Expedient synthesis of 4-O-methylhonokiol via Suzuki-Miyaura cross-coupling

Article abstract of DOI:10.1016/j.tet.2011.09.115

Concise and practical synthesis of 4-O-methylhonokiol was achieved in 34% overall yield. The key features of our synthesis include chemoselective ortho-mono bromination of phenol as well as biaryl formation via Suzuki-Miyaura cross-coupling, in which bromophenol was reacted with potassium aryltrifluoroborate using Pd(OAc)₂ and RuPhos under microwave conditions.

Full text of DOI:10.1016/j.tet.2011.09.115

Tetrahedron 67 (2011) 9401e9404
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Expedient synthesis of 4-O-methylhonokiol via SuzukieMiyaura cross-coupling
Jae-Hwan Kwak a, Young Ae Cho b, Jae-Yong Jang a, Seung-Yong Seo c, Heesoon Lee a, Jin Tae Hong a,
,
a,
*
Sang-Bae Han a, Kiho Lee d, Young-Shin Kwak b , Jae-Kyung Jung
*
a College of Pharmacy and Medical Research Center (MRC), Chungbuk National University, Cheongju 361-763, Republic of Korea
b Korea Research Institute of Bioscience and Biotechnology, Ochang 363-883, Republic of Korea
c College of Pharmacy, Woosuk University, Wanju 565-701, Republic of Korea
d College of Pharmacy, Korea University, Chochiwon 339-700, 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 30 August 2011
Received in revised form 24 September 2011
Accepted 25 September 2011
Available online 1 October 2011
Concise and practical synthesis of 4-O-methylhonokiol was achieved in 34% overall yield. The key fea-
tures of our synthesis include chemoselective ortho-mono bromination of phenol as well as biaryl for-
mation via SuzukieMiyaura cross-coupling, in which bromophenol was reacted with potassium
aryltrifluoroborate using Pd(OAc)2 and RuPhos under microwave conditions.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Neolignan
4-O-Methylhonokiol
SuzukieMiyaura cross-coupling
Potassium aryltrifluoroborate
1. Introduction
O-methylhonokiol (1). For future profiling and development of 4-O-
methylhonokiol (1) and its analogs, we needed to plan ahead and
4-O-Methylhonokiol (1) was isolated from Magnolia species1
and found to exhibit various biological activities.2 The bark of the
root and stem of Magnolia species has long been used as a tradi-
tional medicine to treat various disorders and the main bioactive
compounds isolated from M. families are biphenyl-neolignans,
such as honokiol (2), magnolol (3), and obovatol (4) as shown in
Fig. 1.2 Interestingly, 4-O-methylhonokiol (1) has the higher anti-
develop a scalable synthesis suitable for quickly securing multi-
gram quantities. Herein, we describe a short and efficient synthe-
sis of 4-O-methylhonokiol (1) featuring a SuzukieMiyaura cross-
coupling as the key step.
inflammatory activity (e.g., IC50 of 0.06 mM for COX-2) than hono-
kiol (2) and a variety of honokiol analogs.3 Moreover, 4-O-meth-
ylhonokiol (1) was recently found to exhibit neurotropic and
memory improving activity.2 The structural feature of 4-O-meth-
ylhonokiol (1) is the unsymmetrical 5,30-diallyl-biphenyl, which
differs from honokiol (2) by the methoxy group at C4 of the B ring
(Fig. 1).
In spite of its interesting biological activities, only pioneering
total synthesis of 4-O-methylhonokiol (1) has been reported by
Denton group.4 On the other hand, the synthesis of the congener,
honokiol, has been reported by four groups.5 However, to the best
of our knowledge, regioselective O-methylation at the honokiol’s B
ring is very difficult to achieve for establishing a viable access to 4-
* Corresponding authors. Tel.: þ82 43 2612635; fax: þ82 43 2682732 (J.-K.J.); tel.:
þ82 43 2406017 (Y.-S.K.); e-mail addresses: yskwak@kribb.re.kr (Y.-S. Kwak),
orgjkjung@chungbuk.ac.kr (J.-K. Jung).
Fig. 1. Representative neolignans isolated from the Magnolia species.
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.115

9402
J.-H. Kwak et al. / Tetrahedron 67 (2011) 9401e9404
2. Results and discussion
With multi-gram quantities of bromophenol 5 and aryltri-
fluoroborate 6 in hand, we addressed the key SuzukieMiyaura
cross-coupling. To this end, we screened a variety of conditions
varying palladium catalysts, ligands and solvents.6 Representative
results are illustrated in Table 1. In initial studies, it was revealed
that typical coupling conditions were not eligible to afford the
desired biaryl adduct (Table 1, entry 1e8), implying that the cou-
pling is potentially challenged by the un-protected phenol of 5,12
although the treatment of PdCl2(dppf)$CH2Cl2 and Cs2CO3 in
MeOH gave the desired product in 12% yield (entry 5). We also
conducted the microwave reaction using PdCl2(dppf)$CH2Cl2 and
K2CO3, but the desired product was not obtained (entry 7). Next, we
exploited the Molander’s modified condition utilizing Pd(OAc)2,
K2CO3, and Buchwald’s phosphine (RuPhos and XPhos). To our
delight, the coupling reaction using RuPhos as the phosphine ligand
and a solvent mixture of DME and water at 130 ꢀC (microwave,
10 min) afforded the desired product in 72% yield (entry 11). In case
of XPhos ligand, the relatively moderate yield arose in the mixture
of toluene and water, similar with using RuPhos (entries 9 and 12).
It should be noted that the optimized condition could be useful for
the synthesis of various analogs of 4-O-methylhonokiol.
Our plan for the preparation of 4-O-methylhonokiol (1) entailed
linking of 4-allylphenol part (A ring) with 2-allylanisole part (B
ring) via a SuzukieMiyaura cross-coupling.6 This strategy would
permit significant flexibility in synthesis of 1 and thereby adapt
a platform that leads to a variety of derivatives for further struc-
tureeactivity relationship studies. In addition, since the potassium
aryltrifluoroborate salts (RBF3K) have emerged as very important
organometallic reagents for SuzukieMiyaura cross-coupling due to
their stability in air and moisture,6aec we envisioned our synthesis
would become very useful for a future large-scale synthesis by
establishing the key SuzukieMiyaura cross-coupling utilizing
a potassium aryltrifluoroborate. The previous reports5c,d for hono-
kiol synthesis involved a methyl ether protection on the A-ring’s
phenol moiety for the SuzukieMiyaura coupling. We predicted that
the selective mono-deprotection after coupling the two aryl units
would be extremely challenging for 4-O-methylhonokiol (1) syn-
thesis. With all these perspectives, we were thus prompted at de-
signing our synthesis by exploring the SuzukieMiyaura coupling of
the un-protected bromophenol (5) and the potassium aryltri-
fluoroborate (6) (Scheme 1).
3. Conclusion
In summary, the total synthesis of 4-O-methylhonokiol (1) has
been completed in 34% overall yield from the 4-bromophenol.
Prominent features include the chemoselective ortho-mono bro-
mination of 4-allylphenol and the SuzukieMiyaura biaryl forma-
tion with the potassium aryltrifluoroborate and the un-protected
bromophenol. Further efforts are in progress for the synthesis of 4-
O-methylhonokiol derivatives in light of the structureeactivity
relationship for anti-inflammatory and neurotropic effects.
Scheme 1. Retrosynthetic analysis of 4-O-methylhonokiol (1).
We set out the synthesis of 1 by the practical preparation of two
segments; 2-bromide-4-allylphenol (5) and potassium 3-allyl-4-
methoxyphenyl-trifluoroborate (6), respectively (Scheme 2). We
previously reported the synthesis of obovatol (4) via chemo-
selective ortho-bromination of phenol and Cu-catalyzed diaryl
ether synthesis.7 Thus, aryl bromide 5 was prepared using our
modified bromination conditions from 4-allylphenol, which was
obtained via the demethylation of the commercially available 4-
allylanisole (MeMgI, 180 ꢀC). 4-Allylphenol was treated with i-
Table 1
SuzukieMiyaura cross-coupling of 2-bromo-4-allylphenol 5 and potassium aryltri-
fluoroborate 6a
PrMgCl (1 equiv) as
a base and DBDMH (1,3-dibromo-5,5-
dimethylhydantoin, 0.5 equiv) to afford the resulting mono-
bromide 5 in good yield (54%, 85% brsm). It is noteworthy that
this mono bromination is preferable to the previous procedures in
terms of chemical yield and the number of steps and amenable to
large-scale preparation of product.8 On the other hand, aryltri-
fluoroborate 6 was obtained as a crystalline solid through the
treatment of the known 2-allyl-4-bromoanisole 79,10 with n-BuLi
and B(Oi-Pr)3, followed by the addition of inexpensive KHF2.11 It’s
worth to note that the two sequences could be run on large scale.
Entry Pd catalyst and
ligand
Base
Solvent
Temp Time
Yield
(%)
NRb
(ꢀC)
(h)
1
2
Pd(PPh3)4
Pd(PPh3)4
K2CO3
K2CO3
MeOH
Toluene/H2O
80
80
2
2
Trace
3
4
Pd2(dba)3
Pd(OAc)2
K2CO3
K2CO3
Toluene/H2O
Toluene/H2O
80
80
2
2
NR
Trace
5
6
7
PdCl2(dppf)CH2Cl2
PdCl2(dppf)$CH2Cl2 Cs2CO3 Toluene/H2O
PdCl2(dppf)$CH2Cl2 K2CO3
Cs2CO3 MeOH
80
80
2
2
12
NR
Toluene/H2O 70c
20 min NR
8
PdCl2(TPP)
K2CO3
Toluene/H2O
80
2
Trace
9
Pd(OAc)2/RuPhos
Pd(OAc)2/RuPhos
Pd(OAc)2/RuPhos
K2CO3
K2CO3
K2CO3
Toluene/H2O
DME/H2O
DME/H2O
80
80
130
2
1
27
66
10
11c
10 min 72
12
13
Pd(OAc)2/XPhos
Pd(OAc)2/XPhos
K2CO3
K2CO3
Toluene/H2O
DME/H2O
80
80
2
4
32
Trace
a
Reaction condition: Conducted with Pd (10 mol %), ligand (20 mol %), base
(3 equiv), 5 (1 equiv), and 6 (1 equiv).
Scheme 2. Reagents and conditions: (a) MeMgI, 180 ꢀC, 81%. (b) i-PrMgCl, DBDMH,
Et2O, ꢁ78 ꢀC to rt, 24 h, 54% (brsm 85%) (c) n-BuLi, B(Oi-Pr)3, THF, 1 h, then 1 N KHF2
(aq), 30 min, 61%.
b
No reaction.
c
Microwave-assisted reaction (irradiation power 100 W).

J.-H. Kwak et al. / Tetrahedron 67 (2011) 9401e9404
9403
4. Experimental section
4.1. General information
(213 mg, 1.00 mmol), Pd(OAc)2 (22.5 mg, 0.100 mmol, 10 mol %),
RuPhos
(2-dicyclohexylphosphino-20,60-diisopropoxy-biphenyl,
94.0 mg, 0.20 mmol, 20 mol %), and K2CO3 (420 mg, 3.00 mmol).
The vessel was sealed with a septum, and DME/H2O (v/v¼5:1,
20 mL) was added via syringe. The reaction was heated by micro-
wave (BiotageÒ Initiator, EXP EU 355301, 115 W) at 130 ꢀC for
10 min. After the aryl bromide was totally consumed (the reaction
was monitored by TLC), the reaction mixture was cooled to rt. The
residual compound was dissolved in ethyl acetate (100 mL), and the
insoluble salts were filtered through a thin pad of silica gel. The
combined organic layers were washed with H2O, and brine, dried
over MgSO4, and concentrated in vacuo. Purification via flash col-
umn chromatography (EtOAc/hexanes¼1:10) of the residue affor-
ded 202 mg (72%) of 1 as a colorless oil; 1H NMR (400 MHz, CDCl3)
Unless noted otherwise, all starting materials and reagents were
obtained from commercial suppliers and were used without further
purification. 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 us-
ing 0.25 mm silica gel plates (Merck). Melting points were mea-
sured on an Electrothermal IA 9100 melting point apparatus and
are uncorrected. Infrared spectra were recorded on a Jasco FT-IR
4100 spectrometer. Low and high-resolution fast atom bombard-
ment (FAB) mass spectra were obtained with JEOL JMS-700 in-
strument. 1H and 13C NMR spectra were recorded on either a Bruker
AVANCE III 400 MHz or Bruker AVANCE 500 MHz Spectrometer as
solutions in deuteriochloroform (CDCl3) or deuterioacetone
(CD3COCD3). 1H NMR data were reported in the order of chemical
shift, multiplicity (s, singlet; d, doublet; t, triplet; m, multiplet and/
or multiple resonances), number of protons, and coupling constant
in hertz (Hz).
d
7.30 (d, J¼8.4 Hz, 1H), 7.25 (m, 1H), 7.05 (m, 2H), 6.97 (d, J¼8.4 Hz,
1H), 6.92 (d, J¼8.4 Hz, 1H), 6.08e5.93 (m, 2H), 5.13e5.05 (m, 5H),
3.89 (s, 3H), 3.44 (d, J¼6.8 Hz, 2H), 3.36 (d, J¼6.6 Hz, 2H); 13C NMR
(100 MHz, CDCl3)
d 157.2, 151.0, 138.0, 136.7, 132.4, 130.7, 130.4,
130.0, 129.2, 129.0, 128.1, 128.0, 116.1, 115.8, 115.7, 111.1, 55.7, 39.6,
34.5; LRMS (FAB) m/z 281 (MþHþ).
Acknowledgements
4.2. Experimental procedure
This research was supported by the Medical Research Center
program (2010-0029480), the Regional Core Research Program
(Chungbuk BIT Research-Oriented University Consortium) through
the National Research Foundation of Korea, and by the Ministry of
Land, Transport and Maritime Affairs, Republic of Korea.
4.2.1. 2-Allyl-4-bromo-1-methoxybenzene (7). A mixture of anhy-
drous K2CO3 (4.2 g, 30 mmol), 2-allyl-4-bromophenol (3.2 g,
15 mmol), and acetone (30 mL) was stirred for 30 min then iodo-
methane (2.7 g, 19 mmol) was added at room temperature. After
4 h, solvent was evaporated then water (15 mL) was added. The
mixture was extracted with ether (3ꢂ20 mL). The combined ex-
tracts were washed with water (10 mL), dried over anhydrous
MgSO4 and the solvent was evaporated. Purification on silica gel
(hexane only) provided 2-allyl-4-bromo-1-methoxybenzene (7)
(3.7 g, 94%) as a pale yellow oil; IR (thin film) 3081,1638, 1488, 1242,
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2011.09.115. These data in-
clude MOL files and InChiKeys of the most important compounds
described in this article.
1032, 803, 654 cmꢁ1 1H NMR (500 MHz, CDCl3)
; d 7.29 (dd, 1H,
J¼8.6, 2.5 Hz), 7.24 (ds,1H, J¼2.5 Hz), 6.72 (d,1H, J¼8.6 Hz), 5.94 (m,
1H), 5.06 (m, 2H), 3.80 (s, 3H), 3.34 (d, 2H, J¼6.6 Hz); 13C NMR
(100 MHz, CDCl3)
112.0, 55.6, 33.9.
d. 156.4, 136.0, 132.4, 131.0, 129.8, 116.1, 112.7,
References and notes
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J.-H. Kwak et al. / Tetrahedron 67 (2011) 9401e9404
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