Efficient synthesis of 3-benzoyl Benzo[b]thiophenes and raloxifene via Mercury(II)-Catalyzed cyclization of 2-alkynylphenyl alkyl sulfoxides

Article abstract of DOI:10.1016/j.tet.2018.03.067

The unique selective estrogen receptor modulator, Raloxifene (1), and antitubulin agent 2 were synthesized through the key intermediate, 4-methoxybenzyl 2-bromo-4-methoxyphenyl sulfoxide (6), respectively. It was found that compared with the o-sulfanyl aryl bromides, the sulfinyl group at ortho position accelerated the Sonogashira coupling reaction of aryl bromides. Thus, compound 6 was coupled with 3,4,5-trimethoxyphenyl acetylene, followed by mercury-catalyzed cyclization reaction afford compound 2 in 79% overall yield. Raloxifene (1) was prepared from compound 6 in four steps and 33% overall yield via coupling reaction with 1-trimethylsily-2-(4-tert-butyldimethylsiloxy)phenylethyne, mercury-catalyzed cyclization reaction, alkylation and demethylation.

Full text of DOI:10.1016/j.tet.2018.03.067

Accepted Manuscript
Efficient Synthesis of 3-Benzoyl Benzo[b]thiophenes and Raloxifene via Mercury(II)-
Catalyzed Cyclization of 2-Alkynylphenyl Alkyl Sulfoxides
Shi-Ming Wen, Cheng-Han Lin, Chin-Chau Chen, Ming-Jung Wu
PII:
S0040-4020(18)30340-5
10.1016/j.tet.2018.03.067
TET 29407
DOI:
Reference:
To appear in: Tetrahedron
Please cite this article as: Wen S-M, Lin C-H, Chen C-C, Wu M-J, Efficient Synthesis of 3-Benzoyl
Benzo[b]thiophenes and Raloxifene via Mercury(II)-Catalyzed Cyclization of 2-Alkynylphenyl Alkyl
Sulfoxides, Tetrahedron (2018), doi: 10.1016/j.tet.2018.03.067.
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ACCEPTED MANUSCRIPT
Efficient Synthesis of 3-Benzoyl Benzo[b]thiophenes and Raloxifene via
Mercury(II)-Catalyzed Cyclization of 2-Alkynylphenyl Alkyl Sulfoxides
Shi-Ming Wen,a Cheng-Han Lin,a Chin-Chau Chena and Ming-Jung Wu a,b,*
aDepartment of Chemistry, National Sun Yat-sen University, Kaohsiung, Taiwan
bDepartment of Medicinal and Applied Chemistry, Kaohsiung Medical University,
Kaohsiung, Taiwan
mijuwu@faculty.nsysu.edu.tw
Abstract
The unique selective estrogen receptor modulator, Raloxifene (1), and
antitubulin agent 2 were synthesized through the key intermediate, 4-methoxybenzyl
2-bromo-4-methoxyphenyl sulfoxide (6), respectively. It was found that compared
with the o-sulfanyl aryl bromides, the sulfinyl group at ortho position accelerated the
Sonogashira coupling reaction of aryl bromides. Thus, compound 6 was coupled with
3,4,5-trimethoxyphenyl acetylene, followed by mercury-catalyzed cyclization reaction
afford compound 2 in 79% overall yield. Raloxifene (1) was prepared from compound
6
in four steps and 33% overall yield via coupling reaction with
1-trimethylsily-2-(4-tert-butyldimethylsiloxy)phenylethyne,
mercury-catalyzed
cyclization reaction, alkylation and demethylation.
Raloxifene (1) is a unique selective estrogen receptor modulator and is used to
prevent osteoporosis and reduce the risk of invasive breast cancer in
postmenopausal women.1 Compound 2 was found to be a potent antitubulin
drug.2Both of these compounds exhibit 3-benzoyl benzo[b]thiophene core structure.
Therefore, the construction of 3-benzoyl benzo[b]thiophenes has become an
important issue for new drug development. Most of the common method to
construct this ring system is by way of Friedel-Crafts acylation reaction between
2-substituted benzo[b]thiophenes and the corresponding benzoyl chlorides.3
Recently, we reported the cyclization reaction of 2-alkynylphenyl alkyl sulfoxides
catalyzed by mercury chloride that provides a new synthetic way to construct
3-benzoyl benzo[b]thiophenes.4 Herein, we wish to report our application of this
methodology to synthesize raloxifene (1) and compound 2 We also report the
.
development of Sonogashira coupling reaction of various terminal alkynes with
o-sulfinyl aryl bromides.

ACCEPTED MANUSCRIPT
OMe
O
OMe
OMe
N
O
O
OH
OMe
S
HO
S
MeO
Raloxifene (1)
2
For the synthesis of compound 2, 3-iodoanisole (3) was chosen as the starting
material. Bromination of 3 with NBS gave compound 4 in 95% yield. Selective C-S
bond formation of 4 with 4-methoxylbenzylmercaptan using copper iodide as the
catalyst gave sulphide 5 in 60% yield. Attempt to do the bromo-Sonogashira coupling
reaction of 5 with 3,4,5-trimethoxyphenyl acetylene under the literature’s
procedure5a failed to produce the coupling product. According to the descriptions of
that paper and literature’s report,5b the electron-rich aryl halides always undergo the
coupling reaction slowly. We therefore switch our synthetic procedures, thus,
sulphide 5 was oxidized first to sulfoxide 6 using mCPBA. The resulting sulfoxide 6
was coupled with 3,4,5-trimethoxyphenyl acetylene under the reported reaction
conditions to give the desired compound 7 in 70% yield. Finally, cyclization reaction
of compound 7 was carried out under our reported mercury(II)-catalyzed conditions
to give compound 2 in 97% yield. (Scheme 1)
Scheme 1. Synthesis Strategy to Compound 2 a
Br
Br
i
iii
ii
N.R.
MeO
S
MeO
I
MeO
I
5
3
4
OMe
OMe
OMe
Br
OMe
iv
v
iii
2
5
MeO
S
MeO
S
O
6
OMe
7
O
OMe
a (i) NBS, DMF, 80 oC, 6 h, 95%. (ii) p-methoxybenzyl mercaptan, CuI (15 mol %), pipecolic acid,
CsCO3, DMF/dioxane (1:9), 110 oC, 24 h, 60%. (iii) 3,4,5-trimethoxyphenyl acetylene, Pd(OAc)2,
PPh3, K3PO4, DMF, 80 oC, 6 h. 70% from 6 to 7 (iv) mCPBA, NaHCO3, CH2Cl2, ice bath, 2 h,
81%. (v) HgCl2 (10 mol %), DDQ (1 equiv), benzene, reflux, 24 h, 97%.
Since the sulfide and sulfonyl groups have strong influences on the
Sonogashira coupling reaction of aryl bromides, the substituent effects on the
reactivity with different aryl halides were explored. The results were summarized in
Table 1. For the aryl iodides 8a and 9a, both of them undergo the coupling reaction
very smoothly to give the coupling products in good yields. (Table 1, entries 1 and 4)

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But the sulfoxide 9a reacts much faster than 8a to give the product in higher yield.
For the bromo cases, (Table 1, entries 2 and 5) compound 8b undergoes the coupling
reaction much slower than 9b and the yield is also poor. Compound 9b proceeds in
reasonable rate to give the product 11 in acceptable yield. Finally, both chlorides, 8c
and 9c, do not undergo the coupling reactions even after stirring the reaction
mixtures for 24 hours under the described reaction conditions. (Table 1, entries 3
and 6) We also carried out the coupling reaction of o-bromoanisole and
o-bromoacetophenone with phenylacetylene under the described reaction
conditions, respectively. The reaction of o-bromoanisole with phenylacetylene for 24
h
gave trace amount of the coupling product detected by GC-MS and recovered most
the starting o-bromoanisole. For the reaction of o-bromoacetophenone with
phenylacetylene, the starting materials consumed within two hours and gave a
complicated product mixture and no desired coupling product was detected.
Table 1. Substituent Effects on Sonogashira Coupling Reaction.
Entry Compounds Time (h) Products/Yields (%)
1
2
3
4
5
6
8a, X = I
12
24
24
2
11a/87
11a/28
11a/0 a
12a/95
12a/74
12a/0 [a]
8b, X = Br
8c, X = Cl
9a, X = I
9b, X = Br
9c, X = Cl
6
24
aStarting materials 8c and 9c were recovered respectively.
Further exploration on the relative reactivity of the coupling reaction of aryl
bromides 8b and 9b with various terminal alkynes were also carried out. The results
were summarized in Table 2. The coupling reactions of sulfide 8b take place very
slowly to give the coupling products in low yields except when 8b was coupled with
alkyne 10d. (Table 2, entries 1-3) The electron-poor alkynes 10e and 10f do not
undergo coupling reaction under the described reaction conditions. (Table 2, entries

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4-5) However for sulfoxide 9b, the coupling reaction took place very smoothly with
electron-rich alkynes to give the products in good yields. (Table 2, entries 6-8)
Although the electron-poor p-nitrophenyl acetylene 10e does not undergo coupling
reaction with 9b, the other electron-poor p-trifluoromethylphenyl acetylene 10f
does react with 9b to give the coupling product 12f albeit in low yield.
Table 2. Relative reactivity of 8b and 9b on Sonogashira coupling reaction.
Entry Compounds
Alkynes
Time (h) Products/Yields (%)
1
2
8b
8b
8b
8b
8b
9b
9b
9b
9b
9b
10b, R2 = 4-MeOC6H4
10c, R2 = n-Bu
24
24
24
24
24
6
11b/trace
11c/36
11d/82
11e/0 a
11f/0 a
12b/78
12c/60
12d/83
12e/0 a
12f/37
3
10d, R2 = t-Bu
4
10e, R2 = 4-NO2C6H4
10f, R2 = 4-CF3C6H4
10b, R2 = 4-MeOC6H4
10c, R2 = n-Bu
5
6
7
6
8
10d, R2 = t-Bu
6
9
10e, R2 = 4-NO2C6H4
10f, R2 = 4-CF3C6H4
6
10
6
aStarting materials 8b and 9b were recovered respectively.
To synthesize raloxifene (1), we anticipated that using our reported
mercury(II)-catalyzed cyclization reaction of compound 13 followed by demethylation
would allow us to complete the synthesis of raloxifene (1). Compound 13 should be
easily prepared by Sonogashira coupling reaction of the sulfoxide substituted aryl
bromide 6 with acetylene 14. (Scheme 2)
Scheme 2. Retrosynthetic analysis of raloxifene (1)

ACCEPTED MANUSCRIPT
Thus, compound 9 was synthesized and the procedure is summarized in
scheme 3. Alkylation of 4-iodophenol (15) with 16 gave phenyl ether 17 in 77% yield.
Sonogashira coupling reaction6 of 17 with trimethylsilyl acetylene afforded 18 in 60%
yield. Finally, desilylation of 18 using TBAF in THF gave acetylene 14 in 92% yield.
With acetylene 14 in hand, we then attempt the coupling reaction of 6 with 14 under
the described reaction conditions. Surprisingly no desired product was formed and
recovered most of the starting materials. (Eq. 2) The failure to produce the coupling
product probably due to the coordination of amino ether functionality on the alkyne
14 with the central metal of the catalyst or reduction of palladium(II) with tertiary
amine7 to reduce the reactivity.
Scheme 3.The Synthetic strategy of acetylene14a

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In the revised synthetic pathway, we decided to do the coupling and
cyclization reactions before introducing the amino ether side chain. (Scheme 4) Thus,
4-iodophenol (15) was converted to tert-butyldimetylsilyl ether 19 first. Compound
19 was then coupled with trimethylsilyl acetylene to give 20. It was found that the
acetylene 20 can be used directly without removing the trimethylsilyl group to
couple with aryl bromide 6 under the described reaction conditions to give the
product 21 in 70% yield. Under this reaction conditions, both silyl groups were
removed spontaneous after the reaction. Cyclization of 21 was carried out using 10
mol % of mercury chloride in the presence of one equivalent of DDQ in refluxing
benzene for six hours to give the product 22 in 87% yield. The amino ether side chain
was
then
introduced
at
this
stage.8
Treatment
of
22
with
N-(2-chloroethyl)pipperidine hydrogen chloride salt using K2CO3 as the base in DMF
gave the ether 23 in 90% yield. Finally, demethylation9 was carried out using BBr3 in
CH2Cl2 to give the final product, raloxifene (1), in 60% yield. The residues of mercury
in this final product is 22 ng/g detected by ICP-MS spectrometry.

ACCEPTED MANUSCRIPT
Scheme 4. Total Synthesis to Raloxifene (1) a
In conclusion, the mercury-catalyzed cyclization reaction of 2-alkynylphenyl
alkyl sulfoxides became a powerful tool to construct 3-benzoyl benzo[b]thiophenes.
Herein, we have successfully applied this methodology to synthesize the selective
estrogen receptor modulator raloxifene (1) and antitubulin agent 2. During this study,
we also found the sulfoxide could assist the Sonogashira coupling reaction of aryl
bromides. We believe that these findings will have a strong impact to synthetic
organic chemistry and pharmaceutical industry.
Experimental Section
4-Bromo-3-iodoanisole (4)
To a round bottomed flask (100 mL) containing a magnetic stirrer and
3-iodoanisole (3) (2.0 g, 8.5 mmol) in DMF (20 mL) was added N-bromosuccinimide
o
(1.54 g, 8.67 mmol). The reaction mixture was heated to 80 C and stirred at this
temperature for 6 hours. After cooling to room temperature, the mixture was
quenched with the saturated aqueous NaCl solution (100 mL), 6N aqueous solution
of HCl (10 mL), and extracted with EtOAc (50 mL × 3).The combined organic extracts
were dried over anhydrous MgSO4(S). After filtration and removal of solvent, the
residue was purified by column chromatography on silica using 20/1 (Hexane/EtOAc)

ACCEPTED MANUSCRIPT
as elution to give product 4 (2.40 g, 90%) as a yellow oil. Rf = 0.65 (20:1 Hex/EtOAc);
1H NMR (500 MHz,CDCl3) δ 3.75 (s, 3H), 6.74 (dd, J = 9.0, 3.0 Hz, 1 H), 7.36 (d, J = 3.0
Hz, 1H), 7.44 (d, J = 9.0 Hz, 1H); 13C{H} NMR (125 MHz, CDCl3) δ 55.6, 101.0, 115.9,
120.1, 125.3, 132.5, 158.6; MS (EI, m/z) 314 (M++2, 100), 312 (M+, 100), 297 (14), 269
(12), 185 (12), 170 (21), 78 (16), 63 (33); HRMS (EI-magnetic sector) m/z: calcd for
C7H6BrIO 311.8647, found 311.8646.
4-Bromo-3-(4-methoxybenzylmercapto)anisole (5)
To a flame-dried two-necked flask (100 mL) containing a magnetic stirrer, CuI
(0.183 g, 0.96 mmol), DL-pipecolic acid (0.124 g, 0.96 mmol) and Cs2CO3 (4.18 g ,
12.80 mmol) in 50 mLof DMF/1,4-dioxane (1/9) was added 4-methoxylbenzyl
mercaptan (1.07 mL, 7.69 mmol) and the reaction mixture was stirred at room
temperature for 3 minutes. 4-Bromo-3-iodoanisole (4)(2.0 g, 6.41 mmol) was then
added into the mixture and the resulting solution was heated to 100 oC and stirred at
this temperature for 24 hours. After cooling to room temperature, the mixture was
filtrated through celite and washed with EtOAc (20 mL), the organic layer was added
saturated aqueous NaCl solution (100 mL) and was extracted with EtOAc (50 mL × 3).
The combined organic extracts were dried over anhydrous MgSO4(S). After filtration
and removal of solvent, the residue was purified by column chromatography on silica
gel using 10/1 (Hexane/EtOAc) as elution to give compound 5 (1.60 g, 75%) as a red
oil. Rf = 0.30 (20:1 Hex/EtOAc); 1H NMR (500 MHz, CDCl3) δ 3.72 (s, 3H), 3.79 (s, 3H),
4.10 (s, 2H), 6.58 (dd, J = 9.0, 3.0 Hz, 1H), 6.78 (d, J = 3.0 Hz, 1H), 6.85 (d, J = 9.0 Hz,
2H), 7.29 (d, J = 9.0 Hz, 2H), 7.41 (d, J = 9.0 Hz, 1H); 13C{H} NMR (125 MHz, CDCl3) δ
37.3, 55.2, 55.4, 112.3, 113.6, 113.9, 114.4, 127.8, 130.0, 133.2, 138.9, 158.9, 159.0;
MS (EI, m/z) 340 (M+, 7), 338 (6), 138 (7), 121 (100), 71 (8), 57 (8); HRMS
(EI-magnetic sector) m/z: calcd for C15H15BrO2S 339.9956, found 339.9979.
2-Bromo-5-methoxyphenyl 4-methoxybenzyl sulfoxide (6)
To a round bottomed flask (100 mL) containing a magnetic stirrer and
compound 5 (1.60 g, 4.7 mmol) in dichloromethane (40 mL) was added mCPBA
(0.817 g, 4.7 mmol) and sodium bicarbonate (0.395 g, 4.7 mmol). The reaction
mixture was stirred at room temperature for 2 hours and quenched with saturated
aqueous Na2S2O3 solution (100 mL) and extracted with dichloromethane (30 mL × 3).
The combined organic extracts were dried over anhydrous MgSO4(S). After filtration
and removal of solvent, the residue was purified by column chromatography on silica
gel using 1/1 (Hexane/EtOAc) as elution to give product 6 (1.35 g, 81%) as a colorless
1
oil. Rf = 0.65 (1:1 Hex/EtOAc); H NMR (500 MHz, CDCl3) δ 3.66 (s, 3H), 3.77 (s, 3H),
3.95 (d, J = 13.5 Hz, 1H), 4.24 (d, J = 13.5 Hz, 1H), 6.78 (d, J = 8.5 Hz, 2H), 6.84 (dd, J =

ACCEPTED MANUSCRIPT
8.5, 3.0 Hz, 1H), 6.90 (d, J = 3.0 Hz, 1H), 6.97 (d, J = 8.5 Hz, 2H), 7.40 (d, J = 8.5 Hz, 1H);
13C{H} NMR (125 MHz, CDCl3) δ 55.2, 55.6, 58.9, 108.5, 110.8, 113.6, 119.8, 121.1,
131.6, 133.3, 143.1, 159.6, 159.7; MS (EI, m/z) 235 (7), 233 (7), 121 (100), 106 (4), 91
(11), 78 (19), 77 (15); HRMS (EI-magnetic sector) m/z: calcd for C15H15BrO3S 355.9905,
found 355.9927.
1,2,3-Trimethoxy-5-((4-methoxy-2-((4-methoxybenzyl)sulfinyl)phenyl)ethynyl)benz
ene (7)
To a flame-dried two-necked flask (100 mL) containing a magnetic stirrer and
compound 6 (1.0 g, 2.8 mmol) in DMF (20 mL) was added Pd(OAc)2 (75 mg, 0.285
mmol), PPh3 (349 mg, 1.13 mmol) and K3PO4 (2.0 g, 5.6 mmol) subsequently. Then,
the flask was evacuated and backfilled with nitrogen and the mixture was stirred at
room temperature for 3 minutes. 3,4,5-trimethoxyphenylacetylene (0.8 g, 4.2 mmol)
was then added into the reaction mixture. The reaction mixture was heated to 100 oC
and stirred at this temperature for 6 hours. After cooling to room temperature, the
mixture was quenched with the saturated aqueous NaCl solution (50 ml), 6N
aqueous solution of HCl (10 mL) and extracted with EtOAc (40 mL × 3).The combined
organic extracts were dried over anhydrous MgSO4(S). After filtration and removal of
solvent, the residue was purified by column chromatography on silica gel using 1/1
(Hexane/EtOAc) as elution to give product 7 (0.92 g, 70%) as a yellow solid.
mp 114-116 oC; Rf = 0.40 (1:1 Hex/EtOAc); 1H NMR (500 MHz, CDCl3) δ 3.76 (d, J = 4.5
Hz, 6H), 3.89 (d, J = 5.5 Hz, 9H), 3.96 (d, J = 13.0 Hz, 1H), 4.32 (d, J = 13.0 Hz, 1H), 6.76
(s, 2H), 6.76 (d, J = 8.5 Hz, 2H), 6.95 (dd, J = 8.0, 2.5 Hz, 1H), 7.02 (d, J = 8.5 Hz, 2H),
7.11 (d, J = 2.5 Hz, 1H), 7.48 (d, J = 8.5 Hz, 1H); 13C{H} NMR (125 MHz, CDCl3) δ 55.3,
55.7, 56.2, 60.5, 61.0, 83.6, 96.6, 108.4, 108.6, 111.3, 113.8, 117.5, 117.9, 121.9,
131.6, 133.4, 139.3, 146.5, 153.2, 159.7, 160.5; MS (EI, m/z) 466 (M+, 4), 345 (6), 257
(25), 141 (19), 121 (72), 97 (59), 85 (94), 71 (100), 57 (87); HRMS (EI-magnetic sector)
m/z: calcd for C26H26O6S 466.1450, found 466.1451.
(6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)(3,4,5-trimethoxyphenyl)m
ethanone (2)
To a round bottomed flask (100 mL) containing a magnetic stirrer and
compound 7 0.9 g (1.93 mmol) in benzene (20 mL) was added HgCl2 (52.4 mg, 0.193
mmol) and 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (0. 44 g, 1.93 mmol). The
reaction mixture was heated to refluxing temperature and stirred for 24 hours. After
cooling to room temperature, the reaction mixture was filtrated through celite and
washed with EtOAc (20 mL). The organic solvent was the removed in vacuum and the
residue was purified by column chromatography on silica gel using 1/1

ACCEPTED MANUSCRIPT
(Hexane/EtOAc) as elution to give compound 2 (0.65 g, 97%) as a yellow solid. mp
109-111 oC; Rf = 0.75 (1:1 Hex/EtOAc); 1H NMR (500 MHz, CDCl3) δ 3.73 (s, 6H), 3.75
(s, 3H), 3.83 (s, 3H), 3.89 (s, 3H), 6.75 (d, J = 8.5 Hz, 2H), 7.00 (dd, J = 9.0, 2.0 Hz, 1H),
7.07 (s, 2H), 7.30 (d, J = 8.5 Hz, 2H), 7.33 (d, J = 2.0 Hz, 1H), 7.65 (d, J = 9.0 Hz, 1H);
13C{H} NMR (125 MHz, CDCl3) δ 55.3, 55.7, 56.1, 60.9, 104.5, 107.5, 114.1, 114.9,
124.3, 126.1, 129.9, 130.4, 132.3, 133.9, 140.1, 142.6, 143.8, 152.7, 157.8, 159.9,
193.0; MS (EI, m/z) 464 (M+, 13), 169 (14), 141 (20), 127 (24), 99 (40), 85 (95), 71
(100), 57 (94); HRMS (EI-magnetic sector) m/z: calcd for C26H24O6S 464.1294, found
464.1292.
1-iodo-2-(methylsulfinyl)benzene (9a)
To a flask was added 2-iodothioanisole (1.0 g, 4.0 mmol), mCPBA (0.99 g, 4.0
mmol) and NaHCO3(0.34 g, 4.0 mmol) at 0 oC in CH2Cl2 (40 mL) for 2 hr. Then, 100 mL
of Na2S2O3(aq) was poured into the flask and extract ed by CH2Cl2 (30 mL x 3). The
combined organic layer was dried by MgSO4 and was purified by chromatography in
silica gel (n-hexane/EtOAc = 2/1 as eluent) to give compound 9a (1.0 g, 95%). The
1
status of compound 9a: Colorless oil, Rf = 0.33 (2:1 Hex/EtOAc); H NMR (500 MHz,
CDCl3) δ 2.79 (s, 3H), 7.22 (td, J = 7.5, 1.5 Hz, 1H), 7.61 (td, J = 7.5, 1.0 Hz, 1H), 7.81
(dd, J = 8.0, 1.0 Hz, 1H), 7.90 (dd, J = 8.0, 1.5 Hz, 1H); 13C{H} NMR (125 MHz, CDCl3) δ
42.1, 91.3, 125.7, 129.5, 132.5, 139.3, 148.2; MS (ESI, m/z) 289 (M++23, 100), 267
(31); HRMS (EI-magnetic sector) m/z: calcd for C7H7INaOS 288.9155, found 288.9153.
1-bromo-2-(methylsulfinyl)benzene (9b)
To a flask was added 2-bromothioanisole (1.0 g, 5.0 mmol), mCPBA (1.22 g, 5.0
mmol) and NaHCO3(0.42 g, 5.0 mmol) at 0 oC in CH2Cl2 (40 mL) for 2 hr. Then, 100 mL
of Na2S2O3(aq) was poured into the flask and extract ed by CH2Cl2 (30 mL x 3). The
combined organic layer was dried by MgSO4 and was purified by chromatography in
silica gel (n-hexane/EtOAc = 2/1 as eluent) to give compound 9b (1.06 g, 98%). The
1
status of compound 9b: Colorless oil, Rf = 0.33 (2:1 Hex/EtOAc); H NMR (500 MHz,
CDCl3) δ 2.81 (s, 3H), 7.36 (td, J = 7.5, 1.5 Hz, 1H), 7.54-7.59 (m, 2H), 7.93 (dd, J = 8.0,
1.5 Hz, 1H); 13C{H} NMR (125 MHz, CDCl3) δ 41.8, 118.3, 125.6, 128.7, 132.2, 132.9,
145.2; MS (ESI, m/z) 219 (M++1, 100), 221 (100); HRMS (EI-magnetic sector) m/z:
calcd for C7H7BrOS 218.9474, found 218.9472.
1-chloro-2-(methylsulfinyl)benzene (9c)
To a flask was added 2-chlorothioanisole (1.0 g, 6.33 mmol), mCPBA (1.56 g,
o
6.33 mmol) and NaHCO3(0.53 g, 6.33 mmol) at 0 C in CH2Cl2 (40 mL) for 2 hr. Then,
100 mL of Na2S2O3(aq) was poured into the flask and extract ed by CH2Cl2 (30 mL x 3).

ACCEPTED MANUSCRIPT
The combined organic layer was dried by MgSO4 and was purified by
chromatography in silica gel (n-hexane/EtOAc = 2/1 as eluent) to give compound 9c
(1.06 g, 96%). The status of compound 9c: Colorless oil, Rf = 0.33 (2:1 Hex/EtOAc); 1H
NMR (400 MHz, CDCl3) δ 2.83 (s, 3H), 7.39-7.48 (m, 2H), 7.54 (td, J = 7.6, 1.2 Hz, 1H),
7.96 (td, J = 8.0, 1.6 Hz, 1H); 13C{H} NMR (125 MHz, CDCl3) δ 41.6, 125.2, 128.1, 129.7,
131.9, 143.5; MS (ESI, m/z) 199 (M++25, 38), 197 (M++23, 100), 177 (7), 175 (21);
HRMS (EI-magnetic sector) m/z: calcd for C7H7ClOS 196.9798, found 196.9796.
General Procedure for the Testing of Bromo-Sonogashira Coupling Reaction:
To a flame-dried two-necked flask (25 mL) containing a magnetic stirrer and
aryl bromide(0.5 mmol) in DMF (5 mL) was added Pd(OAc)2 (11 mg, 0.05 mmol), PPh3
(52 mg, 0.2 mmol) and K3PO4 (0.13 g, 0.6 mmol) subsequently. Then, the flask was
evacuated and backfilled with nitrogen and the mixture was stirred at room
temperature for 3 minutes. Acetylene (0.74 mmol) was then added into the reaction
mixture. The reaction mixture was heated to 80 oC and stirred at this temperature for
6 hours. After cooling to room temperature, the mixture was quenched with the
saturated aqueous NaCl solution (10 mL), 6N aqueous solution of HCl (5 mL) and
extracted with EtOAc (10 mL × 3).The combined organic extracts were dried over
anhydrous MgSO4(S). After filtration and removal of solvent, the residue was purified
by column chromatography on silica gel using 1/1 (Hexane/EtOAc) as elution to give
the product.
2-(2-phenylethynyl)thioanisole (11a)
Compound 11a was obtained in 28% yield (31 mg) as yellow oil by the reaction
of phenylacetylene (76 mg, 0.74 mmol) and 2-bromoanisole (0.1 g, 0.5 mmol). Rf =
0.44 (Hex); 1H NMR (500 MHz, CDCl3) δ 2.53 (s, 3H), 7.13 (t, J = 7.5 Hz, 1H), 7.19 (d, J
= 8.0 Hz, 1H), 7.30-7.37 (m, 4H), 7.50 (d, J = 7.5 Hz, 1H), 7.60 (dd, J = 7.5, 1.5 Hz, 2H);
13C{H} NMR (125 MHz, CDCl3) δ 15.1, 86.8, 95.8, 121.3, 123.1, 124.1, 124.2, 128.3,
128.4, 128.7, 131.6, 132.2, 141.7; MS (EI, m/z) 224 (M+, 14), 58 (55), 57 (100); HRMS
(EI-magnetic sector) m/z: calcd for C15H12S 224.0660, found 224.0658.
2-(Hexyn-1-yl)thioanisole (11c)
Compound 11c was obtained in 36% yield (37 mg) as yellow oil by the reaction
of 2-bromothioanisole (0.1 g, 0.50 mmol) and 1-hexyne (61 mg, 0.74 mmol). Rf =
1
0.48 (Hex); H NMR (500 MHz, CDCl3) δ 0.96 (t, J = 7.5 Hz, 3H), 1.51-1.57 (m, 2H),
1.61-1.67 (m, 2H), 2.48 (s, 3H), 2.50 (t, J = 7.0 Hz, 2H), 7.05 (td, J = 7.5, 1.0 Hz, 1H),
7.11 (d, J = 7.5 Hz, 1H), 7.25 (td, J = 8.0, 1.0 Hz, 1H), 7.35 (dd, J = 7.5, 1.0 Hz, 1H);
13C{H} NMR (125 MHz, CDCl3) δ 13.6, 14.9, 19.3, 22.0, 30.8, 78.0, 97.4, 122.1, 123.8,

ACCEPTED MANUSCRIPT
124.1, 128.0, 132.2, 141.1; MS (EI, m/z) 189 (M+-15, 38), 162 (21), 147 (100); HRMS
(EI-magnetic sector) m/z: calcd for C13H16S 205.1051, found 205.1044.
2-(3,3-Dimethylbutyn-1-yl)thioanisole (11d)
Compound 11d was obtained in 82% yield (84 mg) as yellow oil by the reaction
of 2-bromothioanisole (0.1 g, 0.50 mmol) and 3,3-dimethylbut-1-yne (61 mg, 0.74
mmol). Rf = 0.44 (Hex); 1H NMR (500 MHz, CDCl3) δ 1.36 (s, 9H), 2.46 (s, 3H), 7.04 (td,
J = 7.5, 1.0 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H), 7.23 (td, J = 7.8, 1.3 Hz, 1H), 7.33 (dd, J =
7.5, 1.0 Hz, 1H); 13C{H} NMR (125 MHz, CDCl3) δ 14.9, 28.3, 31.0, 76.6, 105.5, 121.9,
123.6, 124.0, 127.9, 132.0, 141.3; MS (EI, m/z) 204 (M+, 100), 189 (50), 174 (31), 147
(36); HRMS (EI-magnetic sector) m/z: calcd for C13H16S 204.0971, found 204.097
2-(2-phenylethynyl)phenyl methyl sulfoxide (12a)
Compound 12a was obtained in 74% yield (82 mg) as yellow oil by the reaction
of 2-bromophenyl methyl sulfoxide (100.0 mg, 0.46 mmol) and phenylacetylene (70
1
mg, 0.69 mmol). Rf = 0.33 (2:1 Hex/EtOAc); H NMR (400 MHz, CDCl3) δ 2.89 (s, 3H),
7.38-7.42 (m, 3H), 7.46-7.62 (m, 5H), 8.00 (dd, J = 8.0, 1.2 Hz, 1H); 13C{H} NMR (125
MHz, CDCl3) δ 29.7, 42.1, 84.2, 98.0, 119.3, 122.0, 123.3, 128.6, 129.2, 129.5, 130.4,
131.5, 132.4, 147.2; MS (ESI, m/z) 241 (M++1, 100), 194 (7); HRMS (EI-magnetic
sector) m/z: calcd for C15H13OS 241.0682, found 241.0680.
2-(2-(4-(Methoxyphenyl)ethynyl)phenyl methyl sulfoxide (12b)
Compound 12b was obtained in 78% yield (97 mg) as yellow oil by the reaction
of 2-bromophenyl methyl sulfoxide (100 mg, 0.46 mmol) and
1
4-methoxyphenylacetylene (91 mg, 0.69 mmol). Rf = 0.29 (1:1 Hex/EtOAc); H NMR
(500 MHz, CDCl3) δ 2.88 (s, 3H), 3.85 (s, 3H), 6.91 (d, J = 8.5 Hz, 2H), 7.46 (d, J = 9.0
Hz, 3H), 7.56 (q, J = 7.5 Hz, 2H), 7.98 (d, J = 8.0 Hz, 1H); 13C{H} NMR (125 MHz, CDCl3)
δ 42.0, 55.4, 83.1, 98.3, 114.0, 114.2, 119.7, 123.3, 129.2, 130.3, 132.2, 133.0, 146.9,
160.4; MS (EI, m/z) 255 (M+-15, 100), 227 (84), 184 (53), 152 (23); HRMS
(EI-magnetic sector) m/z: calcd for C16H14O2S 270.0715, found 270.0714.
2-(Hexyn-1-yl)phenyl methyl sulfoxide (12c)
Compound 12c was obtained in 60% yield (61 mg) as yellow oil by the reaction
of 2-bromophenyl methyl sulfoxide (100 mg, 0.46 mmol) and 1-hexyne (57 mg, 0.69
mmol). Rf = 0.49 (2:1 Hex/EtOAc); 1H NMR (500 MHz, CDCl3) δ 0.96 (t, J = 7.0 Hz, 3H),
1.45-1.53 (m, 2H), 1.58-1.64 (m, 2H), 2.47 (t, J = 7.0 Hz, 2H), 2.82 (s, 3H), 7.36-7.43
(m, 2H), 7.52 (td, J = 8.0, 2.0 Hz, 1H), 7.91 (d, J = 7.5 Hz, 1H); 13C{H} NMR (125 MHz,
CDCl3) δ 13.5, 19.2, 22.0, 30.4, 41.9, 75.9, 99.9, 120.1, 123.1, 128.8, 130.2, 132.5,

ACCEPTED MANUSCRIPT
146.9; MS (ESI, m/z) 243 (M++23, 100), 221 (M++1, 36); HRMS (EI-magnetic sector)
m/z: calcd for C13H16NaOS 243.0814, found 243.0812.
2-(3,3-Dimethylbutyn-1-yl)phenyl methyl sulfoxide (12d)
Compound 12d was obtained in 83% yield (84 mg) as yellow oil by the reaction
of 2-bromophenyl methyl sulfoxide (100 mg, 0.46 mmol) and 3,3-dimethylbut-1-yne
1
(57 mg, 0.69 mmol). Rf = 0.58 (1:1 Hex/EtOAc); H NMR (500 MHz, CDCl3) δ 1.33 (s,
9H), 2.82 (s, 3H), 7.38-7.41 (m, 2H), 7.48-7.54 (m, 1H), 7.90 (d, J = 8.0 Hz, 1H); 13C{H}
NMR (125 MHz, CDCl3) δ 28.3, 30.6, 41.7, 74.6, 107.8, 120.0, 123.0, 128.7, 130.1,
132.1, 146.9; MS (EI, m/z) 220 (M+, 26), 205 (28), 164 (91), 135 (100); HRMS
(EI-magnetic sector) m/z: calcd for C13H16OS 220.0922, found 220.0922.
2-(2-(4-(Trifluoromethylphenyl)ethynyl)phenyl methyl sulfoxide (12f)
Compound 12f was obtained in 37% yield (52 mg) as yellow oil by the reaction
of 2-bromophenyl methyl sulfoxide (100.0 mg, 0.46 mmol) and
4-(trifluoromethyl)phenylacetylene (0.12 g, 0.69 mmol). Rf = 0.33 (2:1 Hex/EtOAc);
1H NMR (500 MHz, CDCl3) δ 2.88 (s, 3H), 7.51 (td, J = 7.5, 1.0 Hz, 1H), 7.59-7.67 (m,
6H), 8.02 (dd, J = 8.0, 0.5 Hz, 1H); 13C{H} NMR (125 MHz, CDCl3) δ 29.7, 42.2, 86.3,
96.1, 118.6, 123.5, 125.4, 125.5, 125.5, 125.6, 130.2, 130.5, 131.8, 132.6; MS (ESI,
m/z) 331 (M++23, 100), 309 (M++1, 68); HRMS (EI-magnetic sector) m/z: calcd for
C16H11F3NaOS 331.0375, found 331.0373.
1-(2-(4-Iodophenoxy)ethyl)piperidine (17)
To a round bottomed flask (250 mL) containing a magnetic stirrer and
4-iodophenol (2.0 g, 9.1 mmol) in DMF (100 mL) was added
1-(2-chloroethyl)piperidine hydrochloride (2.01 g, 10.9 mmol) and potassium
o
carbonate (3.01 g, 21.8 mmol). The reaction mixture was heated to 110 C and
stirred at this temperature for 6 hours. After cooling to room temperature, the
mixture was quenched with the saturated aqueous NH4Cl solution (100 mL) and
extracted with EtOAc (100 mL × 3). The combined organic extracts were dried over
anhydrous MgSO4(S). After filtration and removal of solvent, the residue was purified
by column chromatography on silica gel using 10/1 (dichloromethane/methanol) as
elution to give compound 17 (2.32 g, 77%) as a yellow oil. Rf = 0.50 (10:1
Dichloromethane/MeOH); 1H NMR (500 MHz, CDCl3) δ 1.39 (s, 2H), 1.53-1.57 (m, 4H),
2.44 (s, 4H), 2.69 (t, J = 6.0 Hz, 2H), 4.00 (t, J = 6.0 Hz, 2H), 6.62 (d, J = 9.0 Hz, 2H),
7.48 (d, J = 9.0 Hz, 2H); 13C{H} NMR (125 MHz, CDCl3) δ 24.1, 25.8, 55.0, 57.7, 66.0,
82.7, 116.9, 138.1, 158.6; MS (EI, m/z) 331 (M+, 4), 203 (10), 99 (71), 98 (100), 76 (15),
55 (13); HRMS (EI-magnetic sector) m/z: calcd for C13H18INO 331.0433, found

ACCEPTED MANUSCRIPT
331.0433.
1-(2-(4-(2-Trimethylsilylethynyl)phenoxy)ethyl)piperidine (18)
To a flame-dried two-necked flask (100 mL) containing a magnetic stirrer and
compound 17 (1.0 g, 3.02 mmol) in ethyl ether (30 mL) was added Pd(PPh3)4 (0.17 g,
0.15 mmol). After stirring for
3
minutes, CuI (0.03 g, 0.15 mmol),
trimethylsilylacetylene (0.44 g, 4.53 mmol) and n-butylamine (0.89 ml, 9.06 mmol)
were added into the flask. The reaction mixture was stirred at room temperature for
6 hours. The reaction mixture was quenched with saturated aqueous NH4Cl solution
(50 mL) and extracted with EtOAc (30 mL × 3).The combined organic extracts were
dried over anhydrous MgSO4(S). After filtration and removal of solvent, the residue
was purified by column chromatography on silica using 10/1 (Hexane/EtOAc) as
eluent to give compound 18 (0.55 g, 60%) as a yellow oil. Rf = 0.45 (10:1
Dichloromethane/MeOH); 1H NMR (500 MHz, CDCl3) δ 0.23 (s, 9H), 1.49 (s, 2H), 1.71
(t, J = 5.5 Hz, 4H), 2.67 (s, 4H), 2.91 (t, J = 5.5 Hz, 2H), 4.20 (t, J = 5.5 Hz, 2H), 6.81 (d, J
= 9.0 Hz, 2H), 7.39 (d, J = 9.0 Hz, 2H); 13C{H} NMR (125 MHz, CDCl3) δ 0.03, 14.1, 22.7,
23.6, 25.1, 29.3, 29.6, 31.9, 54.7, 57.4, 65.2, 92.6, 105.0, 114.4, 115.6, 133.5, 158.5;
MS (ESI, m/z) 302 (M++1, 100); HRMS (EI-magnetic sector) m/z: calcd for C18H27NOSi
302.1935, found 302.1935.
1-(2-(4-Ethynylphenoxy)ethyl)piperidine (14)
To a round-button flask containing 18 (0.30 g, 0.99 mmol) in THF (10 mL) was
o
added TBAF (0.39 g, 1.49 mmol) slowly at 0 C. The reaction mixture was allowed to
warm to room temperature and stirred for another one hour. The reaction mixture
was quenched with saturated aqueous NH4Cl solution (30 mL) and extracted with
EtOAc (30 mL x 3). The combined organic extracts were dried over anhydrous
MgSO4. After filtration and removal of solvent, the residue was purified by column
chromatography on silica gel using hexanes as eluent to give 14 (0.21 g, 92%) as
yellow oil. Rf = 0.43 (10:1 Dichloromethane/MeOH); 1H NMR (500 MHz, CDCl3) δ 1.46
(s, 2H), 1.64 (t, J = 5.5 Hz, 4H), 2.55 (s, 4H), 2.81 (t, J = 6.0 Hz, 2H), 2.99 (s, 1H), 4.14 (t,
J = 6.0 Hz, 2H), 6.84 (d, J = 9.0 Hz, 2H), 7.41 (d, J = 9.0 Hz, 2H); 13C{H} NMR (125 MHz,
CDCl3) δ 23.9, 25.7, 29.7, 54.9, 57.7, 65.8, 75.8, 83.6, 114.2, 114.5, 133.6, 159.1; MS
(ESI, m/z) 230 (M++1, 100); HRMS (EI-magnetic sector) m/z: calcd for C15H19NO
230.1539, found 230.1539.
4-Iodophenyl tert-butyldimethylsilyl ether (19)
To a flame-dried two-necked flask (100 mL) containing a magnetic stirrer and
o
compound 15 (2.0 g, 9.0 mmol) in dichloromethane (50 mL) was cooled to 0 C and

ACCEPTED MANUSCRIPT
added tert-butyldimethylsilyl chloride (60 g, 10.0 mmol) followed by imidazole (0.68
g, 10.0 mmol). The reaction mixture was stirred for 30 minutes at this temperature
then warmed to room temperature and stirred for another 24 hours. During which
time a white solid precipitated and that was removed by filtration. The filtrate was
concentrated under vacuum and the residue was purified by column
chromatography on silica using Hexane as eluent to give compound 19 (2.90 g, 98%)
as a colorless oil. Rf = 0.65 (Hexane); 1H NMR (500 MHz, CDCl3) δ 0.21 (s, 6H), 0.99 (s,
9H), 6.63 (d, J = 9.0 Hz, 2H), 7.52 (d, J = 9.0 Hz, 2H); 13C{H} NMR (125 MHz, CDCl3) δ
-4.5, 18.2, 25.6, 83.7, 122.5, 138.3, 155.6; MS (EI, m/z) 334 (M+, 34), 277 (100), 150
(68), 279 (6), 135 (27); HRMS (EI-magnetic sector) m/z: calcd for C12H19IOSi
334.0250, found 334.0252.
4-tert-Butyldimethylsiloxyphenyl trimethylsily acetylene (20)
To a flame-dried two-necked flask (100 mL) containing a magnetic stirrer and
compound 19 (2.0 g, 6.0 mmol) in ethyl ether (50 mL) was added Pd(PPh3)4 (0.35 g,
0.3 mmol). After stirring for 3 minutes, CuI (0.11 g, 0.6 mmol), trimethylsilylacetylene
(1.28 mL, 9.0 mmol) and n-butylamine (2.0 mL, 18.0 mmol) were added into the flask.
The reaction mixture was stirred at room temperature for 6 hours. The reaction
mixture was quenched with saturated aqueous NH4Cl solution (100 mL) and
extracted with EtOAc (50 mL × 3).The combined organic extracts were dried over
anhydrous MgSO4(S). After filtration and removal of solvent, the residue was purified
by column chromatography on silica using 10/1 (Hexane/EtOAc) as eluent to give
1
compound 20 (1.67 g, 92%) as a yellow oil. Rf = 0.50 (Hexane); H NMR (500 MHz,
CDCl3) δ 0.19 (s, 6H), 0.25 (s, 9H), 0.98 (s, 9H), 6.76 (d, J = 9.0 Hz, 2H), 7.36 (d, J = 9.0
Hz, 2H); 13C{H} NMR (125 MHz, CDCl3) δ -4.5, 0.1, 18.2, 25.6, 92.6, 105.2, 115.9,
120.1, 133.4, 156.1; MS (EI, m/z) 304 (M+, 27), 247 (100), 116 (13), 73 (34); HRMS
(EI-magnetic sector) m/z: calcd for C17H28OSi2 304.1679, found 304.1679.
2-(2-(4-Hydroxyphenyl)ethynyl)-5-methoxyphenyl 4-methoxybenzyl sulfoxide (21)
To a flame-dried two-necked flask (100 mL) containing a magnetic stirrer and
compound 6 (1.0 g, 2.8 mmol) in DMF (20 mL) was added Pd(OAc)2 (75 mg, 0.285
mmol), PPh3 (349 mg, 1.13 mmol) and K3PO4 (2.0 g, 5.6 mmol) subsequently. Then,
the flask was evacuated and backfilled with nitrogen and the mixture was stirred at
room temperature for 3 minutes. Compound 20 (1.5 g, 4.2 mmol) was then added
o
into the reaction mixture. The reaction mixture was heated to 100 C and stirred at
this temperature for 6 hours. After cooling to room temperature, the mixture was
quenched with the saturated aqueous NaCl solution (50 mL), 6N aqueous solution of
HCl (10 mL) and extracted with EtOAc (40 mL × 3). The combined organic extracts

ACCEPTED MANUSCRIPT
were dried over anhydrous MgSO4(S). After filtration and removal of solvent, the
residue was purified by column chromatography on silica gel using 1/1
(Hexane/EtOAc) as eluent to give product 217 (0.78 g, 70%) as a yellow solid. mp
159-161 oC; Rf = 0.40 (1:1 Hex/EtOAc); 1H NMR (500 MHz, CDCl3) δ 3.75 (d, J = 4.0 Hz,
6H), 4.00 (d, J = 13.0 Hz, 1H), 4.33 (d, J = 13.0 Hz, 1H), 6.10 (s, 1H), 6.75 (d, J = 9.0 Hz,
2H), 6.85 (d, J = 8.5 Hz, 2H), 6.94 (dd, J = 8.5, 2.5 Hz, 1H), 6.98 (d, J = 8.5 Hz, 2H), 7.06
(d, J = 2.5 Hz, 1H), 7.41 (d, J = 8.5 Hz, 2H), 7.46 (d, J = 8.5 Hz, 1H); 13C{H} NMR (125
MHz, CDCl3) δ 55.3, 55.7, 60.0, 83.0, 96.8, 108.5, 111.9, 113.8, 114.3, 115.8, 117.9,
121.6, 131.7, 133.1, 133.3, 145.6, 156.7, 159.7, 160.2; MS (EI, m/z) 394 (M++2, 1),
257 (11), 111(21), 97 (38), 85 (64), 57 (100); HRMS (EI-magnetic sector) m/z: calcd
for C23H20O4S 392.1082, found 392.1082.
2-(4-Methoxyphenyl)-3-(4-hydroxybenzoyl)-6-methoxythiophene (22)
To a round bottomed flask (100 mL) containing a magnetic stirrer and
compound 21 (0.78 g, 2.0 mmol) in benzene (20 mL) was added HgCl2 (54 mg, 0.198
mmol) and 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (0.45 g, 2.0 mmol). The
reaction mixture was heated to refluxing temperature and stirrer for 24 hours. After
cooling to room temperature, the reaction mixture was filtrated through celite and
washed with EtOAc (30 mL). The organic solvent was the removed in vacuum and the
residue was purified by column chromatography on silica gel using 1/1
(Hexane/EtOAc) as eluent to give product 22 (0.65 g, 84%) as a yellow oil. Rf = 0.55
(1:1 Hex/EtOAc); 1H NMR (500 MHz, CDCl3) δ 3.74 (s, 3H), 3.88 (s, 3H), 6.41 (brs, OH),
6.67 (d, J = 9.0, 2.0 Hz, 1H), 7.32 (s, 1H), 7.33 (d, J = 8.5 Hz, 2 H), 7.51 (d, J = 9.0 Hz,
1H), 7.70 (d, J = 8.5 Hz, 2H); 13C{H} NMR (125 MHz, CDCl3) δ 55.2, 55.6, 104.5, 114.1,
114.8, 115.3, 124.0, 125.9, 130.2, 130.3, 130.4, 132.7, 133.9, 140.0, 142.9, 157.6,
159.7, 160.7, 193.6; MS (EI, m/z) 390 (M+, 12), 85 (69), 71 (98), 57 (100); HRMS
(EI-magnetic sector) m/z: calcd for C23H18O4S 390.0926, found 390.0925.
2-(4-Methoxyphenyl)-3-(4-(2-pipperidinylethoxy)benzoyl)-6-methoxythiophene
(23)
To a round bottomed flask (100 mL) containing a magnetic stirrer and
compound 22 (0.65 g, 1.7 mmol) in DMF (20 mL) was added
1-(2-chloroethyl)piperidine hydrogen chloride salt (0.37 g , 2.0 mmol) and potassium
carbonate (0.55 g, 4.0 mmol). The reaction mixture was heated to 110 oC and stirred
at this temperature for 6 hours. After cooling to room temperature, the mixture was
quenched with the saturated aqueous NH4Cl solution (100 mL) and extracted with
EtOAc (30 mL × 3). The combined organic extracts were dried over anhydrous
MgSO4(S). After filtration and removal of solvent, the residue was purified by column

ACCEPTED MANUSCRIPT
chromatography on silica gel using 10/1 (dichloromethane/methanol) as eluent to
give compound 23 (0.69 g, 83%) as a yellow oil. Rf = 0.45 (10:1
1
Dichloromethane/MeOH); H NMR (500 MHz, CDCl3) δ 1.44 (d, J = 5.5 Hz, 2H),
1.57-1.62 (m, 4H), 2.48 (s, 4H), 2.74 (t, J = 6.0 Hz, 2H), 3.75 (s, 3H), 3.88 (s, 3H), 4.09
(t, J = 6.0 Hz, 2H), 6.76 (dd, J = 9.0, 3.0 Hz, 4H), 6.95 (dd, J = 9.0, 2.5 Hz, 1H), 7.31 (d, J
= 8.5 Hz, 1H), 7.34 (d, J = 9.0 Hz, 2H), 7.51 (d, J = 8.5 Hz, 1H), 7.75 (d, J = 9.0 Hz, 2H);
13C{H} NMR (125 MHz, CDCl3) δ 24.1, 25.8, 55.0, 55.2, 55.6, 57.6, 66.1, 104.5, 114.0,
114.2, 114.7, 124.0, 125.9, 130.2, 130.4, 130.5, 132.3, 133.9, 140.0, 142.4, 157.6,
159.7, 162.9, 193.2; MS (EI, m/z) 501 (M+, 5), 98 (100), 71 (89), 57 (86); HRMS
(EI-magnetic sector) m/z: calcd for C30H31NO4S 501.1974, found 501.1976.
Raloxifene (1)
To a flame-dried two-necked flask (100 mL) containing a magnetic stirrer and
compound 23 (0.69 g, 1.4 mmol) in dried dichloromethane (40 mL) was added BBr3
(12 mL, 12 mmol, 1 M solution in dichloromethane) slowly at 0 oC. After stirring at 0
0C for 30 minutes, the reaction mixture was allowed to warm to room temperature
and stirred for another 24 hours. The saturated aqueous NaHCO3solution was added
slowly into the reaction mixture and the pH value of the solution was controlled at
7.0. After stirring for 30 minutes, the reaction mixture was added saturated aqueous
NaCl solution (100 mL) and extracted with EtOAc (40 mL × 3). The combined organic
extracts were dried over anhydrous MgSO4(S). After filtration and removal of solvent,
the residue was purified by column chromatography on silica gel using 10/1
(dichloromethane/methanol) as eluent to give raloxifene 1 (0.39 g, 60 %) as a yellow
o
1
solid. mp 120-125 C; Rf = 0.23 (10:1 Dichloromethane/MeOH); H NMR (500 MHz,
DMSO-d6) δ 1.33 (d, J = 5.0 Hz, 2H), 1.45 (t, J = 6.0 Hz, 4H), 2.40 (s, 4 H), 2.62 (t, J =
5.5 Hz, 2H), 4.06 (t, J = 5.5 Hz, 2H), 6.68 (d, J = 8.5 Hz, 2H), 6.86 (dd, J = 9.0, 2.0 Hz,
1H), 6.89 (d, J = 9.0 Hz, 2H), 7.18 (d, J = 9.0 Hz, 2H), 7.26 (d, J = 8.5 Hz, 1H), 7.35 (d, J
= 2.0 Hz, 1H), 7.65 (d, J = 8.5 Hz, 2H), 9.82 (br, 2OH); 13C{H} NMR (125 MHz, DMSO-d6)
δ 23.8, 25.4, 54.3, 57.0, 65.8, 107.2, 114.5, 115.2, 115.7, 123.4, 123.8, 129.73, 129.75,
131.8, 132.3, 139.3, 140.4, 155.5, 157.9, 162.8, 192.6; MS (EI, m/z) 475 (M++2, 31),
474 (M++1, 100); HRMS (EI-magnetic sector) m/z: calcd for C28H27NO4S 474.1734,
found 474.1731.
Acknowledgments
We thank the Ministry of Science and Technology of the Republic of China for
financial support.
References:

ACCEPTED MANUSCRIPT
(1) (a) Maximov, P. Y.; Lee, T. M.; Jordan, V. C. Curr. Clin. Pharmacol. 2013, 8, 135.
(b) Muchmore, D. B. The Oncologist 2000, 5, 388.
(2) (a) Pinney, K. G.; Bounds, A. D.; Dingeman, K. M.; Mocharla, V. P.; Pettit, G. R.;
Bai, R.; Hamel, E. Bioorg. Med. Chem. Lett. 1999, 9, 1081. (b) Palkowitz, A.
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