 293.1752;
1H NMR (400 MHz, CDCl3): δ 6.61 (s, 1H), 6.47 (s, 1H), 4.74
(s, 2H), 4.71-4.66 (m, 1H), 4.03-3.97 (m, 1H), 3.79 (s, 3H),
3.57 (dt, J = 3.2, 11.2 Hz, 1H), 2.87 (dd, J = 11.2, 16.0 Hz,
1H), 2.64 (br s, 1H), 2.60 (dd, J = 3.2, 16.0 Hz, 1H), 1.92-1.76
(m, 6H), 1.62-1.53 (m, 2H), 1.22 (d, J = 6.8 Hz, 3H); 13C{1H}
NMR (100 MHz, CDCl3): δ 148.8, 146.0, 126.1, 124.8, 112.5,
110.8, 80.5, 78.0, 69.1, 68.0, 56.0, 32.6 (2C), 26.7, 23.9 (2C),
17.6.
3-Benzoyl-7-benzyloxy-6-methoxyisochroman-1-one (6b).
Yield = 94% (365 mg); Colorless solid; mp = 143-145 oC (re-
crystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z:
1
[M + H]+ calcd for C24H21O5 389.1389, found 389.1385; H
NMR (400 MHz, CDCl3): δ 7.98-7.96 (m, 2H), 7.64-7.58 (m,
1H), 7.62 (s, 1H), 7.50-7.44 (m, 4H), 7.39-7.29 (m, 3H), 6.64
(s, 1H), 5.90 (dd, J = 6.0, 6.8 Hz, 1H), 5.15 (d, J = 12.0 Hz,
1H), 5.11 (d, J = 12.0 Hz, 1H), 3.88 (s, 3H), 3.37 (dd, J = 6.0,
16.8 Hz, 1H), 3.31 (dd, J = 6.8, 16.8 Hz, 1H); 13C{1H} NMR
(100 MHz, CDCl3): δ 194.0, 163.8, 154.4, 147.8, 136.5, 134.0,
133.7, 131.3, 128.9 (2C), 128.8 (2C), 128.5 (2C), 128.0, 127.5
(2C), 116.8, 113.6, 109.7, 77.9, 70.9, 56.1, 29.3.
1-(7-n-Butoxy-6-methoxyisochroman-3-yl)ethanol
(5d).
Yield = 84% (235 mg); Colorless oil; HRMS (ESI-TOF) m/z:
1
[M + H]+ calcd for C16H25O4 281.1753, found 281.1756; H
NMR (400 MHz, CDCl3): δ 6.62 (s, 1H), 6.49 (s, 1H), 4.76 (s,
2H), 4.05-3.99 (m, 1H), 3.95 (dt, J = 1.6, 6.8 Hz, 2H), 3.82 (s,
3H), 3.58 (dt, J = 3.6, 11.2 Hz, 1H), 2.89 (dd, J = 11.2, 15.6
Hz, 1H), 2.54 (dd, J = 3.2, 16.0 Hz, 1H), 2.50 (br s, 1H), 1.83-
1.76 (m, 2H), 1.52-1.43 (m, 2H), 1.23 (d, J = 6.4 Hz, 3H), 0.96
(t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 148.2,
147.0, 126.1, 126.8, 112.3, 108.7, 78.0, 69.1, 68.8, 68.1, 56.0,
31.2, 26.7, 19.1, 17.7, 13.8.
3-Benzoyl-7-cyclopentyloxy-6-methoxyisochroman-1-one
(6c). Yield = 90% (329 mg); Colorless solid; mp = 108-110 oC
(recrystallized from hexanes and EtOAc); HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C22H23O5 367.1546, found 367.1546;
1H NMR (400 MHz, CDCl3): δ 8.01-7.98 (m, 2H), 7.64-7.60
(m, 1H), 7.55 (s, 1H), 7.52-7.48 (m, 2H), 6.62 (s, 1H), 5.89 (t,
J = 6.0 Hz, 1H), 4.84-4.80 (m, 1H), 3.87 (s, 3H), 3.34 (br d, J
= 6.4 Hz, 2H), 2.04-1.93 (m, 2H), 1.90-1.76 (m, 4H), 1.67-
1.57 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 194.1,
163.9, 154.9, 147.4, 134.0, 133.9, 130.6, 129.1 (2C), 128.9
(2C), 116.8, 114.5, 109.7, 80.6, 78.0, 56.2, 32.7, 32.6, 29.3,
24.04, 24.02.
3-(1-Hydroxyethyl)-6-methoxyisochroman-7-ol (5e). Yield
= 67% (150 mg); Colorless solid; mp = 135-137 oC
(recrystallized from hexanes and EtOAc); HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C12H17O4 225.1127, found 225.1123;
1H NMR (400 MHz, CDCl3): δ 6.61 (s, 1H), 6.55 (s, 1H), 5.53
(br s, 1H), 4.75 (s, 2H), 4.06-4.00 (m, 1H), 3.86 (s, 3H), 3.58
(dt, J = 3.6, 11.2 Hz, 1H), 2.89 (dd, J = 11.2, 16.0 Hz, 1H),
2.54 (dd, J = 3.2, 16.0 Hz, 1H), 2.18 (br s, 1H), 1.24 (d, J =
6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 145.4, 144.0,
127.0, 124.2, 111.2, 109.8, 77.9, 69.2, 68.0, 56.0, 26.8, 17.7.
3-Benzoyl-7-n-butoxy-6-methoxyisochroman-1-one
(6d).
Yield = 91% (322 mg); Colorless solid; mp = 131-133 oC (re-
crystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z:
1
[M + H]+ calcd for C21H23O5 355.1546, found 355.1545; H
A representative synthetic procedure of compounds 6a-6m
and 7a-7e is as follows: mCPBA (70%, 270 mg, 1.1 mmol)
NMR (400 MHz, CDCl3): δ 7.98-7.96 (m, 2H), 7.63-7.59 (m,
1H), 7.53 (br d, J = 1.2 Hz, 1H), 7.51-7.47 (m, 2H), 6.61 (s,
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The Journal of Organic Chemistry
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2
1H), 5.91 (dd, J = 5.6, 7.2 Hz, 1H), 4.04 (dt, J = 1.2, 6.8 Hz,
2H), 7.66-7.62 (m, 1H), 7.53-7.49 (m, 2H), 7.09 (dt, J = 2.4,
2H), 3.88 (br d, J = 1.6 Hz, 3H), 3.38 (dd, J = 5.6, 16.4 Hz,
1H), 3.32 (dd, J = 6.8, 16.4 Hz, 1H), 1.86-1.79 (m, 2H), 1.53-
1.43 (m, 2H), 0.97 (dt, J = 1.2, 7.2 Hz, 3H); 13C{1H} NMR
(100 MHz, CDCl3): δ 194.1, 163.9, 154.2, 148.2, 134.0, 133.8,
130.6, 129.0 (2C), 128.9 (2C), 116.9, 112.7, 109.5, 78.0, 68.8,
56.1, 31.0, 29.3, 19.1, 13.8.
8.4 Hz, 1H), 6.91 (dd, J = 2.4, 8.4 Hz, 1H), 5.97 (dd, J = 5.6,
6.4 Hz, 1H), 3.49 (dd, J = 5.6, 16.8 Hz, 1H), 3.39 (dd, J = 6.4,
16.8 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 193.5,
165.9 (d, J = 255.5 Hz), 163.0, 139.4 (d, J = 9.8 Hz), 134.3,
133.5, 133.3 (d, J = 9.9 Hz), 129.01 (2C), 128.98 (2C), 121.3
(d, J = 3.1 Hz), 115.7 (d, J = 21.9 Hz), 114.5 (d, J = 21.9 Hz),
77.5, 29.8.
3
4
5
6
7
8
9
3-Benzoyl-7-isopropoxy-6-methoxyisochroman-1-one (6e).
Yield = 89% (303 mg); Colorless oil; HRMS (ESI-TOF) m/z:
3-Benzoyl-7-methoxyisochroman-1-one (6j). Yield = 90%
(254 mg); Colorless oil; HRMS (ESI-TOF) m/z: [M + H]+
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
1
[M + H]+ calcd for C20H21O5 341.1389, found 341.1388; H
1
NMR (400 MHz, CDCl3): δ 8.00-7.98 (m, 2H), 7.64-7.60 (m,
1H), 7.57 (s, 1H), 7.52-7.48 (m, 2H), 6.64 (s, 1H), 5.89 (t, J =
6.4 Hz, 1H), 4.64-4.58 (m, 1H), 3.88 (s, 3H), 3.35 (d, J = 6.4
Hz, 2H), 1.38 (d, J = 6.0 Hz, 6H); 13C{1H} NMR (100 MHz,
CDCl3): δ 194.1, 163.9, 155.1, 147.0, 134.0, 133.9, 130.9,
129.0 (2C), 128.9 (2C), 116.9, 115.0, 109.8, 78.0, 71.4, 56.1,
29.3, 22.0, 21.8.
calcd for C17H15O4 283.0970, found 283.0970; H NMR (400
MHz, CDCl3): δ 7.97-7.94 (m, 2H), 7.63-7.61 (m, 2H), 7.53-
7.48 (m, 2H), 7.11-7.06 (m, 2H), 5.96 (dd, J = 5.6, 6.4 Hz, 1H),
3.85 (s, 3H), 3.46 (dd, J = 5.6, 16.4 Hz, 1H), 3.32 (dd, J = 6.4,
16.4 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 194.0,
164.1, 159.2, 134.1, 133.6, 129.5, 129.0 (2C), 128.9 (2C),
128.7, 128.3, 121.9, 112.8, 78.1, 56.6, 29.2.
3-Benzoylisochroman-1-one (6f). Yield = 93% (234 mg);
Colorless solid; mp = 128-130 oC (recrystallized from hexanes
and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd for
3-Benzoyl-5,7-dimethoxyisochroman-1-one (6k). Yield =
89% (278 mg); Colorless oil; HRMS (ESI-TOF) m/z: [M +
1
H]+ calcd for C18H17O5 313.1076, found 313.1078; H NMR
1
C16H13O3 253.0865, found 253.0866; H NMR (400 MHz,
(400 MHz, CDCl3): δ 7.97-7.95 (m, 2H), 7.64-7.60 (m, 1H),
7.52-7.48 (m, 2H), 7.23 (d, J = 2.0 Hz, 1H), 6.61 (d, J = 2.4
Hz, 1H), 5.97 (t, J = 6.0 Hz, 1H), 3.85 (s, 3H), 3.76 (s, 3H),
3.37 (dd, J = 6.0, 17.2 Hz, 1H), 3.27 (dd, J = 6.0, 17.2 Hz, 1H);
13C{1H} NMR (100 MHz, CDCl3): δ 194.1, 164.1, 159.8,
156.8, 134.0, 133.5, 128.93 (2C), 128.88 (2C), 126.2, 117.9,
104.4, 103.4, 77.8, 55.70, 55.68, 23.5.
CDCl3): δ 8.12 (dd, J = 0.8, 7.6 Hz, 1H), 7.97-7.95 (m, 2H),
7.64-7.60 (m, 1H), 7.54-7.47 (m, 3H), 7.40 (d, J = 8.0 Hz, 1H),
7.20 (d, J = 7.6 Hz, 1H), 5.97 (dd, J = 5.6, 6.8 Hz, 1H), 3.49
(dd, J = 5.6, 16.8 Hz, 1H), 3.38 (dd, J = 6.8, 16.8 Hz, 1H);
13C{1H} NMR (100 MHz, CDCl3): δ 193.8, 163.9, 136.3,
134.1, 134.0, 133.6, 130.2, 128.93 (2C), 128.91 (2C), 128.0,
127.5, 124.9, 77.8, 29.8.
3-Benzoyl-7-benzyloxy-5-methoxyisochroman-1-one
(6l).
7-Allyloxy-3-benzoyl-6-methoxyisochroman-1-one
(6g).
Yield = 84% (326 mg); Colorless oil; HRMS (ESI-TOF) m/z:
1
Yield = 93% (314 mg); Colorless solid; mp = 141-143 oC (re-
[M + H]+ calcd for C24H21O5 389.1389, found 389.1388; H
crystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z:
NMR (400 MHz, CDCl3): δ 7.98-7.96 (m, 2H), 7.64-7.61 (m,
1H), 7.52-7.34 (m, 8H), 6.70 (d, J = 2.4 Hz, 1H), 5.97 (t, J =
6.0 Hz, 1H), 5.09 (s, 2H), 3.75 (s, 3H), 3.38 (dd, J = 6.0, 17.2
Hz, 1H), 3.28 (dd, J = 6.8, 17.2 Hz, 1H); 13C{1H} NMR (100
MHz, CDCl3): δ 194.0, 164.1, 159.0, 156.9, 136.2, 134.1,
133.5, 128.93 (2C), 128.89 (2C), 128.7 (2C), 128.2, 127.8
(2C), 126.2, 118.2, 104.9, 104.3, 77.8, 70.4, 55.7, 23.5.
1
[M + H]+ calcd for C20H19O5 339.1233, found 339.1235; H
NMR (400 MHz, CDCl3): δ 7.98-7.95 (m, 2H), 7.62-7.58 (m,
1H), 7.53 (s, 1H), 7.50-7.46 (m, 2H), 6.63 (s, 1H), 6.11-6.01
(m, 1H), 5.90 (dd, J = 5.6, 6.8 Hz, 1H), 5.42 (dq, J = 1.2, 17.2
Hz, 1H), 5.30 (dq, J = 1.2, 10.4 Hz, 1H), 4.61 (dt, J = 1.2, 6.4
Hz, 2H), 3.88 (s, 3H), 3.37 (dd, J = 5.6, 16.8 Hz, 1H), 3.31 (dd,
J = 6.8, 16.8 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ
194.0, 163.8, 154.2, 147.5, 134.0, 133.7, 132.4, 131.1, 128.9
(2C), 128.8 (2C), 118.6, 116.8, 113.2, 109.6, 77.9, 69.7, 56.1,
29.3.
3-Benzoyl-7-n-butoxy-5-methoxyisochroman-1-one
Yield = 88% (312 mg); Colorless solid; mp = 96-98 C (re-
(6m).
o
crystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z:
1
[M + H]+ calcd for C21H23O5 355.1546, found 355.1545; H
3-Benzoyl-6-fluoroisochroman-1-one (6h). Yield = 94%
NMR (400 MHz, CDCl3): δ 7.97-7.95 (m, 2H), 7.64-7.60 (m,
1H), 7.52-7.47 (m, 2H), 7.22 (d, J = 2.4 Hz, 1H), 6.62 (d, J =
2.4 Hz, 1H), 5.97 (t, J = 6.4 Hz, 1H), 4.01 (t, J = 6.8 Hz, 2H),
3.76 (s, 3H), 3.37 (dd, J = 6.0, 17.2 Hz, 1H), 3.26 (dd, J = 6.0,
17.2 Hz, 1H), 1.81-1.74 (m, 2H), 1.54-1.46 (m, 2H), 0.98 (t, J
= 7.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 194.1,
164.2, 159.4, 156.8, 134.0, 130.1, 128.92 (2C), 128.90 (2C),
126.1, 117.7, 104.7, 104.1, 77.8, 68.1, 55.7, 31.2, 23.5, 19.2,
13.8.
o
(254 mg); Colorless solid; mp = 117-119 C (recrystallized
from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+
1
calcd for C16H12FO3 271.0771, found 271.0771; H NMR (400
MHz, CDCl3): δ 8.14 (dd, J = 5.6, 8.8 Hz, 1H), 7.98-7.95 (m,
2H), 7.66-7.61 (m, 1H), 7.53-7.49 (m, 2H), 7.08 (dt, J = 2.4,
8.4 Hz, 1H), 6.91 (dd, J = 2.4, 8.4 Hz, 1H), 5.97 (t, J = 6.4 Hz,
1H), 3.49 (dd, J = 5.6, 16.8 Hz, 1H), 3.39 (dd, J = 6.4, 16.8 Hz,
1H); 13C{1H} NMR (100 MHz, CDCl3): δ 193.5, 165.9 (d, J =
254.7 Hz), 163.0, 139.4 (d, J = 9.8 Hz), 134.3, 133.5, 133.3 (d,
J = 9.8 Hz), 129.00 (2C), 128.97 (2C), 121.3 (d, J = 3.1 Hz),
115.7 (d, J = 22.0 Hz), 114.5 (d, J = 22.7 Hz), 77.5, 29.8 (d, J
= 1.5 Hz).
3-Acetyl-6,7-dimethoxyisochroman-1-one (7a). Yield = 94%
o
(235 mg); Colorless solid; mp = 136-138 C (recrystallized
from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+
1
calcd for C13H15O5 251.0920, found 251.0922; H NMR (400
3-Benzoyl-7-fluoroisochroman-1-one (6i). Yield = 93%
MHz, CDCl3): δ 7.50 (s, 1H), 6.67 (s, 1H), 4.87 (dd, J = 4.8,
8.8 Hz, 1H), 3.92 (s, 3H), 3.89 (s, 3H), 3.19 (dd, J = 5.2, 16.4
Hz, 1H), 3.11 (dd, J = 8.8, 16.4 Hz, 1H), 2.35 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3): δ 205.6, 163.8, 154.1, 148.7, 131.8,
116.6, 111.6, 109.3, 81.5, 56.2, 56.1, 28.6, 26.6.
o
(251 mg); Colorless solid; mp = 110-112 C (recrystallized
from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+
1
calcd for C16H12FO3 271.0771, found 271.0775; H NMR (400
MHz, CDCl3): δ 8.15 (dd, J = 5.6, 8.8 Hz, 1H), 7.98-7.96 (m,
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8
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3-Acetyl-7-benzyloxy-6-methoxyisochroman-1-one
Yield = 96% (313 mg); Colorless solid; mp = 160-162 C (re-
(7b).
diluted with saturated NaHCO3(aq) (10 mL) and the mixture
o
was extracted with CH2Cl2 (2 x 20 mL). The combined organ-
ic layers were washed with saturated NaHCO3(aq) (3 x 20 mL),
dried, filtered and evaporated to afford crude product under
reduced pressure. Purification on silica gel (hexanes/EtOAc =
10/1~3/1) afforded compounds 8a-8e and 9a.
crystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z:
[M + H]+ calcd for C19H19O5 327.1233, found 327.1235; H
1
NMR (400 MHz, CDCl3): δ 7.59 (s, 1H), 7.43-7.29 (m, 5H),
6.69 (s, 1H), 5.16 (d, J = 12.0 Hz, 1H), 5.13 (d, J = 12.0 Hz,
1H), 4.86 (dd, J = 5.2, 8.8 Hz, 1H), 3.93 (s, 3H), 3.18 (dd, J =
5.2, 16.8 Hz, 1H), 3.12 (dd, J = 8.8, 16.4 Hz, 1H), 2.37 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 205.7, 163.7, 154.7,
147.9, 136.1, 132.1, 128.6 (2C), 128.1, 127.5 (2C), 116.5,
113.8, 109.7, 81.5, 70.9, 56.2, 28.7, 26.7.
3-Chlorobenzoic acid 4-hydroxy-7,8-dimethoxy-3-phenyl-
1,3,4,5-tetrahydrobenzo[c]oxepin-1-ylmethyl ester (8a). Two
isomers (ratio = 1:1); Yield = 73% (342 mg); Colorless gum;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C26H26ClO6
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13
14
15
16
17
18
19
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469.1418, found 469.1419; H NMR (400 MHz, CDCl3): δ
3-Acetyl-7-cyclopentyloxy-6-methoxyisochroman-1-one (7c).
Yield = 96% (292 mg); Colorless solid; mp = 152-154 oC (re-
crystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z:
8.03-8.02 (m, 1H), 7.95-7.92 (m, 1H), 7.54-7.51 (m, 1H),
7.39-7.22 (m, 6H), 6.97 (s, 1/2H), 6.95 (s, 1/2H), 6.792 (s,
1/2H), 6.788 (s, 1/2H), 6.31-6.26 (m, 1H), 4.14-4.08 (m, 1H),
4.02-3.81 (m, 2H), 3.873 (s, 3H), 3.868 (s, 3/2H), 3.86 (s,
3/2H), 3.61 (d, J = 2.4 Hz, 1/2H), 3.50 (dd, J = 4.4, 15.2 Hz,
1/2H), 3.31-3.22 (m, 1H), 3.17-3.12 (m, 1H), 2.40 (br s, 1H);
13C{1H} NMR (100 MHz, CDCl3): δ 164.91 (1/2C), 164.87
(1/2C), 149.14 (1/2C), 149.09 (1/2C), 148.27 (1/2C), 148.23
(1/2C), 136.92 (1/2C), 136.85 (1/2C), 134.53 (1/2C), 134.51
(1/2C), 133.16 (1/2C), 133.12 (1/2C), 131.76 (1/2C), 131.70
(1/2C), 129.7 (1C), 129.6 (1C), 128.59 (1/2C), 128.52 (1/2C),
128.44 (2C), 128.21 (1/2C), 128.18 (1/2C), 127.81 (1/2C),
127.78 (1/2C), 127.74 (1/2C), 127.28 (1/2C), 125.6 (2C),
113.6 (1/2C), 113.0 (1/2C), 109.8 (1/2C), 109.7 (1/2C), 74.6
(1C), 65.7 (1/2C), 65.4 (1/2C), 63.3 (1/2C), 62.6 (1/2C), 59.1
(1/2C), 57.7 (1/2C), 56.1 (1/2C), 56.0 (1/2C), 55.90 (1/2C),
55.86 (1/2C), 35.4 (1/2C), 34.1 (1/2C).
1
[M + H]+ calcd for C17H21O5 305.1389, found 305.1387; H
NMR (400 MHz, CDCl3): δ 7.51 (s, 1H), 6.66 (s, 1H), 4.87
(dd, J = 5.2, 8.8 Hz, 1H), 4.83-4.79 (m, 1H), 3.90 (s, 3H), 3.17
(dd, J = 5.2, 16.4 Hz, 1H), 3.11 (dd, J = 8.8, 16.4 Hz, 1H),
2.38 (s, 3H), 2.03-1.96 (m, 2H), 1.95-1.76 (m, 4H), 1.67-1.58
(m, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 205.8, 163.9,
155.1, 147.5, 131.4, 116.5, 114.6, 109.7, 81.6, 80.6, 56.2, 32.7,
32.6, 28.7, 26.7, 24.0 (2C).
3-Acetyl-7-butoxy-6-methoxyisochroman-1-one (7d). Yield
= 95% (277 mg); Colorless solid; mp = 142-144 oC (recrystal-
lized from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M +
1
H]+ calcd for C16H21O5 293.1389, found 293.1390; H NMR
(400 MHz, CDCl3): δ 7.51 (s, 1H), 6.66 (s, 1H), 4.87 (dd, J =
4.8, 8.8 Hz, 1H), 4.04 (dt, J = 2.8, 6.8 Hz, 2H), 3.91 (s, 3H),
3.18 (dd, J = 5.2, 16.4 Hz, 1H), 3.12 (dd, J = 8.8, 16.4 Hz, 1H),
2.37 (s, 3H), 1.86-1.79 (m, 2H), 1.53-1.43 (m, 2H), 0.97 (t, J =
7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 205.7, 163.9,
154.5, 148.3, 131.5, 116.5, 112.9, 109.5, 81.6, 68.9, 56.2, 31.0,
28.2, 26.7, 19.1, 13.8.
3-Chlorobenzoic acid 8-benzyloxy-4-hydroxy-7-methoxy-3-
phenyl-1,3,4,5-tetrahydrobenzo[c]oxepin-1-ylmethyl ester (8b).
Yield = 70% (381 mg); Colorless gum; HRMS (ESI-TOF) m/z:
1
[M + H]+ calcd for C32H30ClO6 545.1731, found 545.1733; H
NMR (400 MHz, CDCl3): δ 7.97 (br s, 1H), 7.84-7.82 (m, 1H),
7.54-7.51 (m, 1H), 7.41-7.18 (m, 11H), 6.96 (s, 1/2H), 6.93 (s,
1/2H), 6.824 (s, 1/2H), 6.818 (s, 1/2H), 6.24-6.20 (m, 1H),
5.20-5.12 (m, 2H), 4.01-3.81 (m, 2H), 3.89 (s, 3/2H), 3.88 (s,
3/2H), 3.66-3.63 (m, 1H), 3.44 (dd, J = 4.4, 14.8 Hz, 1/2H),
3.30-3.24 (m, 3/2H), 3.16-3.08 (m, 1H), 2.60 (br s, 1H);
13C{1H} NMR (100 MHz, CDCl3): δ 164.70 (1/2C), 164.65
(1/2C), 149.64 (1/2C), 149.60 (1/2C), 147.0 (1/2C), 146.9
(1/2C), 136.9 (1/2C), 136.79 (1/2C), 136.75 (1/2C), 136.72
(1/2C), 134.3 (1/2C), 133.00 (1/2C), 132.96 (1/2C), 131.5
(1/2C), 129.6 (1/2C), 129.5 (1C), 128.9 (1/2C), 128.4 (4C),
128.12 (1C), 128.10 (1C), 127.74 (1/2C), 127.72 (2C), 128.68
(1/2C), 127.6 (1C), 127.08 (1C), 127.07 (1C), 125.5 (2C),
113.9 (1/2C), 113.3 (1/2C), 112.9 (1/2C), 112.8 (1/2C), 74.31
(1/2C), 74.28 (1/2C), 71.1 (1C), 65.5 (1/2C), 65.3 (1/2C), 63.2
(1/2C), 62.5 (1/2C), 59.0 (1/2C), 57.7 (1/2C), 55.9 (1/2C),
55.8 (1/2C), 35.3 (1/2C), 34.1 (1/2C).
3-Acetyl-7-isopropoxy-6-methoxyisochroman-1-one
(7e).
Yield = 94% (261 mg); Colorless solid; mp = 146-148 oC (re-
crystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z:
1
[M + H]+ calcd for C15H19O5 279.1233, found 279.1235; H
NMR (400 MHz, CDCl3): δ 7.53 (s, 1H), 6.67 (s, 1H), 4.87
(dd, J = 5.2, 8.8 Hz, 1H), 4.62-4.56 (m, 1H), 3.90 (s, 3H), 3.18
(dd, J = 5.2, 16.4 Hz, 1H), 3.11 (dd, J = 8.8, 16.4 Hz, 1H),
2.37 (s, 3H), 1.37 (d, J = 6.0 Hz, 3H), 1.36 (d, J = 6.0 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 205.7, 163.8, 155.3,
147.0, 131.6, 116.5, 115.1, 109.8, 81.5, 71.5, 56.2, 28.7, 26.7,
21.9, 21.8.
A representative synthetic procedure of compounds 8a-8e
and 9a is as follows: tBuOK (200 mg, 1.8 mmol) was added to
a solution of Ph3PCH3I (810 mg, 2.0 mmol) in anhydrous THF
o
o
(8 mL) at 25 C. The reaction mixture was stirred at 25 C for
10 min. Then, 1a-1e and 1k (1.0 mmol) in anhydrous THF (2
3-Chlorobenzoic
acid
8-cyclopentyloxy-4-hydroxy-7-
o
mL) was added to the reaction mixture at 25 C. The reaction
methoxy-3-phenyl-1,3,4,5-tetrahydrobenzo[c]oxepin-1-
ylmethyl ester (8c). Yield = 66% (345 mg); Colorless gum;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C30H32ClO6
o
mixture was stirred at 25 C for 30 min. Then, water (1 mL)
o
was added to the reaction mixture at 25 C and the reaction
mixture was concentrated. Then, the residue was diluted with
water (10 mL) and the mixture was extracted with CH2Cl2 (3 x
20 mL). The combined organic layers were washed with brine,
dried, filtered and evaporated to afford crude product under
reduced pressure. Without further purification, mCPBA (70%,
550 mg, 2.2 mmol) was added to a solution of the resulting
1
523.1888, found 523.1886; H NMR (400 MHz, CDCl3): δ
8.03 (t, J = 1.2 Hz, 1H), 7.95-7.92 (m, 1H), 7.55-7.52 (m, 1H),
7.40-7.24 (m, 5H), 6.99 (s, 1/2H), 6.97 (s, 1/2H), 6.78 (s,
1/2H), 6.77 (s, 1/2H), 6.31-6.26 (m, 1H), 4.78-4.75 (m, 2H),
4.12-3.91 (m, 2H), 3.84 (s, 3/2H), 3.83 (s, 3/2H), 3.63-3.62 (m,
1H), 3.45 (dd, J = 4.4, 14.8 Hz, 1/2H), 3.30-3.22 (m, 3/2H),
3.16-3.09 (m, 1H), 2.20 (br s, 1H), 1.95-1.76 (m, 8H); 13C{1H}
o
crude product in CH2Cl2 (10 mL) at 25 C. The reaction mix-
o
ture was stirred at 25 C for 30 h. The reaction mixture was
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NMR (100 MHz, CDCl3): δ 164.92 (1C), 150.2 (1/2C), 150.1
MHz, CDCl3): δ 137.5 (1C), 136.13 (1/2C), 136.08 (1/2C),
(1/2C), 146.9 (1C), 137.0 (1/2C), 136.9 (1/2C), 134.6 (1C),
133.2 (1/2C), 133.1 (1/2C), 131.9 (1/2C), 131.8 (1/2C), 129.8
(1C), 129.7 (1C), 128.5 (2C), 128.3 (1/2C), 128.24 (1/2C),
128.21, (1/2C), 127.8 (1/2C), 127.7 (1/2C), 128.6 (1/2C),
127.1 (1C), 125.6 (2C), 114.2 (1/2C), 113.6 (1C), 113.4 (1/2C),
80.6 (1C), 74.5 (1C), 65.9 (1/2C), 65.6 (1/2C), 63.4 (1/2C),
62.7 (1/2C), 59.1 (1/2C), 57.8 (1/2C), 56.1 (1/2C), 56.0 (1/2C),
35.5 (1/2C), 34.2 (1/2C), 32.8 (1C), 32.6 (1C), 24.0 (2C).
135.4 (1/2C), 135.0 (1/2C), 129.7 (1/2C), 129.6 (1/2C), 128.4
(2C), 128.0 (1C), 127.9 (1/2C), 127.8 (1/2C), 127.2 (1/2C),
127.1 (1/2C), 125.4 (2C), 124.7 (1/2C), 124.6 (1/2C), 62.3
(1/2C), 62.2 (1/2C), 58.3 (1/2C), 58.2 (1/2C), 50.3 (1/2C),
50.20 (1/2C), 50.15 (1/2C), 50.1 (1/2C), 35.1 (1/2C), 34.9
(1/2C).
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ASSOCIATED CONTENT
Supporting Information
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3-Chlorobenzoic acid 8-butoxy-4-hydroxy-7-methoxy-3-
phenyl-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl methyl ester
(8d). Yield = 60% (306 mg); Colorless gum; HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C29H32ClO6 511.1888, found 511.1885;
1H NMR (400 MHz, CDCl3): δ 8.04-8.02 (m, 1H), 7.95-7.92
(m, 1H), 7.54-7.52 (m, 1H), 7.41-7.23 (m, 6H), 6.98 (s, 1/2H),
6.96 (s, 1/2H), 6.79 (s, 1/2H), 6.78 (s, 1/2H), 6.30-6.25 (m,
1H), 4.14-3.91 (m, 4H), 3.88-3.85 (m, 1H), 3.86 (s, 3/2H),
3.85 (s, 3/2H), 3.61 (d, J = 2.0 Hz, 1/2H), 3.49 (dd, J = 4.4,
15.2 Hz, 1/2H), 3.31-3.22 (m, 1H), 3.16-3.11 (m, 1H), 2.30 (br
s, 1H), 1.82-1.75 (m, 2H), 1.52-1.43 (m, 2H), 0.94 (t, J = 7.2
Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 164.92 (1/2C),
164.89 (1/2C), 149.62 (1/2C), 149.57 (1/2C), 147.79 (1/2C),
147.75 (1/2C), 136.98 (1/2C), 136.90 (1/2C), 134.5 (1C),
133.16 (1/2C), 133.13 (1/2C), 131.80 (1/2C), 131.74 (1/2C),
129.74 (1C), 129.65 (1C), 128.45 (2C), 128.21 (1/2C), 128.19
(1/2C), 127.8 (1C), 127.77 (1/2C), 128.72 (1/2C), 127.21 (1C),
125.6 (2C), 114.1 (1/2C), 113.4 (1/2C), 111.6 (1/2C), 111.5
(1/2C), 74.6 (1C), 69.0 (1/2C), 68.9 (1/2C), 65.7 (1/2C), 65.5
(1/2C), 63.3 (1/2C), 62.7 (1/2C), 59.1 (1/2C), 57.7 (1/2C),
56.01 (1/2C), 55.97 (1/2C), 35.4 (1/2C), 34.1 (1/2C), 31.1
(1C), 19.1 (1C), 13.8 (1C).
Scanned photocopies of NMR spectral data for all compounds
and X-ray analysis data of 2a, 3b, 4a, 4d, 5b and 6a. This infor-
mation is available free of charge via the Internet at http:
//pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Email: mychang@kmu.edu.tw
ORCID
Meng-Yang Chang: 0000-0002-1983-8570
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
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).
REFERENCES
(1) Review on o-carbonyl allylarenes, see: Hassam, M.; Taher, A.;
Arnott, G. E.; Green, I. R.; van Otterlo, W. A. L. Isomerization
of Allylbenzenes. Chem. Rev. 2015, 115, 5462-5569.
(2) Key example on synthesis of o-carbonyl allylarene, Hu, X.-Q.;
Hu, Z.; Zhang, G. Sivendran, N.; Gooßen, L. J. Catalytic C–N
and C–H Bond Activation: ortho-Allylation of Benzoic Acids
with Allyl Amines. Org. Lett. 2018, 20, 4337-4340.
3-Chlorobenzoic acid 4-hydroxy-8-isopropoxy-7-methoxy-
3-phenyl-1,3,4,5-tetrahydrobenzo[c]oxepin-1-ylmethyl ester
(8e). Yield = 67% (332 mg); Colorless gum; HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C28H30ClO6 497.1731, found 497.1732;
1H NMR (400 MHz, CDCl3): δ 8.05-8.02 (m, 1H), 7.96-7.91
(m, 1H), 7.52-7.48 (m, 1H), 7.41-7.23 (m, 6H), 7.02 (s, 1/2H),
7.00 (s, 1/2H), 6.794 (s, 1/2H), 6.788 (s, 1/2H), 6.31-6.26 (m,
1H), 4.55-4.47 (m, 1H), 4.11-3.88 (m, 1H), 3.84 (s, 3H), 3.83
(s, 3/2H), 3.82 (s, 3/2H), 3.64 (d, J = 2.0 Hz, 1/2H), 3.43 (dd, J
= 4.4, 15.2 Hz, 1/2H), 3.29-3.23 (m, 1H), 3.16-3.09 (m, 1H),
1.35 (d, J = 6.8 Hz, 3H), 1.31 (d, J = 6.4 Hz, 3H); 13C{1H}
NMR (100 MHz, CDCl3): δ 164.84 (1/2C), 164.81 (1/2C),
150.4 (1/2C), 150.3 (1/2C), 146.23 (1/2C), 146.19 (1/2C),
136.9 (1/2C), 136.8 (1/2C), 134.4 (1C), 133.01 (1/2C), 132.99
(1/2C), 131.72 (1/2C), 131.67 (1/2C), 129.6 (1C), 129.5 (1C),
128.3 (2C), 128.10 (1/2C), 128.08 (1/2C), 127.74 (1/2C),
127.67 (1C), 127.6 (1/2C), 125.5 (2C), 119.6 (1/2C), 114.6
(1/2C), 114.5 (1/2C), 114.1 (1/2C), 113.5 (1/2C), 111.8 (1/2C),
74.47 (1/2C), 74.45 (1/2C), 71.56 (1/2C), 71.52 (1/2C), 65.6
(1/2C), 65.4 (1/2C), 63.2 (1/2C), 62.6 (1/2C), 59.0 (1/2C),
57.8 (1/2C), 55.83 (1/2C), 55.80 (1/2C), 32.3 (1/2C), 34.1
(1/2C), 22.00 (1/2C), 21.97 (1/2C), 21.9 (1/2C), 21.7 (1/2C).
(3) Examples on synthesis of indene, for Ni(0), see: (a) Ogoshi, S.;
Haba, T.; Ohashi, M. Nickel-Catalyzed Direct Conjugate Addi-
tion of Simple Alkenes to Enones. J. Am. Chem. Soc. 2009, 131,
10350-10351. For Ir(I), see: (b) Fernandez, D. F.; Gulias, M.;
Mascarenas, J. L.; Lopez, F. Iridium(I)-Catalyzed Intramolecular
Hydrocarbonation of Alkenes: Efficient Access to Cyclic Sys-
tems Bearing Quaternary Stereocenters. Angew. Chem. Int. Engl.
2017, 56, 9541-9545. For Cu(I), see: (c) Ni, J.; Xue, Y.; Sun, L.;
Zhang, A. Cu-Mediated Sulfonyl Radical-Enabled 5-exo-trig
Cyclization of Alkenyl Aldehydes: Access to Sulfonylmethyl
1H-Indenes. J. Org. Chem. 2018, 83, 4598-4605.
(4) Examples on synthesis of 1-indanol, for Ru(II), see: (a) Fustero,
S.; Rodriguez, E.; Lazaro, R.; Herrera, L.; Catalan, S.; Barrio, P.
Relay Catalysis: Enantioselective Synthesis of Cyclic Benzo-
Fused Homoallylic Alcohols by Chiral Brønsted Acid-Catalyzed
Allylboration/Ring Closing Metathesis. Adv. Synth. Catal. 2013,
355, 1058-1064. For Ni(0), see: (b) Hayashi, Y.; Hoshimoto, Y.;
Kumar, R.; Ohashi, M.; Ogoshi, S. Nickel(0)-Catalyzed Intramo-
lecular Reductive Coupling od Alkenes and Aldehydes or Ke-
tones with Hydrosilanes. Chem. Commun. 2016, 52, 6237-6240.
(5) Examples on synthesis of 1-indanone, for Fe(II), see: (a) Liu, W.;
Li, Y.; Liu, K.; Li, Z. Iron-Catalyzed Carbonylation-
Peroxidation of LAkenes with Aldehydes and Hydroperoxides. J.
Am. Chem. Soc. 2011, 133, 10756-10759. For Ni(0)/NHC, see:
(b) Hoshimoto, Y.; Hayashi, Y.; Suzuki, H.; Ohashi, M.; Ogoshi,
S. Synthesis of Five- and Six-Membered Benzocyclic Ketones
2-[2-(3-Phenyl-2,3-oxiranyl)phenyl]oxirane (9a). Yield =
78% (197 mg); Two isomers, ratio = 1 : 1; Colorless gum;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H17O2 253.1229,
found 253.1233; 1H NMR (400 MHz, CDCl3): δ 7.39-7.28 (m,
9H), 4.16-4.13 (m, 1H), 3.74 (d, J = 1.6 Hz, 1/2H), 3.71 (d, J =
1.2 Hz, 1/2H), 3.29-3.18 (m, 4H), 2.79 (dd, J = 2.8, 6.0 Hz,
1/2H), 2.74 (dd, J = 2.8, 5.6 Hz, 1/2H); 13C{1H} NMR (100
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Page 11 of 11
The Journal of Organic Chemistry
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Synthesis
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Li, X.; Lu, Y.; Liu, W.; Hu, L.; Lin, D.; Wang, M.; Zheng, X.;
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(15) CCDC 1854753 (2a), 1854754 (3b), 1854755 (4a), 1854757
(4d), 1854758 (5b) and 1854759 (6a) contain the supplementary
crystallographic data for this paper. This data can be obtained
free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or
from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax:
44-1223-336033; e-mail: deposit@ccdc.cam.ac.uk).
(10) Examples on synthesis of isoquinoline, for Os(VIII), see: (a)
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Unified Approach for the Synthesis of β-Carbolines and Other
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