Chemoselective reduction of quinols as an alternative to Sonogashira coupling: Synthesis of polysubstituted benzofurans

Article abstract of DOI:10.1039/c6ob01941b

An efficient synthetic approach to polysubstituted benzofurans is described, using 2-methoxyquinone as a benzofuran backbone. Nucleophilic addition of terminal alkynes to 2-methoxy-1,4-benzoquinone afforded the corresponding quinols containing an alkyne unit, which were converted to phenols via mild Zn-mediated reduction. After proper protection of the free phenolic OH, 5-endo-dig iodocyclization allowed facile access to a number of 3-iodobenzofurans. In addition, it was demonstrated for the first time that o-methoxyarylalkynes underwent intramolecular hydroalkoxylation under the influence of AgOTf furnishing the corresponding benzofurans.

Full text of DOI:10.1039/c6ob01941b

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Page 1 of 44
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Chemoselective Reduction of Quinols As an Alternative to Sonogashira
Coupling: Synthesis of Polysubstituted Benzofurans
Youngeun Jung and Ikyon Kim*
College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University
85 Songdogwahakꢀro, Yeonsuꢀgu, Incheon, 21983, Republic of Korea
* Corresponding author. Tel.: +82 32 749 4515; fax: +82 32 749 4105; eꢀmail:
ikyonkim@yonsei.ac.kr
Table of Contents
Abstract: An efficient synthetic approach to polysubstituted benzofurans is described by
using 2ꢀmethoxyquinone as a benzofuran backbone. Nucleophilic addition of terminal
alkynes to 2ꢀmethoxyꢀ1,4ꢀbenzoquinone afforded the corresponding quinols containing an
alkyne unit, which were converted to phenols via mild Znꢀmediated reduction. After proper
protection of the free phenolic OH, 5ꢀendoꢀdig iodocyclization allowed facile access to a
number of 3ꢀiodobenzofurans. In addition, it was demonstrated for the first time that oꢀ
methoxyarylalkynes underwent intramolecular hydroalkoxylation under the influence of

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AgOTf furnishing the corresponding benzofurans.
Keywords: Benzofuran; Quinol; Reduction; Cyclization; Iodine; Silver Triflate; Natural
Product Synthesis.
Introduction
Many naturally occurring or synthetic benzofurans with important biological activities have
hydroxyl group(s) at 5 and/or 6 positions (Figure 1).1 Previously, we have reported the
synthesis of 5ꢀhydroxybenzofuran 3 from quinol 1 bearing an alkyne via 2 through a domino
cyclohexadienoneꢀphenol rearrangement/intramolecular 5ꢀendoꢀdig cyclization sequence
(Scheme 1a).2 As an extension of our continued study on benzofurans,3 we envisioned that
quinol having a methoxy group (highlighted in blue) 4 might be used for the synthesis of 6ꢀ
hydroxybenzofuran 6 (Scheme 1b). We expected that if chemoselective reduction of quinol 4
to phenol 5 would be viable, subsequent electrophilic cyclization would lead to 6ꢀ
hydroxybenzofuran. Typically, arylalkyne 4 could be accessed by Sonogashira crossꢀcoupling
of aryl halide and terminal alkyne.4 Despite tremendous advances in these metalꢀcatalyzed
coupling reactions, however, electronꢀrich aryl halides tend to give a relatively low yield of
the desired crossꢀcoupling product. In some cases, alkyne homodimer is often produced as a
major product as a result of competitive GlaserꢀEglingtonꢀHay type reaction. As an
alternative to Sonogashira coupling, we decided to evaluate a reaction sequence consisting of
nucleophilic addition of terminal alkyne to quinone and chemoselective quinol reduction in
the course of our approach to 6ꢀhydroxybenzofuran, which is a topic of this paper.
Figure 1. Some Benzofuran Natural Products

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Scheme 1. Synthetic Plans
Results and discussion
To test the feasibility of our idea, we first prepared quinol 4a by nucleophilic addition of
phenylacetylide to 2ꢀmethoxyꢀ1,4ꢀbenzoquinone (Scheme 2). Several examples of quinol
reduction appeared in the literature.5 To the best of our knowledge, however, chemoselective

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reduction of quinol possessing an alkyne to the corresponding phenol has not been disclosed
yet. After screening several reductants, we were pleased to find that Znꢀmediated reduction of
4a in AcOH/H2O at room temperature provided the desired phenol 5a in 99% yield.
Scheme 2. Synthesis of 5a
Ph
Ph
O
OH
Zn
Li
Ph
- 78 °C
90%
AcOH/H2O
99%
O
OMe
HO
OMe
O
OMe
4a
5a
At this point, we initially examined the direct cyclization of 5a to 7. Reactions under several
acid catalysts (PTSA, Cu(OTf)2, AgOTf, InCl3, FeCl3, or AuCl3) at elevated temperature gave
a complex mixture, which might result from the unprotected phenolic OH group (Scheme 3).
Thus, we decided to protect the hydroxyl in 5a with several protecting groups. For this
purpose, 5a was converted to the methyl ether 8, acetate 9, and sulfonate 10a, respectively.6
Scheme 3. Direct Cyclization Attempts and Protection

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Since 2ꢀalkoxyarylalkynes are good substrates for iodocyclization,7,8 8, 9, and 10a were
treated under several different iodocyclization conditions (Table 1). While 8 was reacted with
I2 and NaHCO3 to afford the corresponding 3ꢀiodobenzofuran 11 in 49% yield, use of ICl
provided the impure mixture of products (entries 1 and 2). Exposure of 9 to either I2/NaHCO3
or ICl led to the desired product 12 in similar yields (entries 3 and 4). When 10a was used as
a cyclization substrate, 87% of the cyclized product 13a was obtained by treatment with I2
and NaHCO3 (entry 5). Again, IClꢀmediated cyclization of 10a at ꢀ20 °C resulted in the
desired product contaminated with unidentified inseparable compound (entry 6). Subjection
of 10a to I2 (3 equiv) delivered 13a in 79% yield (entry 7). These data clearly revealed that
the protecting group of the phenolic OH in 5a plays a crucial role in iodineꢀmediated
cyclization reactions.
Table 1. Iodocyclizationa
starting
material
entry
reagents
temperature (°C)
yield (%)b
1
2
3
4
5
6
I2 (5 equiv), NaHCO3 (5 equiv)
ICl (1.5 quiv)
0 to rt
ꢀ20
49
8
8
11
c
c
I2 (5 equiv), NaHCO3 (5 equiv)
ICl (1.5 equiv)
0
55
52
87
9
12
12
ꢀ20
9
I2 (5 equiv), NaHCO3 (5 equiv)
ICl (1.5 equiv)
0 to rt
ꢀ20
10a
10a
10a
13a
7
I2 (3 equiv)
0 to rt
79
13a
a
A solution of starting material (0.1 mmol) in CH2Cl2 (2 mL) was treated with reagents as
b
c
noted above at the indicated temperature. Isolated yield (%). The desired product was
contaminated with unidentified inseparable impurity.

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With these optimized conditions in hand, generality of this sequence was investigated (Table
2). The required quinols 4b-4j were readily accessed by nucleophilic addition reactions of
various terminal alkynes to 2ꢀmethoxyꢀ1,4ꢀbenzoquinone at ꢀ78 °C.9 The corresponding
phenols 5b-5j were obtained in good to excellent yields upon reduction of 4 with Zn in
AcOH/H2O. With respect to R moiety, alkyl as well as (hetero)aryl groups in 4 seemed to
exhibit good tolerance under these conditions. Tosylation followed by iodineꢀmediated
cyclization led to various 3ꢀiodobenzofurans in good overall yields.
Table 2. Synthesis of 13a
entry
1
R
4b
5b
10b
13b
4b (87)
5b (85)
10b (100)
13b (100)
2
3
4c (96)
4d (84)
5c (72)
5d (83)
10c (91)
10d (97)
13c (94)
13d (93)
4
5
4e (94)
4f (93)
5e (86)
10e (98)
10f (83)
13e (92)
13f (91)
5f (100)
6
7
8
4g (93)
4h (73)
4i (65)
5g (64)
5h (89)
5i (73)
10g (86)
10h (83)
10i (58)
13g (95)
13h (87)
13i (56)

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9
4j (80)
5j (62)
10j (99)
13j (89)
a
A solution of 4 (1.18 mmol) and Zn (2.0 equiv) in AcOH/EtOH/H2O (4:1:1, 3 mL) was
stirred at 0 °C for 18 h. A mixture of 5 (0.22 mmol), TsCl (1.2 equiv), and Et3N (2.0 equiv) in
CH2Cl2 (5 mL) was stirred at 0 °C to rt for 1 h. A mixture of 10 (0.1 mmol), I2 (5.0 equiv),
b
and NaHCO3 (5.0 equiv) in CH2Cl2 (2 mL) was stirred at 0 °C to rt for 3 h. Isolated yield
(%).
Not only pꢀtoluenesulfonyl group but also benzylsulfonyl or trifluoromethanesulfonyl groups
were used to protect the free hydroxyl in 5 (Scheme 4). The resulting sulfonates, 14 and 16,
were also successfully converted to the corresponding 3ꢀiodobenzofurans, 15 and 17, under
similar conditions.
Scheme 4.
Further functionalization of the resulting product 17 was examined (Scheme 5). Due to the
different reactivity of the two sites (I and TfO) in 17 toward Pdꢀcatalyzed crossꢀcoupling
reactions, selective installation of different groups was realized to deliver 2,3,6ꢀtrisubstituted
benzofuran 20.
Scheme 5. Further Elaborations

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Pd(PPh3)4
ArB(OH)2
Ar
Pd(OAc)2
MeO
17
OMe
SPhos
C6H5B(OH)2
K2CO3
K2CO3
OMe
O
TfO
18 (Ar = Ph): 78%
19 (Ar = 3,5-(MeO)2C6H3): 82%
52%
OMe
O
(83% BORSM)
20
In the meantime, we decided to test the viability of assembling benzofurans by switching the
roles of alkyne and quinone of the approach mentioned above (Scheme 6). Thus, nucleophilic
addition of lithium acetylide derived from 2110 to benzoquinone resulted in quinol 22, which
was subjected to Zn in AcOH to furnish 23 in excellent yield. Methylation and subsequent
iodocyclization cleanly afforded the desired 3ꢀiodobenzofuran 25, demonstrating that 1,4ꢀ
benzoquinone could be used as a 4ꢀalkoxyphenyl surrogate.
Scheme 6. Synthesis of 25
OR
O
Zn
AcOH
LHMDS, THF
OH
O
OMe
98%
O
O
O
OMe
O
OMe
21
90%
22
23 (R = H)
Cs2CO3
MeI
99%
I
I2
NaHCO3
OMe
24 (R = Me)
O
O
100%
25
Finally, we also investigated the intramolecular 5ꢀendoꢀdig hydroalkoxylation of 10 (Table 3).
Among the catalysts screened, we were pleased to find that treatment of 10b with silver
triflate11 afforded the cyclized product 26a in 83% yield. Examples on the hydroalkoxylation
of oꢀalkoxyarylalkynes leading to the formation of benzofurans have been disclosed in the
literature.12 However, use of silver salts as catalysts for the synthesis of benzofuran via

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intramolecular hydroalkoxylation have not been reported. Triflic acid did not give rise to the
desired product. Other silver salts such as AgSbF6 were not effective in this transformation,
either. Worthy of note is that the amount of silver triflate is highly dependent on the substrates;
some needed a catalytic amount of AgOTf whereas others required stoichiometric amount of
catalyst. Exposure of 10j to AgOTf (2 equiv) at 100 °C resulted in a complex mixture
although the reason is unclear at this point (entry 6).
Table 3. Intramolecular Hydroalkoxylation of 10a
AgOTf
(equiv)
yield
(%)b
entry
1
time (hr)
72
10
26
1
83
10b
26a
26b
2
0.2
10
69
10c
3
4
0.6
1.2
48
48
74
10d
10e
26c
Me
99
86
26d
26e
O
TsO
5
6
2
2
72
72
10h
10j
c
a
b
A solution of 10 (0.08 mmol) and AgOTf in DCE (1 mL) was stirred at 100 °C. Isolated
yield (%). c The starting material was decomposed.
For the synthesis of 6ꢀhydroxybenzofurans from 13 and 26, deprotection of the Ts group in
13 and 26 was required. The tosyl group in 26b was easily removed by TBAF treatment to
give a dimethylether analogue 27 of moracin M, a basic skeleton of many moracin family

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natural products (Scheme 7).13
Scheme 7. Synthesis of Dimethylether 27 of Moracin M
In summary, we have developed a highly efficient strategy for the synthesis of
polysusbstituted benzofurans by utilizing 2ꢀmethoxyꢀ1,4ꢀbenzoquinone as a benzofuran core.
Quinols containing an alkyne easily prepared by nucleophilic addition of terminal alkynes to
2ꢀmethoxyꢀ1,4ꢀbenzoquinone were chemoselectively reduced to the corresponding phenols
under the influence of Zn in AcOH/H2O. We are confident that this nucleophilic additionꢀ
quinol reduction sequence could be a good alternative to Sonogashira coupling reactions in
some difficult situations. After protection of the free hydroxyls with sulfonyl groups, 5ꢀendoꢀ
dig iodocyclization provided 3ꢀiodobenzofurans in good to excellent yields. Further
diversification via introduction of different functional moieties onto this skeleton was
conducted by Pdꢀcatalyzed crossꢀcoupling reactions. Intramolecular hydroalkoxylation of 2ꢀ
methoxyarylalkynes facilitated by AgOTf was also demonstrated for the first time. Currently
underway in our laboratory is the application of this route to the natural product synthesis.
Experimental Section
General Methods
Unless specified, all reagents and starting materials were purchased from commercial sources
and used as received without purification. “Concentrated” refers to the removal of volatile
solvents via distillation using a rotary evaporator. “Dried” refers to pouring onto, or passing
through, anhydrous magnesium sulfate followed by filtration. Flash chromatography was
performed using silica gel (230−400 mesh) with hexanes, ethyl acetate, and dichloromethane

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as eluent. All reactions were monitored by thinꢀlayer chromatography on 0.25 mm silica
plates (Fꢀ254) visualizing with UV light. Melting points were measured using a capillary
1
melting point apparatus. H and 13C NMR spectra were recorded on 400 MHz NMR
spectrometer and were described as chemical shifts, multiplicity (s, singlet; d, doublet; t,
triplet; q, quartet; m, multiplet), coupling constant in hertz (Hz), and number of protons.
HRMS were measured with electrospray ionization (ESI) and QꢀTOF mass analyzer.
General Procedure for the Synthesis of 4
To a stirred solution of alkyne (3.76 mmol, 1.3 equiv) in anhydrous THF (10 mL) at ꢀ78 °C
was added 2.5 M nꢀBuLi (1.39 mL, 1.2 equiv). After the mixture was stirred for 5 min under
nitrogen atmosphere, a solution of 2ꢀmethoxyꢀ1,4ꢀbenzoquinone (400 mg, 2.89 mmol) in
anhydrous THF (15 mL) was added at ꢀ78 °C. After 15 min, the reaction mixture was
quenched with saturated aq. NH4Cl, warmed to rt, and concentrated under reduced pressure to
give the crude residue, which was extracted with CH2Cl2 (2 x 20 mL). The combined organic
layers were dried over MgSO4 and concentrated in vacuo. The residue was purified by silica
gel column chromatography (hexanes/ethyl acetate/dichloromethane = 3:1:2) to give 4.
4-Hydroxy-3-methoxy-4-(phenylethynyl)cyclohexa-
2,5-dien-1-one (4a). Pale brown solid, mp: 144.0ꢀ
OH
145.2 °C (624.9 mg, 90%); 1H NMR (400 MHz, CDCl3)
O
OMe
4a
δ 7.44 (d, J = 6.8 Hz, 2H), 7.41ꢀ7.28 (m, 3H), 6.80 (d, J
= 9.6 Hz, 1H), 6.19 (d, J = 9.6 Hz, 1H), 5.55 (s, 1H),
3.87 (s, 3H), 3.52 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 186.9, 171.4, 142.2, 132.1, 129.4,
128.5, 126.9, 121.4, 100.5, 85.6, 85.5, 64.3, 56.6; HRMS (ESIꢀQTOF) m/z [M+H]+ calcd for
C15H13O3 241.0859 found 241.0858.

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4-Hydroxy-3-methoxy-4-((4-
OMe
methoxyphenyl)ethynyl)cyclohexa-2,5-dien-1-one
OH
(4b). Pale brown solid, mp: 152.6ꢀ153.4 °C (679.6 mg,
1
87%); H NMR (400 MHz, CDCl3) δ 7.38 (d, J = 8.4
O
OMe
4b
Hz, 2H), 6.84 (d, J = 8.4 Hz, 2H), 6.79 (d, J = 9.6 Hz,
1H), 6.18 (d, J = 9.6 Hz, 1H), 5.54 (s, 1H), 3.88 (s, 3H), 3.81 (s, 3H), 3.28 (s, 1H); 13C NMR
(100 MHz, CDCl3) δ 186.8, 171.4, 160.4, 142.3, 133.7, 126.8, 114.1, 113.4, 100.5, 85.7, 84.3,
64.4, 56.6, 55.5; HRMS (ESIꢀQTOF) m/z [M+H]+ calcd for C16H15O4 271.0965 found
271.0968.
4-((3,5-Dimethoxyphenyl)ethynyl)-4-hydroxy-3-
OMe
methoxycyclohexa-2,5-dien-1-one (4c). Pale brown
1
OH
OMe
solid, mp: 190.0ꢀ190.6 °C (833 mg, 96%); H NMR
(400 MHz, CDCl3) δ 6.79 (d, J = 10.0 Hz, 1H), 6.59 (s,
1H), 6.58 (s, 1H), 6.47 (s, 1H), 6.19 (d, J = 10.0 Hz,
O
OMe
4c
1H), 5.55 (s, 1H), 3.88 (s, 3H), 3.78 (s, 6H), 3.30 (s, 1H); 13C NMR (100 MHz, CDCl3) δ
186.7, 171.2, 160.7, 142.0, 127.1, 122.6, 109.9, 102.8, 100.6, 85.5, 85.1, 64.3, 56.6, 55.6;
HRMS (ESIꢀQTOF) m/z [M+H]+ calcd for C17H17O5 301.1071 found 301.1072.
4-Hydroxy-3-methoxy-4-((4-methoxy-2-
OMe
methylphenyl)ethynyl)cyclohexa-2,5-dien-1-one (4d).
OH
Brown solid, mp: 120.7ꢀ121.8 °C ( 690.2 mg, 84%); 1H
Me
O
OMe
4d

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NMR (400 MHz, CDCl3) δ 7.32 (d, J = 8.4 Hz, 1H), 6.81 (d, J = 9.6 Hz, 1H), 6.72 (s, 1H),
6.67 (d, J = 8.4 Hz, 1H), 6.17 (d, J = 10.0 Hz, 1H), 5.54 (s, 1H), 3.86 (s, 3H), 3.79 (s, 3H),
2.35 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 187.0, 171.8, 160.3, 142.9, 142.6, 133.8, 126.6,
115.3, 113.3, 111.4, 100.3, 88.2, 84.7, 64.4, 56.5, 55.4, 20.8; HRMS (ESIꢀQTOF) m/z
[M+H]+ calcd for C17H17O4 285.1121 found 285.1120.
4-Hydroxy-3-methoxy-4-(p-tolylethynyl)cyclohexa-
2,5-dien-1-one (4e). Brown solid, mp: 125.2ꢀ126.8 °C
1
(690.8 mg, 94%); H NMR (400 MHz, CDCl3) δ 7.33
(d, J = 6.8 Hz, 2H), 7.12 (d, J = 7.2 Hz, 2H), 6.79 (d, J
= 9.6 Hz, 1H), 6.18 (d, J = 9.6 Hz, 1H), 5.54 (s, 1H),
3.86 (s, 3H), 3.56 (s, 1H), 2.34 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 186.9, 171.6, 142.4,
139.7, 132.0, 129.2, 126.7, 118.3, 100.4, 85.7, 84.9, 64.3, 56.6, 21.7; HRMS (ESIꢀQTOF)
m/z [M+H]+ calcd for C16H15O3 255.1016 found 255.1017.
4-Hydroxy-3-methoxy-4-((6-methoxynaphthalen-2-
OMe
yl)ethynyl)cyclohexa-2,5-dien-1-one (4f). Pale brown
OH
solid, mp: 189.4.6ꢀ190.2 °C (861.0 mg, 93%); 1H NMR
(400 MHz, CDCl3) δ 7.91 (s, 1H), 7.72ꢀ7.63 (m, 2H),
O
OMe
7.43 (d, J = 8.4 Hz, 1H), 7.16 (d, J = 8.8 Hz, 1H ), 7.10
4f
(s, 1H), 6.83 (d, J = 10.0 Hz, 1H), 6.21 (d, J = 9.6 Hz, 1H), 5.57 (s, 1H), 3.92 (s, 3H), 3.90 (s,
3H), 3.37 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 186.8, 171.4, 158.8, 142.2, 134.7, 132.3,
129.5, 128.9, 128.3, 127.0, 126.9, 119.8, 116.2, 105.9, 100.5, 86.2, 85.2, 64.4, 56.6, 55.5;

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HRMS (ESIꢀQTOF) m/z [M+H]+ calcd for C20H17O4 321.1121 found 321.1120.
4-([1,1'-Biphenyl]-4-ylethynyl)-4-hydroxy-3-
methoxycyclohexa-2,5-dien-1-one (4g). Pale brown
Ph
OH
1
solid, mp: 152.4ꢀ154.0 °C (850.3 mg, 93%); H NMR
(400 MHz, CDCl3) δ 7.65ꢀ7.48 (m, 6H), 7.44 (t, J = 7.6
Hz, 2H), 7.36 (t, J = 7.2 Hz, 1H), 6.82 (d, J = 10.0 Hz,
O
OMe
4g
1H), 6.20 (t, J = 10.0 Hz, 1H), 5.56 (s, 1H), 3.99 (s, 1H), 3.88 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 186.9, 171.6, 142.5, 142.0, 140.1, 132.5, 129.0, 128.0, 127.1, 127.1, 126.7, 120.3,
100.5, 86.3, 85.3, 64.3, 56.6; HRMS (ESIꢀQTOF) m/z [M+H]+ calcd for C21H17O3 317.1172
found 317.1170.
4-Hydroxy-3-methoxy-4-(thiophen-3-
S
ylethynyl)cyclohexa-2,5-dien-1-one (4h). Pale yellow
OH
1
solid, mp: 123.5ꢀ124.1 °C (519.6 mg, 73%); H NMR
O
OMe
4h
(400 MHz, CDCl3) δ 7.52 (s, 1H), 7.27 (s, 1H), 7.11 (d,
J = 4.8 Hz, 1H), 6.78 (d, J = 9.6 Hz, 1H), 6.18 (d, J =
10.0 Hz, 1H), 5.54 (s, 1H), 3.87 (s, 3H), 3.45 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 186.8,
171.3, 142.2, 130.6, 130.0, 126.9, 125.8, 120.5, 100.5, 85.3, 80.8, 64.3, 56.6; HRMS (ESIꢀ
QTOF) m/z [M+H]+ calcd for C13H11O3S 247.0423 found 247.0425.
4-(Cyclohex-1-en-1-ylethynyl)-4-hydroxy-3-
OH
O
OMe
4i

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methoxycyclohexa-2,5-dien-1-one (4i). Yellow gum, (458.9 mg, 65%); 1H NMR (400 MHz,
CDCl3) δ 6.71 (d, J = 10.0 Hz, 1H), 6.19 (s, 1H), 6.13 (d, J = 9.6 Hz, 1H), 5.49 (s, 1H), 3.84
(s, 3H), 3.39 (s, 1H), 2.17ꢀ2.02 (m, 4H), 1.69ꢀ1.48 (m, 4H); 13C NMR (100 MHz, CDCl3) δ
187.0, 171.7, 142.7, 137.8, 126.5, 119.4, 100.3, 87.4, 82.9, 64.2, 56.5, 28.8, 25.8, 22.2, 21.4;
HRMS (ESIꢀQTOF) m/z [M+H]+ calcd for C15H17O3 245.1172 found 245.1171.
4-(Hex-1-yn-1-yl)-4-hydroxy-3-methoxycyclohexa-
2,5-dien-1-one (4j). Yellow solid, mp: 77.5ꢀ78.2 °C
OH
1
(509.3 mg, 80%); H NMR (400 MHz, CDCl3) δ 6.68
O
OMe
(d, J = 10.0 Hz, 1H), 6.11 (dd, J = 1.2, 10.0 Hz, 1H),
5.48 (d, J = 1.2 Hz, 1H), 3.84 (s, 3H), 3.12 (s, 1H), 2.22
4j
(t, J = 7.2 Hz, 2H), 1.55ꢀ1.44 (m, 2H), 1.44ꢀ1.31 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 187.0, 171.7, 142.8, 126.4, 100.2, 87.3, 63.9, 56.5, 30.3, 22.0, 18.6,
13.7; HRMS (ESIꢀQTOF) m/z [M+H]+ calcd for C13H17O3 221.1172 found 221.1173.
General Procedure for the Synthesis of 5
To a stirred solution of 4 (1.18 mmol) in AcOH/EtOH/H2O (4:1:1, 3 mL) was added Zn
powder (154.2 mg, 2.0 equiv) at 0 °C. After being stirred at rt for 18 h, the reaction mixture
was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure
to afford the crude residue. Purification by silica gel column chromatography (hexanes/ethyl
acetate/dichloromethane = 20:1:2) furnished compound 5.

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3-Methoxy-4-(phenylethynyl)phenol (5a). Red gum,
1
(262.0 mg, 99%); H NMR (400 MHz, CDCl3) δ 7.53
(dd, J = 1.6, 8.0 Hz, 2H), 7.37ꢀ7.27 (m, 4H), 6.45ꢀ6.36
(m, 2H), 3.86 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
161.5, 157.4, 134.6, 131.6, 128.3, 128.0, 123.9, 107.6,
HO
OMe
5a
105.0, 99.2, 92.3, 85.8, 56.0; HRMS (ESIꢀQTOF) m/z [M+H]+ calcd for C15H13O2 225.0910
found 225.0911.
3-Methoxy-4-((4-methoxyphenyl)ethynyl)phenol (5b).
OMe
1
Brown gum, (255.1 mg, 85%); H NMR (400 MHz,
CDCl3) δ 7.47 (d, J = 8.8 Hz, 2H), 7.34 (d, J = 8.0 Hz,
1H), 6.86 (d, J = 8.8 Hz, 2H), 6.42 (d, J = 2.0 Hz, 1H),
6.39 (dd, J = 2.0, 8.0 Hz, 1H), 5.05 (s, 1H), 3.87 (s, 3H),
HO
OMe
5b
3.82 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.4, 157.1, 134.4, 133.1, 116.1, 114.0, 108.1,
107.5, 105.4, 99.1, 92.1, 84.2, 56.0, 55.4; HRMS (ESIꢀQTOF) m/z [M+H]+ calcd for
C16H15O3 255.1016 found 255.1017.
4-((3,5-Dimethoxyphenyl)ethynyl)-3-methoxyphenol
OMe
1
(5c). Yellow gum, (241.5 mg, 72%); H NMR (400
OMe
MHz, CDCl3) δ 7.35 (d, J = 8.0 Hz, 1H), 6.69 (s, 2H),
6.45ꢀ6.36 (m, 3H), 5.42 (s, 1H), 3.86 (s, 3H), 3.76 (s,
HO
OMe
6H); 13C NMR (100 MHz, CDCl3) δ 161.5, 160.5,
5c
157.6, 134.7, 125.2, 109.4, 107.7, 104.7, 101.7, 99.2, 92.2, 85.5, 56.0, 55.6; HRMS (ESIꢀ

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QTOF) m/z [M+H]+ calcd for C17H17O4 285.1121 found 285.1120.
3-Methoxy-4-((4-methoxy-2-
methylphenyl)ethynyl)phenol (5d). White solid, mp:
OMe
1
100.9ꢀ102.7 °C (262.8 mg, 83%); H NMR (400 MHz,
Me
CDCl3) δ 7.41 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 8.4 Hz,
1H), 6.76 (d, J = 2.4 Hz, 1H), 6.69 (dd, J = 2.4, 8.4 Hz,
HO
OMe
5d
1H), 6.41 (d, J = 10.0 Hz, 1H), 6.38 (dd, J = 2.4, 8.4 Hz, 1H), 5.15 (s, 1H), 3.85 (s, 3H), 3.80
(s, 3H), 2.49 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.3, 159.3, 157.0, 142.0, 134.1, 133.0,
116.1, 115.2, 111.2, 107.5, 105.7, 99.2, 91.3, 88.2, 56.0, 55.4, 21.1; HRMS (ESIꢀQTOF) m/z
[M+H]+ calcd for C17H17O3 269.1172 found 269.1171.
3-Methoxy-4-(p-tolylethynyl)phenol (5e). Pale brown
Me
1
solid, mp: 115.8ꢀ118.0 °C (241.8 mg, 86%); H NMR
(400 MHz, CDCl3) δ 7.42 (d, J = 7.6 Hz, 2H), 7.34 (d, J
= 8.0 Hz, 1H), 7.13 (d, J = 7.2 Hz, 2H), 6.48ꢀ6.34 (m,
2H), 5.23 (s, 1H), 3.86 (s, 3H), 2.35 (s, 3H); 13C NMR
HO
OMe
5e
(100 MHz, CDCl3) δ 161.4, 157.2, 138.0, 134.5, 131.5, 129.1, 120.8, 107.6, 105.2, 99.2, 92.4,
85.0, 56.0, 21.6; HRMS (ESIꢀQTOF) m/z [M+H]+ calcd for C16H15O2 239.1067 found
239.1068.
3-Methoxy-4-((6-methoxynaphthalen-2-
OMe
HO
OMe
5f

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1
yl)ethynyl)phenol (5f). Brown solid, mp: 150.9ꢀ152.1 °C (359.0 mg, 100%); H NMR (400
MHz, CDCl3) δ 7.97(s, 1H), 7.69 (t, J = 8.4 Hz, 2H), 7.55 (d, J = 8.4 Hz, 1H), 7.39 (d, J = 8.0
Hz, 1H), 7.15 (dd, J = 2.0, 9.2 Hz, 1H), 7.11 (d, J = 1.6 Hz, 1H), 6.44 (s, 1H), 6.41 (dd, J =
1.2, 8.4 Hz, 1H), 3.92 (s, 3H), 3.90 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.5, 158.3,
157.2, 134.6, 134.0, 131.1, 129.5, 129.3, 128.7, 126.8, 119.4, 118.9, 107.6, 106.0, 105.3, 99.2,
92.8, 85.4, 56.1, 55.5; HRMS (ESIꢀQTOF) m/z [M+H]+ calcd for C20H17O3 305.1172 found
305.1170.
4-([1,1'-Biphenyl]-4-ylethynyl)-3-methoxyphenol
Ph
(5g). White solid, mp: 178.6ꢀ188.9 °C (226.8 mg, 64%);
1H NMR (400 MHz, CDCl3) δ 7.68ꢀ7.54 (m, 6H), 7.44
(t, J = 7.2 Hz, 2H), 7.40ꢀ7.31 (m, 2H), 6.43 (s, 1H),
HO
OMe
13
6.41 (d, J = 8.4 Hz, 1H), 5.17 (s, 1H), 3.89 (s, 3H); C
5g
NMR (100 MHz, CDCl3) δ 161.6, 157.4, 140.6, 134.6, 132.1, 129.0, 127.7, 127.1, 127.0,
122.9, 107.6, 105.1, 99.2, 92.1, 86.5, 56.1; HRMS (ESIꢀQTOF) m/z [M+H]+ calcd for
C21H17O2 301.1223 found 301.1222.
3-Methoxy-4-(thiophen-3-ylethynyl)phenol
(5h).
1
S
Yellow gum, (241.8 mg, 89%); H NMR (400 MHz,
CDCl3) δ 7.48 (dd, J = 1.2, 3.2 Hz, 1H), 7.33 (d, J = 8.0
Hz, 1H), 7.28ꢀ7.24 (m, 1H), 7.18 (dd, J = 1.2, 4.8 Hz,
1H), 6.44ꢀ6.37 (m, 2H), 5.54 (s, 1H), 3.83 (s, 3H); 13C
HO
OMe
5h
NMR (100 MHz, CDCl3) δ 161.4, 157.4, 134.5, 130.1, 128.3, 125.2, 122.7, 107.7, 104.8,

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99.2, 87.3, 85.1, 56.0; HRMS (ESIꢀQTOF) m/z [M+H]+ calcd for C13H11O2S 231.0474 found
231.0475.
4-(Cyclohex-1-en-1-ylethynyl)-3-methoxyphenol (5i).
1
Red gum, (196.6 mg, 73%); H NMR (400 MHz,
CDCl3) δ 7.24 (d, J = 8.0 Hz, 1H), 6.42ꢀ6.31 (m, 2H),
HO
OMe
6.22ꢀ6.13 (m, 1H), 5.34 (s, 1H), 3.80 (s, 3H), 2.26ꢀ2.18
(m, 2H), 2.16ꢀ2.07 (m, 2H), 1.70ꢀ1.54 (m, 4H); 13C
5i
NMR (100 MHz, CDCl3) δ 161.1, 157.0, 134.7, 134.3, 121.0, 107.5, 105.4, 99.1, 94.2, 82.8,
55.9, 29.5, 25.9, 22.5, 21.7; HRMS (ESIꢀQTOF) m/z [M+H]+ calcd for C15H17O2 229.1223
found 229.1222.
4-(Hex-1-yn-1-yl)-3-methoxyphenol (5j). Red gum,
1
(149.4 mg, 62%); H NMR (400 MHz, CDCl3) δ 7.22
(d, J = 8.4 Hz, 1H), 6.38 (d, J = 2.0 Hz, 1H), 6.35 (dd, J
HO
OMe
= 2.0, 8.4 Hz, 1H), 3.81 (s, 3H), 2.43 (t, J = 7.2 Hz, 2H),
1.65ꢀ1.53 (m, 2H), 1.53ꢀ1.41 (m, 2H), 0.93 (t, J = 7.2
5j
13
Hz, 3H); C NMR (100 MHz, CDCl3) δ 161.2, 156.6, 134.5, 107.4, 105.6, 99.1, 93.3, 76.4,
55.9, 31.1, 22.2, 19.6, 13.8; HRMS (ESIꢀQTOF) m/z [M+H]+ calcd for C13H17O2 205.1223
found 205.1223.
Synthesis of 8

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To a solution of 5a (50 mg, 0.22 mmol) in CH3CN (3 mL) were added Cs2CO3 (145 mg, 2.0
equiv) and MeI (0.021 mL, 1.5 equiv). After being stirred at rt for 1 h, the reaction mixture
was concentrated under reduced pressure to give the crude residue, which was diluted with
H2O. The water layer was extracted with CH2Cl2 (5 mL x 2) two more times. The combined
organic layers were dried over MgSO4 and concentrated in vacuo to afford 8.
2,4-Dimethoxy-1-(phenylethynyl)benzene
(8).
1
Colorless gum, (51.4 mg, 98%); H NMR (400 MHz,
CDCl3) δ 7.58ꢀ7.45 (m, 2H), 7.41 (d, J = 8.4 Hz, 1H),
7.37ꢀ7.22 (m, 3H), 6.51ꢀ6.43 (m, 2H), 3.88(s, 3H), 3.81
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.3, 161.3,
MeO
OMe
8
134.4, 131.6, 128.3, 127.9, 124.0, 105.1, 105.0, 98.6, 92.1, 85.9, 56.0, 55.6; HRMS (ESIꢀ
QTOF) m/z [M+H]+ calcd for C16H15O2 239.1067 found 239.1066.
Synthesis of 9
To a solution of 5a (50 mg, 0.22 mmol) in CH2Cl2 (3 mL) were added Et3N (0.062 mL, 2.0
equiv) and Ac2O (0.032 mL, 1.5 equiv) at 0 °C. After being stirred at rt for 1 h, the reaction
mixture was diluted with CH2Cl2 (3 mL) and washed with 10% aq. HCl and aq. NaHCO3,
successively. The water layer was extracted with CH2Cl2 (5 mL x 2) two more times. The
combined organic layers were dried over MgSO4 and concentrated in vacuo to afford 9.
3-Methoxy-4-(phenylethynyl)phenyl acetate (9).
1
Colorless gum, (58.0 mg, 99%); H NMR (400 MHz,
CDCl3) δ 7.58ꢀ7.52 (m, 2H), 7.48 (d, J = 8.0 Hz, 1H),
AcO
OMe
7.37ꢀ7.29 (m, 3H), 6.70 (dd, J = 2.0, 8.4 Hz, 1H), 6.67
9

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13
(d, J = 2.0 Hz, 1H), 3.89 (s, 3H), 2.30 (s, 3H); C NMR (100 MHz, CDCl3) δ 169.2, 160.8,
151.8, 134.0, 131.8, 128.4, 128.3, 123.6, 113.7, 110.3, 105.1, 93.5, 85.1, 56.2, 21.3; HRMS
(ESIꢀQTOF) m/z [M+H]+ calcd for C17H15O3 267.1016 found 267.1018.
General Procedure for the Synthesis of 10
To a solution of 5 (0.99 mmol) in CH2Cl2 (5 mL) were added Et3N (0.28 mL, 2.0 equiv) and
TsCl (227 mg, 1.2 equiv) at 0 °C. After being stirred at rt for 1 h, the reaction mixture was
concentrated under reduced pressure to give the crude residue, which was purified by silica
gel column chromatography (hexanes/ethyl acetate = 50:1) to give 10.
3-Methoxy-4-(phenylethynyl)phenyl
4-
methylbenzenesulfonate (10a). White solid, mp: 98.7ꢀ
1
100.1 °C (374.6 mg, 100%); H NMR (400 MHz,
TsO
OMe
10a
CDCl3) δ 7.72 (d, J = 8.4 Hz, 2H), 7.58ꢀ7.47 (m, 2H),
7.40ꢀ7.28 (m, 6H), 6.58 (d, J = 2.0 Hz, 1H), 6.50 (dd, J
= 2.0, 8.4 Hz, 1H), 3.79 (s, 3H), 2.44 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.7, 150.4,
145.7, 133.9, 132.2, 131.8, 129.9, 128.8, 128.5, 128.4, 123.2, 114.3, 111.7, 105.9, 94.4, 84.5,
56.2, 21.9; HRMS (ESIꢀQTOF) m/z [M+H]+ calcd for C22H19O4S 379.0999 found 379.0998.
3-Methoxy-4-((4-methoxyphenyl)ethynyl)phenyl 4-
OMe
methylbenzenesulfonate (10b). White solid, mp:
105.1ꢀ106.5 °C (404.4 mg, 100%); 1H NMR (400 MHz,
CDCl3) δ 7.71 (d, J = 6.4 Hz, 2H), 7.46 (d, J = 6.8 Hz,
TsO
OMe
10b

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2H), 7.37ꢀ7.27 (m, 3H), 6.86 (d, J = 6.8 Hz, 2H), 6.57 (s, 1H), 6.49 (d, J = 8.0 Hz, 1H), 3.82
(s, 3H), 3.78 (s, 3H), 2.45 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.6, 159.9, 150.1, 145.7,
133.8, 133.3, 132.3, 129.9, 128.8, 115.4, 114.3, 114.1, 112.0, 105.9, 94.5, 83.2, 56.2, 55.4,
21.9; HRMS (ESIꢀQTOF) m/z [M+H]+ calcd for C23H21O5S 409.1104 found 409.1104.
4-((3,5-Dimethoxyphenyl)ethynyl)-3-methoxyphenyl
OMe
4-methylbenzenesulfonate (10c). White solid, mp:
1
OMe
84.6ꢀ86.1 °C (395.0 mg, 91%); H NMR (400 MHz,
CDCl3) δ 7.69 (d, J = 8.4 Hz, 2H), 7.334 (d, J = 8.4 Hz,
TsO
OMe
1H), 7.29 (d, J = 8.0 Hz, 2H), 6.66 (s, 1H), 6.65 (s, 1H),
10c
6.56 (s, 1H), 6.48 (dd, J = 1.6, 8.4 Hz, 1H), 6.43 (s, 1H), 3.77 (s, 9H), 2.42 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 160.7, 160.6, 150.4, 145.7, 134.0, 132.2, 129.9, 128.7, 124.5, 114.3,
111.5, 109.5, 105.9, 102.0, 94.4, 84.1, 56.2, 55.6, 21.8; HRMS (ESIꢀQTOF) m/z [M+H]+
calcd for C24H23O6S 439.1210 found 439.1212.
3-Methoxy-4-((4-methoxy-2-
OMe
methylphenyl)ethynyl)phenyl
4-
methylbenzenesulfonate (10d). White solid, mp: 96.9ꢀ
98.5 °C (405.7 mg, 97%); 1H NMR (400 MHz, CDCl3)
δ 7.72 (d, J = 8.0 Hz, 2H), 7.42 (d, J = 8.8 Hz, 1H),
Me
TsO
OMe
10d
7.36ꢀ7.29 (m, 3H), 6,76 (d, J = 2.4 Hz, 1H), 6.70 (dd, J = 2.4, 8.4 Hz, 1H), 6.58 (d, J = 2.0
Hz, 1H), 6.49 (dd, J = 2.0, 8.0 Hz, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 2.48 (s, 3H), 2.45 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 160.5, 159.8, 150.0, 145.7, 142.3, 133.4, 133.3, 132.3, 129.9,

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128.8, 115.4, 115.2, 114.2, 112.4, 111.4, 105.9, 93.7, 87.1, 56.2, 55.4, 21.9, 21.1; HRMS
(ESIꢀQTOF) m/z [M+H]+ calcd for C24H23O5S 423.1261 found 423.1264.
3-Methoxy-4-(p-tolylethynyl)phenyl
4-
Me
methylbenzenesulfonate (10e). White solid, mp:
1
108.6ꢀ109.4 °C (380.8 mg, 98%); H NMR (400 MHz,
CDCl3) δ 7.71 (d, J = 7.6 Hz, 2H), 7.41 (d, J = 7.6 Hz,
2H), 7.38ꢀ7.28 (m, 3H), 7.14 (d, J = 7.6 Hz, 2H), 6.58
TsO
OMe
10e
(s, 1H), 6.50 (d, J = 8.4 Hz, 1H), 3.79 (s, 3H), 2.45 (s, 3H), 2.36 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 160.6, 150.3, 145.7, 138.7, 133.9, 132.2, 131.7, 129.9, 129.2, 128.8, 120.2,
114.3, 111.9, 105.9, 94.7, 83.9, 56.2, 21.9, 21.7.; HRMS (ESIꢀQTOF) m/z [M+H]+ calcd for
C23H21O4S 393.1155 found 393.1153.
3-Methoxy-4-((6-methoxynaphthalen-2-
yl)ethynyl)phenyl 4-methylbenzenesulfonate (10f).
White solid, mp: 131.8ꢀ133.1 °C (376.8 mg, 83%);
1H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.79ꢀ
7.63 (m, 4H), 7.53 (d, J = 8.4 Hz, 1H), 7.38 (d, J =
8.4 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.14 (d, J = 8.8 Hz, 1H), 7.10 (s, 1H), 6.59 (s, 1H),
6.52 (d, J = 8.0 Hz, 1H ), 3.90 (s, 3H), 3.80 (s, 3H), 2.43 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 160.7, 158.5, 150.3, 145.7, 134.3, 133.9, 132.2, 131.4, 129.9, 129.5, 129.1, 128.7,
128.5, 126.9, 119.5, 118.1, 114.3, 111.9, 105.9, 105.9, 95.0, 84.2, 56.2, 55.4, 21.8; HRMS
(ESIꢀQTOF) m/z [M+H]+ calcd for C27H23O5S 459.1261 found 459.1260.

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4-([1,1'-Biphenyl]-4-ylethynyl)-3-methoxyphenyl 4-
Ph
methylbenzenesulfonate (10g). White solid, mp:
1
121.8ꢀ123.0 °C (387.0 mg, 86%); H NMR (400 MHz,
CDCl3) δ 7.71 (d, J = 8.0 Hz, 2H), 7.63ꢀ7.51 (m, 6H),
7.43 (t, J = 7.2 Hz, 2H), 7.39ꢀ7.26 (m, 4H), 6.58 (d, J =
TsO
OMe
10g
1.6 Hz, 1H), 6.50 (dd, J = 1.6, 8.0 Hz, 1H), 3.79 (s, 3H), 2.43 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 160.7, 150.4, 145.7, 141.2, 140.4, 133.9, 132.3, 132.2, 129.9, 129.0, 128.8, 127.8,
127.1, 127.1, 122.2, 114.3, 111.7, 105.9, 94.3, 85.3, 56.2, 21.9; HRMS (ESIꢀQTOF) m/z
[M+H]+ calcd for C28H23O4S 455.1312 found 455.1312.
3-Methoxy-4-(thiophen-3-ylethynyl)phenyl
4-
S
methylbenzenesulfonate (10h). Pale yellow solid, mp:
1
105.2ꢀ106.7 °C (315.9 mg, 83%); H NMR (400 MHz,
CDCl3) δ 7.71 (d, J = 8.4 Hz, 2H), 7.52 (dd, J = 1.2, 3.2
Hz, 1H), 7.38ꢀ7.26 (m, 4H), 7.18 (dd, J = 1.2, 5.2 Hz,
TsO
OMe
10h
1H), 6.57 (d, J = 2.0 Hz, 1H), 6.50 (dd, J = 2.0, 8.4 Hz, 1H), 3.78 (s, 3H), 2.44 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 160.7, 150.3, 145.7, 133.9, 132.2, 130.0, 129.9, 129.0, 128.7,
125.4, 122.2, 114.3, 111.6, 105.9, 89.5, 84.0, 56.2, 21.8; HRMS (ESIꢀQTOF) m/z [M+H]+
calcd for C20H17O4S2 385.0563 found 385.0565.
4-(Cyclohex-1-en-1-ylethynyl)-3-methoxyphenyl 4-
TsO
OMe
10i

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methylbenzenesulfonate (10i). White solid, mp: 110.8ꢀ112.5 °C (219.6 mg, 58%); 1H NMR
(400 MHz, CDCl3) δ 7.70 (d, J = 7.6 Hz, 2H), 7.38ꢀ7.20 (m, 3H), 6.53 (s, 1H), 6.45 (d, J =
8.0 Hz, 1H), 6.22 (s, 1H), 3.75 (s, 3H), 2.44 (s, 3H), 2.27ꢀ2.18 (m, 2H), 2.18ꢀ2.09 (m, 2H),
13
1.73ꢀ1.57 (m, 4H); C NMR (100 MHz, CDCl3) δ 160.4, 150.0, 145.6, 135.8, 133.7, 132.3,
129.9, 128.8, 120.8, 114.2, 112.2, 105.8, 96.4, 81.8, 56.2, 29.3, 25.9, 22.4, 21.9, 21.6; HRMS
(ESIꢀQTOF) m/z [M+H]+ calcd for C22H23O4S 383.1312 found 383.1311.
4-(Hex-1-yn-1-yl)-3-methoxyphenyl
4-
methylbenzenesulfonate (10j). White solid, mp: 53.8ꢀ
54.6 °C (351.3 mg, 99%); 1H NMR (400 MHz, CDCl3)
δ 7.69 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H),
7.23 (d, J = 8.4 Hz, 1H), 6.51 (d, J = 2.0 Hz, 1H), 6.44
TsO
OMe
10j
(dd, J = 2.4, 8.4 Hz, 1H), 3.74 (s, 3H), 2.48ꢀ2.38 (m, 2H), 2.43 (s, 3H), 1.64ꢀ1.53 (m, 2H),
1.53ꢀ1.40 (m, 2H), 0.93 (t, J = 7.6 Hz, 3H),; 13C NMR (100 MHz, CDCl3) δ 160.5, 149.7,
145.6, 133.9, 132.2, 129.8, 128.7, 114.1, 112.3, 105.7, 95.8, 75.6, 56.1, 30.9, 22.1, 21.8, 19.5,
13.7; HRMS (ESIꢀQTOF) m/z [M+H]+ calcd for C20H23O4S 359.1312 found 359.1311.
General Procedure for the Synthesis of 11, 12, and 13
To a solution of 8, 9, or 10 (0.1 mmol) in CH2Cl2 (2 mL) were added NaHCO3 (42 mg, 5.0
equiv) and I2 (127 mg, 5.0 equiv) at 0 °C. After being stirred at rt for 3 h, the reaction mixture
was concentrated under reduced pressure to give the crude residue, which was purified by
silica gel column chromatography (hexane to hexanes/ethyl acetate = 50:1) to give 11, 12, or
13, respectively.

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DOI: 10.1039/C6OB01941B
3-Iodo-6-methoxy-2-phenylbenzofuran (11). Yellow
solid, mp: 55.6ꢀ56.9 °C (17.2 mg, 49%); 1H NMR (400
MHz, CDCl3) δ 8.14 (d, J = 7.6 Hz, 2H), 7.48 (t, J = 8.0
Hz, 2H), 7.40 (t, J = 7.6 Hz, 1H), 7.31 (d, J = 8.8 Hz,
1H), 7.03 (d, J = 2.4 Hz, 1H), 6.94 (dd, J = 2.0, 8.4 Hz,
I
O
MeO
11
1H), 3.88 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.3, 154.8, 152.3, 130.3, 128.9, 128.6,
127.2, 126.1, 122.1, 112.7, 95.7, 61.0, 56.0; HRMS (ESIꢀQTOF) m/z [M+H]+ calcd for
C15H12IO2 350.9876 found 350.9877.
3-Iodo-2-phenylbenzofuran-6-yl acetate (12). Pale
1
yellow solid, mp: 117.8ꢀ118.9 °C (20.8 mg, 55%); H
I
NMR (400 MHz, CDCl3) δ 8.15 (d, J = 7.2 Hz, 2H),
O
AcO
7.50 (t, J = 7.2 Hz, 2H), 7.47ꢀ7.40 (m, 2H), 7.30 (d, J =
1.2 Hz, 1H), 7.07 (dd, J = 2.0, 8.4 Hz, 1H), 2.35 (s, 3H);
12
13C NMR (100 MHz, CDCl3) δ 169.7, 154.2, 153.6, 149.1, 130.5, 129.9, 129.5, 128.7, 127.5,
122.1, 117.9, 105.2, 60.7, 21.3; HRMS (ESIꢀQTOF) m/z [M+H]+ calcd for C16H12IO3
378.9826 found 378.9823.
3-Iodo-2-phenylbenzofuran-6-yl
4-
methylbenzenesulfonate (13a). White solid, mp:
I
1
107.9ꢀ110.1 °C (42.7 mg, 87%); H NMR (400 MHz,
O
TsO
CDCl3) δ 8.15ꢀ8.09 (m, 2H), 7.72 (d, J = 8.4 Hz, 2H),
13a

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DOI: 10.1039/C6OB01941B
7.54ꢀ7.40 (m, 3H), 7.31 (dd, J = 1.6, 8.0 Hz, 3H), 7.22 (d, J = 2.0 Hz, 1H), 6.92 (dd, J = 2.0,
8.8 Hz, 1H), 2.45 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 154.9, 153.2, 147.9, 145.7, 132.3,
131.6, 130.0, 129.7, 129.6, 128.7, 127.6, 122.1, 118.5, 106.2, 60.5, 21.9; HRMS (ESIꢀQTOF)
m/z [M+H]+ calcd for C21H16IO4S 490.9808 found 490.9808.
3-Iodo-2-(4-methoxyphenyl)benzofuran-6-yl
4-
methylbenzenesulfonate (13b). White solid, mp:
I
1
110.2ꢀ111.8 °C (52.0 mg, 100%); H NMR (400 MHz,
OMe
O
TsO
CDCl3) δ 8.06 (d, J = 8.8 Hz, 2H), 7.72 (d, J = 8.0 Hz,
2H), 7.36ꢀ7.22 (m, 3H), 7.19 (d, J = 1.6 Hz, 1H), 7.01
13b
(d, J = 8.8 Hz, 2H), 6.89 (dd, J = 1.6, 8.4 Hz, 1H), 3.87 (s, 3H), 2.45 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 160.7, 155.1, 153.0, 147.5, 145.6, 132.3, 131.7, 130.0, 129.1, 128.7, 122.2,
121.7, 118.4, 114.2, 106.1, 58.8, 55.5, 21.9; HRMS (ESIꢀQTOF) m/z [M+H]+ calcd for
C22H18IO5S 520.9914 found 520.9912.
2-(3,5-Dimethoxyphenyl)-3-iodobenzofuran-6-yl 4-
methylbenzenesulfonate (13c). Yellow solid, mp:
I
OMe
OMe
1
133.1ꢀ134.6 °C (51.7 mg, 94%); H NMR (400 MHz,
O
TsO
CDCl3) δ 7.72 (d, J = 8.0 Hz, 2H), 7.35ꢀ7.26 (m, 5H),
7.23 (d, J = 1.6 Hz, 1H), 6.91 (dd, J = 1.6, 8.4 Hz, 1H),
13c
6.55(s, 1H), 3.87 (s, 3H), 2.45 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.9, 154.5, 153.1,
148.0, 145.7, 132.3, 131.6, 131.1, 130.0, 128.7, 122.2, 118.6, 106.2, 105.6, 102.3, 61.0, 55.7,
21.9; HRMS (ESIꢀQTOF) m/z [M+H]+ calcd for C23H20IO6S 551.0020 found 551.0021.

Organic & Biomolecular Chemistry
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DOI: 10.1039/C6OB01941B
3-Iodo-2-(4-methoxy-2-methylphenyl)benzofuran-6-
yl 4-methylbenzenesulfonate (13d). White solid, mp:
I
1
65.7ꢀ67.0 °C (49.7 mg, 93%); H NMR (400 MHz,
OMe
O
TsO
Me
CDCl3) δ 7.73 (d, J = 8.0 Hz, 2H), 7.31 (t, J = 8.4 Hz,
3H), 7.19 (d, J = 2.0 Hz, 1H), 6.91 (dd, J = 2.4, 8.4 Hz,
13d
1H), 6.87ꢀ6.80 (m, 2H), 3.86 (s, 3H), 2.45 (s, 3H), 2.33 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 161.0, 158.2, 153.7, 147.5, 145.6, 140.2, 132.6, 132.4, 130.6, 130.0, 128.7, 121.7, 121.4,
118.3, 116.2, 111.2, 106.3, 64.1, 55.4, 21.9, 20.8; HRMS (ESIꢀQTOF) m/z [M+H]+ calcd for
C23H20IO5S 535.0071 found 535.0070.
3-Iodo-2-(p-tolyl)benzofuran-6-yl
4-
methylbenzenesulfonate (13e). Pale yellow solid, mp:
I
1
115.7ꢀ116.9 °C (46.4 mg, 92%); H NMR (400 MHz,
Me
O
TsO
CDCl3) δ 8.01 (d, J = 8.0 Hz, 2H), 7.72 (d, J = 8.0 Hz,
2H), 7.35ꢀ7.26 (m, 5H), 7.20 (s, 1H), 6.90 (d, J = 8.8
13e
Hz, 1H), 2.45 (s, 3H), 2.42 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 155.2, 153.2, 147.7,
145.6, 140.0, 132.3, 131.7, 130.0, 129.4, 128.7, 127.5, 126.8, 121.9, 118.4, 106.1, 59.8, 21.9,
21.6; HRMS (ESIꢀQTOF) m/z [M+H]+ calcd for C22H18IO4S 504.9965 found 504.9966.
3-Iodo-2-(6-methoxynaphthalen-2-yl)benzofuran-
6-yl 4-methylbenzenesulfonate (13f). White solid,
1
mp: 146.1ꢀ147.6 °C (51.9 mg, 91%); H NMR (400

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DOI: 10.1039/C6OB01941B
MHz, CDCl3) δ 8.53 (s, 1H), 8.15 (dd, J = 1.6, 8.8 Hz, 1H), 7.80 (t, J = 8.8 Hz, 2H), 7.72 (d,
J = 8.4 Hz, 2H), 7.35ꢀ7.25 (m, 3H), 7.22 (d, J = 1.6 Hz, 1H), 7.18 (dd, J = 2.4, 8.8 Hz, 1H),
7.13 (d, J = 2.0 Hz, 1H), 6.91 (dd, J = 2.0, 8.8 Hz, 1H), 3.93 (s, 3H), 2.43 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 158.9, 155.1, 153.2, 147.8, 145.7, 135.0, 132.3, 131.8, 130.3, 130.0,
128.7, 128.5, 127.3, 127.2, 124.9 124.7, 122.0, 119.8, 118.5, 106.1, 105.9, 60.0, 55.5, 21.9;
HRMS (ESIꢀQTOF) m/z [M+H]+ calcd for C26H20IO5S 571.0071 found 571.0073.
2-([1,1'-Biphenyl]-4-yl)-3-iodobenzofuran-6-yl
4-
methylbenzenesulfonate (13g). White solid, mp:
I
1
170.6ꢀ171.1 °C (53.8 mg, 95%); H NMR (400 MHz,
Ph
O
TsO
CDCl3) δ 8.22 (d, J = 8.4 Hz, 2H), 7.77ꢀ7.70 (m, 4H),
7.65 (d, J = 7.2 Hz, 2H), 7.48 (t, J = 7.2 Hz, 2H), 7.39 (t,
13g
J = 7.6 Hz, 1H), 7.32 (d, J = 8.4 Hz, 3H), 7.24 (d, J = 1.2 Hz, 1H), 6.93 (dd, J = 1.2, 8.4 Hz,
1H), 2.46 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 154.6, 153.3, 147.9, 145.7, 142.4, 140.3,
132.3, 131.7, 130.0, 129.1, 128.7, 128.5, 128.0, 127.9, 127.4, 127.2, 122.1, 118.6, 106.2, 60.6,
21.9; HRMS (ESIꢀQTOF) m/z [M+H]+ calcd for C27H20IO4S 567.0121 found 567.0122.
3-Iodo-2-(thiophen-3-yl)benzofuran-6-yl
4-
methylbenzenesulfonate (13h). Yellow gum, (43.2 mg,
I
S
1
87%); H NMR (400 MHz, CDCl3) 8.15 (dd, J = 1.2,
O
TsO
3.2 Hz, 1H), 7.86 (dd, J = 1.2, 5.2 Hz, 1H), 7.71 (d, J =
8.0 Hz, 2H), 7.43 (dd, J = 3.2, 5.2 Hz, 1H), 7.31 (d, J =
13h
8.0 Hz, 2H), 7.26 (d, J = 8.4 Hz, 1H), 7.20 (d, J = 2.0 Hz, 1H), 6.89 (dd, J = 2.0, 8.8 Hz, 1H),