Electrochemical construction of the diaryl ethers: A synthetic approach to o-methylthalibrine

Article abstract of DOI:10.1016/j.tetlet.2010.07.037

Electrochemical dimerization of halogenated p-hydroxyphenylacetic acid derivatives followed by Zn reduction provided the corresponding diaryl ethers. Manipulation of the reduction step using several procedures increased its efficiency, which enabled the construction of o-methylthalibrine, an isoquinoline-class alkaloid.

Full text of DOI:10.1016/j.tetlet.2010.07.037

Tetrahedron Letters 51 (2010) 4776–4778
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Electrochemical construction of the diaryl ethers: a synthetic approach to
o-methylthalibrine
*
Yu Naito, Takamasa Tanabe, Yuki Kawabata, Yuichi Ishikawa, Shigeru Nishiyama
Department of Chemistry, Faculty of Science and Technology, Keio University, Hiyoshi 3-14-1, Kohoku-ku, Yokohama 223-8522, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Electrochemical dimerization of halogenated p-hydroxyphenylacetic acid derivatives followed by Zn
reduction provided the corresponding diaryl ethers. Manipulation of the reduction step using several pro-
cedures increased its efficiency, which enabled the construction of o-methylthalibrine, an isoquinoline-
class alkaloid.
Received 21 May 2010
Revised 2 July 2010
Accepted 7 July 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
standard procedure from p-hydroxyphenylacetic acid (6) indicated
that their anodic oxidation reactions provided complex mixtures.6
o-Methylthalibrine (1) is
a
bisbenzylisoquinoline alkaloid,
Accordingly, the halogenated derivative 5 was examined under
anodic oxidation conditions (Table 1). Using bromine substituents
(5-Br), anodic oxidation under acidic conditions provided the de-
sired diaryl ether (7-Br)11 in yields of 17–35%, along with the cor-
responding two-electron oxidation product 8-Br, whereas the
pyridine condition (entry 1) gave the products in very low yields.
Undesirable oxidative polymerization caused low material bal-
ances. However, the reactions at 0 °C (entries 6 and 8) provided
the products in relatively good yields, as well as recovery of the
starting materials. In the following entries (9–14) using chlorine
substituents (5-Cl), the reaction temperature was fixed at 0 °C,
and the optimized yield of 7-Cl11 was obtained in entry 14.7
isolated from the plant Thalictrum revolutum DC,1 which is used
as a folk medicine in central Asia. In addition to antimalarial and
cytotoxic activities, its structural similarity to tubocurarine alka-
loid (2) prompted us to initiate a synthetic study as part of our
ongoing phenolic oxidation approach to both natural and unnatu-
ral bioactive substances (Fig. 1).2 In the key step of this approach,
anodic or thallium(III) salt oxidation of the appropriately dihalo-
genated phenol derivatives (A) will effect one-electron oxidation
to provide the corresponding dimers (B), providing the expected
diaryl ethers3 (C) on treatment with Zn powder in the presence
of AcOH (Scheme 1). Two halogen atoms located at ortho positions
play an important role in controlling the oxidation potential of the
phenol functions and regioselectivity of the coupling reactions. The
tandem protocol developed in our laboratory enabled the total
synthesis of isodityrosine and the related natural products. How-
ever, improvement of Zn reduction was required to circumvent
undesirable adsorption of substrates to the metal powder, and to
avoid problematic activation of Zn powder by washing in aqueous
acidic solution. Herein, we report the synthesis of 1 along with a
new manipulation of Zn reduction.4
2. Reductive procedure in the preparation of the diaryl ethers
In our previous investigation, we employed the Zn powder with
AcOH conditions, which enabled the synthesis of natural products
carrying the diaryl ether moiety (Scheme 2). However, the reduc-
tion requires an excess amount of Zn powder, which often causes
marked adsorption of substrates and lowers the isolated yield. In
In the retrosynthetic analysis of the target alkaloid 1, oxidative
dimerization of the phenol derivatives carrying (1) a dihydroiso-
quinoline residue (3), (2) an isoquinoline precursor (4), along with
(3) a simple dihalogenated p-hydroxyphenylacetate (5) would pro-
vide the corresponding coupling product 10. Although use of the
former two substrates seemed to be shorter synthetic processes
to the target 1, the attached additional aromatic moieties were
anticipated to impede clear phenolic oxidation.5 Indeed, a previous
study using 3 (X = Br, P = Ac) and 4 (X = Br) synthesized by the
MeO
MeO
Me
NMe
O
N
H
HO
OMe
OMe
O
MeO
O
H
HO
N
Me
H
Me
OMe
OMe
MeN
2
Tubocurarine ( )
o-Methylthalibrine (1)
* Corresponding author. Tel./fax: +81 45 566 1717.
E-mail address: nisiyama@chem.keio.ac.jp (S. Nishiyama).
Figure 1. o-Methylthalibrine (1) and tubocurarine (2).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.037

Y. Naito et al. / Tetrahedron Letters 51 (2010) 4776–4778
4777
R
MeO
Anodic Oxid.
in R'OH
R
R'O
R
R
Zn, H+
X
R
Cl
X
R
R
Cl
or
HO
Cl
O
X
O
or Tl(III) salts
Cl
O
X
Cathodic reduction
R = CH2COOMe
A
B
O
Cl
O
X
7-Cl
HO
Cl
9-Cl
R
Reduction
with Zn-H
X
R
Scheme 2. Reduction of 7.
X
O
C
X= Cl, Br
OH
X
of the electrode gave the desired diaryl ether in high yield.
Using the Zn-plate procedure for 7-Cl, the desired diaryl ether
9-Cl11 was obtained in 61% yield.10a To acquire better yields of
the reduction, the dichlorodienone 7-Cl was subjected to electrol-
ysis using Zn plate to give the diaryl ether in 99% yield.10b Under
the same reaction conditions, 7-Br was converted into the
corresponding 9-Br11 in 60% yield. This result indicated that
electrochemically accumulated Zn at the cathode surface contrib-
uted to the reaction efficiency. Indeed, when electrolysis was
performed using a Pt-electrode in the presence of a zinc ion, the
diaryl ether was produced in 85% yield.
Phenolic Oxidation Approach
1
MeO
COOMe
X
R
NP
Anodic
Oxidation
R
MeO
X
X
X
3
X
OH
O
OH
5
OH
X
X
1'
MeO
MeO
As mentioned above, the anodic oxidation and the following
reduction including new Zn-plate and electrochemical methods
enabled adequate supply of the diaryl ether derivative 9. We then
applied our method to the production of o-methylthalibrine (1).
COOH
HN
X
O
OH
4
X
6
OH
Anodic Oxidarion Substrates
3. Synthetic approach to o-methylthalibrine (1) from the diaryl
ethers (9)
P = protecting group
X = halogen
R = appropriate functional group
The free phenol group of 99 was protected as a methyl ether un-
der standard conditions, followed by alkaline hydrolysis to give the
dicarboxylic acid 10 in high yield, which on condensation with
dimethoxytyramine (11) using the BOP reagent [(benzotriazol-1-
yloxy)-tris(dimetylamino)phosphonium hexafluorophosphate],
and Et3N provided 12. Spontaneous construction of both the iso-
quinoline moieties was performed by the Bischler–Napieralski pro-
tocol using POCl3, followed by NaBH4 reduction of the newly
produced iminium salts, leading to 13. After introduction of
N-methyl functions, the halogens in 14 were removed by hydrog-
enolysis. In contrast to unsuccessful results in the case of the
chlorines, the bromine derivative was smoothly transformed into
the desired plane structure of 1 (Scheme 3).
Scheme 1. Phenolic oxidation approach and retrosynthetic analysis of 1.
Table 1
Anodic oxidationa of the dihalogenated phenols 5
R
R
MeO
X
MeO
X
R
X
R
Anodic Oxidation
HO
X
X
O
X
in MeOH
O
7
O
X
5
8
R = CH2COOMe
Entriesb
X
Anode
Additive
F (mol)
Yields (%)
7
8
5
1
2
3
4
5
6
7
8
Br
Pt
Pt
Pt
C
C
C
L, pyr.
L, H
H
L, H
L, H
L, H
L, H
L, H
3
3
3
2
3.5
3
2.5
2.5
3
33
17
35
31
27
24
23
3
18
16
12
3
26
44
34
—
—
—
—
—
35
7
MeO
R
NH
O
O
MeO
NH2
MeO
MeO
X
R
X
11
Pt
Pt
X
O
17
X
OMe
R'O
X
b
O
9
Cl
C
H
2.5
1.5
3.5
2
3
3
52
47
43
53
51
60
17
20
2
—
—
—
—
—
—
10
11
12
13c
14
Pt
Pt
Pt
Pt
Pt
L, H
L, H
H
H
H
9
R = CH2COOMe, R' = H
X
a
OMe
8
HN
10 R = CH2COOH, R' = Me
12
Trace
—
OMe
MeO
c
a
NR
General procedure: compound 5 (30–50 mg scale, 10 mmol concentration) in
MeO
MeOH in the presence of additives [LiClO4 (L) 0.1 M concentration, HClO4 (H) 0.1 M
concentration, or pyridine 3 equiv mol vs 5] was oxidized under constant current
electrolysis conditions (CCE, 10 mA/cm2, anode = glassy carbon beaker: 25 mL (C),
Pt net 3/ ꢀ 2.5 cm (Pt); cathode = Pt wire 0.1 ꢀ 1 cm). The reaction mixture was
partitioned between EtOAc and H2O. The organic layer was dried and purified by
preparative TLC to give the products.
X
e
1
X
OMe
O
13
14
R = H
d
X
b
R = Me
The reactions were performed at room temperature in entries 1–5 and 7, and at
OMe
RN
0 °C in entries 6 and 8–15.
c
This entry used 2 mmol concentration.
OMe
Scheme 3. Reagents and conditions: (a) (i) MeI, K2CO3, DMF (X = Br 100%, X = Cl
70%); (ii) NaOH (X = Br 100%, X = Cl 100%); (b) BOP reagent, Et3N, 11 (X = Br 100%,
X = Cl 69%); (c) POCl3, PhMe, then NaBH4 (X = Br 100%, X = Cl 34% in two steps); (d)
(CH2O)n, AcOH, NaBH3CN (X = Br 100%, X = Cl 100%); (e) H2, 5% Pd/C (X = Br 48%).
a related reduction during the synthesis of isodityrosine,8 it was
observed that a Zn electrode dipped in acidic solution showed
the same effect as Zn powder, and the following simple rinsing

4778
Y. Naito et al. / Tetrahedron Letters 51 (2010) 4776–4778
SO2Cl2, AcOH, then Zn (62% in two steps). Compounds 3 and 4 were synthesised
In conclusion, the zinc-mediated reduction of the oxidized
by essentially the same procedure as depicted in Scheme 3.
derivative was improved by an electrochemical procedure for effi-
cient conversion to the expected diaryl ether derivative using the
environmentally benign newly manipulated zinc reduction proto-
col. The dimeric products were successfully converted into the tar-
get framework of 1. Further investigation to obtain the target
molecule in optically active form is in progress.
7. When 5-Br was subjected to the same conditions as entry 14, 7-Br was
produced in 28% yield. In the anodic oxidation of 5, the chloro derivative
provided better result than that of the bromo derivative, however, the latter
exhibited effective conversion to the target molecule.
8. Uno, K.; Tanabe, T.; Nishiyama, S. ECS Trans. 2009, 25, 91–95.
9. For the preparative procedure, 9 was synthesized by the successive two-step
manipulation of 5: 9-Br, 36%, 9-Cl, 66% yields, respectively.
10. (a) A solution of 7-Cl (30.0 mg, 0.065 mmol) in MeOH (12.5 mL) and AcOH
(0.4 mL) was kept in the presence of a couple of Zn plates (15 ꢀ 20 ꢀ 0.5 mm).
The reaction was gradually warmed from 0 °C to ambient temperature. After
being reacted overnight, the mixture was partitioned between CHCl3 and H2O.
The organic layer was washed with brine, dried, then purified by preparative
TLC (hexane/EtOAc = 3:1) to give 9-Cl (17.1 mg, 61%).; (b) A solution of 7-Cl
(24.5 mg, 0.053 mmol) in MeOH (21 mL), AcOH (0.4 mL) and 60% aq HClO4
(0.2 mL) was electrolyzed under the CCE conditions (anode, cathode = Zn plate
15 ꢀ 20 ꢀ 0.5 mm, ꢁ10 mA, undivided cell). The reaction was gradually
warmed from 0 °C to ambient temperature. After being reacted overnight,
Acknowledgments
This work was supported by the financial support from the Sci-
entific Research C and High-Tech Research Center Project for Pri-
vate Universities Matching Fund (2006–2011) from MEXT, and
The Science Research Promotion Fund from The Promotion and
Mutual Aid Corporation for Private Schools of Japan.
work-up provided 9-Cl (22.7 mg, 99%).; (c)
A solution of 7-Cl (31.2 mg,
0.067 mmol) and Zn(OAc)2ꢂH2O (210 mg, 0.96 mmol) in MeOH (10 mL) and
60% aq HClO4 (0.2 mL) was setted to a cathode chamber (Pt plate electrode of
the H-type divided cell, EOS-30, Technosigma) with anion exchange membrane
(Neosepta AHA), and Na2SO4 (284 mg) in H2O (10 mL) in an anode chamber (Pt
wire electrode). After being reacted overnight, the mixture was worked up to
give 9-Cl (24.8 mg, 85%).
References and notes
1. (a) Wagner, H.; Lin, L. Z.; Seligmann, O. Planta Med. 1984, 50, 14–16; (b) Wu,
W.-N.; Liao, W.-T.; Mahmoud, Z. F.; Beal, J. L.; Doskotch, R. W. J. Nat. Prod. 1980,
43, 472–481.
2. Several related investigations, see: (a) Yamamura, S.; Nishiyama, S. Synlett
2002, 533–543; (b) Doi, F.; Ogamino, T.; Sugai, T.; Nishiyama, S. Synlett 2003,
411–413; (c) Ito, M.; Yamanaka, M.; Kutsumura, N.; Nishiyama, S. Tetrahedron
Lett. 2003, 44, 7949–7952; (d) Ogamino, T.; Obata, R.; Nishiyama, S. Tetrahedron
Lett. 2006, 47, 727–731; (e) Tanabe, T.; Ogamino, T.; Shimizu, Y.; Imoto, M.;
Nishiyama, S. Bioorg. Med. Chem. 2006, 14, 2753–2762.
3. Review, see: (a) Frlan, R.; Kikelj, D. Synthesis 2006, 2271–2285; (b) Hentschel,
F.; Lindel, T. Synthesis 2010, 181–204.
4. Part of this work was presented in ECS Meeting, Vienna, 2009.
5. In the case of verbenachalcone (Ref. 2e), the oxidation of phenolic function
attached with another aryl group gave a complex mixture.
11. Selected data: Compound 7-Cl: IR (film) 1736, 1692 cmꢁ1; dH (CDCl3, 400 MHz)
2.68 (1H, d, J = 14 Hz), 2.73 (1H, d, J = 14 Hz), 3.18 (3H, s), 3.61 (2H, s), 3.64 (3H,
s), 3.75 (3H, s), 5.51 (1H, d, J = 2.4 Hz), 7.17 (1H, d, J = 2.4 Hz), 7.34 (2H, s);
HRFABMS Calcd for C19 H17O735Cl3: 462.0062 (M), found m/z 462.0040.
Compound 7-Br: IR (film) 1734 cmꢁ1
; dH (CDCl3, 400 MHz) 2.67 (1H, d,
J = 15 Hz), 2.72 (1H, d, J = 15 Hz), 3.22 (3H, s), 3.61 (2H, s), 3.65 (3H, s), 3.75 (3H,
s), 5.49 (1H, d, J = 2.4 Hz), 7.45 (1H, d, J = 2.4 Hz), 7.54 (2H, s); HRFABMS Calcd
for C19 H18O779Br3 (M+1): 593.8564, found m/z 593.8524. Compound 9-Cl: IR
(film) 1735 cmꢁ1; dH (CDCl3, 400 MHz) 3.41 (2H, s), 3.63 (2H, s), 3.65 (3H, s),
3.76 (2H, s), 6.06 (1H, s), 6.29 (1H, d, J = 2 Hz), 7.15 (1H, d, J = 2 Hz), 7.56 (2H, s);
37
HRFABMS Calcd for C18 H16O635Cl2 Cl: 569.8373 (M+1), found m/z 569.8357.
Compound 9-Br: IR (film) 1734 cmꢁ1; dH (CDCl3, 400 MHz) 3.41 (2H, s), 3.63
(2H, s), 3.65 (3H, s), 3.76 (2H, s), 6.06 (1H, s), 6.29 (1H, d, J = 2 Hz), 7.15 (1H, d,
J = 2 Hz), 7.56 (2H, s); HRFABMS Calcd for C18 H15O681Br3: 569.8373 (M), found
m/z 569.8357.
6. Upon using 4 (X = Cl), the desired product was obtained up to 37% yield,
however, this process was not adopted for the following conversion in low
yields.
Preparation of 5 from 6: 5-Br, Br2, MeOH (100%); 5-Cl, (i) cat. H2SO4, MeOH; (ii)