Synthesis of functionalized diaryl sulfides based on regioselective one-pot cyclizations of 1,3-bis(trimethylsilyloxy)-1,3-butadienes

Article abstract of DOI:10.1016/j.tet.2008.02.010

Functionalized diaryl sulfides were prepared based on one-pot cyclizations of 1,3-bis(trimethylsilyloxy)-1,3-butadienes.

Full text of DOI:10.1016/j.tet.2008.02.010

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 3782e3793
www.elsevier.com/locate/tet
Synthesis of functionalized diaryl sulfides based on regioselective
one-pot cyclizations of 1,3-bis(trimethylsilyloxy)-
1,3-butadienes
Muhammad A. Rashid a, Nasir Rasool a, Muhammad Adeel a, Helmut Reinke a,
Christine Fischer b, Peter Langer a,b,
*
a Institut fu¨r Chemie, Universita¨t Rostock, Albert-Einstein-Strasse 3a, 18059 Rostock, Germany
b Leibniz-Institut fu¨r Katalyse e. V. an der Universita¨t Rostock, Albert-Einstein-Strasse 29a, 18059 Rostock, Germany
Received 7 January 2008; received in revised form 4 February 2008; accepted 5 February 2008
Available online 8 February 2008
Abstract
Functionalized diaryl sulfides were prepared based on one-pot cyclizations of 1,3-bis(trimethylsilyloxy)-1,3-butadienes.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Arenes; Cyclizations; Diaryl sulfides; Silyl enol ethers
1. Introduction
sometimes be difficult. In addition, the synthesis of the starting
materials, substituted arenes and thiophenols, can be a difficult
task.
A variety of pharmacologically relevant diaryl sulfides
(diaryl thioethers) have been isolated as natural products.1
Non-natural diaryl sulfides are also of considerable pharmaco-
logical relevance. For example, fluorinated diaryl sulfides have
been reported to act as serotonin transporter ligands.2 Most of
the known synthetic approaches to diaryl sulfides are based on
the formation of a carbonesulfur bond. Classic syntheses
(such as the reaction of copper thiolates with aryl halides or
the reduction of aryl sulfones or aryl sulfoxides) are often lim-
ited by their harsh conditions, low regioselectivity, narrow pre-
parative scope, use of toxic reagents (such as HMPTA), or by
the formation of polysulfides.3 In recent years, transition
metal-catalyzed reactions for the synthesis of diaryl sulfides
were developed, which proceed under mild conditions (Buch-
waldeHartwig reaction and related transformations).4,5 Metal-
free reactions have also been reported.6 Despite their great
synthetic usefulness, the synthesis of highly substituted and
sterically encumbered products by these methods can
An alternative approach to diaryl sulfides relies on cycliza-
tion reactions of arylthio-containing building blocks. In contrast
to other methods, this approach relies on the assembly of the
arene moiety by formation of two carbonecarbon bonds. Only
a few examples of this type of reaction have been reported to
date. For example, Hilt and co-workers reported an efficient syn-
thesis of diaryl sulfides by cobalt(I)-catalyzed [4þ2] cycloaddi-
tion of alkynyl sulfides with 1,3-butadienes.7 Chan and Prasad
reported the synthesis of 2-(thiophenoxy)benzoates based on
the cyclization of 1-methoxy-3-thiophenoxy-1-trimethylsilyl-
oxy-1,3-butadiene with 3-siloxy-2-en-1-ones.8 DielseAlder re-
actions of this compound have also been reported.9 Recently, we
reported10 the synthesis of diaryl sulfides based on formal [3þ3]
cyclizations11 of 1,3-bis(trimethylsilyloxy)-1,3-butadienes.12
These reactions provide a convenient and regioselective ap-
proach to sterically encumbered and functionalized diaryl sul-
fides, which are not readily available by other methods.
Herein, full details of the methodology and a comprehensive
study of its preparative scope are reported. In addition to the re-
sults reported in our preliminary communication, we herein
* Corresponding author. Tel.: þ49 381 4986410; fax: þ49 381 4986412.
E-mail address: peter.langer@uni-rostock.de (P. Langer).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.02.010

M.A. Rashid et al. / Tetrahedron 64 (2008) 3782e3793
3783
report the synthesis of diaryl sulfides by cyclization of novel
4-thioaryloxy-1,3-bis(trimethylsilyloxy)-1,3-butadienes with
1,1-diacetylcyclopropane, 3-formylchromone and chromone.
2. Results and discussion
The novel 2-thiophenoxy-3-silyloxy-2-en-1-ones 4aee
were prepared by silylation of 3-(thiophenoxy)pentane-2,4-
diones 3aee, which are available by reaction of 3-chloropen-
tane-2,4-dione (2) with thiophenols 1aee (Scheme 1, Table
1).13 1,3-Diones 3 are completely enolized in solution and in
the solid state. The solid state structures of 3b and 3c were
confirmed by X-ray crystal structure analyses (Figs. 1
and 2).14 The TiCl4-mediated formal [3þ3] cyclization of 1,3-
bis(trimethylsilyloxy)-1,3-dienes 5aed, prepared from the cor-
responding b-ketoesters,15 afforded the diaryl sulfides 6aej.
Figure 1. ORTEP plot of 3b (the position of the H atom between O1 and O1
was calculated from the difference map and refined freely).
OH
O
O
O
SH
Me
Me
R1
Me
Me
S
Cl
2
R1
i
R2
R2
3a-e
1a-e
ii
OH
S
O
R3
OR4
Me3SiO OSiMe3
Me3SiO
Me
O
R3
OR4
Me
Me
Me
5a-d
S
iii
R1
R1
Figure 2. ORTEP plot of 3c (the position of the H atom between O1 and O1
was calculated from the difference map and refined freely).
R2
R2
For substituents R1 - R4,
see Tables 1 and 2
6a-j
4a-e
employed as the Lewis acid. All structures were established by
spectroscopic methods. The structure of 6b was independently
confirmed by X-ray crystal structure analyses (Fig. 3).14
The ethyl 4-(thioaryloxy)acetoacetates 7aed were prepared
by reaction of ethyl 4-chloroacetoacetate with thiophenols
1aed, which were transformed into the novel 4-thioaryloxy-
1,3-bis(trimethylsilyloxy)-1,3-butadienes 9aed (Scheme 2,
Scheme 1. Synthesis of 6aej. Reagents and conditions: (i) method A: pyri-
dine, MeOH, 0/20 ꢀC, 6 h; method B: piperidine, CH2Cl2, MeOH, 0/
20 ꢀC, 6 h; (ii) Me3SiCl, NEt3, C6H6, 20 ꢀC, 72 h; (iii) TiCl4, CH2Cl2,
ꢁ78/20 ꢀC, 20 h.
The best yields were obtained when the reactions were car-
ried out in a highly concentrated solution and when TiCl4 was
Table 1
Synthesis of 6aej
Compounds 3 and 4
Compound 5
Compound 6
R1
R2
R3
R4
%a (3)b
%a (4)
%a (6)
a
a
a
b
b
b
c
d
e
e
a
a
b
c
a
b
c
d
e
f
H
H
H
Me
Et
72 (A)
81
48
40
40
43
35
38
36
33
32
30
H
H
Me
Et
H
H
Et
d
b
c
H
OMe
OMe
OMe
Br
H
Et
33 (B)
90
H
Me
Et
Et
H
Et
a
b
a
b
g
h
i
H
H
Me
Et
28 (B)
81 (B)
73 (B)
79
92
81
H
Me
H
Me
H
OMe
OMe
Me
Et
j
H
Me
Yields of isolated products.
In brackets: method for the synthesis of 3 (see Section 3).
b

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M.A. Rashid et al. / Tetrahedron 64 (2008) 3782e3793
Me3SiO
S
OSiMe3
OEt
OH
R3
O
S
9a-d
OEt
i
R1
Me3SiO
O
R1
R2
R2
R2
R2
+
R3
4a,11a-d
12a-h
Scheme 3. Synthesis of 12aeh. Reagents and conditions: (i) TiCl4, CH2Cl2,
ꢁ78/20 ꢀC, 20 h.
Table 3
Synthesis of 12aeh
a
Compounds Compound 9 Compound 12
4a and 11
R1
H
R2
R3
%
(12)
11a
11b
11c
11d
4a
a
b
a
a
a
b
c
a
b
c
d
e
f
Me
H
H
48
35
37
33
OMe Et
H
H
H
Me Cl
Me Me
Figure 3. ORTEP plot of 6b.
Me PhS 34
4a
OMe Me PhS 34
O
O
11c
11c
a
g
h
Me
Cl
Me Cl
Me Cl
30
34
O
O
Cl
d
OEt
S
i
OEt
Yields of isolated products.
+
R
SH
7a-d
R
The [3þ3] cyclization of 1,3-bis(trimethylsilyloxy)-1,3-di-
1a-d
ii
enes 9aed with 3-silyloxy-2-en-1-ones 4a and 11aed afforded
the diaryl sulfides 12aeh (Scheme 3, Table 3). Products 12e
and 12f represent novel 1,3-bis(sulfides).
Me3SiO
S
O
Me3SiO OSiMe3
S
iii
OEt
The TiBr4-mediated cyclization of 1,3-bis(silyloxy)-1,3-di-
ene 9a with 1,1-diacetylcyclopropane (13) afforded the 3-thio-
phenoxysalicylate 14 containing a remote bromide function
(Scheme 4). Its formation can be explained by a domino
‘[3þ3]-cyclization/homo-Michael’ reaction.18
OEt
R
9a-d
8a-d
R
iv
OMe OMe
OMe
OH
O
MeO
S
OEt
OSiMe3
OEt
Me3SiO
S
R
OH
O
10a,b
S
9a
OEt
Me
i
Scheme 2. Synthesis of 10a and 10b. Reagents and conditions: (i) NEt3,
CH2Cl2, 30 min, 0 ꢀC; (ii) Me3SiCl, NEt3, C6H6, 20 ꢀC, 72 h; (iii) LDA,
THF, ꢁ78/20 ꢀC; (iv) method A: TiCl4, CH2Cl2, ꢁ78/20 ꢀC, 20 h; method
B: Me3SiOTf (0.1 equiv), CH2Cl2, ꢁ78/20 ꢀC, 20 h.
Me
O
O
+
Br
14 (45%)
Me
Me
13
Table 2
Synthesis of 10a and 10b
Scheme 4. Synthesis of 14. Reagents and conditions: (i) TiBr4, CH2Cl2,
ꢁ78/20 ꢀC, 20 h.
Compounds 7e10
R
%a (7)
%a (8)
%a (9)
%a (10)
a
b
c
d
a
H
80
81
77
84
84
78
85
90
89
85
80
87
31b (52)c
TheMe3SiOTf-catalyzedreactionof1,3-bis(silyloxy)-1,3-di-
enes 9aed with 3-formylchromones 15aee afforded the highly
functionalized diaryl sulfides 16aee (Scheme 5, Table 4). The
b
OMe
Me
Cl
30 (42)c
dd
dd
OSiMe3
OEt
Me3SiO
S
Yields of isolated products.
Method A.
Method B (see Ref. 12).
b
c
d
O
O
R2
OEt
OH
9a-d
R1
Experiment was not carried out.
i , ii
O
O
H
OH
R2
+
Table 2). The synthesis of 7a has been previously reported.16
The TiCl4-mediated [3þ3] cyclization of 9a and 9b with
1,1,3,3-tetramethoxypropane afforded the diaryl sulfides 10a
and 10b, respectively. The employment of catalytic amounts
of TMSOTf (0.1 equiv)17 rather than stoichiometric amounts
of TiCl4 resulted in an increase of the yield.
S
R1
O
15a-e
16a-e
Scheme 5. Synthesis of 16aee. Reagents and conditions: (i) Me3SiOTf
(0.3 equiv), 20 ꢀC, 10 min; (ii) (1): 9aed (1.3 equiv), CH2Cl2, 0/20 ꢀC,
12 h; (2) HCl (10%).

M.A. Rashid et al. / Tetrahedron 64 (2008) 3782e3793
3785
Table 4
Synthesis of 16aee
3. Experimental section
Compound 9
Compound 15
Compound 16
R1
R2
%a (16)
3.1. General comments
a
b
c
d
d
a
a
b
c
a
b
c
H
Cl
Et
Br
Me
H
47
38
45
40
50
OMe
Me
Cl
All solvents were dried by standard methods and all reac-
tions were carried out under an inert atmosphere. For 1H
and 13C NMR spectra the deuterated solvents indicated were
used. Mass spectrometric (MS) data were obtained by electron
ionization (EI, 70 eV), chemical ionization (CI, H2O) or elec-
trospray ionization (ESI). For preparative scale chromatogra-
phy, silica gel (60e200 mesh) was used. Melting points are
uncorrected.
d
e
d
e
Cl
Yields of isolated products.
3.2. General procedures for the synthesis of 3-thioaryloxy-
2,4-pentanediones 3aee
Method A. To a stirred pyridine solution (0.1 mL) of
3-chloro-2,4-pentanedione (2) (1.0 mmol) was slowly added
a mixture of benzenethiol 1 (1.0 mmol) and methanol
(0.1 mL) at 0 ꢀC. The mixture was stirred at room temperature
for 6 h. Precipitated pyridine hydrochloride was removed by
filtration and washed with ether (3ꢂ15 mL). The combined fil-
trates were washed with water (5ꢂ25 mL) and dried over
Na2SO4. The solution was filtered and the solvent of the fil-
trate was removed under reduced pressure. The residue was
purified by chromatography (silica gel, EtOAc/n-heptane).
Method B. To a mixture of 3-chloro-2,4-pentanedione (2)
(1.0 mmol) and benzenethiol 1 (1.0 mmol) was dropwise
added (within 10 min) a mixture of piperidine (1.0 mmol)
and dichloromethane (0.1 mL) at 0 ꢀC. After stirring for
5 min, MeOH (0.4 mL) was added and the solution was stirred
for 6 h at room temperature. Precipitated pyridine hydrochlo-
ride was removed by filtration and washed with ether
(3ꢂ15 mL). The combined filtrates were washed with water
(5ꢂ25 mL) and dried over Na2SO4. The solution was filtered
and the solvent of the filtrate was removed under reduced pres-
sure. The residue was purified by chromatography (silica gel,
EtOAc/n-heptane).
Figure 4. ORTEP plot of 16b (the hydrogen atom positions at O1 and O5 were
calculated from the difference map and refined freely).
products are formed by a domino ‘Michael/retro-Michael/
Mukaiyama-aldol’reaction.19 The structure of 16b was indepen-
dently confirmed by X-ray crystal structure analysis (Fig. 4).14
The Me3SiOTf-catalyzed reaction of 9a with chromone
(17) afforded the condensation product 18, which was trans-
formed (without purification) into diaryl sulfide 19 by treat-
ment with triethylamine (Scheme 6). The formation of 19
can be explained by a domino ‘retro-Michael/aldol/lactoniza-
tion’ reaction.20
Me3SiO OSiMe3
O
O
O
O
S
OEt
OEt
9a
3.2.1. 3-Thiophenoxy-2,4-pentanedione (3a)
O
O
i
Method A. Starting with 3-chloro-2,4-pentanedione (5.5 mL,
48.9 mmol), thiophenol (5.0 mL, 48.9 mmol), pyridine (3.9 mL,
48.9 mmol) and methanol (4.9 mL), 3a was isolated as a colour-
less oil (7.30 g, 72%). 1H NMR (250 MHz, CDCl3): d¼2.26 (s,
6H, CH3), 7.01(dd, 2H, J¼1.2, 8.2 Hz, ArH), 7.07 (m, 1H, ArH),
(m, 2H, ArH); 13C NMR (75 MHz, CDCl3): d¼24.7 (2C, CH3),
102.0 (C), 125.0 (2C, CH), 125.6 (CH), 129.6 (2C, CH), 138.1
(C), 198.7 (2C); IR (neat): ~n¼3072 (m), 2925 (m), 2853 (w),
1725 (m), 1582 (s), 1478 (s), 1259 (s), 1069 (m), 739 (s), 690
(s) cmꢁ1; GCeMS (EI, 70 eV): m/z (%): 208.1 (Mþ, 100),
166.1 (30), 147.1 (25), 123.1 (16), 103.1 (18), 88 (13), 43.1
(54); elemental analysis: calcd (%) for C11H12O2S (208.0): C
63.43, H 5.81; found: C 62.9, H 6.40.
S
+
18
17
ii
S
OH
O
O
19 (70% from 17)
Scheme 6. Synthesis of 19. (i) (1) Me3SiOTf (1.3 equiv), 20 ꢀC, 1 h; (2) 9a
(1.3 equiv), CH2Cl2, 0/20 ꢀC, 12 h; (3) HCl (10%); (ii) NEt3 (2.0 equiv),
EtOH, 20 ꢀC, 12 h.
In conclusion, a variety of functionalized and sterically
encumbered diaryl sulfides were prepared by cyclization reac-
tions of 1,3-bis(trimethylsilyloxy)-1,3-butadienes. The prod-
ucts are not readily available by other methods.
3.2.2. 3-(4-Methoxythiophenoxy)-2,4-pentanedione (3b)
Method B. Starting with 3-chloro-2,4-pentanedione (3.8 mL,
33.3 mmol), 4-methoxythiophenol (4.1 mL, 33.3 mmol),

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M.A. Rashid et al. / Tetrahedron 64 (2008) 3782e3793
piperidine (3.3 mL, 33.3 mmol), CH2Cl2 (3 mL) and methanol
(13.5 mL), 3b was isolated as a colourless solid (2.80 g, 33%),
mp¼88 ꢀC. 1H NMR (250 MHz, CDCl3): d¼2.32 (s, 6H,
CH3), 3.75 (s, 3H, OCH3), 6.81 (d, 2H, J¼9.1 Hz, ArH), 7.01
(d, 2H, J¼9.1 Hz, ArH); 13C NMR (75 MHz, CDCl3): d¼24.3
(2C, CH3), 55.2 (CH3), 102.9 (C), 114.8 (2C, CH), 126.8 (2C,
CH), 128.3, 157.8 (C), 197.9 (2C); IR (KBr): ~n¼2998 (m),
2961 (m), 2836 (w), 1492 (s), 1294 (s), 1172 (s), 1330 (s), 910
(w), 819 (s), 516 (w) cmꢁ1; GCeMS (EI, 70 eV): m/z (%):
238 (Mþ, 57), 196 (6), 151 (7), 108.1 (100), 59.1 (4), 43.1
(39); elemental analysis: calcd (%) for C12H14O3S (238.06): C
60.48, H 5.92; found: C 60.71, H 5.99.
70 eV): m/z (%): 238.1 (Mþ, 100), 196.1 (50), 153.1 (32),
108.1 (24), 88.1 (18), 43.1 (9); elemental analysis: calcd (%)
for C12H14O3S (238.06): C 60.48, H 5.92; found: C 60.01, H 5.88.
3.3. General procedure for the synthesis of diaryl thioethers
6aej and 12aeh
To a dichloromethane solution (2 mL/mmol) of 4 (1.0 mmol)
and 5 (1.0 mmol) was added TiCl4 (1.0 mmol) at ꢁ78 ꢀC. The
solution was allowed to warm to ambient temperature within
20 h. To the solution was added a saturated solution of NaHCO3
(15 mL). The organic and the aqueous layers were separated and
the latter was extracted with diethyl ether (3ꢂ20 mL). The
filtrate was concentrated in vacuo and the residue was purified
by chromatography (silica gel, EtOAc/n-heptane¼1:4).
3.2.3. 3-(4-Bromothiophenoxy)-2,4-pentanedione (3c)
Method B. Starting with 3-chloro-2,4-pentanedione (1.5 mL,
13.2 mmol), 4-bromothiophenol (2.50 g, 13.2 mmol), piperi-
dine (1.3 mL, 13.2 mmol), CH2Cl2 (1.3 mL) and methanol
(5 mL), 3c was isolated as a colourless solid (1.00 g, 28%),
mp¼79 ꢀC. 1H NMR (250 MHz, CDCl3): d¼2.29 (s, 6H,
CH3), 6.92 (d, 2H, J¼8.8 Hz, ArH), 7.35 (d, 2H, J¼8.9 Hz,
ArH); 13C NMR (75 MHz, CDCl3): d¼24.7 (2C, CH3), 101.5,
119.2 (C), 126.6 (2C, CH), 132.6 (2C, CH), 137.4 (C), 198.7
(2C); IR (KBr): ~n¼3433 (w), 1557 (s), 1472 (s), 1386 (s),
1256 (w), 1020 (m), 909 (w), 809 (s), 479 (w) cmꢁ1; GCeMS
(EI, 70 eV): m/z (%): 288 (Mþ, 81Br, 98), 286 (Mþ, 79Br, 96),
246 (43), 244 (41), 192 (40), 164.1 (42), 117 (33), 88 (27),
43.1 (100); elemental analysis: calcd (%) for C11H11BrO2S
(285.96): C 46.01, H 3.86; found: C 45.98, H 3.94.
3.3.1. Methyl 4,6-dimethyl-5-(thiophenoxy)salicylate (6a)
Starting with 3-(silyloxy)alk-2-en-1-one 4a (200 mg,
0.7 mmol), 1,3-bis(silyl enol ether) 5a (185 mg, 0.71 mmol)
and TiCl4 (0.08 mL, 0.71 mmol), 6a was isolated as a colourless
solid (99 mg, 48%), mp¼83 ꢀC. 1H NMR (250 MHz, CDCl3):
d¼2.40 (s, 3H, CH3), 2.72 (s, 3H, CH3), 3.95 (s, 3H, OCH3),
6.89 (d, 2H, J¼8.2 Hz, ArH), 6.76 (s, 1H, ArH), 6.91 (s, 1H,
ArH), 7.05 (br t, 1H, J¼7.2 Hz, ArH), 7.18 (br t, 1H,
J¼7.4 Hz, ArH), 11.17 (s, 1H, OH); 13C NMR (75 MHz,
CDCl3): d¼21.4, 2.7, 52.3 (CH3), 112.4 (C), 117.7 (CH),
122.7 (C), 124.6 (CH), 125.2 (2C, CH), 128.9 (2C, CH),
138.2, 147.1, 151.4, 162.5, 171.8 (C); IR (KBr): ~n¼3061 (m),
2954 (m), 1663 (s), 1478 (s), 1360 (s), 1233 (s), 1187 (m),
1024 (m), 947 (w), 740 (s), 690 (m), 629 (w) cmꢁ1; GCeMS
(EI, 70 eV): m/z (%): 288.1 (Mþ, 57), 256.1 (100), 185.1 (7),
91 (6); elemental analysis: calcd (%) for C16H16O3S (288.08):
C 66.64, H 5.59; found: C 66.81, H 5.68.
3.2.4. 3-(4-Methylthiophenoxy)-2,4-pentanedione (3d)
Method B. Starting with 3-chloro-2,4-pentanedione (9.1 mL,
80.5 mmol), 4-methylthiophenol (10.00 g, 80.5 mmol), piperi-
dine (8 mL, 80.5 mmol), CH2Cl2 (6 mL) and methanol
(30 mL), 3d was isolated as a colourless solid (14.50 g, 81%),
mp¼56 ꢀC. 1H NMR (250 MHz, CDCl3): d¼2.27 (s, 3H,
CH3), 2.31 (s, 6H, CH3), 6.96 (d, 2H, J¼8.2 Hz, ArH), 7.07
(d, 2H, J¼8.0 Hz, ArH); 13C NMR (75 MHz, CDCl3): d¼24.3
(2C, CH3), 55.6 (CH3), 101.1 (C), 110.9 (2C, CH), 117.3,
130.4 (CH), 139.6, 160.7 (C), 198.7 (2C); IR (KBr): ~n¼3073
(w), 2918 (w), 1576 (s), 1399 (s), 1259 (m), 1085 (w), 1016
(s), 909 (m), 806 (s), 506 (w) cmꢁ1; GCeMS (EI, 70 eV): m/z
(%): 222.1 (Mþ, 100), 180.1 (27), 146.1 (17), 117.1 (25), 88.1
(27), 43.1 (51); elemental analysis: calcd (%) for C12H12O2S
(222.07): C 64.83, H 6.35; found: C 64.94, H 6.31.
3.3.2. Ethyl 3,4,6-trimethyl-5-(thiophenoxy)salicylate (6b)
Starting with 3-(siloxy)alk-2-en-1-one 4a (200 mg,
0.71 mmol), 1,3-bis(silyl enol ether) 5b (204 mg, 0.7 mmol)
and TiCl4 (0.08 mL, 0.7 mmol), 6b was isolated as a colourless
solid (90 mg, 40%), mp¼122 ꢀC. 1H NMR (250 MHz, CDCl3):
d¼1.42 (t, 3H, J¼7.1 Hz, CH3), 2.24 (s, 3H, CH3), 2.47 (s, 3H,
CH3), 2.74 (s, 3H, CH3), 4.44 (q, 2H, J¼7.1 Hz, OCH2), 6.90
(m, 2H, ArH), 7.06 (br t, 1H, J¼7.3 Hz, ArH), 7.18 (m, 2H,
ArH), 11.52 (s, 1H, OH); 13C NMR (75 MHz, CDCl3):
d¼12.7, 14.1, 19.5, 21.6 (CH3), 61.8 (CH2), 112.0, 122.5,
123.9 (C), 124.5 (CH), 125.2 (2C, CH), 128.9 (2C, CH),
138.7, 143.7, 149.1, 160.6, 171.9 (C); IR (KBr): ~n¼3069 (m),
2980 (m), 1644 (s), 1548 (m), 1395 (s), 1343 (s), 1146 (s),
1083 (m), 1025 (s), 868 (w), 735 (s), 688 (m) cmꢁ1; GCeMS
(EI, 70 eV): m/z (%): 316 (Mþ, 38), 270 (100), 242 (20), 165
(10), 77 (11); elemental analysis: calcd (%) for C18H20O3S
(316.11): C 68.33, H 6.37; found: C 68.23, H 6.48.
3.2.5. 3-(3-Methoxythiophenoxy)-2,4-pentanedione (3e)
MethodB. Starting with3-chloro-2,4-pentanedione (3.85 mL,
34.1 mmol), 3-methoxythiophenol (4.23 mL, 34.1 mmol), piper-
idine (3.38 mL, 34.1 mmol), CH2Cl2 (3 mL) and methanol
1
(13 mL), 3e was isolated as a colourless oil (5.90 g, 73%). H
NMR (250 MHz, CDCl3): d¼2.30 (s, 6H, CH3), 3.75 (s, 3H,
OCH3), 6.60 (m, 1H, ArH), 6.63 (br d, 1H, J¼7.6 Hz, ArH),
6.66 (s, 1H, ArH), 7.16 (t, 1H, J¼7.6 Hz, ArH); 13C NMR
(75 MHz, CDCl3): d¼21.1 (CH3), 24.8 (2C, CH3), 102.4 (C),
125.3 (2C, CH), 130.3 (CH), 134.5, 135.5 (C), 198.6 (2C); IR
(neat): ~n¼3061 (w), 2958 (m), 2835 (m), 1590 (s), 1425 (s),
1182 (m), 857 (m), 686 (s), 534 (w) cmꢁ1; GCeMS (EI,
3.3.3. Ethyl 4,6-dimethyl-3-ethyl-5-(thiophenoxy)salicylate
(6c)
Starting with 3-(silyloxy)alk-2-en-1-one 4a (200 mg,
0.7 mmol), 1,3-bis(silyl enol ether) 5c (214 mg, 0.7 mmol) and
TiCl4 (0.08 mL, 0.7 mmol), 6c was isolated as a yellow highly

M.A. Rashid et al. / Tetrahedron 64 (2008) 3782e3793
3787
viscous oil (90 mg, 40%). 1H NMR (250 MHz, CDCl3): d¼1.04
(t, 3H, J¼7.4 Hz, CH3), 1.32 (t, 3H, J¼7.1 Hz, CH3), 2.40 (s,
3H, CH3), 2.64 (s, 3H, CH3), 2.68 (q, 2H, J¼7.4 Hz, OCH2),
4.35 (q, 2H, J¼7.1 Hz, OCH2), 6.82 (dd, 2H, J¼1.5, 8.3 Hz,
ArH), 6.97 (br t, 1H, J¼7.3 Hz, ArH), 7.10 (br t, 2H, J¼7.4 Hz,
ArH), 11.38 (s, 1H, OH); 13C NMR (75 MHz, CDCl3): d¼12.1,
13.1, 17.6 (CH3), 19.4 (CH2), 20.5 (CH3), 60.8 (CH2), 111.1,
121.6 (C), 123.4 (CH), 124.1 (2C, CH), 127.8 (2C, CH), 129.0,
137.7, 142.9, 147.4, 159.4, 170.9 (C); IR (neat): ~n¼3057 (m),
2970 (s), 2873 (m), 1732 (w), 1653 (s), 1583 (s), 1551 (s), 1439
(s), 1230 (s), 1084 (m), 866 (w), 813 (m), 689 (m) cmꢁ1; GCe
MS (EI, 70 eV): m/z (%): 330.2 (Mþ, 63), 284.1 (100), 256.1
(24), 139 (9), 165.1 (7), 91.1 (8); HRMS (EI): calcd for
C19H22O3S [Mþ]þ: 330.12828, found 330.12842.
and TiCl4 (0.15 mL, 1.3 mmol), 6f was isolated as a colourless
highly viscous oil (175 mg, 38%). 1H NMR (250 MHz,
CDCl3): d¼1.09 (t, 3H, J¼7.4 Hz, CH3), 1.37 (t, 3H,
J¼7.0 Hz, CH3), 2.47 (s, 3H, CH3), 2.71 (s, 3H, CH3), 2.73
(q, 2H, J¼7.3 Hz, OCH2), 3.71 (s, 3H, OCH3), 4.40 (q, 2H,
J¼7.1 Hz, OCH2), 6.73 (d, 2H, J¼9.1 Hz, ArH), 6.83 (d,
2H, J¼9.1 Hz, ArH), 11.38 (s, 1H, OH); 13C NMR
(75 MHz, CDCl3): d¼13.2, 14.1, 18.7 (CH3), 20.4 (CH2),
21.7, 55.2 (CH3), 61.7 (CH2), 112.1 (C), 114.6 (2C, CH),
124.0 (C), 127.1 (2C, CH), 129.3, 129.9, 143.5, 148.2,
157.3, 160.2, 171.9 (C); IR (neat): ~n¼2968 (m), 2834 (m),
1729 (w), 1652 (s), 1592 (s), 1437 (s), 1372 (s), 1260 (s),
1108 (s), 865 (w), 820 (s), 622 (m), 516 (w) cmꢁ1; GCe
MS (EI, 70 eV): m/z (%): 360 (Mþ, 83), 300 (100), 286
(33), 271 (10), 178 (9), 57 (6); elemental analysis: calcd
(%) for C20H24O4S (360.13): C 66.64, H 6.71; found: C
66.04, H 6.97.
3.3.4. Ethyl 4,6-dimethyl-5-(4-methoxythiophenoxy)-
salicylate (6d)
Starting with 3-(silyloxy)alk-2-en-1-one 4b (300 mg,
0.96 mmol), 1,3-bis(silyl enol ether) 5d (263 mg, 0.96 mmol)
and TiCl4 (0.1 mL, 0.96 mmol), 6d was isolated as a colourless
solid (138 mg, 43%), mp¼77 ꢀC. 1H NMR (250 MHz, CDCl3):
d¼1.38 (t, 3H, J¼7.0 Hz, CH3), 2.39 (s, 3H, CH3), 2.73 (s, 3H,
CH3), 3.71 (s, 3H, OCH3), 4.40 (q, 2H, J¼7.1 Hz, OCH2), 6.73
(d, 2H, J¼9.1 Hz, ArH), 6.81 (s, 1H, ArH), 6.84 (d, 2H,
J¼9.1 Hz, ArH), 11.10 (s, 1H, OH); 13C NMR (75 MHz,
CDCl3): d¼13.1, 20.5, 22.1, 54.3 (CH3), 60.8 (CH2), 111.4
113.7 (2C, CH), 116.5 (CH), 123.0 (C), 126.3 (2C, CH), 127.9,
145.8, 150.0, 156.5, 161.3, 170.3 (C); IR (KBr): ~n¼2991 (m),
2954 (m), 2833 (m), 1653 (s), 1558 (m), 1494 (s), 1450 (s),
1341 (s), 1286 (s), 1125 (w), 871 (m), 623 (m) cmꢁ1; GCeMS
(EI, 70 eV): m/z (%): 332.1 (Mþ, 84), 286 (100), 243 (10), 218
(11), 178 (8) 139 (7), 91 (6); elemental analysis: calcd (%) for
C18H20O4S (332.10): C 65.04, H 6.06; found: C 64.78, H 6.19.
3.3.7. Methyl 4,6-dimethyl-5-(4-bromothiophenoxy)-
salicylate (6g)
Starting with 3-(silyloxy)alk-2-en-1-one 4c (200 mg,
0.55 mmol), 1,3-bis(silyl enol ether) 5a (144 mg, 0.55 mmol)
and TiCl4 (0.06 mL, 0.55 mmol), 6g was isolated as a colour-
1
less solid (73 mg, 36%), mp¼114 ꢀC. H NMR (250 MHz,
CDCl3): d¼2.32 (s, 3H, CH3), 2.62 (s, 3H, CH3), 3.88 (s,
3H, OCH3), 6.68 (d, 2H, J¼8.5 Hz, ArH), 6.80 (s, 1H,
ArH), 7.20 (d, 2H, J¼8.5 Hz, ArH), 11.10 (s, 1H, OH); 13C
NMR (75 MHz, CDCl3): d¼20.3, 21.9, 51.3 (CH3), 11.5,
116.8 (C), 117.1 (CH), 121.1 (C), 12.7 (2C, CH), 130.9 (2C,
CH), 136.5, 146.1, 150.2, 161.7, 170.6 (C); IR (KBr):
~n¼3068 (w), 2953 (m), 1660 (s), 1594 (s), 1472 (s), 1355
(s), 1230 (s), 1188 (m), 1005 (s), 944 (w), 824 (w), 807 (s),
503 (w) cmꢁ1; GCeMS (EI, 70 eV): m/z (%): 368 (Mþ,
81Br, 49), 366 (Mþ, 79Br, 48), 336 (100), 334 (95), 184 (11),
127 (6), 91 (11); elemental analysis: calcd (%) for
C16H15BrO3S (365.99): C 52.33, H 4.12; found: C 52.18, H
4.31.
3.3.5. Ethyl 3,4,6-trimethyl-5-(4-methoxythiophenoxy)-
salicylate (6e)
Starting with 3-(silyloxy)alk-2-en-1-one 4b (300 mg,
0.96 mmol), 1,3-bis(silyl enol ether) 5b (277 mg, 0.96 mmol)
and TiCl4 (0.1 mL, 0.96 mmol), 6e was isolated as a colourless
oil (116 mg, 35%). 1H NMR (250 MHz, CDCl3): d¼1.32 (t, 3H,
J¼7.1 Hz, CH3), 2.14 (s, 3H, CH3), 2.39 (s, 3H, CH3), 2.66 (s,
3H, CH3), 3.66 (s, 3H, OCH3), 4.34 (q, 2H, J¼7.0 Hz, OCH2),
6.67 (d, 2H, J¼8.8 Hz, ArH), 6.78 (d, 2H, J¼8.8 Hz, ArH),
11.39 (s, 1H, OH); 13C NMR (75 MHz, CDCl3): d¼11.7, 13.1,
18.6, 20.7, 54.2 (CH3), 60.8 (CH2), 110.9, 113.6 (2C, CH),
122.8, 122.9 (C), 126.2 (2C, CH), 128.4, 142.3, 147.9, 156.3,
159.1, 170.9 (C); IR (KBr): ~n¼2978 (m), 2835 (m), 1645 (s),
1572 (s), 1491 (s), 1343 (s), 1287 (s), 1183 (s), 1099 (m), 868
(w), 800 (m), 621 (w) cmꢁ1; GCeMS (EI, 70 eV): m/z (%):
346 (Mþ, 83), 300 (100), 278 (14), 246 (23), 196 (26), 108
(36), 77 (14); elemental analysis: calcd (%) for C19H22O4S
(345.11): C 65.87, H 6.40; found: C 65.71, H 6.59.
3.3.8. Ethyl 3,4,6-trimethyl-5-(4-methylthiophenoxy)-
salicylate (6h)
Starting with 3-(silyloxy)alk-2-en-1-one 4d (500 mg,
1.8 mmol), 1,3-bis(silyl enol ether) 5b (520 mg, 1.8 mmol)
and TiCl4 (0.2 mL, 1.8 mmol), 6h was isolated as a colourless
solid (188 mg, 33%), mp¼75 ꢀC. 1H NMR (250 MHz,
CDCl3): d¼1.33 (t, 3H, J¼7.1 Hz, CH3), 2.15 (s, 3H, CH3),
2.18 (s, 3H, CH3), 2.38 (s, 3H, CH3), 2.65 (s, 3H, CH3),
4.35 (q, 2H, J¼7.3 Hz, CH2), 6.72 (d, 2H, J¼8.2 Hz, ArH),
6.92 (d, 2H, J¼8.2 Hz, ArH), 11.41 (s, 1H, OH); 13C NMR
(62 MHz, CDCl3): d¼12.9, 14.3, 19.7, 20.9, 21.7 (CH3),
61.9 (CH2), 112.4, 123.3, 124.0 (C), 125.4 (2C, CH), 129.8
(2C, CH), 134.4, 135, 143.7, 149.2, 160.6, 172.1 (C); IR
(KBr): ~n¼3015 (w), 2936 (m), 1647 (s), 1551 (m), 1490 (s),
1392 (s), 1288 (s), 1185 (s), 1100 (m), 1014 (m), 868 (w),
801 (s) cmꢁ1; GCeMS (EI, 70 eV): m/z (%): 330.1 (Mþ,
70), 284.1 (100), 256 (17), 241 (41), 165 (7), 91 (11); elemen-
tal analysis: calcd (%) for C19H22O3S (330.12): C 69.06, H
6.71; found: C 68.89, H 6.98.
3.3.6. Ethyl 4,6-dimethyl-3-ethyl-5-(4-methoxythiophenoxy)-
salicylate (6f)
Starting with 3-(silyloxy)alk-2-en-1-one 4b (400 mg,
1.3 mmol), 1,3-bis(silyl enol ether) 5c (387 mg, 1.3 mmol)

3788
M.A. Rashid et al. / Tetrahedron 64 (2008) 3782e3793
3.3.9. Methyl 4,6-dimethyl-5-(3-methoxythiophenoxy)-
salicylate (6i)
dichloromethane (146 mL), 7a was isolated as a colourless oil
1
(13.80 g, 80%). H NMR (250 MHz, CDCl3): d¼1.26 (t, 3H,
Starting with 3-(silyloxy)alk-2-en-1-one 4e (500 mg,
1.7 mmol), 1,3-bis(silyl enol ether) 5a (455 mg, 1.7 mmol)
and TiCl4 (0.18 mL, 1.7 mmol), 6i was isolated as a colourless
solid (174 mg, 32%), mp¼78 ꢀC. 1H NMR (250 MHz,
CDCl3): d¼2.28 (s, 3H, CH3), 2.60 (s, 3H, CH3), 3.59 (s,
3H, OCH3), 3.83 (s, 3H, OCH3), 6.32 (m, 1H, ArH), 6.37
(m, 1H, ArH), 6.48 (br m, 1H, ArH), 6.74 (s, 1H, ArH),
6.97 (t, 1H, J¼8.1 Hz, ArH), 11.01 (s, 1H, OH); 13C NMR
(62 MHz, CDCl3): d¼21.4, 23.1, 52.4, 55.2 (CH3), 109.8,
110.7 (CH), 112.2 (C), 117.4, 117.5 (CH), 122.3 (C), 129.5
(CH), 139.5, 147.0, 151.2, 159.9, 162.4, 171.6 (C); IR
(KBr): ~n¼3002 (w), 2947 (m), 1663 (s), 1591 (s), 1474 (s),
1357 (s), 1229 (s), 1110 (m), 1046 (s), 877 (w), 847 (w),
768 (s), 686 (w) cmꢁ1; GCeMS (EI, 70 eV): m/z (%): 318
(Mþ, 59), 286 (100), 256 (17), 225 (10), 179 (16), 91 (8),
57 (8); elemental analysis: calcd (%) for C17H18O4S
(318.09): C 64.13, H 5.70; found: C 64.41, H 5.93.
J¼7.1 Hz, CH3), 3.63 (s, 2H, CH2), 3.81 (s, 2H, CH2), 4.18
(q, 2H, J¼7.1 Hz, OCH2), 7.23e7.27 (m, 2H, ArH), 7.29e
7.31 (m, 1H, ArH), 7.32e7.37 (m, 2H, ArH); 13C NMR
(75 MHz, CDCl3): d¼14.4 (CH3), 44.3, 46.9, 61.9 (CH2),
127.6 (CH), 129.6 (2C, CH), 130.2 (2C, CH), 134.4, 167.4,
198.3 (C); IR (neat): ~n¼3059 (w), 2982 (m), 2937 (w), 1743
(s), 1716 (s), 1583 (m), 1439 (m), 1320 (s), 1188 (s), 1026
(s), 741 (s), 691 (s) cmꢁ1; GCeMS (EI, 70 eV): m/z (%):
238 (Mþ, 40), 192 (18), 166 (5), 150 (53), 123 (100), 110
(29), 77 (16), 65 (10); elemental analysis: calcd (%) for
C12H14O3S (238): C 60.48, H 5.92; found: C 59.90, H 5.91.
3.4.2. Ethyl 4-(4-methoxythiophenoxy)acetoacetate (7b)
Starting with 4-chloroacetoacetate (3.3 mL, 24.2 mmol),
thiophenol (3 mL, 25 mmol), NEt3 (3.6 mL, 25.5 mmol) and
dichloromethane (50 mL), 7b was isolated as a colourless oil
1
(5.40 g, 81%). H NMR (300 MHz, CDCl3): d¼1.11 (t, 3H,
J¼7.1 Hz, CH3), 3.48 (s, 2H, CH2), 3.52 (s, 2H, CH2), 3.62
(s, 3H, OCH3), 4.02 (q, 2H, J¼7.0 Hz, OCH2), 6.68 (d, 2H,
J¼8.9 Hz, ArH), 7.10 (d, 2H, J¼8.7 Hz, ArH); 13C NMR
(62 MHz, CDCl3): d¼14.4 (CH3), 46.2, 46.9 (CH2), 55.6
(CH3), 61.8 (CH2), 115.2 (2C, CH), 124.5 (C), 134.3 (2C,
CH), 159.2 (C), 167.7 (C), 198.2 (C); IR (neat): ~n¼2981
(m), 2939 (w), 2837 (w), 1743 (s), 1714 (s), 1592 (s), 1495
(s), 1367 (m), 1284 (s), 1181 (s), 1029 (s), 828 (m), 638
(w), 525 (w) cmꢁ1; GCeMS (EI, 70 eV): m/z (%): 268 (Mþ,
24), 222 (16), 196 (26), 180 (12), 153 (100), 139 (28), 109
(39), 96 (10), 69 (20); elemental analysis: calcd (%) for
C13H16O3S: C 59.19, H 6.01; found: C 58.34, H 6.34.
3.3.10. Ethyl 3,4,6-trimethyl-5-(3-methoxythiophenoxy)-
salicylate (6j)
Starting with 3-(silyloxy)alk-2-en-1-one 4e (500 mg,
1.7 mmol), 1,3-bis(silyl enol ether) 5b (490 mg, 1.7 mmol)
and TiCl4 (0.18 mL, 1.7 mmol), 6j was isolated as a colourless
1
oil (177 mg, 30%). H NMR (250 MHz, CDCl3): d¼1.33 (t,
3H, J¼7.1 Hz, CH3), 2.15 (s, 3H, CH3), 2.38 (s, 3H, CH3),
2.65 (s, 3H, CH3), 3.64 (s, 3H, OCH3), 4.35 (q, 2H,
J¼7.1 Hz, OCH2), 6.38 (m, 1H, ArH), 6.42 (m, 1H, ArH),
6.52 (br m, 1H, ArH), 7.02 (t, 1H, J¼8.2 Hz, ArH), 11.44
(s, 1H, OH); 13C NMR (75 MHz, CDCl3): d¼11.7, 13.1,
18.5, 20.5, 54.1 (CH3), 60.8 (CH2), 108.8, 109.9 (CH), 110.9
(C), 116.5 (CH), 121.2, 122.9 (C), 128.7 (CH), 139.2, 142.8,
148.1, 159.0, 159.6, 170.9 (C); IR (KBr): ~n¼3058 (w), 2933
(s), 1729 (w), 1652 (s), 1590 (s), 1475 (s), 1376 (s), 1283
(s), 1242 (s), 1181 (s), 1045 (s), 860 (s), 686 (m), 566 (w)
cmꢁ1; GCeMS (EI, 70 eV): m/z (%): 346 (Mþ, 80), 300
(100), 256 (17), 257 (20), 164 (6), 69 (13), 57 (5); elemental
analysis: calcd (%) for C19H22O4S (346.12): C 65.87, H
6.40; found: C 65.47, H 6.64.
3.4.3. Ethyl 4-(4-methylthiophenoxy)acetoacetate (7c)
Starting with 4-chloroacetoacetate (5.3 mL, 39.0 mmol),
thiophenol (5.00 g, 40.2 mmol), NEt3 (5.7 mL, 41.0 mmol)
and dichloromethane (78 mL), 7c was isolated as a colourless
1
oil (7.8 g, 77%). H NMR (300 MHz, CDCl3): d¼1.16 (t, 3H,
J¼7.1 Hz, CH3), 2.22 (s, 3H, CH3), 3.53 (s, 2H, CH2), 3.65 (s,
2H, CH2), 4.07 (q, 2H, J¼7.0 Hz, OCH2), 7.01 (d, 2H,
J¼8.1 Hz, ArH), 7.17 (d, 2H, J¼8.2 Hz, ArH); 13C NMR
(75 MHz): d¼14.4, 21.4 (CH3), 42.2, 43.6, 61.8 (CH2),
130.4 (2C, CH), 130.8 (2C, CH), 131.5, 137.9, 167.4, 198.3
(C); IR (neat): ~n¼2981 (m), 2924 (w), 1744 (s), 1715 (s),
1652 (w), 1494 (m), 1320 (s), 1186 (s), 1030 (s), 942 (w),
800 (s), 733 (w); MS (EI, 70 eV): m/z (%): 252 (Mþ, 30),
206 (15), 164 (28), 137 (100), 119 (9), 91 (24), 77 (7), 45
(28); elemental analysis: calcd (%) for C13H16O3S (252.0):
C 61.88, H 6.39; found: C 61.40, H 6.34.
3.4. General procedure for the synthesis of ethyl
4-(thioaryloxy)acetoacetates 7aeb
A solution of 4-chloroacetoacetate (1.0 mmol), NEt3
(1.05 mmol) and thiophenol 1 (1.03 mmol) in CH2Cl2
(2 mL) was stirred at 0 ꢀC for 30 min. The reaction mixture
was diluted with EtOAc and washed with an aqueous solution
of NaOH (1 M), hydrochloric acid (1 M) and brine. The com-
bined organic layers were dried (Na2SO4), filtered and the sol-
vent of the filtrate was removed under reduced pressure. The
residue was purified by chromatography (silica gel, EtOAc/
n-heptane).
3.4.4. Ethyl 4-(4-methylthiophenoxy)acetoacetate (7d)
Starting with 4-chloroacetoacetate (13.8 mL, 101.1 mmol),
4-chlorothiophenol (15.00 g, 104.0 mmol), NEt3 (14.7 mL,
106.1 mmol) and dichloromethane (202 mL), 7d was isolated
as a colourless oil (23.8 g, 84%). 1H NMR (250 MHz, CDCl3):
d¼1.21 (t, 3H, J¼7.0 Hz, CH3), 3.58 (s, 2H, CH2), 3.76 (s, 2H,
3.4.1. Ethyl 4-(thiophenoxy)acetoacetate (7a)
Starting with 4-chloroacetoacetate (10 mL, 73 mmol), thio-
phenol (7.7 mL, 75.5 mmol), NEt3 (10.7 mL, 76.7 mmol) and
CH2), 4.11 (q, 2H, J¼7.4 Hz, OCH2), 7.23 (m, 4H, ArH); 13
C
NMR (62 MHz): d¼14.1 (CH3), 44.0, 46.5, 61.5 (CH2), 129.3

M.A. Rashid et al. / Tetrahedron 64 (2008) 3782e3793
3789
(2C, CH), 130.8 (2C, CH), 132.7, 133.2, 172.2, 197.7 (C); IR
(neat): ~n¼2982 (m), 2937 (w), 1743 (s), 1716 (s), 1653 (w),
1478 (s), 1321 (s), 1250 (m), 1188 (m), 1095 (s), 815 (m),
744 (w); MS (EI, 70 eV): m/z (%): 274 (Mþ, 37Cl, 1), 272
(Mþ, 35Cl, 3), 200 (5), 184 (3), 157 (13), 88 (29), 86 (92),
84 (100), 51 (74); HRMS (EI): calcd for C12H13O3ClS
(CH2), 111.5, 116.9 (C), 124.8, 124.9 (CH), 125.9 (2C, CH),
128.6 (2C, CH), 137.2, 142.4, 150.2, 163.4, 172.4 (C); IR
(KBr): ~n¼3054 (w), 2959 (w), 2935 (m), 2935 (m), 2809
(w), 2742 (w), 1639 (s), 1605 (s), 1476 (s), 1447 (s), 1376
(s), 1296 (s), 1259 (s), 1211 (s), 1108 (w), 1015 (m), 820
(m), 741 (s), 459 (w); MS (EI, 70 eV): m/z (%): 302.1 (Mþ,
61), 256.1 (100), 241.1 (22), 184.1 (14), 165.1 (5), 128 (5),
91.1 (7); elemental analysis: calcd (%) for C17H18O3S
(302.1): C 67.52, H 6.00; found: C 67.48, H 6.24.
[Mþþ 35Cl]: 272.02660, found 272.02684.
,
3.4.5. Ethyl 3-(thiophenoxy)salicylate (10a)
Starting with tetramethoxy (0.26 mL, 1.57 mmol), 1,3-bis-
(silyl enol ether) 9a (600 mg, 1.57 mmol) and TiCl4 (0.17 mL,
1.57 mmol), 10a was isolated as a highly viscous oil (133 mg,
31%). 1H NMR (300 MHz, CDCl3): d¼1.34 (t, 3H, J¼7.1 Hz,
CH3), 4.34 (q, 2H, J¼7.0 Hz, OCH2), 6.74 (t, 1H, J¼7.7 Hz,
ArH), 7.17e7.27 (m, 5H, ArH), 7.29e7.31 (m, 1H, ArH),
7.69e7.73 (dd, 1H, J¼1.5, 8.0 Hz, ArH), 11.39 (s, 1H, OH);
13C NMR (75 MHz, CDCl3): d¼13.1 (CH3), 60.7 (CH2),
111.8 (C), 118.3 (CH), 123.0 (C), 126.2, 128.0 (CH), 128.2
(2C, CH), 130.2 (2C, CH), 133.0 (C), 136.8 (CH), 158.8,
169.1 (C); IR (neat): ~n¼3074 (w), 2983 (m), 2936 (w), 1669
(s), 1601 (m), 1428 (s), 1318 (s), 1251 (s), 1188 (s), 1023 (m),
752 (s), 690 (m) cmꢁ1; GCeMS (EI, 70 eV): m/z (%): 274
(Mþ, 66), 228 (100), 200 (14), 171 (37), 139 (5), 95 (6), 51
(4); elemental analysis: calcd (%) for C15H14O3S (274.07): C
65.67, H 5.14; found: C 65.23, H 5.13.
3.4.8. Ethyl 4,6-diethyl-3-(4-methoxythiophenoxy)salicylate
(12b)
Starting with 3-(silyloxy)alk-2-en-1-one 11b (400 mg,
2.0 mmol), 1,3-bis(silyl enol ether) 9b (824 mg, 2.0 mmol)
and TiCl4 (0.22 mL, 2.0 mmol), 12b was isolated as a highly
viscous oil (251 mg, 35%). 1H NMR (300 MHz, CDCl3):
d¼1.06e1.18 (m, 6H, CH3), 1.35 (t, 3H, J¼7.1 Hz, CH3),
2.78e2.83 (m, 4H, CH2), 3.67 (s, 3H, OCH3), 4.35 (q, 2H,
J¼7.2 Hz, OCH2), 6.68 (d, 2H, J¼8.9 Hz, ArH), 6.99 (d,
2H, J¼8.7 Hz, ArH), 7.11 (s, 1H, ArH), 11.07 (s, 1H, OH);
13C NMR (75 MHz, CDCl3): d¼14.4, 15.5, 16.3 (CH3),
28.7, 29.7 (CH2), 55.7 (CH3), 62.1 (CH2), 112.0 (C), 124.8
(CH), 114.9 (2C, CH), 117.4 (C), 122.5 (CH), 128.3 (C),
129.1 (2C, CH), 148.4, 155.3, 158.3, 162.5, 171.2 (C); IR
(neat): ~n¼3375 (w), 2963 (s), 2930 (s), 2872 (m), 1728 (s),
1653 (s), 1595 (s), 1493 (s), 1374 (s), 1247 (s), 1107 (s),
1070 (m), 947 (w), 820 (m), 525 (w); MS (EI, 70 eV): m/z
(%): 360.2 (Mþ, 65), 314.1 (100), 281.2 (10), 207 (7), 163
(13), 135 (15), 77 (7); HRMS (EI): calcd for C20H24O4S
[Mþ]þ: 360.13898, found 360.138235.
3.4.6. Ethyl 3-(4-methoxythiophenoxy)salicylate (10b)
Starting with 1,1,3,3-tetramethoxypropane (0.26 mL,
1.6 mmol), 1,3-bis(silyl enol ether) 9b (648 mg, 1.6 mmol)
and TiCl4 (0.17 mL, 1.6 mmol), 10b was isolated as a highly
viscous oil (143 mg, 30%). 1H NMR (300 MHz, CDCl3):
d¼1.23 (t, 3H, J¼7.1 Hz, CH3), 3.63 (s, 3H, OCH3), 4.23
(q, 2H, J¼7.2 Hz, OCH2), 6.55 (t, 1H, J¼7.8 Hz, ArH), 7.73
(d, 2H, J¼8.9 Hz, ArH), 6.82e6.86 (dd, 1H, J¼2.1, 7.6 Hz,
ArH), 7.25 (d, 2H, J¼8.7 Hz, ArH), 7.47e7.50 (dd, 1H,
J¼1.7, 8.0 Hz, ArH), 11.28 (s, 1H, OH); 13C NMR
(75 MHz, CDCl3): d¼14.8, 55.7 (CH3), 62.3 (CH2), 112.5
(C), 115.5 (2C, CH), 119.6 (C), 122.9, 127.6 (CH), 127.7
(CH), 134.6 (CH), 136.2 (2C, CH), 158.5, 160.4, 170.6 (C);
IR (KBr): ~n¼3074 (w), 2987 (m), 2942 (w), 2835 (w), 1670
(s), 1569 (m), 1492 (s), 1372 (s), 1289 (s), 1180 (s), 1023
(s), 831 (s), 760 (s), 731 (m), 527 (m) cmꢁ1; GCeMS (EI,
70 eV): m/z (%): 304.1 (Mþ, 68), 258.1 (100), 243.1 (6),
215.1 (9), 187.1 (16), 159.1 (4), 115.1 (7), 95.1 (6), 63.1
(3); elemental analysis: calcd (%) for C16H16O4S (304.08):
C 63.14, H 5.30; found: C 63.14, H 5.37.
3.4.9. Ethyl 5-chloro-4,6-dimethyl-3-(thiophenoxy)salicylate
(12c)
Starting with 3-(siloxy)alk-2-en-1-one 11c (339 mg,
1.65 mmol), 1,3-bis(silyl enol ether) 9a (573 mg, 1.5 mmol)
and TiCl4 (0.18 mL, 1.65 mmol), 12c was isolated as a highly
viscous oil (222 mg, 37%). 1H NMR (250 MHz, CDCl3):
d¼1.34 (t, 3H, J¼7.0 Hz, CH3), 2.48 (s, 3H, CH3), 2.51 (s,
3H, CH3), 4.35 (q, 2H, J¼7.1 Hz, CH2), 6.89 (d, 1H,
J¼1.4 Hz, ArH), 7.12 (m, 2H, ArH), 7.18 (m, 2H, ArH),
9.41 (s, 1H, OH); 13C NMR (75 MHz, CDCl3): d¼14.1,
19.6, 20.4 (CH3), 62.1 (CH2), 116.6 (C), 117.4 (C), 125.8
(C), 126.4 (2C, CH), 127.5 (CH), 128.9 (2C, CH), 135.5,
138.6, 146.0, 157.2 (C), 169.1 (C]O); IR (KBr): ~n¼3387
(w), 3058 (w), 2982 (m), 2932 (w), 1730 (m), 1657 (m),
1582 (m), 1478 (m), 1439 (m), 1372 (s), 1219 (s), 1023 (m),
793 (m), 689 (m) cmꢁ1; GCeMS (EI, 70 eV): m/z (%): 338
(Mþ, 37Cl, 14), 336 (Mþ, 35Cl, 48), 290 (100), 275 (14), 261
(9), 184 (12); HRMS (EI): calcd for C17H17O3ClS [M]þ:
336.05814, found 336.05807.
3.4.7. Ethyl 4,6-dimethyl-3-(thiophenoxy)salicylate (12a)
Starting with 3-(silyloxy)alk-2-en-1-one 11a (400 mg,
2.3 mmol), 1,3-bis(silyl enol ether) 9a (887 mg, 2.3 mmol)
and TiCl4 (0.25 mL, 2.3 mmol), 12a was isolated as a colour-
1
less solid (336 mg, 48%), mp¼79 ꢀC. H NMR (250 MHz,
3.4.10. Ethyl 4,5,6-trimethyl-3-(thiophenoxy)salicylate
(12d)
Starting with 3-(siloxy)alk-2-en-1-one 11d (308 mg,
1.65 mmol), 1,3-bis(silyl enol ether) 9a (573 mg, 1.5 mmol)
and TiCl4 (0.18 mL, 1.65 mmol), 12d was isolated as a highly
viscous oil (173 mg, 33%). 1H NMR (250 MHz, CDCl3):
CDCl3): d¼1.34 (t, 3H, J¼7.1 Hz, CH3), 2.33 (s, 3H, CH3),
2.47 (s, 3H, CH3), 4.35 (q, 2H, J¼7.3 Hz, OCH2), 6.66 (s,
1H, ArH), 6.94e6.97 (dd, 2H, J¼1.5, 8.2 Hz, ArH), 7.01
(m, 1H, ArH), 7.09e7.13 (m, 2H, ArH), 11.75 (s, 1H, OH);
13C NMR (62 MHz, CDCl3): d¼14.0, 21.5, 23.7 (CH3), 61.6

3790
M.A. Rashid et al. / Tetrahedron 64 (2008) 3782e3793
d¼1.33 (t, 3H, J¼7.0 Hz, CH3), 2.12 (s, 3H, CH3), 2.30 (s, 3H,
CH3), 2.37 (s, 3H, CH3), 4.35 (q, 2H, J¼7.1 Hz, CH2), 6.95
(m, 1H, ArH), 7.09 (m, 2H, ArH), 7.13 (m, 2H, ArH), 8.63
(s, 1H, OH); 13C NMR (75 MHz, CDCl3): d¼14.2, 16.4,
18.6, 19.1 (CH3), 61.6 (CH2), 115.1 (C), 116.9 (C), 125.4
(C), 126.1 (2C, CH), 128.3 (CH), 129.0 (2C, CH), 136.2,
138.2, 145.5, 155.4 (C), 169.6 (C]O); IR (KBr): ~n¼3394
(m), 3057 (w), 2981 (m), 2929 (m), 1727 (s), 1654 (m),
1582 (s), 1478 (m), 1439 (m), 1374 (m), 1272 (m), 1228 (s),
and TiCl4 (0.18 mL, 1.65 mmol), 12g was isolated as a colour-
1
less solid (166 mg, 30%), mp¼79 ꢀC. H NMR (250 MHz,
CDCl3): d¼1.34 (t, 3H, J¼7.0 Hz, CH3), 2.20 (s, 3H, CH3),
2.46 (s, 3H, CH3), 2.51 (s, 3H, CH3), 4.32 (q, 2H, J¼7.2 Hz,
CH2), 6.86e6.90 (m, 2H, ArH), 6.94e6.97 (m, 2H, ArH),
9.21 (s, 1H, OH); 13C NMR (62 MHz, CDCl3): d¼12.9,
18.4, 19.3, 19.9 (CH3), 61.0 (OCH2), 115.9, 116.9 (C), 125.9
(2C, CH), 126.1 (C), 128.9 (2C, CH), 130.8, 134.8, 137.2,
144.6, 155.8 (C), 167.9 (C]O); IR (KBr): ~n¼2986 (w),
2962 (w), 2917 (w), 1727 (w), 1644 (m), 1573 (w), 1565
(w), 1491 (m), 1434 (m), 1371 (m), 1277 (m), 1213 (s),
1013 (s), 804 (s), 583 (m) cmꢁ1; GCeMS (EI, 70 eV): m/z
(%): 352 (Mþ, 37Cl, 16), 350 (Mþ, 43), 304 (100), 289 (9),
269 (15), 213 (6), 198 (6), 119 (7); HRMS (EI): calcd for
C18H19O3ClS (Mþ, 35Cl): 350.07379, found 350.07338.
1178 (s), 1045 (m), 1023 (m), 739 (s), 689 (m) cmꢁ1
;
GCeMS (EI, 70 eV): m/z (%): 316 (Mþ, 42), 270 (100),
255 (22), 241 (9), 184 (5), 165 (7), 105 (6); HRMS (EI): calcd
for C18H20O3S [M]þ: 316.11277, found 316.11321.
3.4.11. Ethyl 4,6-dimethyl-3-(4-methoxythiophenoxy)-5-
(thiophenoxy)salicylate (12e)
Starting with 3-(siloxy)alk-2-en-1-one 4a (400 mg,
1.41 mmol), 1,3-bis(silyl enol ether) 9b (582 mg, 1.41 mmol)
and TiCl4 (0.15 mL, 1.41 mmol), 12e was isolated as a highly
viscous oil (212 mg, 34%). 1H NMR (300 MHz, CDCl3):
d¼1.33 (t, 3H, J¼7.1 Hz, CH3), 2.34 (s, 3H, CH3), 2.68 (s,
3H, CH3), 3.71 (s, 3H, OCH3), 4.34 (q, 2H, J¼7.1 Hz,
OCH2), 6.68 (d, 2H, J¼8.9 Hz, ArH), 6.73e6.81 (m, 5H,
ArH), 7.32 (d, 2H, J¼8.9 Hz, ArH), 11.12 (s, 1H, OH); 13C
NMR (62 MHz, CDCl3): d¼14.5, 21.9, 24.8, 55.7 (CH3),
62.2 (CH2), 112.9 (C), 115.1 (2C, CH), 118.0 (CH), 124.5
(C), 127.7 (2C, CH), 128.1, 128.8 (2C), 133.0 (2C, CH),
147.2, 151.4, 157.9, 160.3, 162.8, 171.7 (C); IR (Nujol):
~n¼2954 (s), 2925 (s), 2855 (s), 2932 (s), 1653 (m), 1591 (s),
1492 (s), 1461 (s), 1372 (s), 1245 (m), 1106 (m), 1034 (s),
871 (s), 802 (w), 620 (w), 522 (m), 423 (w).
3.4.14. Ethyl 5-chloro-4,6-dimethyl-3-(4-chlorothio-
phenoxy)salicylate (12h)
Starting with 3-(siloxy)alk-2-en-1-one 11c (339 mg,
1.65 mmol), 1,3-bis(silyl enol ether) 9d (625 mg, 1.5 mmol)
and TiCl4 (0.18 mL, 1.65 mmol), 12h was isolated as a colour-
1
less solid (206 mg, 34%), mp¼100 ꢀC. H NMR (250 MHz,
CDCl3): d¼1.35 (t, 3H, J¼7.4 Hz, CH3), 2.52 (s, 6H, 2CH3),
4.32 (q, 2H, J¼7.4 Hz, CH2), 6.91 (d, 2H, J¼8.9 Hz, ArH),
7.09 (d, 2H, J¼8.9 Hz, ArH), 9.90 (s, 1H, OH); 13C NMR
(62 MHz, CDCl3): d¼14.1, 19.9, 20.5 (CH3), 62.3 (OCH2),
115.8, 117.4 (C), 127.7 (2C, CH), 129.1 (2C, CH), 131.6,
134.5, 139.2, 146.5, 158.1 (C), 169.5 (C]O); IR (neat):
~n¼3065 (w), 2990 (w), 2956 (w), 2922 (m), 1727 (m), 1644
(s), 1564 (w), 1528 (w), 1473 (s), 1423 (m), 1372 (s), 1298
(w), 1276 (s), 1214 (s), 1090 (s), 1009 (s), 865 (w), 814 (s),
735 (m), 684 (m) cmꢁ1; GCeMS (EI, 70 eV): m/z (%): 374
37
3.4.12. Ethyl 4,6-dimethyl-3,5-(dithiophenoxy)salicylate
(12f)
([M]þ, [2ꢂ Cl], 6), 372 ([M]þ, [37Cl], [35Cl], 28), 370
([M]þ, [2ꢂ Cl], 41), 324 (100), 309 (15), 289 (14), 261
35
Starting with 3-(siloxy)alk-2-en-1-one 4a (400 mg,
1.41 mmol), 1,3-bis(silyl enol ether) 9a (539 mg, 1.41 mmol)
and TiCl4 (0.15 mL, 1.41 mmol), 12f was isolated as a highly
viscous oil (196 mg, 34%). 1H NMR (250 MHz, CDCl3):
d¼1.27 (t, 3H, J¼7.0 Hz, CH3), 2.51 (s, 6H, CH3), 4.30 (q,
2H, J¼7.1 Hz, OCH2), 6.76e6.80 (dd, 2H, J¼1.2, 8.2 Hz,
ArH), 6.88e6.92 (m, 2H, ArH), 6.94e7.09 (m, 6H, ArH),
9.37 (s, 1H, OH); 13C NMR (62 MHz, CDCl3): d¼14.1,
20.6, 21.4 (CH3), 62.0 (CH2), 116.7, 116.8, 124.5 (C), 124.8
(CH), 125.2 (2C, CH), 125.6 (CH), 126.2 (2C, CH), 128.9
(2C, CH), 129.0 (2C, CH), 135.1, 137.7, 146.6, 154.2,
159.1, 169.2 (C); IR (KBr): ~n¼3373 (s), 3057 (s), 2981 (s),
2932 (s), 2869 (m), 1728 (s), 1653 (s), 1439 (s), 1121 (s),
998 (m), 857 (m), 738 (s), 689 (s), 582 (w), 471 (w); MS
(EI, 70 eV): m/z (%): 410 (Mþ, 69), 364 (100), 340 (44),
290 (18), 253 (12), 219 (12), 177 (74), 161 (48), 109 (35),
83 (56), 57 (93), 43 (54); HRMS (EI): calcd for C23H22O3S2
[Mþ]þ: 410.10049, found 410.09973.
(8), 198 (8), 144 (10); HRMS (EI): calcd for C17H16O3Cl2S
35
([M]þ, [2ꢂ Cl]): 370.01917, found 370.073380.
3.4.15. Ethyl 4,6-dimethyl-5-(2-bromoethyl)-3-(thio-
phenoxy)salicylate (14)
Starting with 1,1-diacetylcyclopropane (13) (500 mg,
3.9 mmol), 1,3-bis(silyl enol ether) 9a (2.200 g, 5.5 mmol),
TiBr4 (1.400 g, 3.9 mmol) and CH2Cl2 (110 mL), 14 was iso-
lated as a yellowish highly viscous compound (715 mg, 45%).
1H NMR (250 MHz, CDCl3): d¼1.32 (t, 3H, J¼7.1 Hz, CH3),
2.34 (s, 3H, CH3), 2.41 (s, 3H, CH3), 3.15 (m, 2H, CH2), 3.30
(m, 2H, CH2), 4.36 (q, 2H, J¼7.1 Hz, CH2), 6.92 (m, 2H,
ArH), 7.05 (m, 1H, ArH), 7.15 (m, 2H, ArH), 8.67 (s, 1H,
OH); 13C NMR (62 MHz, CDCl3): d¼14.2, 17.8, 18.5
(CH3), 29.4, 34.2, 61.7 (CH2), 116.3, 117.7 (C), 125.7 (CH),
126.2 (2C CH), 129.1 (2C CH), 129.2 (C), 133.6, 138.5,
145.8, 156.4, 169.2 (C); IR (neat): ~n¼3386 (s), 2979 (s),
2934 (m), 1728 (s), 1655 (s), 1582 (s), 1478 (s), 1373 (s),
1228 (s), 1048 (m), 739 (m), 690 (s) cmꢁ1; GCeMS (EI,
70 eV): m/z (%): 410 (Mþ, 81Br, 59), 408 (Mþ, 79Br, 57),
364 (100), 329 (18), 283 (85), 269 (24), 77 (12); HRMS
(EI): calcd for C19H21O3BrS ([Mþ1]þþ): 408.03893, found
408.03884.
3.4.13. Ethyl 5-chloro-4,6-dimethyl-3-(4-methylthio-
phenoxy)salicylate (12g)
Starting with 3-(siloxy)alk-2-en-1-one 11c (339 mg,
1.65 mmol), 1,3-bis(silyl enol ether) 9c (594 mg, 1.5 mmol)

M.A. Rashid et al. / Tetrahedron 64 (2008) 3782e3793
3791
3.5. General procedure for the synthesis of benzophenones
16aee
(%): 452 (Mþ, 100), 406 (97), 258 (31), 230 (6), 177 (10),
149 (49), 111 (24), 83 (36), 57 (62); elemental analysis: calcd
(%) for C25H24O6S (452.52): C 66.35, H 5.35; found: C 66.58,
H 5.37.
Me3SiOTf (0.3 equiv) was added to 3-formylchromone
(1.0 equiv) at 20 ꢀC. After stirring for 10 min, CH2Cl2
(8 mL) was added, the solution was cooled to 0 ꢀC and 1,3-
bis(silyl enol ether) (1.3 equiv) was added. The mixture was
stirred at 20 ꢀC for 12 h and was subsequently poured into
an aqueous solution of HCl (10%). The organic and the aque-
ous layers were separated and the latter was extracted three
times with 15 mL of CH2Cl2. The combined organic layers
were washed with 25 mL of brine and dried over Na2SO4.
The solution was filtered and the solvent of the filtrate was
removed under reduced pressure. The residue was purified
by chromatography (silica gel, EtOAc/n-heptane).
3.5.3. Ethyl 5-(2-hydroxy-3-bromobenzoyl)-3-(4-methyl-
thiophenoxy)salicylate (16c)
Starting with 6-bromo-3-formylchromone 15c (380 mg,
1.5 mmol), 1,3-bis(silyl enol ether) 9c (594 mg, 1.5 mmol)
and Me3SiOTf (0.08 mL, 0.45 mmol), 16c was isolated as
a colourless solid (329 mg, 45%), mp¼125 ꢀC. 1H NMR
(250 MHz, CDCl3): d¼1.33 (t, 3H, J¼7.0 Hz, CH3), 2.24 (s,
3H, CH3), 4.36 (q, 2H, J¼7.1 Hz, CH2), 6.81 (d, 1H,
J¼9.4 Hz, ArH), 7.12 (d, 2H, J¼7.9 Hz, ArH), 7.18 (d, 1H,
J¼2.0 Hz, ArH), 7.32 (d, 2H, J¼10.1 Hz, ArH), 7.41e7.45
(m, 2H, J¼10.1 Hz, ArH), 7.98 (d, 1H, J¼2.2 Hz, ArH),
11.47 (s, 1H, OH), 11.86 (s, 1H, OH); 13C NMR (62 MHz,
CDCl3): d¼11.9, 19.1 (CH3), 60.2 (CH2), 108.0, 110.0,
117.9 (C), 118.3 (CH), 124.7, 126.1, 126.7 (C), 127.0 (CH),
128.6 (2C, CH), 131.6 (CH), 132.2 (2C, CH), 132.5, 136.5
(CH), 137.1, 159.0, 159.6, 167.5, 195.4 (C); IR (ATR):
~n¼3017 (w), 2982 (w), 2865 (w), 1627 (s), 1568 (s), 1467
(s), 1398 (s), 1285 (s), 1163 (s), 1018 (s), 996 (m), 836 (m),
736 (s), 613 (w) cmꢁ1; GCeMS (EI, 70 eV): m/z (%): 488
(Mþ, 81Br, 100), 486 (Mþ, 79Br, 92), 442 (87), 440 (78),
242 (25), 199 (20), 125 (12), 111 (20), 57 (45); elemental anal-
ysis: calcd (%) for C23H19BrO5S (486.01): C 56.68, H 3.93;
found: C 56.12, H 4.40.
3.5.1. Ethyl 5-(2-hydroxy-3-chlorobenzoyl)-3-(thio-
phenoxy)salicylate (16a)
Starting with 3-formylchromone 15a (400 mg, 1.91 mmol),
1,3-bis(silyl enol ether) 9a (806 mg, 2.1 mmol) and Me3SiOTf
(0.1 mL, 0.57 mmol), 16a was isolated as a colourless solid
1
(385 mg, 47%), mp¼104 ꢀC. H NMR (250 MHz, CDCl3):
d¼1.33 (t, 3H, J¼7.1 Hz, CH3), 4.38 (q, 2H, J¼7.2 Hz,
CH2), 6.86 (dd, 1H, J¼0.8, 8.3 Hz, ArH), 7.16e7.34 (m,
6H, ArH), 7.41 (dd, 2H, J¼1.7, 8.2 Hz, ArH), 8.02 (d, 1H,
J¼2.2 Hz, ArH), 11.53 (s, 1H, OH), 11.89 (s, 1H, OH); 13C
NMR (62 MHz, CDCl3): d¼12.9 (CH3), 61.3 (CH2), 111.2,
118.3 (C), 118.9 (CH), 122.2, 126.5, 127.2, 127.6 (C), 128.6
(CH), 128.7 (2C, CH), 130.0, 130.5 (CH), 132.4 (2C, CH),
133.8, 134.9 (CH), 160.2, 160.5, 168.4, 196.4 (C); IR (KBr):
~n¼3073 (w), 2958 (w), 2854 (w), 1661 (s), 1576 (s), 1473
(s), 1314 (s), 1290 (s), 1195 (m), 1022 (m), 864 (m), 787
(s), 690 (s), 418 (w) cmꢁ1; GCeMS (EI, 70 eV): m/z (%):
430 (Mþ, 37Cl, 40), 428 (Mþ, 35Cl, 95), 382 (100), 302 (5),
228 (18) 200 (10), 171 (17), 155 (21), 99 (5); HRMS (EI):
3.5.4. Ethyl 5-(2-hydroxy-3-methylbenzoyl)-3-(4-chloro-
thiophenoxy)salicylate (16d)
Starting with 6-methyl-3-formylchromone 15d (255 mg,
1.35 mmol), 1,3-bis(silyl enol ether) 9d (566 mg, 1.35 mmol)
and Me3SiOTf (0.07 mL, 0.40 mmol), 16d was isolated as
a colourless solid (240 mg, 40%), mp¼98 ꢀC. 1H NMR
(250 MHz, CDCl3): d¼1.32 (t, 3H, J¼7.1 Hz, CH3), 2.13 (s,
3H, CH3), 4.38 (q, 2H, J¼7.1 Hz, CH2), 6.85 (d, 1H,
J¼8.5 Hz, ArH), 7.10 (d, 1H, J¼1.4 Hz, ArH), 7.16e7.29
(m, 5H, ArH), 7.51 (d, 1H, J¼2.0 Hz, ArH), 8.09 (d, 1H,
J¼2.2 Hz, ArH), 11.47 (s, 1H, OH), 11.86 (s, 1H, OH); 13C
NMR (75 MHz, CDCl3): d¼15.0, 21.4 (CH3), 63.4 (CH2),
113.5 (C), 119.2 (CH), 119.3, 126.3, 128.7, 130.2 (C), 130.6
(2C, CH), 131.7 (CH), 132.2 (C), 133.2 (CH), 134.5 (2C,
CH), 135.2 (C), 138.2, 138.3 (CH), 161.9, 163.1, 170.6,
199.2 (C); IR (ATR): ~n¼2994 (w), 2919 (w), 2855 (w), 1628
(s), 1581 (s), 1412 (s), 1377 (s), 1218 (s), 1190 (m), 1090
(m), 994 (m), 815 (m), 666 (m), 536 (w) cmꢁ1; GCeMS
(EI, 70 eV): m/z (%): 444 (Mþ, 37Cl, 31), 442 (Mþ, 35Cl,
86), 396 (100), 308 (10), 262 (40), 205 (10), 171 (10), 135
(42), 69 (50); HRMS (EI): calcd for C23H19ClO5S
calcd for C22H17ClO5S [Mþþ
428.04797.
,
35Cl]: 428.04744, found
3.5.2. Ethyl 5-(2-hydroxy-3-ethylbenzoyl)-3-(4-methoxy-
thiophenoxy)salicylate (16b)
Starting with 6-ethyl-3-formylchromone 15b (500 mg,
2.47 mmol), 1,3-bis(silyl enol ether) 9b (10.17 g, 2.47 mmol)
and Me3SiOTf (0.15 mL, 0.86 mmol), 16b was isolated as
a colourless solid (422 mg, 38%), mp¼124 ꢀC. 1H NMR
(250 MHz, CDCl3): d¼1.06 (t, 3H, J¼7.5 Hz, CH3), 1.29 (t,
3H, J¼7.0 Hz, CH3), 2.40 (q, 2H, J¼7.7 Hz, CH2), 3.60 (s,
3H, OCH3), 4.34 (q, 2H, J¼7.2 Hz, CH2), 6.82 (m, 3H,
ArH), 7.13e7.25 (m, 3H, ArH), 7.38 (d, 2H, J¼8.8 Hz,
ArH), 7.96 (d, 1H, J¼2.0 Hz, ArH), 11.50 (s, 1H, OH),
11.80 (s, 1H, OH); 13C NMR (62 MHz, CDCl3): d¼14.1,
15.8 (CH3), 27.9 (CH2), 55.3 (CH3), 62.1 (CH2), 111.6 (C),
115.4 (2C, CH), 118.2 (CH), 118.5, 120.7 (C), 129.1 (CH),
129.1, 129.3 (C), 131.4, 133.5 (CH), 134.2 (C), 136.1 (CH),
136.5 (2C, CH), 160.5, 160.6, 161.0, 169.8, 198.6 (C); IR
(ATR): ~n¼2994 (w), 2912 (w), 2839 (w), 1677 (s), 1588 (s),
1349 (s), 1241 (s), 1217 (s), 1166 (s), 1019 (m), 833 (m),
810 (m), 670 (m), 567 (w) cmꢁ1; GCeMS (EI, 70 eV): m/z
[Mþþ 35Cl]: 442.06469, found 442.06362.
,
3.5.5. Ethyl 5-(2-hydroxybenzoyl)-3-(4-chlorothio-
phenoxy)salicylate (16e)
Starting with 3-formylchromone 15e (500 mg, 2.87 mmol),
1,3-bis(silyl enol ether) 9d (12.01 g, 2.87 mmol) and
Me3SiOTf (0.15 mL, 0.86 mmol), 16e was isolated as a highly

3792
M.A. Rashid et al. / Tetrahedron 64 (2008) 3782e3793
viscous oil (385 mg, 47%). 1H NMR (250 MHz, CDCl3):
d¼1.32 (t, 3H, J¼7.2 Hz, CH3), 4.38 (q, 2H, J¼7.2 Hz, CH2),
6.74 (m, 1H, ArH), 6.95 (dd, 1H, J¼0.9, 8.3 Hz, ArH), 7.18e
7.43 (m, 6H, ArH), 7.50 (d, 1H, J¼1.8 Hz, ArH), 8.09 (d, 1H,
J¼2.0 Hz, ArH), 11.57 (s, 1H, OH), 11.85 (s, 1H, OH); 13C
NMR (62 MHz, CDCl3): d¼15.0 (CH3), 63.4 (CH2), 113.4
(C), 119.5, 119.6 (CH), 119.7, 126.4, 130.0 (C), 130.6 (2C,
CH), 131.7 (CH), 132.2 (C), 133.5 (CH), 134.5 (2C, CH),
135.2 (C), 137.3, 138.3 (CH), 163.2, 163.9, 170.5, 199.2 (C);
IR (ATR): ~n¼2979 (w), 2906 (w), 2871 (w), 1670 (s), 1623
(s), 1575 (s), 1338 (s), 1236 (s), 1184 (s), 1091 (m), 987 (m),
816 (m), 792 (m), 561 (w) cmꢁ1; GCeMS (EI, 70 eV): m/z
(%): 430 (Mþ, 37Cl, 36), 428 (Mþ, 35Cl, 81), 382 (100), 262
(16), 205 (9), 205 (10), 171 (11), 121 (71), 65 (14); HRMS
Acknowledgements
Financial support from the State of Pakistan (HEC scholar-
ships for M.A.R. and N.R.) is gratefully acknowledged.
References and notes
1. For dibenzothiophenes, see for example: (a) Mori, Y.; Taneda, S.; Haya-
shi, H.; Sakushima, A.; Kamata, K.; Suzuki, A. K.; Yoshino, S.; Sakata,
M.; Sagai, M.; Seki, K.-i. Biol. Pharm. Bull. 2002, 25, 145; For lissocli-
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L. R.; Ireland, C. M. J. Am. Chem. Soc. 1991, 113, 4709; (c) Behar, V.;
Danishefsky, S. J. J. Am. Chem. Soc. 1993, 115, 7017; (d) Toste, F. D.;
Still, I. W. J. J. Am. Chem. Soc. 1995, 117, 7261; For lissoclibadins,
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da Rocha, R.; Ireland, C. M. Tetrahedron 2003, 59, 2855; (f) Liu, H.;
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K.; Kobayashi, H.; Mangindaan, R. E. P.; Namikoshi, M. Tetrahedron
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(EI): calcd for C22H17ClO5S [Mþþ
428.04797.
,
35Cl]: 428.04840, found
3.6. Synthesis of 7-hydroxy-6H-benzo[c]chromen-6-one 19
Me3SiOTf (1.3 equiv) was added to chromone (1.0 equiv)
at 20 ꢀC. After stirring for 1 h, CH2Cl2 (8 mL) was added.
The solution was cooled to 0 ꢀC and 1,3-bis(silyl enol ether)
(1.3 equiv) was added. The mixture was stirred at 20 ꢀC for
12 h and was subsequently poured into an aqueous solution
of HCl (10%). The organic and the aqueous layers were sep-
arated, the latter was extracted three times with 15 mL of
CH2Cl2 and the combined organic layers were dried over
Na2SO4. The solution was filtered and the solvent of the fil-
trate was removed under reduced pressure to give crude 18.
To an EtOH solution (10 mL) of crude 18 was added NEt3
(2.0 equiv) and the mixture was stirred for 12 h at 20 ꢀC. Hy-
drochloric acid (1 M) was added, the organic and the aqueous
layers were separated and the latter was extracted with EtOAc.
The combined organic layers were dried over Na2SO4. The so-
lution was filtered and the solvent of the filtrate was removed
under reduced pressure. The residue was purified by chroma-
tography (silica gel, EtOAc/n-heptane) to give 19.
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~
Starting with chromone 17 (310 mg, 2.1 mmol), 1,3-bis-
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1
as a colourless solid (461 mg, 68%), mp¼178 ꢀC. H NMR
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J. D., III; Volante, R. P. J. Org. Chem. 1998, 63, 9606; (k) Hartwig,
(250 MHz, CDCl3): d¼7.20e7.28 (m, 5H, ArH), 7.35e7.42
(m, 5H, ArH), 7.86 (dd, 1H, J¼1.9, 8.5 Hz, ArH), 11.8 (s,
1H, OH); 13C NMR (75 MHz, CDCl3): d¼105.9 (C), 112.5,
117.6 (CH), 118.1 (C), 123.1 (CH), 124.3 (C), 125.3, 127.9
(CH), 129.4 (2C, CH), 130.6 (CH), 132.2 (2C, CH), 132.9,
133.6 (C), 138.2 (CH), 150.4, 159.7, 165.4 (C); IR (KBr):
~n¼3068 (w), 3046 (w), 1673 (w), 1606 (s), 1555 (m), 1422
(s), 1320 (m), 1271 (s), 1150 (s), 1025 (w), 830 (m), 759
(s), 691 (m), 456 (w) cmꢁ1; GCeMS (EI, 70 eV): m/z (%):
320 (Mþ, 100), 302 (5), 288 (5), 258 (4), 215 (3), 143 (5),
77 (3); HRMS (EI): calcd for C19H12O3S [M]þ: 320.05025,
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