Facile synthesis of diarylmethanes via quinone methides

Article abstract of DOI:10.1016/j.tet.2012.10.087

A novel acid-mediated generation of quinone methides followed by nucleophilic addition of electronrich aromatic compounds to furnish diarylmethanes has been developed. A wide range of electronrich aromatic compounds including some heterocycles can be employed for this reaction to provide the corresponding diarylmethanes in good yields and regioselectivities.

Full text of DOI:10.1016/j.tet.2012.10.087

Accepted Manuscript
Facile synthesis of diarylmethanes via quinone methides
Kassrin Tangdenpaisal, Wong Phakhodee, Somsak Ruchirawat, Poonsakdi
Ploypradith
PII:
S0040-4020(12)01683-3
10.1016/j.tet.2012.10.087
TET 23705
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 21 August 2012
Revised Date: 20 September 2012
Accepted Date: 5 October 2012
Please cite this article as: Tangdenpaisal K, Phakhodee W, Ruchirawat S, Ploypradith P, Facile
synthesis of diarylmethanes via quinone methides, Tetrahedron (2012), doi: 10.1016/j.tet.2012.10.087.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Facile synthesis of diarylmethanes via
quinone methides
Leave this area blank for abstract info.
Kassrin Tangdenpaisal, Wong Phakhodee*, Somsak Ruchirawat, Poonsakdi Ploypradith*
Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, 54 Kamphaeng Phet 6 Road, Bangken,
Bangkok 10210, Thailand
OR
OR
n
n
X
X
PTS-Si
OAc
+
25 examples
PhMe or
EtOH:PhMe (4:1)
up to 97%
YO
Z
YO
Z
X =Br or H; Y =MOM or Me
X =Br or H; Y =H or Me
Z =OMOM or H
Z =OH or H

ACCEPTED MANUSCRIPT
1
Tetrahedron
journal homepage: www.elsevier.com
Facile synthesis of diarylmethanes via quinone methides
Kassrin Tangdenpaisala,b, Wong Phakhodeec,*, Somsak Ruchirawata,b, and Poonsakdi Ploypraditha,b,
aProgram in Chemical Biology, Chulabhorn Graduate Institute and Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, 54 Kampaeng Phet 6
Road, Bangken, Bangkok 10210, Thailand
bCenter of Excellence on Environmental Health and Toxicology, Commission on Higher Education (CHE), Ministry of Education, Thailand
cSchool of Science, Mae Fah Luang University, 333 Moo 1, Tambon Tasud, Muang District, Chiang Rai, 57100 Thailand
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A novel acid-mediated generation of quinone methides followed by nucleophilic addition of
electron-rich aromatic compounds to furnish diarylmethanes has been developed. A wide range
of electron-rich aromatic compounds including some heterocycles can be employed for this
reaction to provide the corresponding diarylmethanes in good yields and regioselectivities.
Available online
2012 Elsevier Ltd. All rights reserved.
Keywords:
Quinone methide
Diarylmethane
Electrophilic aromatic substitution
Nucleophilic addition
Regioselective process
Figure 1. Some natural and synthetic biologically active diarylmethanes
1. Introduction
A number of different strategies have been developed for the
Diarylmethane constitutes an important core of some natural
products and synthetic compounds (1–5; Figure 1) with
interesting biological activities. Recent studies have been
directed to profile some diarylmethane derivatives as thyroid
hormone analogs (1),1–3 macrocyclic receptors for some amino
acids,4,5 anti-implantation agents (2),6 as well as inhibitors of
matrix metalloproteinase (3),7 phosphodiesterase-4 (PDE-4; 4),8
and C-C chemokine receptor type 5 (CCR5; 5).9
synthesis of the diarylmethane core.10 Benzylation via tandem
Grignard
reaction-iodotrimethylsilane
(TMSI)
mediated
reduction,11 Cu- and Pd-catalyzed reactions,5,12–16 benzotriazole-
mediated reaction,17 L-proline-catalyzed multicomponent
Mannich-type Friedel-Crafts reaction,18 organocatalyzed Friedel-
Crafts arylation,19 and TfOH/HNTf2-catalyzed electrophilic
aromatic substitution20 have been reported as the effective means.
———
Corresponding author. Tel.: +662-574-0622; fax: +662-574-2027; e-mail: poonsakdi@cri.or.th

O
ACCEPTED MANUSCRIPT
OH
HO
O
CO2H
S
N
H
O
O
1
3
2
Tetrahedron
Ph
O
toluene was employed for the reaction using PTS-Si as
R1
R2
F2HCO
previously reported.22,23 In the case of InCl3 (entry 3) and PtCl4
(entry 5), a stoichiometric amount of these Lewis acids gave
complex mixtures.
O
H
N
S
2
4
The scope of aromatic compounds containing different
electron-donating groups (EDGs) was investigated using the
optimized conditions from Table 1 (PTS-Si in toluene) and the
results are summarized in Table 2. In most cases, the reactions
proceeded with high regioselectivity, providing the
corresponding products 8 and 9a-m up to 96% yield (entries 3
and 11). As expected, the regiochemistry of the products was
determined by the position of the EDGs (hydroxyl or methoxy).
When unsubstituted, the position para to the hydroxyl group was
attacked by the electrophilic quinone methide generated from the
precursor 6. 3-Methoxyphenol (entry 8), on the other hand, gave
the product 9g as a 1:1 inseparable mixture of regioisomers
arising from the reaction at the position para to either the
methoxy or the hydroxyl group. Interestingly, when the position
para to the hydroxyl or methoxy group was not available (entries
9, 11 and 12), the reactions proceeded to furnish the products
from the exclusive attack on the position ortho to these EDGs
instead. In addition, heterocyclic aromatic compounds such as
benzofuran and N-methylindole (entries 13 and 14) also gave the
corresponding diarylmethanes 9l and 9m arising from the
reactions at position 3 on both heterocycles in 32% and 84%
yields, respectively. However, furan, N-protected pyrroles,
thiophene, or thianaphthene gave no desired products.
N
CF3
F3C OH
O
O
N
N
N
5
O
During the past few years, our research group has reported the
use of solid-supported reagents, especially p-TsOH on silica
(PTS-Si), in organic synthesis including the total synthesis of
(OR)n
(OR)n
Br
Br
acid/Lewis acid
OAc
+
MeO
OMOM
MeO
OH
7
6
lamellarins,21 the facile deprotection of aromatic ethers,22 and the
generation of ortho-quinone methides (o-QMs) as well as their
formal
intermolecular/intramolecular
[4+2]-cycloaddition
reactions to form chromans.23 As shown in Scheme 1, we now
envisioned that the reactions between electron-rich aromatic
compounds24 and quinone methides derived from the precursors
such as 623 may furnish the diarylmethane core 7. Herein, we
wish to report our investigation in the use of PTS-Si as well as
other transition metal Lewis acids to generate quinone methides
(QMs) and their subsequent reactions with aromatic compounds
to provide the corresponding diarylmethanes.
It should be noted that all the reactions were first performed
using condition A and other conditions (B or C) were employed
when condition A gave either low yields of the expected products
or complex mixtures. For condition A, toluene, a non-polar
solvent was used (Table 1) in order to suppress other side
reactions when the aromatic compounds, especially those
Scheme 1. General schematic representation of the diarylmethane synthesis
2. Results and Discussion
We first investigated the reaction between the QM precursor 6
with 1,3,5-trimethoxybenzene under various conditions. The
results are summarized in Table 1.
Table 1
Screening of the acid/Lewis acid-mediated reactions for
diarylmethane 8.a
OMe
MeO
OMe
OMe
Br
Br
OAc
acid/L.A.
0 oC, 2-4h
+
MeO
OMOM MeO
OMe
MeO
OH
6
8
Entry
1c
Acid/Lewis Acid
ZnCl2
ZrCl4
InCl3
PtCl2
mol (%)
Yield (%)b
100
100
10
100
10
32
64
36
46
52
71
2c
3
4c
5
PtCl4
PTS-Si
6c,d
110
a
Unless otherwise noted, the reactions were performed in CH2Cl2. Five
equivalents of 1,3,5-trimethoxybenzene were employed.
b Isolated yields.
c Catalytic amount (10 mol%) of these acids/Lewis acids led to incomplete
consumption of starting material.
d Toluene was used as solvent.
From Table 1, the best condition (PTS-Si) gave the
corresponding diarylmethane 8 in 71% yield (entry 6) while other
acid/Lewis acids gave lower yields. While CH2Cl2 was used for
the conditions using metal salts as Lewis acids (entries 1–5),

ACCEPTED MANUSCRIPT
3
g
Condition A gave a complex mixture while condition B gave 9i in
Table 2
55% yield.
Scope of oxygenated aromatic compounds in the synthesis of
diarylmethanes 8 and 9a-n.
h Condition A gave 9k in 29% yield.
Br
Br
PTS-Si
Ar
OH
8 and 9a-n
OAc
i Condition A gave 9l in 24% yield.
Ar
+
conditions
MeO
MeO
OMOM
j
Condition A gave 9m in 9% yield while the starting compound 6 was
6
Entry
Ara
Conditionb Product
Yield (%)c
recovered in 79% yield.
containing free phenolic group(s), were employed (entries 4–12).
Ethanol (conditions B or C) was anticipated to help improve
solubility of some of the aromatic compounds as well as to
prevent their polymerization under the reaction conditions. After
some experimentation, the optimal ratio between ethanol and
toluene was found to be 4:1 (v/v). However, the presence of
ethanol in the reaction conditions B or C rendered them more
ionic in character than condition A.
1
A
9a
78
MeO
OMe
OMe
2
A
8
71
MeO
MeO
OMe
OMe
3
4
C
B
9b
9c
96
54
OMe
OH
We also investigated the extent and contribution of the ortho-
and para-quinone methides toward this PTS-Si-mediated
preparation of diarylmethanes. As summarized in Table 3, it is
evident that the p-quinone methide derived from the precursors 6
and 10c–h contributed significantly toward the formation of the
corresponding diarylmethanes 8, 11c–e. Better yield (76%) of
the product 11c was obtained from the p-OMOM containing
precursor 10c while the corresponding precursor 10b22a
containing only the o-OMOM gave the corresponding product
11b in much lower yield (38%). Other protecting groups (Me, i-
Pr and Ac) were investigated; compounds 10d and 10f25 gave
11d and 11e25 in 95% and 81% yields, respectively, whose i-Pr
and methyl groups were not cleaved. On the other hand,
compound 10e gave 11c in 75% yield. Thus, it appears that the
cleavage of the protecting groups occurred after the nucleophilic
addition to the QMs. Without any electron-donating group either
at the ortho- or para-position (10a), there was no reaction. In
addition, compounds 10g and 10h23a, with the difference only in
their positions of the OMe and OMOM as the substituents either
at Y or Z, did not provide the corresponding products 11f–g;
compound 12 was obtained instead in 56% and 23% yields,
respectively, as shown in Scheme 2.26
5d
6
C
C
9d
9e
70
72
HO
HO
OH
OH
OH
OMe
7e
8f
C
C
9f
59
95
OH
OH
OH
9g
MeO
MeO
9
C
C
9h
9i
60
61
MeO
10g
OH
OH
Table 3
11
A
9j
96
Extent of ortho- and para-quinone methidesa
OMe
OMe
12h
13i
C
C
9k
9l
49
32
OMe
MeO
OMe
X
B
X
Y
OAc
PTS-Si
+
MeO
O
conditions
OMe
A
Z
6, 10a-h
8, 11a-g
Comp
X
Y
Z
Prod
A
B
Yield
14j
C
9m
84
(%)b
0
N
Me
10a
10b
10c
10d
10e
10f
10g
10h
6
H
H
H
H
H
H
H
H
H
H
H
11a
H
OH
H
H
H
H
OMe
OH
H
H
a
OMOM 11b
38
76
95c
75
81
0
The arrows on the structures of the aromatic compounds indicate the
OMOM
Oi-Pr
OAc
OMe
OMOM OMe
H
H
H
H
11c
11d
11c
11e
11f
OH
Oi-Pr
OH
OMe
OH
OMe
OMe
position whereby the attack from the electrophilic quinone methide occurred.
Five equivalents of each aromatic compound were employed in each reaction.
b A = toluene at 0 °C to rt; B = EtOH : toluene (4 : 1 v/v) at 0 °C to rt; C =
EtOH : toluene (4 : 1 v/v) at 60 °C. The reactions were monitored by tlc and
normally took 1.5–5 h for completion.
OMe
OMe
OMOM 11g
OMOM
0
71
Br
8
OH
a Unless otherwise noted, the reactions were performed in toluene at 0 °C
to rt until completion (2 h).
c Isolated yields.
d Condition A gave 9d in 52% yield.
b Isolated yields.
e Conditions A and B gave 9f in 15% and 32% yields, respectively.
f A 1 : 1 mixture of inseparable regioisomers was obtained.
c Toluene at 60 °C.
Compound 10c was employed for the reactions with a number
of aromatic compounds as summarized in Table 4. In general,

ACCEPTED MANUSCRIPT
4
Tetrahedron
the reactions using 10c furnished the corresponding products
e The reaction was performed in toluene at 60 °C.
13a–g in better yields (25–97%) than those using 6 with similar
regiocontrol. It was found that one of the two hydroxy groups in
the product 13b was methylated under reaction condition,
presumably from the methyl group of the MOM ether.26 From the
nOe experiment, methylation was tentatively assigned to occur
on the phenol group of the aromatic ring originally from the
starting material 10c (See Supplementary Material). The reaction
using 1,3,5-trimethylbenzene (entry 7), a much less activated
aromatic compound, furnished the product 13g albeit in low yield
(25%).
f No desired product was formed when 6 was used.
OH
PTS-Si
OAc
+
PhMe
60 oC
MOMO
HO
HO
10c
13d
number of times
PTS-Si recycled
yield (%)
0
97
92
71
75
82*
1
2
3
4*
Scheme 2. Reactions of 10g and 10h to 12
*following acid wash
Scheme 3. Yields of 13d from 10c and the number of times PTS-Si recycled
OMe
A plausible reaction mechanism appears to involve a stepwise
process featuring the departure of the protonated acetate via the
assistance from the oxygen atom para to the benzyl acetate to
generate the corresponding p-QMs (intermediate A) which is a
resonance structure of the o-QMs (intermediate B). Ensuing
nucleophilic addition of aromatic compounds and cleavage of the
protecting group then led to the formation of the products
(Scheme 4). In case of the isopropyl group (compound 10c;
Table 3), nucleophilic addition apparently occurred without the
cleavage of the protecting group under the reaction condition.
This observation is consistent with our previous findings that the
cleavage of the isopropyl group using PTS-Si required higher
PTS-Si
OAc
Ar
Ar
PhMe
+
0 oC to rt
3 h
RO
OR' MeO
10g; R =MOM, R' =Me
10h; R =Me, R' =MOM
OMe
HO
OMe
12; Ar =2,4,6-trimethoxybenzene
56%from 10g; 23%from 10h
An advantage of using PTS-Si for these reactions is its
recyclability. Following filtration, the recovered PTS-Si could be
subjected to methanol washing and then used directly (the zeroth
to the third times of recycling; Scheme 3), yielding 13d in 75–
97% from 10c. The lower yields in the third and fourth cycle
could be improved after the same batch of PTS-Si was subjected
to acid washing, which gave 13d in 82% yield.
temperature.22
signifies the importance of the contributions from either the p- or
o-QMs to the observed chemistry. Simple nucleophilic
In addition, the proposed mechanism also
Table 4
Reactions of 10c with various aromatic compoundsa
Entry Arb
Product
Yield (%)c
substitution reaction mechanism (SN1 or SN2) can be clearly ruled
out since the substrate 10a (simple benzyl acetate), capable of
undergoing such reaction, did not proceed to give the
PTS-Si
Ar
OAc
Ar
+
conditions
MOMO
HO
corresponding
product
when
reacted
with
1,3,5-
13a-g
10c
trimethoxybenzene under similar reaction conditions (Table 3,
entry 1).
MeO
1
13a
13b
83
86
MeO
O
OH
-AcOH
OAc
H
2d
RO
X =OR' or H
X
RO
X
RO
RO
X
X
O
OH
A
B
Ar
Ar
3
13c
78
Ar
-R+
Ar
H+
Ar
HO
X
RO
H
X
OH
D
C
Scheme 4. A plausible mechanism
OH
4e
5
13d
13e
97
73
Our previous studies on the formal [4+2]-cycloaddition of the
o-QMs and styrene derivatives23 also prompted us to carry out a
competitive reaction between the cycloaddition and nucleophilic
addition of the QMs using PTS-Si. As shown in Scheme 5, the
nucleophilic addition is the more preferential mode of reaction,
giving the diarylmethane 9j in 60% yield without any detectable
amount of the product from the cycloaddition reaction. Even
when p-methoxystyrene, a more electron-rich styrene derivative,
was employed, no product from cycloaddition reaction could be
detected while 9j was obtained in 92% yield.
OMe
6
13f
77
25
O
7f
13g
Scheme 5. Competitive reactions of 6 with 2-naphthol and styrenes
a Unless otherwise noted, the reactions were performed in EtOH : toluene
(4 : 1 v/v) at 60 °C until completion (1–3 h).
b
The arrows on the structures of the aromatic compounds indicate the
OH
PTS-Si
PhMe
0 oC to rt
1h
position whereby the attack from the electrophilic quinone methide occurred.
Five equivalents of each aromatic compound were employed in each reaction.
HO
Br
Br
OAc
+
c Isolated yields.
MeO
OMOM
MeO
OH
9j, 60% or 92%
6
d
Under the reaction condition, methylation of one of the hydroxy groups
X =H or OMe
X
in the product occurred concomitantly.

ACCEPTED MANUSCRIPT
5
385.0471, found 385.0470, for C17H2079BrO5 (M+H)+,
3. Conclusion
353.0383, found 383.0489.
In summary, we have shown that quinone methides generated
under acidic conditions by PTS-Si can react with a number of
aromatic compounds with electron-donating groups to furnish the
corresponding diarylmethanes in good yields and excellent
regiocontrol. In addition, our mechanistic studies revealed a
significant contribution from the corresponding p-QMs and the
nucleophilic addition reaction to the QMs occurred more
preferentially over the corresponding cycloaddition reaction with
styrene.
4-Bromo-2-(4-hydroxybenzyl)-5-methoxyphenol
(9c).
Following the general procedure and purification by PTLC, the
product was obtained as a white solid (0.026 g, 0.084 mmol,
54%). Rf 0.22 (20% EtOAc/hexanes). Mp 124.5–126.5 °C. FTIR
(UATR): νmax 3388, 1611, 1509, 1444, 1400, 1205, 1130, 1049
1
cm-1. H NMR (MeOH-d4, 300 MHz): δ 3.79 (s, 3H), 3.81 (s,
2H), 6.63 (s, 1H), 6.76 (d, J = 8.5 Hz, 2H), 7.09 (d, J = 8.5 Hz,
2H), 7.16 (s, 1H), 8.20 (br s, 1H), 8.68 (br s, 1H). 13C NMR
(MeOH-d4, 75 MHz): δ 33.6, 55.5, 99.9, 100.5, 115.1 (2C),
122.4, 129.7 (2C), 131.7, 133.7, 154.8, 155.2, 155.6. LRMS (EI)
m/z (rel intensity) 310 (44) [C14H1381BrO3]+, 308 (46)
[C14H1379BrO3]+, 217 (95), 215 (100), 115 (56), 107 (68), 94 (53),
69 (45). TOF-HRMS calcd for C14H1281BrO3 (M-H)+, 308.9945,
found 308.9957, for C14H1279BrO3 (M-H)+, 306.9964, found
306.9957.
4. Experimental Section
General Procedure for the nucleophilic addition to QMs:
The corresponding benzyl acetate (0.16 mmol) was dissolved in
toluene or 4:1 EtOH/toluene (see details in each reaction) (1 mL)
and then aromatic compound (0.80–1.6 mmol) and PTS-Si (0.17
mmol) were sequentially added at 0 °C. The stirring was
continued (for time and temperature noted in each Table) and
then the mixture was filtered through a short pad cotton wool.
Removal of the solvent afforded the crude product, which was
purified by preparative thin-layer chromatography (PTLC).
4-Bromo-2-(2,4-dihydroxybenzyl)-5-methoxyphenol (9d).
Following the general procedure and purification by PTLC, the
product was obtained as a white solid (0.036 g, 0.11 mmol, 70%).
Rf 0.33 (10% MeOH/CH2Cl2). Mp 168.5–169.5 °C. FTIR
(UATR): νmax 3311, 2935, 1614, 1506, 1490, 1443, 1292, 1201,
4-Bromo-5-methoxy-2-(2,4,6-trimethoxybenzyl)phenol (8).
Following the general procedure and purification by PTLC, the
product was obtained as a white solid (0.042 g, 0.11 mmol, 71%).
Rf 0.50 (20% EtOAc/hexanes). Mp 110.5–112.5 °C. FTIR
(UATR): νmax 3370, 2940, 2839, 1594, 1488, 1455, 1196, 1137,
1
1163, 1130, 1049 cm-1. H NMR (MeOH-d4, 300 MHz): δ 3.78
(s, 2H), 3.79 (s, 3H), 6.32 (dd, J = 8.2, 2.4 Hz, 1H), 6.43 (d, J =
2.4 Hz, 1H), 6.60 (s, 1H), 6.98 (d, J = 8.2 Hz, 1H), 7.24 (s, 1H).
13C NMR (MeOH-d4, 75 MHz): δ 28.2, 55.5, 56.6, 100.1, 100.6,
102.6, 107.1, 117.9, 122.0, 131.0, 133.6, 155.0, 155.2, 156.9.
LRMS (EI) m/z (rel intensity) 326 (16) [C14H1381BrO4]+, 324 (16)
[C14H1379BrO4]+, 217 (54), 215 (58), 123 (100), 71 (63), 69 (63).
TOF-HRMS calcd for C14H1881BrO5 (M+H)+, 327.0070, found
327.0051, for C14H1479BrO5 (M+H)+, 325.0070, found 325.0056.
1
1104, 1051 cm-1. H NMR (CDCl3, 300 MHz): δ 3.75 (s, 2H),
3.80 (s, 3H), 3.81 (s, 3H), 3.93 (s, 6H), 6.18 (s, 2H), 6.45 (s, 1H),
7.55 (s, 1H), 7.61 (s, 1H). 13C NMR (CDCl3, 75 MHz): δ 22.6,
55.4, 55.9 (2C), 56.2, 91.2 (2C), 100.7, 100.8, 108.8, 120.2,
135.1, 154.95, 155.04, 157.7 (2C), 159.9. LRMS (EI) m/z (rel
intensity) 384 (4) [C17H1981BrO5]+, 382 (4) [C17H1979BrO5]+, 168
(100), 139 (25). TOF-HRMS calcd for C17H2081BrO5 (M+H)+,
385.0470, found 385.0477, for C17H2079BrO5 (M+H)+, 383.0489,
found 383.0489.
4-Bromo-2-(2,4,6-trihydroxybenzyl)-5-methoxyphenol
(9e).
Following the general procedure and purification by
PTLC, the product was obtained as a white solid (0.038 g, 0.12
mmol, 72%). Rf 0.33 (10% MeOH/CH2Cl2). Mp 199.0–200.0 °C.
FTIR (UATR): νmax 3326, 1614, 1489, 1467, 1199, 1142, 1035
4-Bromo-2-(2,4-dimethoxybenzyl)-5-methoxyphenol (9a).
Following the general procedure and purification by PTLC, the
product was obtained as colorless oil (0.043 g, 0.12 mmol, 78%).
Rf 0.38 (30% EtOAc/hexanes). FTIR (UATR): νmax 3373, 2938,
1
cm-1. H NMR (MeOH-d4, 300 MHz): δ 3.60 (s, 2H), 3.62 (s,
3H), 5.87 (s, 2H), 6.37 (s, 1H), 7.29 (s, 1H), 8.58 (s, 2H). 13C
NMR (MeOH-d4, 75 MHz): δ 22.0, 55.5, 94.9 (2C), 100.1, 100.7,
105.2, 121.7, 134.2, 154.8, 155.0, 155.9 (2C), 157.0. TOF-
HRMS calcd for C14H1481BrO4 (M+H)+, 343.0000, found
343.000, for C14H1479BrO4 (M+H)+, 341.0019, found 341.0003.
2836, 1610, 1587, 1505, 1489, 1464, 1289, 1206, 1153, 1045 cm-
1
.
1H NMR (CDCl3, 300 MHz): δ 3.73 (s, 2H), 3.77 (s, 3H), 3.80
(s, 3H), 3.93 (s, 3H), 6.45 (s, 1H), 6.49 (dd, J = 6.2, 2.3 Hz, 1H),
7.14 (d, J = 6.2 Hz, 1H), 7.16 (d, J = 2.3 Hz, 1H), 7.34 (s, 1H).
13C NMR (CDCl3, 75 MHz): δ 29.3, 55.5, 55.8, 56.2, 98.8, 101.3,
101.4, 105.7, 120.5, 120.8, 130.9, 133.8, 154.4, 155.4, 156.0,
159.8. LRMS (EI) m/z (rel intensity) 354 (4) [C16H1781BrO4]+,
352 (4) [C16H1779BrO4]+, 138 (100). TOF-HRMS calcd for
C16H1881BrO4 (M+H)+, 355.0364, found 355.0349, for
C16H1879BrO4 (M+H)+, 353.0383, found 353.0368.
4-Bromo-2-(4-hydroxy-3-methoxybenzyl)-5-
methoxyphenol (9f). Following the general procedure and
purification by PTLC, the product was obtained as a pale yellow
solid (0.032 g, 0.09 mmol, 59%). Rf 0.49 (60% EtOAc/hexanes).
Mp 110.3–112.4 °C. FTIR (UATR): νmax 3430, 2937, 1059, 1205
1
cm-1. H NMR (CDCl3, 300 MHz): δ 3.81 (s, 3H), 3.82 (s, 5H),
5.18 (brs, 1H), 5.57 (brs 1H), 6.42 (s, 1H), 6.62–6.73 (m, 2H),
6.85 (d, J = 7.8 Hz, 1H), 7.25 (s, 1H). 13C NMR (CDCl3, 75
MHz): δ 35.5, 55.9, 56.2, 101.0, 101.7, 110.9, 114.5, 120.5,
121.1, 130.9, 134.2, 144.3 146.8, 154.2, 155.3. LRMS (EI) m/z
(rel intensity) 340 (17) [C15H1581BrO4]+, 338 (17)
[C15H1579BrO4]+, 217 (39), 215 (43), 124 (100). TOF-HRMS
calcd for C15H1481BrO4 (M-H)+, 339.0062, found 339.0055, for
C15H1479BrO4 (M-H)+, 337.0081, found 337.0074.
4-Bromo-5-methoxy-2-(2,4,5-trimethoxybenzyl)phenol
(9b). Following the general procedure and purification by PTLC,
the product was obtained as a white solid (0.059 g, 0.15 mmol,
96%). Rf 0.38 (20% EtOAc/hexanes, developed three times). Mp
115.0–116.5 °C. FTIR (UATR): νmax 3394, 2993, 2937, 2835,
1610, 1508, 1442, 1398, 1202, 1166, 1028 cm-1. 1H NMR
(CDCl3, 300 MHz): δ 3.74 (s, 2H), 3.81 (s, 3H), 3.85 (s, 3H),
3.87 (s, 3H), 3.96 (s, 3H), 6.46 (s, 1H), 6.55 (s, 1H), 6.76 (s, 1H),
7.36 (s, 1H), 7.38 (s, 1H). 13C NMR (CDCl3, 75 MHz): δ 29.9,
56.5, 56.6, 57.0, 57.2, 98.3, 101.8, 101.9, 114.7, 120.2, 121.3,
134.5, 145.1, 149.5, 149.9, 155.6, 156.4. LRMS (EI) m/z (rel
intensity) 384 (6) [C17H1981BrO5]+, 382 (6) [C17H1979BrO5]+, 168
(100), 153 (31). TOF-HRMS calcd for C17H2081BrO5 (M+H)+,
4-Bromo-2-(4-hydroxy-2-methoxybenzyl)-5-
methoxyphenol
and
4-bromo-2-(2-hydroxy-4-
methoxybenzyl)-5-methoxyphenol (9g). Following the general
procedure and purification by PTLC, the product was obtained as
red brown oil (0.052 g, 0.15 mmol, 95%). Rf 0.49 (60%
EtOAc/hexanes). FTIR (UATR): νmax 3363, 2939, 1613, 1196
1
cm-1. H NMR (CDCl3, 300 MHz): δ 3.66 (s, 3H), 3.67 (s, 3H),

ACCEPTED MANUSCRIPT
6
Tetrahedron
3.70 (s, 2H), 3.73 (s, 2H), 3.77 (s, 3H), 3.82 (s, 3H), 6.31–6.41
56.1, 57.0, 100.9, 101.1, 112.8, 119.2, 120.4, 123.4, 124.0, 127.1,
128.8, 129.1, 130.0, 132.9, 134.3, 152.4, 155.2 (2C). LRMS (EI)
m/z (rel intensity) 374 (5) [C19H1881BrO3]+, 372 (5)
[C19H1879BrO3]+, 158 (100). TOF-HRMS calcd for C19H1981BrO3
(M+H)+, 375.0416, found 375.0401, for C19H1979BrO3 (M+H)+,
373.0434, found 373.0418.
(m, 4H), 6.42–6.49 (m 2H), 7.04 (d, J = 8.7 Hz, 1H), 7.12 (d, J =
8.4 Hz, 1H), 7.32 (s, 1H), 7.34 (s, 1H). 13C NMR (CDCl3, 75
MHz): δ 29.2, 29.3, 55.3, 55.7, 56.1, 56.2, 99.2, 100.9, 101.2,
101.5, 101.9, 102.1, 106.9, 108.4, 119.2, 120.1, 120.8, 120.9,
131.0, 131.1, 133.8, 133.9, 152.8, 153.0, 154.1, 155.1, 155.2,
155.6, 156.0, 159.3. LRMS (EI) m/z (rel intensity) 340 (25)
[C15H1581BrO4]+, 338 (27) [C15H1579BrO4]+, 217 (59), 215 (65),
137 (80), 124 (100). TOF-HRMS calcd for C15H1481BrO4 (M-H)+,
339.0062, found 339.0065, for C15H1479BrO4 (M-H)+, 337.0081,
found 337.0083.
2-(Benzofuran-3-ylmethyl)-4-bromo-5-methoxyphenol (9l).
Following the general procedure and purification by PTLC, the
product was obtained as brown oil (0.017 g, 0.05 mmol, 32%). Rf
0.24 (30% EtOAc/hexanes). FTIR (UATR): νmax 3502, 2925,
2853, 1454, 1205 cm-1. H NMR (CDCl3, 300 MHz): δ 3.84, (s,
1
4-Bromo-2-(2-hydroxy-4,5-dimethoxybenzyl)-5-
3H), 4.02 (s, 2H), 5.46 (s, 1H), 6.42 (s, 1H), 6.47 (s, 1H), 7.20 (t,
J = 7.2 Hz, 2H), 7.36 (s, 1H), 7.41 (d, J = 7.2 Hz, 1H), 7.47 (d, J
= 7.2 Hz, 1H). 13C NMR (CDCl3, 75 MHz): δ 28.9, 56.3, 101.3
102.2, 103.3, 110.9, 116.9, 120.6, 122.8, 123.8, 128.5, 134.4,
154.1, 154.8, 155.7, 156.2. LRMS (EI) m/z (rel int, ensity) 334
(8) [C16H1381BrO3]+, 332 (8) [C16H1379BrO3]+, 178 (100), 57 (70).
TOF-HRMS calcd for C16H1381BrO3 (M)+, 334.0023, found
334.0031, for C16H1379BrO3 (M)+, 332.0043, found 332.0037.
methoxyphenol (9h). Following the general procedure and
purification by PTLC, the product was obtained as a white solid
(0.036 g, 0.10 mmol, 60%). Rf 0.34 (60% EtOAc/hexanes,
developed twice). Mp 188.3–190.0 °C. FTIR (UATR): νmax 3355,
1
2936, 1200 cm-1. H NMR (10:1 CDCl3:MeOH-d4, 300 MHz): δ
3.75 (s, 2H), 3.81 (s, 9H), 6.48 (s, 2H), 6.72 (s, 1H), 7.30 (s, 1H).
13C NMR (10:1 CDCl3:MeOH-d4, 75 MHz): δ 29.3, 55.5, 55.8,
56.4, 100.6, 100.7, 100.8, 114.0, 117.8, 121.2, 133.4, 142.5,
147.1, 148.1, 153.9, 154.7. LRMS (EI) m/z (rel intensity) 370
(10) [C16H1781BrO5]+, 368 (10) [C16H1779BrO5]+, 167 (100), 154
(90). TOF-HRMS calcd for C16H1681BrO5 (M-H)+, 369.0157,
found 339.0184, for C16H1679BrO5 (M-H)+, 367.0176, found
367.0174.
4-Bromo-5-methoxy-2-((1-methyl-1H-indol-3-
yl)methyl)phenol (9m). Following the general procedure and
purification by PTLC, the product was obtained as brown oil
(0.047 g, 0.14 mmol, 84%). Rf 0.24 (30% EtOAc/hexanes). FTIR
(UATR): νmax 3463, 2920, 1049, 740 cm-1. 1H NMR (CDCl3, 300
MHz): δ 3.70 (s, 3H), 3.80 (s, 3H), 4.00 (s, 2H), 6.44 (s, 1H),
6.79 (s, 1H), 7.08 (t, J = 7.3 Hz, 1H), 7.16–7.33 (m, 2H), 7.37 (s,
1H), 7.50 (d, J = 7.9 Hz, 1H). 13C NMR (CDCl3, 75 MHz): δ
26.0, 32.7, 56.2, 101.1, 101.5, 109.3, 111.3, 119.1, 119.2, 119.9,
122.1, 127.0, 127.3, 133.9, 137.4, 154.7, 155.2. LRMS (EI) m/z
(rel intensity) 347 (10) [C17H1681BrNO3]+, 345 (10)
4-(5-Bromo-2-hydroxy-4-methoxybenzyl)naphthalen-1-ol
(9i). Following the general procedure and purification by PTLC,
the product was obtained as a brown solid (0.035 g, 0.10 mmol,
61%). Rf 0.51 (60% EtOAc/hexanes). Mp 124.1–125.8 °C. FTIR
(UATR): νmax 3404, 2925, 1587, 1204 cm-1. 1H NMR (20:1
CDCl3:MeOH-d4, 300 MHz): δ 3.82 (s, 3H), 4.22 (s, 2H), 6.50 (s,
1H), 6.77 (d, J = 7.6 Hz, 1H), 6.98 (s, 1H), 7.06 (d, J = 7.6 Hz,
1H), 7.40–7.52 (m, 2H), 7.85–7.98 (m, 1H), 8.20–8.33 (m, 1H).
13C NMR (20:1 CDCl3:MeOH-d4, 75 MHz): δ 31.3, 56.1, 100.3,
100.8, 107.6, 121.0, 122.5, 123.9, 124.5, 125.2, 126.2, 126.75,
126.81, 132.9, 133.7, 151.6, 154.4, 154.6. LRMS (EI) m/z (rel
intensity) 360 (8) [C18H1581BrO3]+, 358 (9) [C18H1579BrO3]+, 217
(36), 215 (37), 144 (100). TOF-HRMS calcd for C18H1481BrO3
(M-H)+, 359.0102, found 359.0123, for C18H1479BrO3 (M-H)+,
357.0121, found 357.0126.
[C17H1679BrNO3]+, 131 (100).
TOF-HRMS calcd for
C17H1781BrNO3 (M+H)+, 348.0418, found 348.0419, for
C17H1779BrNO3 (M+H)+, 346.0437, found 346.0439. Note that
this compound is not stable and decomposes upon storage even at
low temperature (−20 °C).
4-(Methoxylmethoxy)benzyl acetate (10c). To a solution of
4-hydroxybenzaldehyde (2.50 g, 20 mmol) in DMF (30 mL) was
sequentially added NaH (1.30 g, 30 mmol), and MOMCl (2.30
mL, 30 mmol) at 0 °C. The reaction mixture was stirred for 4 h at
rt and then quenched with water (20 mL). The aqueous layer was
extracted with EtOAc (3 x 20 mL). The combined organic layers
were washed with water (7 x 50 mL), brine (20 mL), dried over
Na2SO4 and filtered. The filtrate was evaporated (aspirator then
vacuo) to give a crude product, which was purified by column
chromatography (0–30% EtOAc/hexane) to furnish the product
1-(5-Bromo-2-hydroxy-4-methoxybenzyl)naphthalen-2-ol
(9j). Following the general procedure and purification by PTLC,
the product was obtained as a red brown solid (0.055 g, 0.15
mmol, 96%). Rf 0.49 (60% EtOAc/hexanes). Mp 111.3–114.4 °C.
1
FTIR (UATR): νmax 3287, 2938, 1199 cm-1. H NMR (CDCl3,
1
300 MHz): δ 3.52 (s, 1H), 3.59 (s, 3H), 4.26 (s, 2H), 6.31 (s, 1H),
7.01 (d, J = 8.8 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.47–7.60 (m,
3H), 7.73 (d, J = 7.8 Hz, 1H), 8.15 (d, J = 7.8 Hz, 1H). 13C NMR
(CDCl3, 75 MHz): δ 24.6, 56.0, 100.8, 101.8, 117.2, 118.0,
119.7, 122.9, 123.5, 127.0, 128.8 (2C), 129.8, 133.1, 134.3,
149.6, 153.8, 155.1. LRMS (EI) m/z (rel intensity) 360 (11)
[C18H1581BrO3]+, 358 (11) [C18H1579BrO3]+, 217 (31), 215 (31),
204 (31), 202 (35), 144 (100). TOF-HRMS calcd for
C18H1481BrO3 (M-H)+, 359.0102, found 359.0118, for
C18H1479BrO3 (M-H)+, 357.0121, found 357.0119.
as colorless oil (2.60 g, 16 mmol, 78%). H NMR (CDCl3, 300
MHz): δ 3.50 (s, 3H), 5.26 (s, 2H), 7.15 (d, J = 8.6 Hz, 2H), 7.84
(d, J = 8.6 Hz, 2H), 9.91 (s, 1H).
A mixture of 4-(methoxylmethoxy)benzaldehyde (1.10 g,
6.80 mmol) in EtOH (10 mL) was added NaBH4 (0.88 g, 17.0
mmol) and stirred for 1 h at rt. The solvent was removed under
reduced pressure and the residue dissolved in EtOAc (15 mL).
The organic layer was washed with water (3 x 10mL), brine (10
mL), dried over Na2SO4 and filtered. The filtrate was evaporated
(aspirator
then
vacuo)
to
give
a
crude
4-
4-Bromo-5-methoxy-2-((2-methoxynaphthalen-1-
(methoxylmethoxy)benzyl alcohol which was used for the next
step without purification.
yl)methyl)phenol (9k). Following the general procedure and
purification by PTLC, the product was obtained as brown oil
(0.029 g, 0.08 mmol, 49%). Rf 0.62 (60% EtOAc/hexanes). FTIR
(UATR): νmax 3354, 2937, 1249 cm-1. 1H NMR (CDCl3, 300
MHz): δ 3.76 (s, 3H), 4.09 (s, 3H), 4.28 (s, 2H), 6.41 (s, 1H),
7.30 (d, J = 8.1 Hz, 1H), 7.38 (t, J = 8.1 Hz, 1H), 7.54 (s, 1H),
7.56 (t, J = 8.1 Hz, 1H), 7.61 (s, 1H), 7.79 (d, J = 8.1 Hz, 2H),
8.17 (d, J = 8.1 Hz, 1H). 13C NMR (CDCl3, 75 MHz): δ 25.2,
To a solution of 4-(methoxylmethoxy)benzyl alcohol in DCM
(20 mL) was sequentially added N,N-dimethylaminopyridine
(DMAP; 1.20 g, 10.2 mmol), Et3N (1.40 mL, 10.2 mmol) and
acetic anhydride (1.00 mL. 10.2 mmol) at 0 °C. The reaction
mixture was stirred for 3 h at rt and then quenched with water (15
mL). The aqueous layer was extracted with DCM (3 x 20 mL).

ACCEPTED MANUSCRIPT
7
The combined organic layers were washed with water (3 x 20
mL), brine (20 mL), dried over Na2SO4 and filtered. The filtrate
was evaporated (aspirator then vacuo) to give a crude product,
which was purified by column chromatography (0–30%
EtOAc/hexane) to give the desired benzyl acetate as colorless oil
(1.10 g, 5.10 mmol, 75%). Rf 0.45 (25% EtOAc/hexanes). FTIR
3.70 g, 30 mmol), Et3N (4.2 mL, 30 mmol) and acetic
anhydride (2.80 mL. 30 mmol) at 0oC. The reaction mixture was
stirred for 3 h at rt and then quenched with water (20 mL). The
aqueous layer was extracted with DCM (3 x 20 mL). The
combined organic layers were washed with water (3 x 20 mL),
brine (20 mL), dried over Na2SO4 and filtered. The filtrate was
evaporated (aspirator then vacuo) to give a crude product, which
was purified by column chromatography (0–40% EtOAc/hexane)
to furnish the desired product as colorless oil (1.10 g, 5.50 mmol,
55%). Rf 0.33 (25% EtOAc/hexanes). FTIR (UATR): νmax 2956,
1
(UATR): νmax 2956, 1736, 1514, 1226 cm-1. H NMR (CDCl3,
300 MHz): δ 2.08 (s, 3H), 3.47 (s, 3H), 5.04 (s, 2H), 5.18 (s, 2H),
7.03 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H). 13C NMR
(CDCl3, 75 MHz): δ 21.0, 56.0, 66.0, 94.3, 116.2 (2C), 129.3,
130.0 (2C), 157.2, 170.9. LRMS (EI) m/z (rel intensity) 210 (M+,
100), 121 (93). TOF-HRMS calcd for C11H14NaO4 (M+Na+)
233.0784, found 233.0786.
1736, 1509, 1188 cm-1. H NMR (CDCl3, 300 MHz): δ 2.10 (s,
1
3H), 2.30 (s, 3H), 5.09 (s, 2H), 7.08 (d, J = 8.3 Hz, 2H), 7.38 (d,
J = 8.3 Hz, 2H). 13C NMR (CDCl3, 75 MHz): δ 21.1 (2C), 65.6,
121.7 (2C), 129.5 (2C), 133.5, 150.5, 169.4, 170.8. LRMS (EI)
m/z (rel intensity) 208 (M+, 10), 166 (64), 124 (59), 107 (100).
TOF-HRMS calcd for C11H12NaO4 (M+Na+) 231.0628, found
231.0621.
4-Isopropoxybenzyl acetate (10d). To a solution of 4-
hydroxybenzaldehyde (1.20 g, 9.80 mmol) in DMF (20 ml) was
sequentially added NaH (0.65 g, 14.7 mmol), and i-PrBr (1.4 mL.
14.7 mmol) at 0 °C. The reaction mixture was stirred for 2 h at rt
and then quenched with water (15 mL). The aqueous layer was
extracted with EtOAc (3 x 20 mL). The combined organic layers
were washed with water (7 x 50 mL), brine (20 mL), dried over
Na2SO4 and filtered. The filtrate was evaporated (aspirator then
vacuo) to give a crude 4-isopropoxybenzaldehyde which was
used for the next step without purification.
2-Methoxy-4-(methoxylmethoxy)benzyl acetate (10g). To a
solution of 2,4-dihydroxybenzaldehyde (2.10 g, 15.0 mmol) in
DMF (30 mL) was sequentially added K2CO3 (2.50 g, 18.0
mmol), and MOMCl (1.40 mL, 18.0 mmol) at 0 °C. The reaction
mixture was stirred for 2 h at rt and then quenched with water (15
mL). The aqueous layer was extracted with EtOAc (3 x 20 mL).
The combined organic layers were washed with water (7 x 50
mL), brine (20 mL), dried over Na2SO4 and filtered. The filtrate
was evaporated (aspirator then vacuo) to give a crude 2-hydroxy-
4-(methoxylmethoxy)benzaldehyde which was used in the next
step without purification.
A mixture of 4-isopropoxybenzaldehyde in EtOH (20 mL)
was added NaBH4 (1.30 g, 24.5 mmol) and stirred for 1 h at rt.
The solvent was removed under reduced pressure and the residue
dissolved in EtOAc (20 mL). The organic layer was washed with
water (3 x 20mL), brine (20 mL), dried over Na2SO4 and filtered.
The filtrate was evaporated (aspirator then vacuo) to give a crude
4-isopropoxybenzyl alcohol which was used for the next step
without purification.
A crude 2-hydroxy-4-(methoxylmethoxy)benzaldehyde was
dissolved in DMF (20 mL) and then NaH (1.00 g, 22.5 mmol)
and iodomethane (1.4 mL, 22.5 mmol) were sequentially added
at rt. The stirring was continued for 1 h at the same temperature
and the reaction was then quenched with water (15 mL). The
aqueous layer was extracted with EtOAc (3 x 20 mL). The
combined organic layers were washed with water (7 x 50 mL),
brine (20 mL), dried over Na2SO4 and filtered. The filtrate was
evaporated (aspirator then vacuo) to give a crude 2-methoxy-4-
(methoxylmethoxy)benzaldehyde which was used in the next
step without purification.
To a solution of 4-isopropoxybenzyl alcohol in DCM (20 mL)
was sequentially added N,N-dimethylaminopyridine (DMAP;
1.80 g, 14.7 mmol), Et3N (2.1 mL, 14.7 mmol) and acetic
anhydride (1.40 mL. 14.7 mmol) at 0 °C. The reaction mixture
was stirred for 3 h at rt and then quenched with water (15 mL).
The aqueous layer was extracted with DCM (3 x 20 mL). The
combined organic layers were washed with water (3 x 20 mL),
brine (20 mL), dried over Na2SO4) and filtered. The filtrate was
evaporated (aspirator then vacuo) to give a crude product, which
was purified by column chromatography (0–30% EtOAc/hexane)
to give the desired benzyl acetate as colorless oil (1.4 g, 6.7
mmol, 70%). Rf 0.30 (25% EtOAc/hexanes). FTIR (UATR): νmax
2978, 1736, 1510, 1223 cm-1. 1H NMR (CDCl3, 300 MHz): δ
1.33 (d, J = 5.9 Hz, 6H), 2.07 (s, 3H), 4.54 (sep, J = 5.9 Hz, 1H),
5.03 (s, 2H), 6.87 (d, J = 8.1 Hz, 2H), 7.27 (d, J = 8.1 Hz, 2H).
13C NMR (CDCl3, 75 MHz): δ 21.1, 22.0 (2C), 66.1, 69.8, 115.8
(2C), 127.7, 130.1 (2C), 158.0, 171.0. LRMS (EI) m/z (rel
intensity) 208 (M+, 20), 166 (27), 124 (64), 107 (100). TOF-
HRMS calcd for C12H16NaO3 (M+Na+) 231.0992, found
231.0988.
To
a
mixture
of
the
crude
2-methoxy-4-
(methoxylmethoxy)benzaldehyde in EtOH (30 mL) was added
NaBH4 (2.00 g, 37.5 mmol) and the mixture was stirred for 1 h at
rt. The solvent was removed under reduced pressure and the
residue dissolved in EtOAc (20 mL). The organic layer was
washed with water (3 x 20mL), brine (20 mL), dried over Na2SO4
and filtered. The filtrate was evaporated (aspirator then vacuo) to
give a crude 2-methoxy-4-(methoxylmethoxy)benzyl alcohol
which was used for the next step without purification.
To
a solution of 2-methoxy-4-(methoxylmethoxy)benzyl
alcohol in DCM (30 mL) was sequentially added N,N-
dimethylaminopyridine (DMAP; 2.80 g, 22.5 mmol), Et3N (3.1
mL, 22.5 mmol) and acetic anhydride (2.10 mL. 22.5 mmol) at 0
°C. The reaction mixture was stirred for 3 h at rt and then
quenched with water (15 mL). The aqueous layer was extracted
with DCM (3 x 20 mL). The combined organic layers were
washed with water (3 x 20 mL), brine (20 mL), dried over
Na2SO4 and filtered. The filtrate was evaporated (aspirator then
vacuo) to give a crude product, which was purified by column
chromatography (0–30% EtOAc/hexane) to give the desired
benzyl acetate as colorless oil (1.30 g, 5.20 mmol, 35%). Rf 0.33
(25% EtOAc/hexanes). FTIR (UATR): νmax 2957, 1733, 1226,
4-(Acetyloxy)benzyl acetate (10e). To a mixture of 4-
hydroxybenzaldehyde (1.20 g, 10 mmol) in EtOH (20 mL) was
added NaBH4 (1.3 g, 25 mmol) and the reaction was stirred for 1
h at rt. The solvent was removed under reduced pressure and the
residue dissolved in water (20 mL). The aqueous layer was
acidified with 6 M HCl to pH 2 and extracted with EtOAc (3 x 20
mL). The combined organic layers were washed with brine (20
mL), dried over Na2SO4 and filtered. The filtrate was evaporated
(aspirator then vacuo) to give a crude 4-hydroxybenzyl alcohol
which was used directly in the next step without purification.
1004 cm-1. H NMR (CDCl3, 300 MHz): δ 2.07 (s, 3H), 3.48 (s,
1
To a solution of 4-hydroxybenzyl alcohol in DCM (50 mL)
was sequentially added N,N-dimethylaminopyridine (DMAP;
3H), 3.82 (s, 3H), 5.09 (s, 2H), 5.18 (s, 2H), 6.60 (s, 1H), 6.62 (d,
J = 9.6 Hz, 1H), 7.23 (d, J = 9.6 Hz, 1H). 13C NMR (CDCl3, 75

ACCEPTED MANUSCRIPT
8
Tetrahedron
MHz): δ 21.1, 55.5, 56.0, 61.6, 94.4, 100.0, 107.0, 117.7, 131.3,
7.29 (s, 1H). 13C NMR (CDCl3, 75 MHz): δ 21.3, 22.6, 55.4 (2C),
55.45, 55.53 (2C), 55.8 (2C), 90.8 (2C), 91.0 (2C), 98.9, 109.7,
110.0, 117.4, 120.7, 130.4, 152.9, 156.7, 157.6 (2C), 159.5 (4C).
LRMS (EI) m/z (rel intensity) 484 (M+, 33), 316 (82), 181 (100),
168 (90). TOF-HRMS calcd for C27H32NaO8 (M+Na+) 507.1989,
found 507.1984.
158.8 (2C), 171.1. LRMS (EI) m/z (rel intensity) 240 (M+, 37),
181 (42), 151 (47), 136 (86), 108 (100). TOF-HRMS calcd for
C12H16O5Na (M+Na+) 263.0890, found 263.0876.
2-(2,4,6-Trimethoxybenzyl)phenol (11b). Following the
general procedure and purification by PTLC, the product was
obtained as colorless oil (0.016 g, 0.068 mmol, 38%). Rf 0.40
(20% EtOAc/hexanes). FTIR (UATR): νmax 3392, 2940, 2838,
1593, 1488, 1455, 1204, 1145, 1114 cm-1. 1H NMR (CDCl3,
300MHz): δ 3.77 (s, 3H), 3.84 (s, 2H), 3.89 (s, 6H), 6.15 (s, 2H),
6.77-6.83 (m, 2H), 7.06 (td, J = 7.5, 1.6 Hz, 1H), 7.41 (dd, J =
7.5, 1.6 Hz, 1H), 7.49 (s, 1H). 13C NMR (CDCl3, 75 MHz): δ
23.5, 55.4, 55.9 (2C), 91.1 (2C), 109.0, 116.0, 119.8, 126.5,
127.6, 131.8, 154.6, 157.8 (2C), 159.8. LRMS (EI) m/z (rel
intensity) 275 (M+H+, 4), 274 (M+, 23), 168 (100), 139 (32).
TOF-HRMS calcd for C16H19O4 (M+H+) 275.1278, found
275.1279.
2-(4-Hydroxybenzyl)-4,5-dimethoxyphenol
(13a).
Following the general procedure and purification by PTLC, the
product was obtained as a white solid (0.034 g, 0.13 mmol, 83%).
Rf 0.34 (60% EtOAc/hexanes). Mp 165.7–167.0 °C. FTIR
(UATR): νmax 3393, 1513, 1203 cm-1. 1H NMR (5:1
CDCl3:MeOH-d4, 300 MHz): δ 3.74 (s, 3H), 3.79 (s, 3H), 3.83 (s,
2H), 6.47 (s, 1H), 6.57 (s, 1H), 6.74 (d, J = 8.2 Hz, 2H), 7.05 (d,
J = 8.2 Hz, 2H). 13C NMR (5:1 CDCl3:MeOH-d4, 75 MHz): δ
34.2, 55.6, 56.4, 100.7, 114.4, 114.9 (2C), 118.9, 129.4 (2C),
132.0, 142.1, 147.6, 148.1, 154.4. LRMS (EI) m/z (rel intensity)
260 (M+, 75), 166 (100). TOF-HRMS calcd for C15H16O4 (M+)
260.1043, found 260.1039.
4-(2,4,6-Trimethoxybenzyl)phenol (11c). Following the
general procedure and purification by PTLC, the product was
obtained as a white solid (0.033 g, 0.12 mmol, 76% from 10b,
0.033 g, 0.12 mmol, 75% from 10c). Rf 0.20 (20%
EtOAc/hexanes). Mp 142.0–143.8 °C. FTIR (UATR): νmax 3415,
4-((6-Methoxybenzo[d][1,3]dioxol-5-yl)methyl)phenol
(13b). Following the general procedure and purification by
PTLC, the product was obtained as a white solid (0.036 g, 0.14
mmol, 86%). Rf 0.33 (80:18:2 CH2Cl2/hexanes/MeOH). Mp
107.8–109.2 °C. FTIR (UATR): νmax 3417, 1508, 1175, 1037 cm-
1. 1H NMR (CDCl3, 300 MHz): δ 3.77 (s, 3H), 3.81 (s, 2H), 4.60
(s, 1H), 5.86 (s, 2H), 6.38 (s, 1H), 6.57 (s, 1H), 6.82 (d, J = 8.2
Hz, 2H), 7.11 (d, J = 8.2 Hz, 2H). 13C NMR (CDCl3, 75 MHz): δ
35.3, 55.3, 98.6, 100.9, 109.9, 114.1 (2C), 119.1, 129.5 (2C),
131.8, 141.4, 146.5, 148.1, 158.2. LRMS (EI) m/z (rel intensity)
258 (M+, 24), 150 (50), 108 (100). TOF-HRMS calcd for
C15H14O4 (M+) 258.0887, found 258.0875.
2939, 2837, 1594, 1456, 1203, 1186, 1146, 1117 cm-1. H NMR
1
(CDCl3, 300MHz): δ 3.77 (s, 6H), 3.79 (s, 3H), 3.83 (s, 2H), 6.14
(s, 2H), 6.67 (d, J = 8.6 Hz, 2H), 7.07 (d, J = 8.6 Hz, 2H). 13C
NMR (CDCl3, 75 MHz): δ 27.3, 55.3, 55.7 (2C), 90.7 (2C),
110.8, 114.8 (2C), 129.4 (2C), 133.9, 153.7, 158.8 (2C), 159.5.
LRMS (EI) m/z (rel intensity) 275 (M+H+, 13), 274 (M+, 75), 181
(40), 168 (100), 137 (27), 121 (29), 107 (36). TOF-HRMS calcd
for C16H19O4 (M+H+) 275.1278, found 275.1279.
2-(4-Isopropoxybenzyl)-1,3,5-trimethoxybenzene
(11d).
4-(4-Hydroxybenzyl)naphthalen-1-ol (13c). Following the
general procedure and purification by PTLC, the product was
obtained as a pale orange solid (0.031 g, 0.12 mmol, 78%). Rf
0.54 (60% EtOAc/hexanes). Mp 182.1–184.5 °C. FTIR (UATR):
Following the general procedure and purification by PTLC, the
product was obtained as colorless oil (0.049 g, 0.15 mmol, 95%).
Rf 0.48 (10% EtOAc/hexanes, developed twice). FTIR (UATR):
νmax 2974, 2936, 1595, 1116 cm-1. 1H NMR (CDCl3, 300 MHz): δ
1.28 (d, J = 6.0 Hz, 6H), 3.77 (s, 6H), 3.79 (s, 3H), 3.85 (s, 2H),
4.44 (sep, J = 6.0 Hz, 1H), 6.14 (s, 2H), 6.73 (d, J = 8.2 Hz, 2H),
7.12 (d, J = 8.2 Hz, 2H). 13C NMR (CDCl3, 75 MHz): δ 22.1
(2C), 27.3, 55.3, 55.7 (2C), 69.7, 90.6 (2C), 110.7, 115.4 (2C),
129.2 (2C), 134.2, 155.6, 158.7 (2C), 159.5. LRMS (EI) m/z (rel
intensity) 316 (M+, 31), 274 (19), 181 (36), 168 (100), 107 (46).
ESITOF-HRMS calcd for C19H24NaO4 (M+Na+) 339.1566, found
339.1563.
1
νmax 3337, 1511, 1223 cm-1. H NMR (4:1 CDCl3:MeOH-d4, 300
MHz): δ 4.25 (s, 2H), 6.72 (d, J = 8.1 Hz, 2H), 6.89 (d, J = 7.6
Hz, 1H), 7.01 (d, J = 8.1 Hz, 2H), 7.08 (d, J = 7.6 Hz, 1H), 7.41
(dd, J = 6.1, 3.1 Hz, 2H), 7.90 (dd, J = 6.1, 3.1 Hz, 1H), 8.26 (dd,
J = 6.1, 3.1 Hz, 1H). 13C NMR (4:1 CDCl3:MeOH-d4, 75 MHz):
δ 37.3, 107.1, 114.7 (2C), 122.2, 123.8, 123.9, 125.1, 125.6,
126.9, 127.8, 129.1 (2C), 132.0, 132.7, 151.4, 154.3. LRMS (EI)
m/z (rel intensity) 250 (M+, 100), 144 (60), 107 (52). TOF-
HRMS calcd for C17H14O2 (M+) 250.0988, found 250.0992.
2-(4-Methoxybenzyl)-1,3,5-trimethoxybenzene
(11e).
1-(4-Hydroxybenzyl)naphthalen-2-ol (13d). Following the
general procedure and purification by PTLC, the product was
obtained as a pale orange solid (0.039 g, 0.15 mmol, 97%). Rf
0.51 (60% EtOAc/hexanes). Mp 203.0–205.4 °C. FTIR (UATR):
Following the general procedure and purification by PTLC, the
product was obtained as colorless oil (0.038 g, 0.13 mmol, 81%).
Rf 0.50 (10% EtOAc/hexanes, developed three times). FTIR
1
1
(UATR): νmax 2937, 2836, 1595, 1116 cm-1. H NMR (CDCl3,
νmax 3345, 1510, 1219 cm-1. H NMR (4:1 CDCl3:MeOH-d4, 300
300 MHz): δ 3.74 (s, 3H), 3.78 (s, 9H), 3.86 (s, 2H), 6.14 (s, 2H),
6.75 (d, J = 8.1 Hz, 2H), 7.15 (d, J = 8.1 Hz, 2H). 13C NMR
(CDCl3, 75 MHz): δ 27.3, 55.1, 55.3, 55.7 (2C), 90.6 (2C), 110.7,
113.3 (2C), 129.2 (2C), 134.4, 157.3, 158.7 (2C), 159.5. LRMS
(EI) m/z (rel intensity) 288 (M+, 36), 257 (15), 181 (27), 121
(100), 91 (23). ESITOF-HRMS calcd for C17H20NaO4 (M+Na+)
311.1253, found 311.1252.
MHz): δ 4.36 (s, 2H), 6.67 (d, J = 8.1 Hz, 2H), 7.06 (d, J = 8.1
Hz, 2H), 7.17 (d, J = 8.8 Hz, 1H), 7.25 (t, J = 7.8 Hz, 1H), 7.36
(t, J = 7.8 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.74 (d, J = 7.8 Hz,
1H), 7.86 (d, J = 7.8 Hz, 1H). 13C NMR (4:1 CDCl3:MeOH-d4,
75 MHz): δ 29.3, 114.7 (2C), 117.6, 118.6, 122.2, 123.2, 125.8,
127.6, 128.0, 128.7, 128.9 (2C), 132.0, 133.6, 151.9, 154.1.
LRMS (EI) m/z (rel intensity) 250 (M+, 56), 157 (100), 128 (36).
TOF-HRMS calcd for C17H14O2 (M+) 250.0988, found 250.0997.
5-Methoxy-2,4-bis(2,4,6-trimethoxybenzyl)phenol
(12).
Following the general procedure and purification by PTLC, the
product was obtained as orange solid (0.044 g, 0.09 mmol, 56%
from 10e, 0.018 g, 0.04 mmol, 23% from 10f). Rf 0.43 (80:18:2
CH2Cl2/hexanes/MeOH). Mp 184.4–186.8 °C. FTIR (UATR):
νmax 3407, 2940, 1594, 1204 cm-1. 1H NMR (CDCl3, 300 MHz): δ
3.61 (s, 2H), 3.69 (s, 6H), 3.71 (s, 6H), 3.74 (s, 3H), 3.79 (s, 5H),
3.85 (s, 3H), 6.06 (s, 2H), 6.21 (s, 2H), 6.37 (s, 1H), 6.66 (s, 1H),
4-((2-Methoxynaphthalen-1-yl)methyl)phenol
(13e).
Following the general procedure and purification by PTLC, the
product was obtained as brown oil (0.031 g, 0.12 mmol, 73%). Rf
0.63 (60% EtOAc/hexanes). FTIR (UATR): νmax 3368, 2929,
1
1509, 1249 cm-1. H NMR (CDCl3, 300 MHz): δ 3.89 (s, 3H),
4.37 (s, 2H), 5.19 (brs, 1H), 6.62 (d, J = 7.9 Hz, 2H), 7.00 (d, J =
7.9 Hz, 2H), 7.22–7.34 (m, 2H), 7.39 (t, J = 7.5 Hz, 1H), 7.76 (d,

ACCEPTED MANUSCRIPT
9
J = 8.8 Hz, 2H), 7.88 (d, J = 8.4 Hz, 1H). 13C NMR (CDCl3, 75
MHz): δ 29.6, 56.6, 133.6, 115.1 (2C), 122.0, 123.2, 123.7,
126.4, 128.2, 128.4, 129.2 (3C), 133.2, 133.3, 153.4, 154.6.
LRMS (EI) m/z (rel intensity) 264 (M+, 100), 233 (43), 158 (46).
TOF-HRMS calcd for C18H16O2 (M+) 264.1145, found 264.1152.
15. Esquivias, J.; Arrayás, R. G.; Carretero, J. C. Angew. Chem. Int.
Ed. 2006, 45, 629–633.
16. Endo, K.; Ishioka, T.; Ohkubo, T.; Shibata,T. J. Org. Chem. 2012,
77, 7223–7231.
17. Katrizky, A. R.; Lan, X.; Lam, J. N. J. Org.Chem. 1991, 56,
4397–4403.
18. Kumar, A.; Kumar, M.; Gupta, M. K. Tetrahedron Lett. 2009, 50,
7024–7027.
19. McCubbin, J. A.; Krokhin, O. V. Tetrahedron Lett. 2010, 51,
2447-2449.
20. Mendoza, O.; Rossey, G.; Ghosez, L. Tetrahedron Lett. 2011, 52,
2235-2239.
4-(Benzofuran-3-ylmethyl)phenol (13f). Following the
general procedure and purification by PTLC, the product was
obtained as yellow oil (0.028 g, 0.12 mmol, 77%). Rf 0.47 (60%
EtOAc/hexanes). FTIR (UATR): νmax 3374, 2924, 1515, 1252,
750 cm-1. 1H NMR (CDCl3, 300 MHz): δ 4.01 (s, 2H), 5.07 (brs,
1H), 6.33 (s, 1H), 6.77 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 8.0 Hz,
2H), 7.16–7.25 (m, 2H), 7.39 (d, J = 7.4 Hz, 1H), 7.45 (d, J = 7.6
Hz, 1H). 13C NMR (CDCl3, 75 MHz): δ 34.1, 103.1, 110.9, 115.4
(2C), 120.3, 122.5, 123.3, 128.8, 129.4, 130.1 (2C), 130.8, 154.3,
158.2. LRMS (EI) m/z (rel intensity) 224 (M+, 93), 223 (100),
131 (38). TOF-HRMS calcd for C15H12O2 (M+) 224.0832, found
224.0841.
21. Ploypradith, P.; Kagan, R. K.; Ruchirawat, S. J. Org. Chem. 2005,
70, 5119–5125.
22. (a) Ploypradith, P.; Cheryklin, P. Niyomtham, N.; Bertoni, D. R.;
Ruchirawat, S. Org. Lett. 2007, 9, 2637–2640. (b) Tangdenpaisal,
K.; Sualek, S.; Ruchirawat, S.; Ploypradith, P. Tetrahedron 2009,
65, 4316–4325.
23. (a) Batsomboon, P.; Phakhodee, W.; Ruchirawat, S.; Ploypradith,
P. J. Org. Chem. 2009, 74, 4009–4012. (b) Tummatorn, J.;
Ruchirawat, S.; Ploypradith, P. Chem. Eur. J. 2010, 16, 1445–
1448. (c) Radomkit, S.; Sarnpitak, P.; Tummatorn, J.;
Batsomboon, P.; Ruchirawat, S.; Ploypradith, P. Tetrahedron
2011, 67, 3904–3914.
24. It has been anticipated that generation of QM under acidic
conditions may not be compatible with electron-rich aromatic
systems and would lead to increased dimerization of QM or side
reactions between QMs and nucleophiles. While nucleophilic
addition to quinone methides has been studied before, the use of
electron-rich aromatic compounds as nucleophiles for such
reaction has been scarcely described before. For some examples,
see: (a) Lau, C. K.; Williams, H. W. R.; Tardiff, S.; Dufresne, C.;
Scheigetz, J.; Belanger, P. C. Can. J. Chem. 1989, 67, 1384–1387.
(b) Chambers, J. D.; Crawford, J.; Williams, H. W. R.; Dufresne,
C.; Scheigetz, J.; Bernstein, M. A.; Lau, C. K. Can. J. Chem.
1992, 70, 1717–1732. (c) Biljic, O.; Young, D. W. J. Chem. Soc,.
Perkin Trans. 1 1980, 1233–1239. (d) Asherson, J. L.; Bilgic, O.;
Young, D. W. J. Chem. Soc., Perkin Trans. 1 1981, 3041–3047.
25. A similar reaction using p-methoxybenzyl alcohol as a starting
material gave 11e in 86% yield but as an inseparable mixture with
a dimer, resulting from dehydration of p-methoxybenzyl alcohol
under the reaction condition. For characterization of 10f, please
see: (a) Prashad, M.; Jigajinni, V. B. Indian J. Chem. 1980, 19B,
822-823. (b) Chakraborti, A. K.; Sharma, L.; Gulhane, R.;
Shivani Tetrahedron 2003, 59, 7661-7668.
4-(2,4,6-Trimethylbenzyl)phenol (13g). Following the
general procedure and purification by PTLC, the product was
obtained as white solid (0.009 g, 0.04 mmol, 25%). Rf 0.49 (30%
EtOAc/hexanes). Mp 91.8–93.2 °C. FTIR (UATR): νmax 3337,
1
2922, 1613, 1509, 1227 cm-1. H NMR (CDCl3, 300 MHz): δ
2.20 (s, 6H), 2.28 (s, 3H), 3.92 (s, 2H), 4.71 (brs, 1H), 6.69 (d, J
= 8.0 Hz, 2H), 6.86 (d, J = 8.0 Hz, 2H), 6.88 (s, 2H). 13C NMR
(CDCl3, 75 MHz): δ 20.1 (2C), 20.9, 33.8, 115.2 (2C), 128.86
(2C), 128.89 (2C), 132.2, 134.1, 135.7, 136.9 (2C), 153.5. LRMS
(EI) m/z (rel intensity) 226 (M+, 17), 211 (48), 149 (33), 132
(100). TOF-HRMS calcd for C16H18O (M+) 226.1352, found
226.1344.
Acknowledgments
Financial support from the Thailand Research Fund (TRF;
Basic Research Grant (BRG5580010)) for P.P. is gratefully
acknowledged.
26. It appears that the [+CH2–OMe] from the cleavage of the MOM
group participated in these reactions differently. For compound
10g and 10h, [+CH2–OMe] was attacked by the resulting
monoalkylated products. Subsequently, the methoxy group was
cleaved and another molecule of 1,3,5-trimethoxybenzene was
incorporated. For compound 13b, [+CH2–OMe] served as a
methylating agent, which methylated the hydroxy group,
generating formaldehyde as a by-product.
References and notes
1. Chiellini, G.; Nguyen, N.-H.; Apriletti, J. W.; Baxter, J. D.;
Scanlan, T. S. Bioorg. Med. Chem. 2002, 10, 333–346.
2. Chiellini, G.; Nguyen, N.-H.; Yoshihara, H. A. I.; Scanlan, T. S.
Bioorg. Med. Chem. Lett. 2000, 10, 26-7–2611.
3. Trivella, D. B. B.; Sairre, M. I.; Foguel, D.; Lima, L. M. T. R.;
Polikarpov, I. J. Struct. Biol. 2011, 173, 323–332.
4. Jullian, V.; Shepherd, E.; Gelbrich, T.; Hursthouse, M. B.;
Kilburn, J. D. Tetrahedron Lett. 2000, 41, 3963–3966.
5. Pernia, G. J.; Kilburn, J. D.; Essex, J. W.; Mortishire-Smith, R. J.;
Rowley, M. J. Am. Chem. Soc. 1996, 118, 10220–10227.
6. Srivastava, N.; Sangita; Ray, S; Singh, M. M.; Dwivedi, A.;
Kumar, A. Bioorg. Med. Chem.. 2004, 12, 1011–1021.
7. Baxter, A. D..; Bhogal, R.; Bird, J.; Keily, J. F.; Manallack, D. T.;
Montana, J. G.; Owen, D. A.; Pitt, W. R.; Watson, R. J.; Wills, R.
E. Bioorg. Med. Chem. Lett. 2001, 11, 1465–1468.
Supplementary Material
Supplementary data related to this article can be found online.
These data include MOL files and InChiKeys of the most
important compounds described in this article.
8. O’Shea, P. D.; Chen, C.-Y.; Chen, W.; Dagneau, P.; Frey, L. F.;
Grabowski, E. J. J.; Marcantonio, K. M.; Reamer, R. A.; Tan, L.;
Tillyer, R. D.; Roy, A.; Wang, X.; Zhao, D. J. Org. Chem. 2005,
70, 3021–3030.
9. Tagat, J. R.; McCombie, S. W.; Steensma, R. W.; Lin, S.-I.;
Nazareno, D. V.; Baroudy, B.; Vantuno, N.; Xu, S.; Liu, J. Bioorg.
Med. Chem. Lett. 2001, 11, 2143–2146.
10. Yadav, J. S.; Bhunia, D. C.; Krishna, K. V.; Srihari, P.
Tetrahedron Lett. 2007, 48, 8306-8310.
11. Stoner, E. J.; Cothron, D. A.; Balmer, M. K.; Roden, B. A.
Tetrahedron 1995, 51, 11043–11062.
12. Waymark, C. P.; Kilburn, J. D.; Gillies, I. Tetrahedron Lett. 1995,
36, 3051–3054.
13. Rong, Y.; Li, R.; Lu, W. Organometallics 2007, 26, 4376–4378.
14. Dohle, W.; Lindsay, D. M.; Knochel, P. Org. Lett. 2001, 3, 2871–
2873.