Synthesis of (+)-O-methylthalibrine by employing a stereocontrolled Bischler-Napieralski reaction and an electrochemically generated diaryl ether

Article abstract of DOI:10.1002/ejoc.201301128

An efficient electrochemical four-step route was developed for the preparation of diaryl ether derivatives by using halogenation and dehalogenation processes in addition to electrochemical phenolic oxidation and reduction reactions. The synthesis of (+)-O

Full text of DOI:10.1002/ejoc.201301128

FULL PAPER
DOI: 10.1002/ejoc.201301128
Synthesis of (+)-O-Methylthalibrine by Employing a Stereocontrolled Bischler–
Napieralski Reaction and an Electrochemically Generated Diaryl Ether
Yuki Kawabata,[a] Yu Naito,[a] Tsuyoshi Saitoh,[a] Kohei Kawa,[a] Toshio Fuchigami,[b] and
Shigeru Nishiyama*[a]
Keywords: Total synthesis / Alkaloids / Electrochemistry / Oxidation / Halogenation / Cyclization
An efficient electrochemical four-step route was developed
for the preparation of diaryl ether derivatives by using halo-
genation and dehalogenation processes in addition to elec-
trochemical phenolic oxidation and reduction reactions. The
synthesis of (+)-O-methylthalibrine was achieved by em-
ploying this strategy along with a stereoselective Bischler–
Napieralski reaction.
Introduction
Electroorganic chemical processes that avoid the use of
expensive reagents and the generation of hazardous waste
materials have served as key steps in a number of synthetic
routes to natural and non-natural organic targets. As part
of an ongoing investigation of this area, we have developed
an anodic oxidation reaction for phenols, which produces
one- or two-electron oxidation products that contain the
respective diaryl ether I[1] and spirocyclic furan II[2] moieties
(see Figure 1). From the perspective of the electron-transfer
steps that are involved, these processes mimic the oxidation
reactions that take place in the biosynthesis of natural prod-
ucts that contain these structural units.
The results of our earlier studies, which focused on the
synthesis of brominated tyrosine derivatives of marine ori-
gin as exemplified by bastadin 1 (see Figure 1),[1,2] suggest
that the oxidations of phenols with halogens at the ortho
positions proceed smoothly to provide diaryl ethers.[3] In
contrast, electrochemical reactions of mono-[4a] and non-
halogen[4b,4c] containing phenols undergo C–C couplings to
lead to diaryl products. In the efficient oxidation reaction
of phenols, the halogen substituents can be considered as
auxiliaries that are introduced to promote efficient diaryl
ether formation and then are cleanly removed after the oxi-
dation process. We have demonstrated the applicability of
this strategy to a general synthetic method for the prepara-
tion of diaryl ethers I from phenols III (see Scheme 1). With
Figure 1. Oxidation reaction of phenols and natural products that
contain the diaryl ether unit.
regard to synthetic methods for diaryl ethers,[1] the oxidat-
ive coupling of the same phenol species is recognized as a
more economic process than other coupling reactions that
use two chemical species. In this approach, halogenated
phenol IV, which is generated from III (see Scheme 1,
step A), is subjected to an anodic oxidation (see Scheme 1,
step B) to give aryloxycyclohexadienone VII through radi-
cal V and coupling product VI. Next, the treatment of VII
with Zn (see Scheme 1, step C) yields phenol VIII, which
provides the target diaryl ether I upon catalytic hydro-
genolysis (see Scheme 1, step D) to remove the halogen aux-
iliary.[5]
[a] Department of Chemistry, Faculty of Science and Technology,
Keio University,
Hiyoshi 3-14-1, Kohoku-ku, Yokohama 223-8522, Japan
E-mail: nisiyama@chem.keio.ac.jp
http://www.chem.keio.ac.jp/~nishiyama_lab/N-lab/HOME.html
[b] Department of Electronic Chemistry, Tokyo Institute of
Technology,
An example of the utility of this strategy is found in our
recently described synthesis of O-methylthalibrine (1),[6]
a
Nagatsuta 4259, Midori-ku, Yokohama 226-8502, Japan
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301128.
bis(benzylisoquinoline) alkaloid that was isolated from the
roots of Thalictrum glandulosissimun,[7a] Thalictrum fab-
Eur. J. Org. Chem. 2014, 99–104
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S. Nishiyama et al.
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Scheme 1. Strategy for the synthesis of diaryl ethers I by electrochemical oxidation of halogenated phenols.
eri,[7b] and Thalictrum minus race B.[7c] In this developed ap- an appropriately substituted diaryl ether and transformed
proach, the bis(benzylisoquinoline) moiety of the target was this substance into optically active 1 by employing a dia-
constructed by using a Bischler–Napieralski reaction[8] of stereoselective Bischler–Napieralski reaction[8] that was me-
an appropriately substituted diaryl ether core, which was diated by (S)-N-(3,4-dimethoxyphenethyl)-1-phenylethan-
generated by the approach outlined in Scheme 1. The ma- amine (9) to simultaneously install the two stereogenic cen-
nipulation of functional groups at a late stage led to a mix- ters of the target.
ture of stereoisomers that have the O-methylthalibrine (1)
structure. Opatz et al.[9b] recently described the synthesis of
Results and Discussion
optically active 1 by employing an Ullmann coupling reac-
tion between two optically active benzylisoquinoline seg-
ments and relied on an α-aminonitrile alkylation[9] followed
by a Noyori reduction. In the investigation described,
Electrochemical Preparation of Diaryl Ethers 4
Initial efforts focused on optimizing the halogenation of
herein, we improved the electrochemical conversion of the phenols. The reactions of methyl 2-(4-hydroxyphenyl)-
phenols into diaryl ethers by the addition of an electro- acetate with anodically generated Br+ or Cl+ ions were first
chemical halogenation (see Scheme 1, step A) and dehalo- explored. In a manner similar to related chemical reac-
genation that was performed by using a unique flow-cell tions,[10] the electrochemical bromination of this substance
system with a Pd electrode and electrochemically generated by using the procedure described in the Experimental Sec-
hydrogen (see Scheme 1, step D). In this effort, we prepared tion with NaBr as the bromine source led to the formation
Table 1. Electrochemical halogenation of methyl 2-(4-hydroxyphenyl)acetate.
Entry
Solvent
X source (Br or Cl)
Potential [V vs. SCE]
[F/mol]
% Yield[a] of 2-Br or 2-Cl
1
2
3
4
5
6
7
8
9
10
11
12
13
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
DMF
MeCN
MeCN
MeCN
MeCN
NaBr
NaBr
NaBr
NaBr
nBu4NBr
LiBr
LiCl
nBu4NCl
LiCl
nBu4NCl
nBu4NCl
nBu4NCl
nBu4NCl
0.77–0.78
0.76
0.76
0.88
0.88
0.83–0.85
1.27–1.36
1.28–1.39
1.02–1.06
0.99–1.04
0.97–1.04
1.02–1.04
0.99
4.5
5
5.5
6
5.5
5.5
5.5
5.5
5.5
5.5
4
86[b]
92[c]
97
86
87
96
14[d]
8[d]
31
44
48
50
48
4.5
5
[a] Entries 1–6 for 2-Br, Entries 7–13 for 2-Cl. [b] Monobrominated derivative was produced in 7% yield. [c] Trace amounts of monobromi-
nated derivative were produced. [d] Oxidation of the solvent occurred.
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Synthesis of (+)-O-Methylthalibrine
of 3,5-dibromo product 2-Br in 97% (see Table 1, Entry 3).
In contrast, dichloro analogue 2-Cl was produced in 50%
yield when nBu4NCl was utilized as the halogen source in
the corresponding anodic process (see Table 1, Entry 12).
The results of a study to compare reactivities under the oxi-
dative dimerization conditions showed that 2-Cl was con-
verted into the desired coupling product 3-Cl in 60% yield,
which was higher than the 35% yield that resulted from
the corresponding reaction to give 3-Br (see Scheme 2).[6]
Cathodic reduction reactions of 3-Br and 3-Cl proceeded
quantitatively to give the desired diaryl ethers 4-Br and 4-
Cl.[6] On the basis of the described observations, 3-Cl was
selected as the substance to be used for further synthetic
studies.
Scheme 3. Synthesis of (+)-O-methylthalibrine (1) by employing di-
aryl ether 6. Reagents and conditions: (a) MeI, K2CO3, N,N-di-
methylformamide (DMF), 0 °C, 7 h, 99%; (b) H2, 5% Pd/C,
MeOH, room temp., 24 h, 86%; (c) NaOH, aqueous MeOH, room
temp., 17 h, quantitative; (d) (1) 9, (benzotriazol-1-yloxy)tris(di-
methylamino)phosphonium hexafluorophosphate (BOP) reagent,
Et3N, MeCN, (2) POCl3, PhMe, reflux, 16 h; (3) NaBH4, MeOH,
–78 °C, 6 h, 92% in two steps; (e) H2, aqueous HCHO, Pd-
(OH)2, room temp., 23 h, 57%; (f) Na, liquid NH3, 2 h, 11 (26%),
12 (quantitative).
Scheme 2. Electrochemical dimerization of halogenated phenols 2
to give diaryl ethers 4 (see ref.[6]).
Pathway for the Successful Synthesis of 1
In a previous report in which the dehalogenation was
carried out at a late stage to give analogues of 1 for struc-
ture–activity relationship studies, the catalytic hydro-
genolysis removed only the bromo groups to give stereoiso-
The sequence that was employed to complete the total
mers of 1.[6,11] In the present approach, dehalogenation was synthesis of nonracemic 1 was initiated by the alkaline hy-
conducted by catalytic hydrogenolysis at an early stage. drolysis of 6 to produce diacid 8 (see Scheme 3). The reac-
Thus, after the methylation of 4-Cl, catalytic hydrogenation tion of 8 with (S)-N-(3,4-dimethoxyphenethyl)-1-phenyl-
of the resulting ether 5 generated 6 in 86% yield (see ethanamine (9) provided the corresponding bis(amide) in
Scheme 3).
81% yield, which underwent a Bischler–Napieralski reac-
A reduction reaction for the dechlorination was also de- tion to give 10 in 92% yield. The one-pot conversion of the
veloped (see Scheme 4).[12] In this process, a MeOH solu- chiral auxiliaries of 10 into methyl groups was carried out
tion that contained diaryl ether 4-Cl was passed through a by using H2, Pd(OH)2, and HCHO to give the desired alka-
Pd tube (cathode) in a flow-cell-type system, and a Pt wire loid 1 with an optical rotation of [α]2D3 = +76.2 (c = 0.36,
(anode) was located in aqueous H2SO4 outside of the sys- CHCl3) that closely matched the reported data {ref.[7f] [α]D
tem. Hydrogen, which was generated by electrolysis, was ab- = +82 (c = 0.36, CHCl3), ref.[9b] [α]D25 = +79.2 (c = 0.45,
sorbed into the Pd tube and supplied through its inner sur- CHCl3)}. To assess the selectivity of the chiral auxiliary in-
face. As a result, the successive reduction [constant current duced Bischler-Napieralski reaction, synthetic 1 was sub-
electrolysis (CCE), 62.5 mA/cm2, 0.8 mL/min] of 4-Cl was mitted to reported Birch reduction conditions[7c] to give ar-
conducted to give 7 in 76% yield.[13] Thus, with the in- mepavin (11) with an optical rotation of [α]D20 = +117 (c =
clusion of this new dehalogenation reaction, the new four- 1.0, CHCl3) {ref.[7d] [α]D22 = +96 (c = 1, CHCl3), ref.[9b]
step conversion of methyl 2-(4-hydroxyphenyl)acetate into [α]2D5 = +94.2 (c = 1, CHCl3)} and O-methylarmepavine (12)
the corresponding diaryl ether 7 was established by using with an optical rotation of [α]2D0 = +83.7 (c = 0.35, CHCl3)
an electrochemical procedure (see Scheme 1). Compound 7 {ref.[7e] [α]D27 = +99 (c = 0.14, CHCl3)}. The optical purities
was converted into 6 under standard methylation condi- of both of these substances were determined by chiral
tions.
HPLC analysis to have an (S)/(R) ratio of 93:7.
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101

S. Nishiyama et al.
FULL PAPER
Scheme 4. Electrochemical dehalogenation of 4-Cl. Reagents and conditions: (a) trimethylsilyldiazomethane (TMSCHN2), MeOH, room
temp., overnight, 90%.
concentrated in vacuo. The crude product was purified by
chromatography.
Conclusions
We developed a concise route for the synthesis of op-
Methyl 2-(3,5-Dibromo-4-hydroxyphenyl)acetate (2-Br): IR (film): ν
˜
tically active O-methylthalibrine (1) by employing an elec-
trochemically prepared diaryl ether derivative. In the se-
quence, the two chiral centers of the target were installed
simultaneously by using a stereoselective Bischler–Napieral-
ski cyclization reaction. Finally, a reduction method was
developed for the dehalogenation of chlorinated diaryl H]+ 324.8853; found 324.8869.
ethers. The latter process should find applications in syn-
= 2957, 1718, 1556 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.37
(s, 2 H, Ar), 5.87 (s, 1 H, ArOH), 3.71 (s, 3 H, CO2CH3), 3.49 (s,
2 H, ArCH2) ppm. 13C NMR (100 MHz, CDCl3): δ = 171.2 (C=O),
148.6 (Ar), 132.8 (Ar), 128.4 (Ar), 109.7 (Ar), 52.3 (CO2CH3), 39.4
(ArCH2) ppm. HRMS (ESI): calcd. for C9H879Br81BrO3 [M +
Methyl 2-(3,5-Dichloro-4-hydroxyphenyl)acetate (2-Cl): Colorless
thetic organic chemistry.
needles (hexane/EtOAc); m.p. 88–89 °C. IR (film): ν = 2960, 2912,
˜
1725, 1570 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.20 (s, 2 H,
Ar), 5.84 (s, 1 H ArOH), 3.71 (s, 3 H, CO2CH3), 3.52 (s, 2 H,
ArCH2) ppm. 13C NMR (100 MHz, CDCl3): δ = 171.1 (C=O),
146.9 (Ar), 129.0 (Ar), 127.1 (Ar), 120.9 (Ar), 52.3 (CO2CH3), 39.7
(ArCH2) ppm. HRMS (ESI): calcd. for C9H935Cl2O3 [M + H]+
234.9884; found 234.9939.
Experimental Section
General Methods: IR spectra were recorded with a JASCO FT/IR-
4200 spectrophotometer. The 1H and 13C NMR spectroscopic data
were recorded with JEOL JNM-α400, JEOL JNM-AL400, and
JEOL JNM-ECX400 spectrometers. High-resolution mass spectra
were obtained with a Waters LCT Premier XE (ESI). Silica gel
column chromatography was carried out by using Kanto Chemical
Silica 60N (spherical, neutral, 63–210 μm). Preparative and analyti-
cal thin-layer chromatography (TLC) was carried out with silica gel
plates (Kieselgel 60 F254, E. Merck AG, Germany). TLC was used
to monitor the reactions, and the plates were visualized by using
UV (254 nm) light or staining with 5% phosphomolybdic acid in
ethanol as a colorizing agent followed by heating on an electric
plate.
Methyl 2-{3-Chloro-5-[2,6-dichloro-4-(2-methoxy-2-oxoethyl)phen-
oxy]-4-methoxyphenyl}acetate (5): A solution of 4-Cl (366.4 mg,
0.845 mmol),[6] K2CO3 (70.0 mg, 0.507 mmol), and MeI (0.16 mL,
3.9 mmol) in DMF (8.5 mL) at 0 °C was stirred for 7 h and then
diluted with aqueous HCl (2 m). The resulting mixture was ex-
tracted with CHCl3. The organic layer was washed with brine, dried
with Na2SO4, and then concentrated in vacuo. The residue was
subjected to silica gel chromatography (hexane/EtOAc, 2:1) to af-
ford 5 (375 mg, 99%) as a colorless oil. IR (film): ν = 3449, 2951,
˜
1738 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.35 (s, 2 H, Ar), 7.01
(d, J = 2 Hz, 1 H, Ar), 6.21 (d, J = 2 Hz, 1 H, Ar) 4.02 (s, 3 H,
ArOCH3), 3.76 (s, 3 H, CO2CH3), 3.65 (s, 3 H, CO2CH3), 3.63 (s,
2 H, ArCH2), 3.43 (s, 2 H, ArCH2) ppm. 13C NMR (100 MHz,
CDCl3): δ = 171.0 (C=O), 170.7 (C=O), 150.3 (Ar), 145.4 (Ar),
144.1 (Ar), 133.1 (Ar), 130.2 (Ar), 130.1 (Ar), 129.4 (Ar), 129.0
(Ar), 124.6 (Ar), 113.5 (Ar), 61.0 (ArOCH3), 52.4 (CO2CH3), 52.1
(CO2CH3), 40.2 (ArCH2), 39.9 (ArCH2) ppm. HRMS (ESI): calcd.
for C19H18O635Cl237Cl [M + H]+ 449.0134; found 449.0139.
General Procedure of Electrochemical Halogenation: Electrolysis
was carried out under constant current electrolysis (CCE, 10 mA/
cm2, 4–6 F/mol) conditions in an H-type cell, in which cathodic
and anodic chambers were separated by an anion-exchange mem-
brane (Neosepta AHA). A Pt plate (1 cm2), Pt wire, and saturated
calomel electrode were used as an anode, a cathode, and a reference
electrode, respectively. The analyte was a solution of methyl 2-(4-
hydroxyphenyl)acetate (5 mm) and the halogen source (0.1 m) in
solvent, and the catholyte was a solution of the halogen source
(0.1 m) and aqueous HCl (0.15 m) in solvent. The resultant mixture
was concentrated in vacuo, and the residue was partitioned between
EtOAc and H2O. The organic layers were dried with Na2SO4 and
Preparation of Methyl 2-{4-Methoxy-3-[4-(2-methoxy-2-oxoethyl)-
phenoxy]phenyl}acetate (6) from Compound 5: A solution of 5
(194.3 mg, 0.434 mmol) in MeOH (4.3 mL), which contained cata-
lytic 5% Pd/C, was stirred at room temp. under hydrogen for 24 h.
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Synthesis of (+)-O-Methylthalibrine
The mixture was filtered, and the filtrate was concentrated in vacuo
to give a residue that was subjected to silica gel chromatography
(hexane/EtOAc, 2:1) to afford 6 (129.4 mg, 0.376 mmol, 86%) as a
(169.9 mg, 0.384 mmol), was stirred at room temp. for 16 h. The
mixture was diluted with aqueous HCl (2 m), and the resulting solu-
tion was extracted with CHCl3 (3ϫ). The combined organic layers
were washed with brine, dried with Na2SO4, and concentrated in
colorless oil. IR (film): ν = 3001, 2952, 2840, 1735, 1609, 1585,
˜
1
1507 cm–1. H NMR (400 MHz, CDCl3): δ = 7.19 (d, J = 8.8 Hz, vacuo to give a residue that was subjected to silica gel column
2 H, Ar), 7.03 (dd, J = 8.6, 2.2 Hz, 1 H, Ar), 6.94 (d, J = 8.6 Hz,
1 H, Ar), 6.896 (d, J = 2.2 Hz, 1 H, Ar), 6.81 (d, J = 8.8 Hz, 2 H,
Ar), 3.81 (s, 3 H, ArOCH3), 3.69 (s, 3 H, CO2CH3), 3.67 (s, 3 H,
chromatography (hexane/EtOAc, 1:3) to afford the coupling prod-
uct (105.8 mg, 81%) as a colorless oil. The NMR spectra showed
a mixture of the corresponding rotamers. [α]2D3 = –57.3 (c = 1.00,
CO2CH3), 3.58 (s, 2 H, ArCH2), 3.52 (s, 2 H, ArCH2) ppm. 13C CHCl ). IR (film): ν = 2934, 1635, 1515 cm–1. HRMS (ESI): calcd.
˜
3
NMR (100 MHz, CDCl3): δ = 172.3 (C=O), 172.1 (C=O), 157.0
(Ar), 150.6 (Ar), 147.5 (Ar), 144.8 (Ar), 130.5 (Ar), 128.1 (Ar),
126.9 (Ar), 125.6 (Ar), 122.2 (Ar), 117.3 (Ar), 112.9 (Ar), 56.2 (Ar-
OCH3), 52.1 (CO2CH3), 40.5 (ArCH2), 40.3 (ArCH2) ppm. HRMS
(ESI): calcd. for C19H21O6 [M + H]+ 345.1338; found 345.1346.
for C53H58N2O8 [M + H]+ 851.4271; found 851.4235. To a solution
of the coupling product (48.6 mg, 57.1 μmol) in PhMe (1.0 mL)
was added POCl3 (0.4 mL) at room temp. The mixture was stirred
and heated at reflux for 16 h and then concentrated in vacuo. The
residue was redissolved in anhydrous MeOH (1.0 mL). To the re-
sulting solution at –78 °C was added NaBH4 (38.9 mg, 1.03 mmol).
After stirring for 6 h, the mixture was diluted with aqueous HCl
(2 m) at 0 °C, and the resulting solution was extracted with CHCl3.
The organic layer was dried with Na2SO4 and concentrated in
vacuo to give a residue, which was subjected to preparative TLC
(hexane/EtOAc, 2:1) to afford 10 (43.0 mg, 92%) as a white solid.
Preparation of Methyl 2-{4-Methoxy-3-[4-(2-methoxy-2-oxoethyl)-
phenoxy]phenyl}acetate (6) from Compound 7: To a solution of 7
(21.6 mg, 0.065 mmol) in MeOH (1.5 mL) was added TMSCHN2
(0.33 mL, 0.196 mmol) at room temp. After stirring overnight, the
mixture was concentrated in vacuo, and the residue was purified
by preparative TLC (hexane/EtOAc, 1:1) to give 6 (20.3 mg, 90%).
[α]2D3 = +59.2 (c = 1.00, CHCl ). IR (film): ν = 3060, 3026, 2964,
˜
3
General Procedure for the Dehalogenation: Electrolysis was carried
out under the CCE conditions in a flow-cell apparatus as shown
in Scheme 4. A Pd tube (3.0ϫ0.2ϫ100 mm, purity = 99.95%) and
Pt wire were used as the cathode and anode, respectively, and were
immersed in a vessel that contained an aqueous solution of H2SO4
(1 m). During the electrolysis at a constant current (62.5 mA/cm2),
a solution of 4-Cl (1 mm) in MeOH was passed through the Pd
tube at a rate of 0.8 min/mL. The eluent was concentrated in vacuo,
and the crude product was purified by chromatography.
2934, 2835, 1609, 1507 cm–1. 1H NMR (400 MHz, CDCl3): δ =
7.16 (m, 6 H, Ar), 7.05 (m, 4 H, Ar), 6.87 (d, J = 8.5 Hz, 2 H, Ar),
6.85 (d, J = 8.5 Hz, 1 H, Ar), 6.77 (d, J = 8.5 Hz, 2 H, Ar), 6.71
(dd, J = 8.5, 2 Hz, 1 H, Ar), 6.62 (d, J = 2 Hz, 1 H, Ar), 6.59 (s,
1 H, Ar), 6.56 (s, 1 H, Ar), 5.97 (s, 1 H, Ar), 5.95 (s, 1 H, Ar), 3.85
(s, 3 H, ArOCH3), 3.848 (s, 3 H, ArOCH3), 3.85 (s, 3 H, ArOCH3),
3.82 (s, 3 H, ArOCH3), 3.7 (m, 4 H), 3.58 (m, 3 H), 3.56 (m, 3 H),
3.38–3.12 (m, 4 H), 3.04 (dd, J = 7, 14 Hz, 1 H), 3.0–2.8 (m, 3 H),
2.71 (dd, J = 7, 14 Hz, 1 H), 2.66 (dd, J = 7, 14 Hz, 1 H), 2.43 (m,
2 H), 1.34 (m, 6 H, CCH3) ppm. 13C NMR (100 MHz, CDCl3): δ
= 156.3 (Ar), 149.8 (Ar), 147.3 (Ar), 147.3 (Ar), 146.5 (Ar), 146.47
(Ar), 146.43 (Ar), 146.3 (Ar), 144.6 (Ar), 134.1 (Ar), 133.3 (Ar),
131.0 (Ar), 129.74 (Ar), 129.66 (Ar), 128.3 (Ar), 128.27 (Ar), 127.4
(Ar), 126.7 (Ar), 126.6 (Ar), 126.1 (Ar), 122.6 (Ar), 116.7 (Ar),
112.4 (Ar), 111.5 (Ar), 111.4 (Ar), 60.7 (CHN), 60.6 (CHN), 59.2
(ArOCH3), 56.3 (ArOCH3), 55.9 (ArOCH3), 55.8 (ArOCH3), 55.7
(ArOCH3), 41.5 (CH2N), 41.4 (CH2N), 39.7 (ArCH2), 39.6
(ArCH2), 23.9 (ArCH2), 22.3 (CCH3), 22.2 (CCH3) ppm. HRMS
(ESI): calcd. for C53H59N2O6 [M + H]+ 819.4373; found 819.4401.
Methyl 2-{4-Hydroxy-3-[4-(2-methoxy-2-oxoethyl)phenoxy]phenyl}-
acetate (7): IR (film): ν = 3005, 2954, 2843, 1733, 1597, 1507 cm–1.
˜
1H NMR (400 MHz, CD3OD): δ = 7.18 (d, J = 8.7 Hz, 2 H, Ar),
6.92–6.81 (m, 5 H, Ar), 3.64 (s, 3 H, CO2CH3), 3.63 (s, 3 H,
CO2CH3), 3.58 (s, 2 H, ArCH2), 3.49 (s, 2 H, ArCH2) ppm. 13C
NMR (100 MHz, CDCl3): δ = 172.1 (C=O), 155.9 (Ar), 146.6 (Ar),
143.3 (Ar), 130.9 (Ar), 129.3 (Ar), 126.4 (Ar), 125.7 (Ar), 119.9
(Ar), 118.2 (Ar), 116.3 (Ar), 52.2 (CO2CH3), 52.1 (CO2CH3), 40.4
(ArCH2), 40.4 (ArCH2) ppm. HRMS (ESI): calcd. for C18H18O6Na
[M + Na]+ 353.1001; found 353.1002.
2-{4-[5-(Carboxymethyl)-2-methoxyphenoxy]phenyl}acetic Acid (8):
To a solution of 6 (101.1 mg, 0.294 mmol) in MeOH (2.2 mL) and
H2O (0.7 mL), was added aqueous NaOH (3 m, 1.0 mL) at 0 °C.
After stirring for 17 h, the reaction mixture was quenched by the
addition of aqueous HCl (2 m) at 0 °C, and the resulting solution
was extracted with CHCl3. The organic layer was washed with
brine and dried with Na2SO4. The filtrate was concentrated in
O-Methylthalibrine (1): A solution of 10 (11.7 mg, 14.3 μmol) and
37% aqueous HCHO (0.10 mL, 1.42 mmol) in EtOAc (0.45 mL)
and MeOH (0.75 mL), which contained catalytic Pd(OH)2, was
stirred under hydrogen for 23 h. Filtration followed by concentra-
tion of the filtrate in vacuo gave a residue that was subjected to
preparative TLC (CHCl3/MeOH, 12:1) to afford 1 (5.2 mg, 57%)
as a colorless oil. [α]2D3 = +76.2 (c = 0.36, CHCl ). IR (film): ν =
˜
3
vacuo to afford 8 (94.5 mg, quantitative) as a white solid. IR (film):
2996, 2935, 2837, 1610, 1508 cm–1. 1H NMR (400 MHz, CDCl3):
δ = 7.00 (d, J = 8.4 Hz, 2 H, Ar), 6.88 (d, J = 8.4 Hz, 1 H, Ar),
6.84 (dd, J = 8.4, 2 Hz, 1 H, Ar), 6.77 (d, J = 8.4 Hz, 2 H, Ar),
6.70 (d, J = 2 Hz, 1 H, Ar), 6.56 (s, 1 H, Ar), 6.52 (s, 1 H, Ar),
6.04 (s, 1 H, Ar), 5.97 (s, 1 H, Ar), 3.83 (s, 3 H, ArOCH3), 3.81 (s,
3 H, ArOCH3), 3.79 (s, 3 H, ArOCH3), 3.77–3.64 (m, 2 H), 3.59
(s, 3 H, ArOCH3), 3.56 (s, 3 H, ArOCH3), 3.25–3.12 (m, 4 H),
2.89–2.73 (m, 7 H), 2.6 (m, 1 H), 2.57 (s, 3 H, NCH3), 2.52 (s, 3
H, NCH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 156.5 (Ar),
149.8 (Ar), 147.54 (Ar), 147.50 (Ar), 146.52 (Ar), 146.47 (Ar), 144.6
(Ar), 133.4 (Ar), 132.6 (Ar), 130.9 (Ar), 128.3 (Ar), 126.1 (Ar),
1
ν = 2957, 2925, 2851, 1714, 1606, 1507 cm–1. H NMR (400 MHz,
˜
CD3OD): δ = 7.19 (d, J = 8.5 Hz, 2 H, Ar), 7.08 (dd, J = 1.5,
8.5 Hz, 1 H, Ar), 7.04 (d, J = 8.5 Hz, 1 H, Ar), 6.94 (d, J = 1.5 Hz,
1 H, Ar), 6.80 (d, J = 8.5 Hz, 2 H, Ar), 3.76 (s, 3 H, ArOCH3),
3.55 (s, 2 H, ArCH2), 3.52 (s, 2 H, ArCH2) ppm. 13C NMR
(100 MHz, CDCl3): δ = 175.8 (C=O), 175.6 (C=O), 158.7 (Ar),
150.6 (Ar), 145.6 (Ar), 131.5 (Ar), 131.5 (Ar), 129.8 (Ar), 129.1
(Ar), 127.2 (Ar), 123.8 (Ar), 123.7 (Ar), 117.5 (Ar), 114.2 (Ar), 56.4
(ArOCH3), 41.1 (ArCH2), 40.1 (ArCH2) ppm. HRMS (ESI): calcd.
for C17H15O6 [M – H]– 315.0869; found 3315.0878.
1-{4-[5-({6,7-Dimethoxy-2-[(S)-1-phenylethyl]-1,2,3,4-tetrahydro- 125.7 (Ar), 122.5 (Ar), 116.8 (Ar), 112.5 (Ar), 111.2 (Ar), 111.19
isoquinolin-1-yl}methyl)-2-methoxyphenoxy]benzyl}-6,7-dimethoxy- (Ar), 111.1 (Ar), 110.9 (Ar), 65.0 (CHN), 64.8 (CHN), 56.2 (Ar-
2-[(S)-1-phenylethyl]-1,2,3,4-tetrahydroisoquinoline (10): A solution
of 8 (48.6 mg, 0.154 mmol) and 9 (131.5 mg, 0.461 mmol) in MeCN
(1.5 mL), which contained Et3N (0.128 mL) and BOP reagent
OCH3), 55.84 (ArOCH3), 55.81 (ArOCH3), 55.7 (ArOCH3), 55.6
(ArOCH3), 46.8 (CH2N), 46.6 (CH2N), 42.5 (NCH3), 42.3 (NCH3),
40.6 (ArCH2), 40.3 (ArCH2), 25.2 (ArCH2), 25.0 (ArCH2) ppm.
Eur. J. Org. Chem. 2014, 99–104
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103

S. Nishiyama et al.
FULL PAPER
HRMS (ESI): calcd. for C39H47N2O6 [M + H]+ 639.3434; found
639.3439.
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10 mA/cm2, Zn(+) – Zn(–)] to give either 4-Br or 4-Cl in 36
and 66% yield, respectively.
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[6]
[7]
Birch-Type Reduction: To a solution of liquid NH3 (10 mL) that
contained Na (60.5 mg) at –78 °C was added dropwise a solution
of 1 (3.9 mg) in 1,4-dioxane (3 mL). After stirring for 2 h, the mix-
ture was diluted with saturated aqueous NH4Cl, and the resulting
mixture was stirred at room temp. for an additional 2 h. The mix-
ture was extracted with CHCl3. The organic layer was concentrated
in vacuo to give a residue that was subjected to preparative TLC
(CHCl3/MeOH/HNEt2, 10:1:0.1) to afford 11 (0.5 mg, 26%) as a
colorless oil {[α]2D0 = +117 (c = 1.0, CHCl3)} and 12 (2.0 mg, quan-
titative) as a colorless oil {[α]2D0 = +83.7 (c = 0.35 CHCl3)}.
Supporting Information (see footnote on the first page of this arti-
cle): Experiments of synthetic approach to 1 by reduction of chlo-
[8]
[9]
1
rine substituents at the final stage, copies of the H and 13C NMR
spectra, and HPLC data.
Acknowledgments
This study was supported by financial contributions from the Sci-
entific Research C, MEXT and MEXT-Supported Programs for
the Strategic Research Foundation at Private Universities, 2009–
2013 and 2012–2016.
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of a 2-step procedure that involved MeOH and cat. H2SO4 and
SO2Cl2 in AcOH and then Zn gave 2-Cl (62% yield in 2 steps).
[11] We found that dechlorination from the O-methylthalibrine
structure proceeded under hydrogen-transfer conditions, al-
though with significant racemization of the isoquinoline moi-
ety (see Supporting Information).
[2] F. Hentschel, T. Lindel, Synthesis 2010, 181–204.
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[13] Reduction of the Br derivative afforded 7 in 77% yield.
Received: July 29, 2013
Published Online: November 13, 2013
104
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Eur. J. Org. Chem. 2014, 99–104