Total synthesis of rodgersinol: A survey of the Cu(II)-mediated coupling of ortho-substituted phenols

Article abstract of DOI:10.1016/j.tet.2010.06.048

Full details of studies directed toward the total synthesis of both enantiomers of rodgersinol are described. The key parts of our synthetic route to rodgersinol included the Cu(II)-mediated coupling of an arylboronic acid with an ortho-alkyl substituted

Full text of DOI:10.1016/j.tet.2010.06.048

Tetrahedron 66 (2010) 6826e6831
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Total synthesis of rodgersinol: a survey of the Cu(II)-mediated coupling
of ortho-substituted phenols
,
Jong-Wha Jung a, Jaebong Jang a, Seung-Yong Seo b, Jae-Kyung Jung c, Young-Ger Suh a
*
a College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea
b College of Pharmacy, Woosuk University, Wanju 565-701, Republic of Korea
c College of Pharmacy, Chungbuk National University, Cheongju 361-763, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 April 2010
Received in revised form 21 June 2010
Accepted 21 June 2010
Available online 25 June 2010
Full details of studies directed toward the total synthesis of both enantiomers of rodgersinol are de-
scribed. The key parts of our synthetic route to rodgersinol included the Cu(II)-mediated coupling of an
arylboronic acid with an ortho-alkyl substituted phenol and regio- and stereoselective construction of the
hydroxypropyl substituent, which avoided tedious protection/deprotection sequence.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
employing facile chiral switching at late stage. In this connection,
the first total synthesis of (S)-(ꢀ)-rodgersinol was recently reported
While 2-arylpropionic acids are well known as an important
class of non-steroidal anti-inflammatory drugs (NSAIDs), 2-aryl-
propanols, such as rodgersinol (1) are unusual and rarely identified
in nature. Rodgersinol (1) is a 2-arylpropanol natural product,
isolated from the aerial parts of Rodgersia podophylla, which is
found in East Asia and has traditionally been used for the treatment
of inflammatory diseases. It exhibits significant inhibitory effects on
iNOS and COX-2 expression in LPS-activated macrophages with IC50
by us.2 Furthermore, comparing both synthetic enantiomers with
natural rodgersinol, the absolute stereochemistry at the C-10
position was also elucidated.2
On the course of our synthetic studies, we encountered in-
evitable difficulties in ordering synthetic sequences to couple two
parts of the rodgersinol skeleton. This was due to the lack of the
related precedents although excellent original papers discussed
conditions and mechanism of the diaryl ether coupling. To the best
of our knowledge, there are few reports presenting diaryl ether
synthesis utilizing various ortho-alkyl substituted phenols, which is
likely due to the limitation by stereoelectronic effects.3,4 Herein, we
disclosed a full account of the total synthesis of rodgersinol (1) and
the subsequent structural determination as well as our endeavors
for Ulmann-type coupling of a series of ortho-substituted phenols
to the corresponding diaryl ethers.
values of 2 and 3 m
M, respectively.1 The main structural feature of
rodgersinol includes an unique diaryl ether bearing a p-hydroqui-
none, appended with a (E)-propenyl moiety at C-1 and a chiral
hydroxylpropanyl unit at C-3 position as shown in Figure 1.
2. Result and discussion
Our retrosynthetic analysis of rodgersinol (1) is shown in
Scheme 1. We hoped to develop a concise and stereo-controlled
route from the three synthetic points of view. First, all issues of
carbonecarbon and carboneoxygen bond formation could be
achieved by metal-mediated processes, which are virtually void of
protecting group manipulations due to their remarkable chemo-
selectivities. Second, based on our preliminary studies, it is im-
portant to introduce the three substituents of the western aromatic
ring in an efficient order (A ring in Scheme 1). Indeed, the in-
troduction of the C-3 substituent would be more favorable to
proceed between diaryl ether formation and propenyl group in-
stallation. Otherwise, we found that such a densely substituted
Figure 1. Structure of rodgersinol (1).
Considering the unique structural features as well as its excel-
lent biological activities, rodgersinol (1) is unarguably a fascinating
target for both synthetic chemists and medicinal chemists. In an
attempt to design a viable route to the both enantiomers of rodg-
ersinol, we aimed to develop a highly convergent synthetic route
* Corresponding author. Tel.: þ82 2 880 7875; fax: þ82 2 888 0649; e-mail
address: ygsuh@snu.ac.kr (Y.-G. Suh).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.06.048

J.-W. Jung et al. / Tetrahedron 66 (2010) 6826e6831
6827
Table 1
Cu(II)-mediated coupling with ortho-functional phenolsa
Entry
1
Phenol 4
Diaryl ether 3
Yieldb (%)
67 (91)c
Scheme 1. Retrosynthetic analysis of both (S)- and (R)-rodgersinol.
aromatic ring unnecessarily required protecting groups and addi-
tional transformations. Third, both (S)- and (R)-enantiomers of
rodgersinol could be addressed from the same intermediate at late
stage in a regio- and stereoselective manner to achieve maximum
efficiency.
Thus, chiral epoxide 2a or 2b was considered to be the optimal
intermediate, which could be conveniently transformed into both
enantiomers of 1. These procedures involve Suzuki cross-coupling5
for the installation of (E)-propenyl group and stereoselective
methyl addition to aryl oxirane 2a or hydride addition to 1-methyl-
1-aryl oxirane 2b, respectively. The chiral epoxides 2a and 2b
would be efficiently introduced via Sharpless asymmetric dihy-
droxylation6 of the vinyl- or isopropenyl substituent of the diaryl
ethers 3a and 3b, which could be obtained from the properly
functionalized phenols 4 by coupling with the appropriate boronic
acids 5.7
2
3
43 (92)c
80
4
NRd
Our synthesis commenced with the preparation of the requisite
diaryl ethers 3. Diaryl ethers have conventionally been prepared by
the classical Ullmann-type diaryl ether synthesis or its variations.
Development of new methods for the preparation of diaryl ethers
has received much attention and there has also been remarkable
recent progresses.3 After considering several effective methods for
diaryl ether formation, we selected the Cu(OAc)2 mediated coupling
reaction developed by Evans group,7a,b because of its mild reaction
condition compared to that of other reaction (room temperature
versus elevated temperature, >80 ꢁC). However, only a few exam-
ples using ortho-alkyl substituted phenol (4, Y¼alkyl group) were
found in the literature. On the other hand, it was well-known that
the reaction of ortho-heteroatom substitued phenols (Y¼halogen)
proceed smoothly to give the desired O-arylation products. Thus,
a number of sterically and electronically diverse substrate 4aee
were initially prepared and evaluated as shown Table 1.
The diaryl ether formation of various phenols 4 with the boronic
acids 5 was carried out according to standard procedure.8 As
expected, the ortho-heteroatom substitued phenol 4c underwent
facile coupling reaction to afford 3c in good yield (Table 1, entry 3).
Next, we explored the diaryl ether formation with the ortho-alkyl
substituted 4a and 4b.9 To our delight, treatment of 4a and 4b with
Cu(OAc)2 in the presence of Et3N and molecular sieve at room
temperature, afforded the desired diaryl ether 3a and 3b in 67% and
43% yield (91% and 92% based on recovered starting materials),
respectively (entry 1 and 2). The relatively moderate yield seems to
arise from the steric factor of ortho-substitued alkyl group; how-
ever, coupling reaction with the unprecedented ortho-alkyl
substituted phenols is truly remarkable. It should be also noted that
the electron-poor phenols 4d and 4e failed to provide the desired
coupling products 3d and 3e (entry 4 and 5).
5
NRd
a
Reaction condition: 3 equiv of boronic acid 5, 1 equiv of Cu(OAc)2, 5 equiv of
ꢀ
Et3N, 4 A MS, CH2Cl2, room temperature, 24 h.
b
Isolated yields after chromatographic purification.
Yield based on recovered starting material.
No reaction.
c
d
the absolute stereochemistry at C-10 and introduce the propenyl
group at C-1. To this end, we initially attempted the synthesis of
chiral 2-methyl-2-aryl oxirane 7, starting from 3b (Scheme 2).
Sharpless asymmetric dihydroxylation of 3b using AD-mix-b pro-
vided the requisite diol 6, which was transformed into the chiral
epoxide 2b by regioselective tosylation of the primary alcohol using
dibutyltin oxide10 followed by basic treatment (KOt-Bu, THF, 0 ꢁC)
of the resulting tosylate. With the requisite epoxide 2b in hand, we
With mutigram quantities of the resulting diaryl ethers 3aec in
hand, the remaining challenges of the synthesis were to establish
Scheme 2. Initial synthetic approach.

6828
J.-W. Jung et al. / Tetrahedron 66 (2010) 6826e6831
explored a variety of reduction conditions for the epoxide-opening
reaction. However, despite extensive efforts involving the use of
Raney Nickel and catalytic hydrogenolysis with Pd(OH)2, all at-
step of coupling aryl chloride 11 with the propenyl group was un-
successful, despite using a variety of cross-coupling reaction con-
ditions including the remarkable catalysts, such as Pd(t-Bu)3 and
Verkade’s proazaphosphatrane.13 Unfortunately, only starting ma-
terial was recovered.
tempts to obtain the desired 2-arylpropanol
7
were
unsuccessful.11,12
Due to the difficulties encountered in epoxide opening together
with the significantly low yield of the diaryl ether formation, we
attempted an alternative route that employs methyl addition to the
epoxide instead of reductive ring-opening (Scheme 3). We per-
Consideration of the synthetic barrier associated with the poor
reactivity of aryl chloride (i.e., 11) toward the projected Suzuki
coupling led us to select 2-vinyl-4-iodo-substitued diaryl ether 3a
as an optimal substrate. Thus, we synthesized the requisite epoxide
2a through three-step sequence (asymmetric dihydroxylation,
selective tosylation, and epoxide formation with base) as shown
Scheme 4. Introduction of methyl group at C-10 could be accessed
to provide each enantiomer from the same intermediate (i.e., 2a) by
employing two different types of protocols.14 Upon treatment of
(R)-epoxide 2a with methyl cuprate, (S)-2-arylpropanol (S)-13 was
obtained with stereochemical inversion in 70% yield and 91% ee14a
In contrast, reaction of the (R)-epoxide 2a with methyl aluminum
provided the (R)-2-arylpropanol (R)-13 as a major product with
retention of configuration in 75% yield and 89% ee,14b along with
a small amount of regioisomer 14 (15%). The inversion of the ste-
reochemistry could be understood by the intermolecular backside
attack of the methyl cuprate promoted by BF3 while the retention
could be explained by an intramolecular methyl migration via
aluminum complexed aryl oxirane. Fukumasa et al. proposed an
intermediary carbenium ion for the rationalization of retention
evidenced by an MO calculation.14b Our transformation employing
these facile chiral switching protocols proved highly effective by
HPLC analysis.2
Completion of the total synthesis of both (S)- and (R)-rodgersi-
nols could be accomplished by the final Suzuki cross-coupling5,15
from (S)-13 and (R)-13, respectively. For the Suzuki reaction of
(S)-13, the commercially available (E)-propenyl boronic acid, Pd
(PPh3)4 as catalyst and CsFas base were used, effecting simultaneous
removal of the TBS group to afford (S)-rodgersinol ((S)-1). As the
resulting product was elucidated to be a mixture of E/Z olefins as
a 6.5:1 ratio on the basis of 1H NMR spectroscopy, (CH3CN)2PdCl2-
induced olefin isomerization of the mixture afforded (S)-rodgersinol
((S)-1) as an exclusive (E)-isomer.16 In the same manner as the
synthesis of (S)-1, (R)-1 could also be obtained from (R)-13.
The 2-arylpropanoic acid moiety17 is a well-known class of non-
steroidal anti-inflammatory agents, such as ibuprofen, naproxen,
Scheme 3. Revised synthetic approach.
formed the conversion of diaryl ether 3c, which was obtained in
highest chemical yield (80%, Table 1, entry 3), to the 2-vinyl-
substituted diaryl ether 8 by Stille coupling (Scheme 3) in 78% yield.
We transformed the 2-vinyl-substituted product 8 into the epoxide
10 according to the same sequence shown in Scheme 2 and the
epoxide 10 could be converted to the 2-arylpropanol 11 upon
methyl cuprate treatment in the presence of BF3. However, the final
Scheme 4. Completion of total synthesis of both (S)- and (R)-rodgersinols.

J.-W. Jung et al. / Tetrahedron 66 (2010) 6826e6831
6829
and ketoprofen.18 Furthermore, it was representatively revealed
that (S)-(þ)-ibuprofen (dexibuprofen) is the active enantiomer
both in vitro and in vivo. Therefore, rodgersinol might be easily
comparable with 2-arylpropanoic acids due to the structural and
biological similarity. As evidenced by the higher anti-inflammatory
activity of 2-arylpropanoic acid with (S)-configuration at the chiral
center, we also anticipated that the stereochemistry of C-10 ster-
the residue via flash column chromatography on silica gel (EtOAc/
hexanes¼1: 6) afforded 375 mg (88%) of 4b as a colorless oil: FT-IR
(thin film, neat) nmax 3503, 1483, 1264 cmꢀ1 1H NMR (CDCl3,
;
400 MHz)
d
7.19e7.16 (m, 2H), 6.75 (d, 1H, J¼9.2 Hz), 5.57 (s, 1H),
5.35 (m, 1H), 5.07 (s, 1H); 13C NMR (CDCl3, 100 MHz)
d
151.0, 150.0,
131.3, 130.8, 130.4, 117.4, 116.7, 112.2, 24.0; LR-MS (FAB) m/z 213
(MþH)þ; HR-MS (FAB) calcd for C9H9BrO (MþH)þ 212.9915; found
212.9910.
eogenic center would be (S)-configuration. As expected, comparing
20
the optical rotation [synthetic (S)-1, [
a]
ꢀ12.7 (c 0.17, MeOH);
D
synthetic (R)-1, [
a
]
D
20 þ12.3 (c 0.05, MeOH); natural 1, [
a]
20 ꢀ14.6 (c
4.1.2. 4-Bromo-2-isopropenyl-1-(4-methoxyphenoxy) benzene (3b).
To a solution of phenol 4b (300 mg, 1.41 mmol), boronic acid 5a
(640 mg, 4.23 mmol), and copper acetate (50 mg, 2.82 mmol) in the
D
0.04, MeOH)] as well as chiral HPLC analysis, the absolute config-
uration of C-10 stereogenic center was finally determined as (S)-
configuration.2
ꢀ
presence of 4 A molecular sieves in CH2Cl2 (28 mL), was added
triethylamine (0.98 mL, 7.05 mmol). The reaction mixture was
vigorously stirred for 24 h at ambient temperature and filtered
through a pad of Celite. The filtrate was concentrated in vacuo and
the residue was purified via flash column chromatography on silica
gel (EtOAc/hexanes¼1: 20) to afford 193 mg (43%, 92% borsm) of 3b
as a colorless oil and 160 mg of the starting phenol 4b (EtOAc/
3. The conclusions
In conclusion, the concise syntheses of both enantiomers of
rodgersinol have been achieved from 4-iodo-2-vinylphenol 4a in
high yields. The key features of the synthesis involved efficient
diaryl ether formation together with the stereoselective methyl
additions to a chiral 2-aryl oxirane for the asymmetric synthesis of
the requisite 2-arylpropanol skeleton. In particular, some of the
previously unreported scope and limitation in diaryl etherification
that could be easily encountered in practical synthesis was eluci-
dated. Our efficient synthetic strategy enabled us to determine the
absolute configuration at C-10 of rodgersinol as well as to expand
the preparation of other enantiomer and its analogs, which would
provide further studies for structure/activity relationship of
rodgersinol.
hexane¼1: 5): FT-IR (thin film, neat) nmax 2953, 1504, 1226 cmꢀ1
;
1H NMR (CDCl3, 300 MHz)
d
7.39 (d, 1H, J¼2.4 Hz), 7.26 (dd, 1H,
J¼8.6, 2.4 Hz), 6.90e6.82 (m, 4H), 6.66 (d, 1H, J¼8.6 Hz), 5.16e5.12
(m, 2H), 3.77 (s, 3H), 2.10 (s, 3H); 13C NMR (CDCl3, 75 MHz)
d
155.8,
150.6, 142.0, 136.8, 132.4, 131.0, 120.0, 119.9,119.6, 116.6,115.4, 114.9,
55.7, 23.0; LR-MS (FAB) m/z 318 (Mþ).
4.1.3. 2-[5-Bromo-2-(4-methoxyphenoxy)phenyl]-1,2-propanediol
(6). To a solution of diaryl ether 3b (150 mg, 0.47 mmol) in t-BuOH/
H2O (5 ml, 1:1) at 0 ꢁC was added the commercially available
AD-mix-b (628 mg). After stirring for 5 h, sodium sulfite was slowly
4. Experimental
4.1. General
added and the suspension was warmed to ambient temperature
with vigorous stirring. The mixture was diluted with EtOAc and the
aqueous layer was extracted with EtOAc. The combined organic
layers were dried over MgSO4 and then concentrated in vacuo.
Purification of the residue via flash column chromatography on
silica gel (EtOAc/hexanes¼1: 1) afforded 146 mg (88%) of 6 as
a colorless oil: FT-IR (thin film, neat) nmax 3465, 2979, 1757, 1482,
Unless noted otherwise, all starting materials and reagents were
obtained from commercial suppliers and were used without further
purification. Reaction flasks were dried at 100 ꢁC. Air and moisture
sensitive reactions were performed under an argon atmosphere.
Flash column chromatography was performed using silica gel 60
(230e400 mesh, Merck) with the indicated solvents. Thin-layer
chromatography was performed using 0.25 mm silica gel plates
(Merck). Optical rotations were measured with JASCO DIP-1000
digital polarimeter at ambient temperature using 100 mm cell of
2 mL capacity. Infrared spectra were recorded on a Perkin/Elmer
1710 FT-IR spectrometer. Mass spectra were obtained with VG Trio-
2 GCeMS instrument. High-resolution mass spectra were obtained
with JEOL JMS-AX 505WA instrument. 1H and 13C NMR spectra
were recorded on either a JEOL JNM-GCX 400 or JEOL JNM-LA 300
spectrometer as solutions in deuteriochloroform (CDCl3). Chemical
1150 cmꢀ1; 1H NMR (CDCl3, 400 MHz)
d
7.69 (d, 1H, J¼2.5 Hz), 7.21
(dd, 1H, J¼8.6, 2.4 Hz), 6.88e6.81 (m, 4H), 6.54 (d, 1H, J¼8.7 Hz),
4.02 (d, 1H, J¼11.0 Hz), 3.79 (s, 3H), 3.72 (d, 1H, J¼11.0 Hz), 1.55 (s,
3H); 13C NMR (CDCl3, 100 MHz)
d 156.4, 154.6, 149.2, 136.1, 131.4,
130.9, 120.8, 119.2, 115.6, 115.2, 74.8, 69.0, 55.7, 24.4; LR-MS (FAB)
m/z 352 (Mþ).
4.1.4. 2-[5-Bromo-2-(4-methoxyphenoxy)phenyl]-2-methyloxirane
(2b). To a solution of diol 6 (57 mg, 0.16 mmol) in CH2Cl2 (1.6 mL) at
0 ꢁC were added dibutyltin oxide (0.8 mg, 3.24
m
mol), p-toluene-
sulfonyl chloride (34 mg, 0.18 mmol), and triethylamine (27 L,
m
0.19 mmol). After stirring for 5 h at ambient temperature, the re-
action mixture was concentrated in vacuo. Purification of the res-
idue via flash chromatography on silica gel (EtOAc/hexanes¼1: 3)
afforded 75 mg (92%) of the mono-tosylate compound as a colorless
shifts are expressed in parts per million (ppm, d) downfield from
tetramethylsilane and are referenced to the deuterated solvent
(CHCl3). 1H NMR data were reported in the order of chemical shift,
multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet
and/or multiple resonances), number of protons, and coupling
constant in hertz (Hz).19
oil: FT-IR (thin film, neat) nmax 3521, 2923, 1505, 1225 cmꢀ1
;
1H
NMR (CDCl3, 300 MHz)
d 7.69e7.64 (m, 3H), 7.28e7.23 (m, 3H),
6.90e6.82 (m, 4H), 6.50 (d, 1H, J¼8.6 Hz), 4.47 (d, 1H, J¼9.7 Hz),
4.37 (d, 1H, J¼9.7 Hz), 3.81 (s, 3H), 3.25 (s, 1H), 2.42 (s, 3H), 1.59 (s,
4.1.1. 4-Bromo-2-isopropenylbenzenol (4b). To a solution of meth-
yltriphenylphosphonium bromide (1.443 g, 4.04 mmol) in THF
(10 mL) at 0 ꢁC was added n-BuLi (2.53 mL of 1.6 M solution in
hexane, 4.04 mmol). After stirring for 1 h, a solution of 1-(5-bromo-
2-hydroxyphenyl)ethanone (430 mg, 2.02 mmol) in THF (3 mL) was
added to this mixture at 0 ꢁC. The reaction mixture was slowly
warmed to ambient temperature and stirred for 3 h. The reaction
mixture was quenched with saturated aqueous NH4Cl, and then
diluted with EtOAc. The organic phase was washed with water and
brine, dried over MgSO4, and concentrated in vacuo. Purification of
1H); 13C NMR (CDCl3, 100 MHz)
d 156.6, 154.5, 148.5, 144.9, 134.0,
132.6, 131.8, 130.8, 129.8, 127.9, 121.1, 118.4, 115.4, 115.1, 75.1, 73.0,
55.7, 24.2, 21.6; LR-MS (FAB) m/z 506 (Mþ); HR-MS (FAB) calcd for
C23H23BrO6S (Mþ) 506.0399; found 506.0396.
To a solution of mono-tosylate (46 mg, 0.09 mmol) in THF (1 mL)
at 0 ꢁC was added potassium tert-butoxide (1 mL of 1.0 M solution
in THF, 0.10 mmol). After stirring for 1 h, the reaction mixture was
quenched with saturated aqueous NH4Cl, and then diluted with
EtOAc. The organic phase was washed with water and brine, dried
over MgSO4, and concentrated in vacuo. Purification of the residue

6830
J.-W. Jung et al. / Tetrahedron 66 (2010) 6826e6831
via flash column chromatography on silica gel (EtOAc/hexanes¼1:
5) afforded 27 mg (89%) of the epoxide 2b as a colorless oil: FT-IR
phenyloxirane 10 (135 mg, 0.49 mmol) was added dropwise at
ꢀ80 ꢁC. The reaction mixture was stirred for 2 h, quenched with
saturated aqueous NH4Cl and NH4OH, and then diluted with
Et2O. The organic phase was washed with water and brine, dried
over MgSO4, and concentrated in vacuo. Purification of the resi-
due via flash column chromatography on silica gel (EtOAc/
hexanes¼1:1) afforded 97 mg (68%) of the 2-arylpropanol 11 as
a colorless oil: FT-IR (thin film, neat) nmax 3366, 2961, 1504,
(thin film, neat) nmax 2928, 1501, 1227 cmꢀ1 1H NMR (CDCl3,
;
300 MHz)
d
7.59 (d, 1H, J¼2.6 Hz), 7.30 (dd, 1H, J¼2.6, 8.8 Hz),
6.95e6.87 (m, 4H), 6.63 (d, 1H, J¼8.8 Hz), 3.81 (s, 3H), 2.92 (d, 1H,
J¼5.3 Hz), 2.79 (m, 1H), 1.67 (s, 3H); 13C NMR (CDCl3, 100 MHz)
d
156.1, 154.8, 149.8, 134.0, 131.6, 130.6, 120.3, 118.7, 115.2, 115.0,
56.0, 55.7, 55.2, 23.0; LR-MS (FAB) m/z 334 (Mþ); HR-MS (FAB) calcd
for C16H15BrO3 (Mþ) 334.0205; found 334.0209.
1229 cmꢀ1
;
1H NMR (CDCl3, 300 MHz)
d
7.27 (d, 1H, J¼2.8 Hz),
7.11 (dd, 1H, J¼2.6, 8.6 Hz) 6.92e6.83 (m, 4H), 6.72 (d, 1H,
4.1.5. 2-Bromo-4-chloro-1-(4-methoxyphenoxy)benzene (3c). By the
same procedure as for the synthesis of diaryl ether 3b, except with
2-bromo-4-chloro-phenol 4c in place of phenol 4b, diaryl ether 3c
was obtained in 80% yield as colorless oil. (EtOAc/hexanes¼1:20):
J¼8.6 Hz), 3.82e3.70 (m, 2H), 3.80 (s, 3H), 3.49 (m, 1H), 1.30 (d,
1H, J¼7.0 Hz); 13C NMR (CDCl3, 100 MHz)
d 155.8, 154.5, 150.5,
136.0, 128.2, 128.0, 127.4, 119.8, 119.1, 115.0, 67.5, 55.7, 35.5, 16.7;
LR-MS (FAB) m/z 292 (Mþ); HR-MS (FAB) calcd for C16H17ClO3
(Mþ) 292.0866; found 292.0864.
FT-IR (thin film, neat) nmax 2952, 1503, 1468, 1235 cmꢀ1 1H NMR
;
(CDCl3, 300 MHz)
d
7.61 (d,1H, J¼2.6 Hz), 7.19 (dd,1H, J¼2.4, 8.8 Hz),
6.97e6.84 (m, 4H), 6.76 (d, 1H, J¼8.8 Hz), 3.81 (s, 3H); 13C NMR
Acknowledgements
(CDCl3, 100 MHz)
d 156.3, 153.9, 149.6, 133.1, 128.5, 128.3, 120.3,
119.2, 115.0, 114.1, 55.7; LR-MS (FAB) m/z 312 (Mþ); HR-MS (FAB)
This work was supported by the Center for Bioactive Molecular
Hybrids, Yonsei University, and this paper is dedicated with respect
and affection to the late Professor Chi Sun Hahn, an inspiring
teacher and mentor, for his contributions to the field of organic
chemistry in Korea.
calcd for C13H10BrClO2 (Mþ) 311.9553; found 311.9540.
4.1.6. 4-Chloro-1-(4-methoxyphenoxy)-2-vinylbenzene (8). To a so-
lution of diaryl ether 3c (310 mg, 0.99 mmol) and tributyl(vinyl)tin
(97%, 320 mg, 0.99 mmol) in toluene (7 ml), tetrakis(triphenyl-
phosphine)palladium (0) (60 mg, 0.05 mmol) was added. The re-
action mixture was stirred for 1 h and heated to reflux for 24 h. The
mixture was cooled and filtered through short pad of silica gel. The
filtrate was concentrated in vacuo. Purification of the residue via
flash chromatography on silica gel (EtOAc/hexanes¼1:20) afforded
234 mg (91%) of the styrene 8 as a colorless oil. FT-IR (thin film,
Supplementary data
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.06.048.
neat) nmax 2952, 1504, 1231 cmꢀ1; 1H NMR (CDCl3, 400 MHz)
d 7.54
References and notes
(d, 1H, J¼2.4 Hz), 7.12 (dd, 1H, J¼2.6, 8.8 Hz), 7.03 (dd, 1H, J¼11.0,
17.7 Hz), 6.91e6.83 (m, 4H) 6.73 (d, 1H, J¼8.7 Hz), 5.82 (d, 1H,
J¼17.7 Hz), 5.34 (d, 1H, J¼11.4 Hz), 3.78 (s, 3H); 13C NMR (CDCl3,
1. Chin, Y.-W.; Park, E. Y.; Seo, S.-Y.; Yoon, K.-D.; Ahn, M.-J.; Suh, Y.-G.; Kim, S. G.;
Kim, J. Bioorg. Med. Chem. Lett. 2006, 16, 4600e4602.
2. Seo, S.-Y.; Jung, J.-W.; Jung, J.-K.; Kim, N.-J.; Chin, Y.-W.; Kim, J.; Suh, Y.-G. J. Org.
Chem. 2007, 72, 666e668.
100 MHz) d 155.7,153.5,150.5,130.3,130.0,128.5,128.2,126.2,119.7,
3. For reviews on diaryl ether formation, see: (a) Evano, G.; Blanchard, N.; Toumi,
M. Chem. Rev. 2008, 108, 3054e3131; (b) Frlan, R.; Kikelj, D. Synthesis 2006, 11,
2271e2285; (c) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42,
5400e5449; (d) Sawyer, J. S. Tetrahedron 2000, 56, 5045e5065; (e) Theil, F.
Angew. Chem., Int. Ed. 1999, 38, 2345e2347; (f) Lindley, J. Tetrahedron 1984, 40,
1433e1456.
4. Kwak, J.-H.; In, J.-K.; Lee, M.-S.; Choi, E.-H.; Lee, H.; Hong, J. T.; Yun, Y.-P.; Lee,
S. J.; Seo, S.-Y.; Suh, Y.-G.; Jung, J.-K. Arch. Pharm. Res. 2008, 31, 1559e1563.
5. For reviews on the Suzuki cross-coupling reaction, see: (a) Miyaura, N.; Suzuki,
A. Chem. Rev. 1995, 95, 2457e2483; (b) Suzuki, A. J. Organomet. Chem. 1999, 576,
147e168.
6. For reviews on asymmetric dihydroxylation, see: (a) Zaitsev, A. B.; Adolfsson, H.
Synthesis 2006, 11, 1725e1756; (b) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless,
K. B. Chem. Rev. 1996, 94, 2483e2547.
7. (a) Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron Lett. 1998, 39, 2937e2940; (b)
Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M. P. Tetrahedron Lett. 1998,
39, 2933e2936; (c) Lee, M.-S.; Yang, J.-E.; Choi, E.-H.; In, J.-K.; Lee, S. Y.; Lee, H.;
Hong, J. T.; Lee, H. W.; Suh, Y.-G.; Jung, J.-K. Bull. Korean Chem. Soc. 2007, 28,
1601e1604.
119.4, 116.3, 114.9, 55.5; LR-MS (FAB) m/z 260 (Mþ); HR-MS (FAB)
calcd for C15H13ClO2 (Mþ) 260.0604; found 260.0599.
4.1.7. 1-[5-Chloro-2-(4-methoxyphenoxy)phenyl]-1,2-ethanediol
(9). By the same procedure as for the synthesis of diol 6, except with
styrene8inplaceofdiarylether3b, diol9wasobtainedin90%yieldas
awhite solid:FT-IR(thin film, neat)nmax 3395, 2930,1505,1228 cmꢀ1
;
1H NMR (CDCl3, 400 MHz)
d
7.50 (d, 1H, J¼2.6 Hz), 7.08 (d, 1H,
J¼8.7 Hz), 7.08e6.80 (m, 4H), 6.61 (d, 1H, J¼8.7 Hz), 5.15 (dd, 1H,
J¼2.9, 7.9 Hz), 3.84 (m, 1H), 3.75 (s, 3H), 3.62 (m, 1H), 3.35e3.19 (m,
2H);13CNMR(CDCl3,100 MHz)
d156.1,153.5,149.5,132.1,128.4,127.9,
127.4, 120.4, 117.8, 115.0, 69.6, 66.5, 55.6; LR-MS (FAB) m/z 294 (Mþ);
HR-MS (FAB) calcd for C15H15ClO4 (Mþ) 294.0659; found 294.0669.
4.1.8. 2-[5-Chloro-2-(4-methoxyphenoxy)phenyl]oxirane
(10). By
8. Increase of amount of the catalyst and boronic acid to compensate competitive
oxidation did not significantly increase the chemical yield, which is in accor-
dance with Evans’ report. Molecular sieves were added to enhance the product
yield because the water formed during the reaction was known to be detri-
mental. For conditions and mechanism: (a) Ref. 7. (b) Beletskaya, I. P.; Che-
prakov, A. V. Coord. Chem. Rev. 2004, 248, 2337e2364.
9. The compound 4b was prepared from commercially available 5-bromo-2-hy-
droxy-acetophenone using Wittig olefination.
10. Martinelli, M. J.; Nayyar, N. K.; Moher, E. D.; Dhokte, U. P.; Pawlak, J. M.;
Vaidyanathan, R. Org. Lett. 1999, 1, 447e450.
11. With the diol 6 we attempted similar experiments, but only the starting
material was recovered.
12. (a) Li, A.; Yue, G.; Li, Y.; Pan, X.; Yang, T.-K. Tetrahedron: Asymmetry 2003, 14,
75e78; (b) Ishibashi, H.; Maeki, M.; Yagi, J.; Ohba, M.; Kanai, T. Tetrahedron
1999, 55, 6075e6080; (c) Archelas, M. C. A.; Furstoss, R. J. Org. Chem. 1999, 64,
5029e5035; (d) Hutchins, R. O.; Taffer, I. M.; Burgoyne, W. J. Org. Chem. 1981, 46,
5214e5215.
13. For a recent review on cross-coupling reactions of aryl chloride, see: (a) Bedford,
R. B.; Cazin, C. S. J.; Holder, D. Coord. Chem. Rev. 2004, 248, 2283e2321; (b) Littke,
A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176e4211.
the same procedure as for the synthesis of phenyloxirane 2b, ex-
cept with diol 9 in place of diol 6, phenyloxirane 10 was obtained
in 77% yield (two steps) as a colorless oil: FT-IR (thin film, neat)
nmax 2925, 1504, 1228 cmꢀ1 1H NMR (CDCl3, 400 MHz)
; d 7.18 (d,
1H, J¼2.4 Hz), 7.13 (dd, 1H, J¼2.6, 8.7 Hz) 6.93e6.85 (m, 4H), 6.70
(d, 1H, J¼8.7 Hz), 4.19 (m, 1H), 3.79 (s, 3H), 3.13 (m, 1H), 2.71 (dd,
1H, J¼2.5, 5.6 Hz); 13C NMR (CDCl3, 75 MHz)
d 156.1, 155.2, 150.2,
130.2, 128.7, 128.5, 125.4, 120.0, 118.5, 115.1, 55.7, 50.9, 48.0; LR-MS
(FAB) m/z 276 (Mþ); HR-MS (FAB) calcd for C15H13ClO3 (Mþ)
276.0553; found 276.0547.
4.1.9. 2-[5-Chloro-2-(4-methoxyphenoxy)phenyl]-1-propanol (11).
To a solution of copper cyanide (222 mg, 2.44 mmol) in THF
(2 mL) was added methyl lithium (1.52 mL of 1.60 M solution in
THF, 2.44 mmol) at ꢀ40 ꢁC. The reaction mixture was stirred for
30 min and BF3$OEt2 (0.48 mL, 2.44 mmol) and a solution of the
14. (a) Botuha, C. B.; Haddad, M.; Larcheveque, M. Tetrahedron: Asymmetry 1998,
9, 1929e1931; (b) Fukumasa, M.; Furuhashi, K.; Umezawa, J.; Takahashi, O.;

J.-W. Jung et al. / Tetrahedron 66 (2010) 6826e6831
6831
Hirai, T. Tetrahedron Lett. 1991, 32, 1059e1062 For reports on related condi-
tions, see: (c) Carde, L.; Davies, H.; Geller, T. P.; Roberts, S. M. Tetrahedron Lett.
1999, 40, 5421e5424; (d) Takano, S.; Yanase, M.; Sugihara, T.; Ogasawara, K. J.
Chem. Soc., Chem. Commun. 1988, 1538e1540 and references therein.
15. For a report on related conditions, see: Miyata, O.; Takeda, N.; Naito, T. Org. Lett.
2004, 6, 1761e1763 and references therein.
17. For a review on the synthesis of 2-arylpropanoic acid, see: Sonawane, H. R.;
Bellur, N. S.; Ahuja, J. R.; Kulkarni, D. G. Tetrahedron: Asymmetry 1992, 3,
163e192.
18. For selected reports, see: (a) Hayball, P. J. Drugs 1996, 52, 47e58; (b) Landoni,
M. F.; Soraci, A. Curr. Drug Metab. 2001, 2, 37e51.
19. For experimental procedures and characterization data including chiral HPLC
for previously described compounds, see Ref. 2.
16. Yu, J.; Gaunt, M. J.; Spencer, J. B. J. Org. Chem. 2002, 67, 4627e4629.