Regioselective synthesis of 3-(methylthio)phenols by formal [3+3]-cyclocondensations of 3-oxo-bis(methylthio)ketenacetals with 1,3-bis(trimethylsilyloxy)-1,3-butadienes and 1,3-dicarbonyl dianions

Article abstract of DOI:10.1016/j.tet.2013.03.069

The cyclization of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with 3-oxo-bis(methylthio)ketenacetals afforded 3-(methylthio)phenols containing an acyl or ester substituent located at position 2. The cyclization of free 1,3-dicarbonyl dianions with 3-oxo-bi

Full text of DOI:10.1016/j.tet.2013.03.069

Tetrahedron 69 (2013) 5998e6007
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Regioselective synthesis of 3-(methylthio)phenols by formal
[3þ3]-cyclocondensations of 3-oxo-bis(methylthio)ketenacetals
with 1,3-bis(trimethylsilyloxy)-1,3-butadienes and 1,3-dicarbonyl
dianionsq
Mathias Lubbe a, Franziska Bendrath a, Tiana Trabhardt a, Alexander Villinger a,
,b,
Christine Fischer b, Peter Langer a
*
a
€
€
Institut fur Chemie, Universitat Rostock, Albert Einstein Str. 3a, 18059 Rostock, Germany
Leibniz-Institut fur Katalyse an der Universitat Rostock e.V., Albert Einstein Str. 29a, 18059 Rostock, Germany
b
€
€
a r t i c l e i n f o
a b s t r a c t
Article history:
The cyclization of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with 3-oxo-bis(methylthio)ketenacetals
afforded 3-(methylthio)phenols containing an acyl or ester substituent located at position 2. The cycli-
zation of free 1,3-dicarbonyl dianions with 3-oxo-bis(methylthio)ketenacetals resulted in the formation
of regioisomeric products containing an acyl group located at position 6.
Received 25 February 2013
Accepted 20 March 2013
Available online 21 March 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Arenes
Cyclizations
Regioselectivity
Silyl enol ethers
Sulfur
1. Introduction
Methylthio-substituted benzene derivatives are available by
various methods, for example, by methylation of thiophenols or by
Methylthio-substituted benzene derivatives represent impor-
tant synthetic building blocks for the synthesis of arylated sulfox-
ides1a and sulfones.1b The methylthio group has also been used as
a leaving group in nucleophilic aromatic substitution reactions
with Grignard reagents.1c In addition, reductions with LiAlH4 to
give the corresponding defunctionalized benzene derivatives have
been reported.1d The methylthio group of 2-(methylthio)benzoates
and related substrates can also be deprotonated. The in situ gen-
erated carbanions can undergo a subsequent cyclocondensation
reaction with a neighbouring ester or amide group to give thio-
indoxyls, thioaurones, or benzothiophenes.1eeg Likewise, benzo[d]
isothiazoles,1h 3H-benzothiazol-2-ones1i and 1,2-benzothiazol-
3(2H)-ones have been prepared.1j Intramolecular aromatic nucle-
ophilic substitution reactions by attack of an amino group to a thi-
omethyl group have also been reported.1k,l The thiomethyl group
has also been cleaved to give thiolates.1m
reduction of arylmethyl-sulfoxides or -sulfones. These methods are
restricted by the availability of the starting materials, especially in
case of highly substituted and functionalized derivatives. To over-
come these limitations, more complex methylthio-substituted
arenes have been prepared by an alternative strategy, which is
based on the use of suitable methylthio-containing building blocks.
For example, Junjappa and Ila reported the synthesis of 2-acyl-3-
(methylthio)phenols by zinc mediated reaction of ethyl bromoa-
cetate with 1,1-bis(methylthio)-1-en-3-ones.2a Other synthetic
approaches rely on the directed ortho metallation,2b on the reaction
of 1-methoxy-3-(methylthio)benzene with carbon dioxide2c and
on formal 5þ1 cyclization reactions of nitro compounds.2d
In recent years, formal 3þ3 cyclizations of 1,3-
bis(trimethylsilyloxy)-1,3-butadienes, masked 1,3-dicarbonyl dia-
nions, with various 1,3-dielectrophiles have been broadly studied.3
Some years ago, we published a preliminary report4 related to the
synthesis of 2-acyl- and 2-alkoxycarbonyl-3-(methylthio)phenols by
cyclization of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with 3-oxo-
bis(methylthio)ketenacetals. These reactions proceeded with excel-
lentregioselectivity. Lateron, the scope of the reactions wasextended
to the use of 4,4-dimethylthio-1,1,1-trifluorobut-3-en-2-one,5a
3-arylthio-1-trimethylsilyloxy-1,3-butadienes5b and ferrocenyl-
q
CCDC 935397e935400 contain all crystallographic details of this publication
and is available free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html or can
be ordered from the following address: Cambridge Crystallographic Data Centre, 12
Union Road, GB-Cambridge CB21EZ; fax: þ44 1223 336 033; or deposit@
ccdc.cam.ac.uk.
* Corresponding author. E-mail address: peter.langer@uni-rostock.de (P. Langer).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.03.069

M. Lubbe et al. / Tetrahedron 69 (2013) 5998e6007
5999
substituted 3-oxo-bis(methylthio)ketenacetals.5c Herein, we report
Table 2
Synthesis of 2reu
a comprehensive study of the scope and limitations. With regard to
our preliminary communication,4 we greatly expanded the range of
products. Inaddition, wereportthesynthesis ofregioisomeric6-acyl-
and 6-alkoxycarbonyl-3-(methylthio)phenolsby usingfreeinstead of
masked 1,3-dicarbonyl dianions.
3
2
R1
R2
% (2)a
a
b
c
r
s
t
Me
Me
Me
n-Pr
Me
Et
Bn
Et
60
60
62
53
d
u
a
Yields of isolated products.
2. Results and discussion
The titanium-tetrachloride mediated cyclization of 2aeu with
1,3-bis(trimethylsilyloxy)-1,3-butadienes 4ael, which were pre-
pared in two steps from the corresponding 1,3-dicarbonyl com-
pounds as previously reported,7 afforded the 2-acyl- and 2-
alkoxycarbonyl-3-(methylthio)phenols 5aeap (Scheme 4, Table
3). All products were formed with very good regioselectivity and
3-Oxo-bis(methylthio)ketenacetales 2aep were prepared, fol-
lowing a known procedure,6 by reaction of ketones with carbon
disulfide and iodomethane in the presence of potassium tert-
butanolate (Scheme 1, Table 1).
O
SMe
O
i
R1
SMe
R1
R2
2a-p
R2
Me3SiO
R3
OSiMe3
R4
1a-p
OH
O
R3
R1
Scheme 1. Synthesis of 2aep: i: (1) THF, KOtBu, 15 min, 20 ꢀC; (2) THF, CS2, MeI, 20 ꢀC,
4a-l
R4
SMe
i
10 h.
+
O
SMe
Table 1
Synthesis of 2aep
R2
5a-ap
R1
SMe
2a-u
R2
1, 2
R1
R2
% (2)a
a
b
c
d
e
f
g
h
i
k
l
Me
Me
Et
Me
Me
t-Bu
c-Hex
e(CH2)3e
e(CH2)4e
e(CH2)5e
e(CH2)6e
2-Naphtyl
4-FC6H4
Ferrocenyl
Ph
H
70
70
46
50
50
61
43
47
62
76
87
94
70
51
61
Scheme 4. Synthesis of 5aeap: i: TiCl4, CH2Cl2, ꢁ78/20 ꢀC, 14 h.
Me
Me
Et
n-Pr
H
Table 3
Synthesis of 5aeap
% (5)a
H
2
4
5
R1
R2
R3
R4
a
l
a
b
c
d
e
f
g
h
i
k
l
m
n
o
p
q
r
s
t
u
v
w
x
y
Me
Me
Me
Et
Et
Me
Me
Me
H
Me
H
H
H
H
H
H
H
H
H
H
OMe
H
H
H
H
H
H
H
H
H
Me
Et
OMe
H
Me
Et
H
OMe
Me
OMe
OMe
OEt
65
70
82
90
89
89
76
79
80
50
14
15
50
55
40
62
69
66
58
44
37
43
37
35
88
62
63
405c
355c
445c
275c
43
82
75
51
73
48
70
58
50
b
b
c
a
g
g
d
d
k
g
k
a
g
c
d
d
k
g
d
g
d
a
d
l
Me
Me
Me
Me
Et
m
n
o
p
H
Cl
H
H
c
d
d
e
e
f
g
g
h
i
OEt
Et
O(CH2)2OMe
OMe
O(CH2)2OMe
Me
OMe
OMe
OEt
n-Pr
n-Pr
H
H
H
a
Yields of isolated products.
Me
t-Bu
c-Hex
c-Hex
e(CH2)3e
e(CH2)4e
e(CH2)4e
e(CH2)5e
e(CH2)5e
e(CH2)6e
e(CH2)6e
2-Napthyl
2-Naphtyl
2-Naphtyl
2-Naphtyl
2-Naphtyl
4-FC6H4
4-FC6H4
4-FC6H4
Ferrocenyl
Ferrocenyl
Ferrocenyl
Ferrocenyl
Me
In contrast to
u-chloro-(4-fluoroacetophenone) 1n, simple
chloroacetone could not be successfully transformed to 4,4-
bis(methylthio)-3-chloro-but-3-en-2-one (2q). However, this com-
pound could be prepared by reactionof 2awithN-chlorosuccinimide
(NCS) in 80% yield (Scheme 2).
OEt
i
O(CH2)OMe
OMe
OEt
OMe
OEt
k
k
l
O
SMe
O
SMe
SMe
l
NCS
m
m
m
m
m
n
n
n
o
o
o
o
q
q
q
q
q
r
H
H
H
H
H
Cl
Cl
Cl
H
H
H
H
Cl
Cl
Cl
Cl
Me
OEt
Me
SMe
Me
i
Cl
2q (80%)
OMe
OMe
OMe
OMe
OMe
OEt
OMe
OEt
OMe
OMe
Me
2a
b
c
g
l
Scheme 2. Synthesis of 2q: i: CH2Cl2, NCS, 20 ꢀC, 2 h.
z
aa
ab
ac
ad
ae
af
ag
ah
ai
ak
al
am
an
ao
ap
The reaction of
b-ketoesters 3aed with carbon disulfide and
f
g
d
b
c
a
g
d
l
e
g
g
g
g
iodomethane in the presence of potassium tert-butanolate afforded
the novel 2-acyl-3,3-bis(methylthio)-acrylates 2reu (Scheme 3,
Table 2).
H
Et
OMe
H
H
H
Me
n-Pr
H
H
H
Me
Me
Me
Me
Me
Me
Me
n-Pr
OMe
OEt
O
O
O
O
i
OMe
OMe
OMe
OMe
OMe
OMe
R1
MeS
OR2
R1
OR2
Cl
CO2Me
CO2Et
CO2Bn
CO2Et
SMe
3a-d
s
t
u
2r-u
H
Scheme 3. Synthesis of 2reu: i: (1) THF, NaH (60%), 15 min, 20 ꢀC; (2) THF, CS2, MeI,
a
20 ꢀC, 10 h.
Yields of isolated products.

6000
M. Lubbe et al. / Tetrahedron 69 (2013) 5998e6007
isolated in moderate to good yields (except for 5l,m). A great va-
riety of different products were successfully prepared. This includes
various alkylated derivatives 5aem, bicyclic products 5net (con-
taining aliphatic five-, six-, seven- and eight-membered rings),
biaryls 5ueab, ferrocenes 5aceaf,5c 4-chlorophenols 5ageal and
isophthalates 5ameap. The regioselective formation of the prod-
ucts can be explained by TiCl4 mediated conjugate addition of the
terminal carbon atom of the diene to the carbonyl group and sub-
sequent cyclization by attack of the central carbon atom of the di-
ene to the carbon attached to the sulfur atoms.
OH
O
OH
O
OEt
SMe
OEt
SMe
Me
Me
5e
5o
In contrast to 4,4-bis(methylthio)-3-chloro-but-3-en-2-one
(2q), the isolation of the corresponding brominated derivative
failed, due to decomposition of the brominated enones. However, it
proved to be possible to generate the enone in situ. The reaction of
2a with N-bromosuccinimide (NBS) resulted in formation of 4,4-
bis(methylthio)-3-bromo-but-3-en-2-one, which was not isolated,
but reacted in situ with dienes 4d,l to give the desired 4-
bromophenols 5aq and 5ar in good yields (Scheme 5, Table 4).
OH
O
OH
O
Me
MeO
OMe
SMe
OMe
SMe
Cl
F
5y
5aa
Scheme 7. 1H,1H-NOESY-experiments.
Me3SiO
R1
OSiMe3
R2
OH
O
R1
4d,l
R2
SMe
NBS
+
O
SMe
i
Me
Br
5aq-ar
Me
SMe
2a
Scheme 5. Synthesis of 5aq,ar: i: (1) CH2Cl2, 2a, NBS, 0 ꢀC, 2 h; (2) 4d,l, TiCl4, CH2Cl2,
ꢁ78/20 ꢀC, 14 h.
Table 4
Synthesis of 5aq and 5ar
2
4
5
R1
R2
% (5)a
a
a
d
l
aq
ar
H
Me
OEt
OMe
73
62
a
Yields of isolated products.
Fig. 1. ORTEP-Plot of 5a (50% probability level).
The structures of products 5 were established by 2D NMR or
X-ray crystal structure analyses. The structure of 5a was confirmed
by HMBC correlation experiments (Scheme 6). Correlations were
observed between carbon atom C-6 and the methyl group located
at C-5 and between carbon C-5 and the methyl group located at C-6.
OH
O
1
Me
Me
6
OMe
SMe
2
3
5
4
5a
Scheme 6. HMBC experiment for 5a with numbering scheme.
The structures of 5e, 5o, 5y and 5aa were established by NOESY
experiments (Scheme 7). For 5e and 5o, diagnosticNOESY interactions
between proton 6-H and the alkyl group located at position 5 were
observed. In case of 5y, a NOESY interaction between the methoxy
group located at position 6 and the naphthyl group was observed. For
5aa, a diagnostic NOESY interaction between the methyl group lo-
cated at position 6 and the phenyl group was observed.
The structures of 5a (Fig. 1), 5h (Fig. 2), 5k (Fig. 3) and 5an
(Fig. 4) were independently confirmed by X-ray crystal structure
analyses.
Fig. 2. ORTEP-Plot of 5h (50% probability level).

M. Lubbe et al. / Tetrahedron 69 (2013) 5998e6007
6001
the bis(methylthio) group of 2p, and subsequent cyclization by
attack of the central carbon atom of the 1,3-dicarbonyl unit to the
carbonyl group (Table 5).
Table 5
Synthesis of 7aed
2
6
7
R1
R2
R3
% (7)a
p
a
a
b
b
a
b
c
Ph
H
H
Me
Me
Me
Me
Et
70
90
m
m
o
2-Naphtyl
2-Naphtyl
Ferrocenyl
74
d
Et
745c
a
Yields of isolated products.
The structure of 7a was confirmed by 1H,1H-NOESY experiments
(Scheme 9). Diagnostic NOESY interactions were observed between
the acetyl group and the phenyl group and between the methylthio
group and the two neighbouring aromatic protons.
OH
O
Fig. 3. ORTEP-Plot of 5k (50% probability level).
Me
MeS
7a
Scheme 9. 1H,1H-NOESY experiment of 7a.
Molecules 5u and 7b are regioisomers. Their structures were
confirmed by 1H,1H-NOESY experiments (Scheme 10). In case of 5u,
diagnostic NOESY interactions were observed between the naph-
thyl group and the neighbouring aromatic protons and between the
methylthio group and the neighbouring aromatic proton. In case of
7b, NOESY interactions were observed between the acetyl and the
naphthyl group and between the methylthio group and the two
neighbouring aromatic protons. Similar results were obtained by
NOESY experiments for 7c.
OH
O
OH
O
Me
Me
SMe
MeS
5u
7b
Fig. 4. ORTEP-Plot of 5an (50% probability level).
Scheme 10. 1H,1H-NOESY correlations of 5u and 7b.
The reaction of 2p,m,o with the dianions of acetylacetone (6a)
and heptane-3,5-dione (6b), in situ generated by means of LDA,
afforded 6-acyl-3-(methylthio)phenols 7aed in good yields
(Scheme 8). The regioselective formation of 7a can be explained by
attack of the most reactive, terminal carbon atom of the dianion to
It is interesting to note that the regioselectivity of the cyclization
reactions of 3-oxo-bis(methylthio)ketenacetals with 1,3-bis(silyloxy)-
1,3-butadienes and 1,3-dicarbonyl dianions provide different
regioisomers. The reason for this different selectivity is unclear at
present. From a preparative viewpoint, the reactions complement
each other very well.
O
O
R2
OH
O
R3
3. Experimental section
R2
6a,b
R3
i
3.1. General procedure for the synthesis of 3-oxo-bis(me-
thylthio)ketenacetals 2aep
+
SMe
O
MeS
R1
To a solution of KOtBu (2.0 equiv) in dry THF (1.0 mL/mmol) was
dropwise added 1aep (1.0 equiv) and the mixture was stirred for
15 min. Subsequently, carbon disulfide (1.0 equiv) and iodomethane
(2.0 equiv) were added and the mixture was stirred at 20 ꢀC for 14 h.
Water was added and the organic layer was separated. The aqueous
MeS
R1
7a-d
2p,m,o
Scheme 8. Synthesis of 7aed: i: (1) THF, LDA (2.5 equiv), 6a,b, 0 ꢀC, 1 h; (2) THF,
2p,m,o, 0/20 ꢀC, 14 h.

6002
M. Lubbe et al. / Tetrahedron 69 (2013) 5998e6007
layer was extracted with dichloromethane and the combined
organic layers were dried (Na2SO4), filtered and concentrated in
vacuo. The residue was purified by chromatography (silica gel,
heptanes/EtOAc¼20:1). The synthesis of 2aem and 2o,p has been
previously reported.6
128.6, 128.5, 128.4 (CH), 67.2 (OCH2), 30.0 (COCH3), 18.6 (SCH3). MS
(EI, 70 eV): m/z (%)¼296 (Mþ, 20), 281 (100), 239 (9), 207 (8), 189
(12), 173 (24). HRMS (EI, 70 eV): calcd for C14H16O3S2 (Mþ)
296.05354, found 296.053989.
3.2.4. Ethyl 2-(n-Butyl)-3,3-bis(methylthio)acrylate (2u). Starting
with ethyl 3-oxohexanoate (1.582 g, 10.0 mmol), sodium hydride
(60%ig, 800 mg, 20.0 mmol), carbon disulfide (0.62 mL, 10.0 mmol)
and iodomethane (1.25 mL, 20.0 mmol) in THF (30 mL), 2u was
isolated as a yellow oil (1.371 g, 53%); Rf 0.82 (heptanes/EtOAc 1:1).
3.1.1. 3,3-Bis(methylthio)-2-chloro-1-(2-fluorophenyl)-prop-2-en-1-one
(2n). Starting with
u-chloro-4-fluoroacetophenone (1.726 g,
10.0 mmol), potassium tert-butanolate (2.245 g, 20.0 mmol), carbon
disulfide (0.61 mL, 10.0 mmol) and iodomethane (1.25 mL, 20.0 mmol)
in THF (30 mL), 2n was isolated as a brownish oil (1.224 mg, 45%). 1H
1H NMR (CDCl3, 300 MHz):
d
¼4.26 (q, 3J¼7.2 Hz, 2H, OCH2CH3), 2.58
NMR (CDCl3, 250 MHz):
d
¼7.96e7.90 (m, 2H, 2ꢂ CH), 7.20e7.13 (m,
(t, 3J¼7.4 Hz, 2H, COCH2), 2.42 (s, 6H, 2ꢂ SCH3), 1.73e1.61 (m, 2H,
CH2CH2CH3), 1.30 (t, 3J¼7.2 Hz, OCH2CH3), 0.94 (t, 3J¼7.4 Hz,
2H, 2ꢂ CH), 2.48 (s, 3H, SCH3), 2.17 (s, 3H, SCH3). 13C NMR (CDCl3,
63 MHz):
d
¼187.5 (C]O), 166.2 (d, JC,F¼256 Hz, C-40), 137.3 (C), 132.3
(CH2)2CH3). 13C NMR (CDCl3, 75 MHz):
d
¼198.5 (C]O), 164.7
(d, JC,F¼10 Hz, C-20), 131.3 (d, JC,F¼3 Hz, C-10), 126.7 (C), 116.0 (d,
(OeC]O), 156.0 (SeCeS), 135.7 (C), 61.4 (OCH2), 44.3 (COCH2), 18.5
JC,F¼256 Hz, C-40), 18.6, 15.8 (SCH3). 19F NMR (CDCl3, 235 MHz):
(CH3), 17.2 (CH2CH2CH3), 14.0, 13.6 (CH3). IR (ATR, cmꢁ1):
n
¼2962
d¼ꢁ103.4 (ArF).
(m), 2928 (m), 2874 (w), 1698 (s), 1666 (m), 1524 (m), 1489 (m),
1463 (m), 1419 (w), 1364 (m), 1235 (s), 1173 (s). MS (EI, 70 eV): m/z
(%)¼262 (Mþ, 14), 247 (59), 219 (100), 201 (12), 173 (15), 147 (28).
Anal. Calcd for C11H18O3S2 (262.39): C, 50.35; H, 6.91. Found: C,
50.32; H, 7.16.
3.2. General procedure for the synthesis of 2reu
To a suspension of NaH (60%, paraffin oil, 2.0 equiv) in dry THF
(1.0 mL/mmol) was added the
b-ketoester (1.0 equiv) and the
mixture was stirred for 15 min. Subsequently, carbon disulfide
(1.0 equiv) and iodomethane (2.0 equiv) were added and the
mixture was stirred at 20 ꢀC for 14 h. Water was added and the
organic layer was separated. The aqueous layer was extracted with
diethyl ether and the combined organic layers were dried (Na2SO4),
filtered and concentrated in vacuo. The residue was purified by
chromatography (silica gel, heptanes/EtOAc¼20:1).
3.3. General procedure for the synthesis of 5aeap
To a solution of 2 (1.0 mmol) and diene 4 (2.0 mmol) in CH2Cl2
(2 mL) was added TiCl4 (1.0 mmol) at ꢁ78 ꢀC under argon. The
temperature of the reaction mixture was allowed to rise to 20 ꢀC
during 14 h, and an aqueous HCl solution (10%, 10 mL) was added.
The organic layer was separated, and the aqueous layer was
extracted with CH2Cl2 (3ꢂ10 mL). The combined organic layers were
dried (Na2SO4), filtered and concentrated in vacuo. After column
chromatography (silica gel, heptanes/EtOAc¼10:1), 5 was isolated.
3.2.1. Methyl 2-acetyl-3,3-bis(methylthio)acrylate (2r). Starting with
methyl acetoacetate (581 mg, 5.0 mmol), sodium hydride (60%ig,
400 mg, 10.0 mmol), carbon disulfide (0.31 mL, 5.0 mmol) and
iodomethane (0.63 mL, 10.0 mmol) in THF (15 mL), 2r was isolated
as a yellow oil (661 mg, 60%); Rf 0.82 (heptanes/EtOAc 1:1). 1H NMR
3.3.1. Methyl3,4-dimethyl-2-hydroxy-6-methylthio-benzoate(5a). Starting
with 2a (162 mg, 1.0 mmol), 4l (549 mg, 2.0 mmol) and titanium tetra-
chloride (0.11 mL, 1.0 mmol) in CH2Cl2 (2 mL), 5a was isolated as a col-
ourless solid (147 mg, 65%); mp¼101e102 ꢀC; Rf 0.49 (heptanes/EtOAc
(CDCl3, 300 MHz):
1H, COCH3). 13C NMR (CDCl3, 75 MHz):
(OeC]O), 157.6 (SeCeS), 134.7 (C), 52.3 (OCH3), 30.0 (COCH3),
18.5 (SCH3). IR (ATR, cmꢁ1):
d
¼3.79 (s, 1H, OCH3), 2.41 (s, 2H, SCH3), 2.32 (s,
d
¼195.4 (C]O), 165.4
1:1). 1H NMR (CDCl3, 250 MHz):
d
¼11.73 (s, 1H, OH), 6.47 (s, 1H, CH), 3.98
n
¼2991 (w), 2922 (w), 1694 (s), 1523
(s, 3H, OCH3), 2.41 (s, 3H, SCH3), 2.28 (s, 3H, CH3), 2.13 (s, 3H, CH3). 13
NMR (63 MHz, CDCl3):
¼171.4 (C]O), 161.5 (CeO), 143.6, 139.4, 120.6 (C),
116.6 (CH), 107.5 (C), 51.8 (OCH3), 20.8, 16.3, 11.2 (CH3). IR (ATR, cmꢁ1):
C
(m), 1418 (m), 1356 (m), 1248 (s), 1205 (s). MS (EI, 70 eV): m/z (%)¼
220 (Mþ, 18), 205 (100), 189 (8), 173 (16), 163 (12), 131 (32).
Anal. Calcd for C8H12O3S2 (220.31): C, 43.61; H, 5.49. Found: C,
43.73; H, 5.35.
d
n
¼3008 (w), 2951 (m), 2852 (w), 1649 (s), 1598 (s), 1559 (m), 1436 (s). MS
(EI, 70 eV): m/z (%)¼226 (Mþ, 73), 195 (19), 194 (100), 166 (38), 151 (34),
121 (39). HRMS (EI, 70 eV): calcd for C11H14O3S (Mþ) 226.06582, found
226.065942.
3.2.2. Ethyl2-acetyl-3,3-bis(methylthio)acrylate(2s). Starting with ethyl
acetoacetate (651 mg, 5.0 mmol), sodium hydride (60%, 400 mg,
10.0 mmol), carbon disulfide (0.31 mL, 5.0 mmol) and iodomethane
(0.63 mL, 10.0 mmol) in THF (15 mL), 2s was isolated as a yellow oil
(664 mg, 60%); Rf 0.82 (heptanes/EtOAc 1:1). 1H NMR (CDCl3,
3.3.2. 6-Hydroxy-3,4-dimethyl-2-methylthio-acetophenone (5b). Starting
with 2b (176 mg, 1.0 mmol), 4a (489 mg, 2.0 mmol) and titanium tet-
rachloride (0.11 mL, 1.0 mmol) in CH2Cl2 (2 mL), 5b was isolated as
a colourless solid (148 mg, 70%); mp¼96e98 ꢀC; Rf 0.42 (heptanes/
300 MHz):
d
¼4.28 (q, 3J¼7.0 Hz, 2H, CH2), 2.43 (s, 6H, SCH3), 2.34 (s, 3H,
COCH3), 1.32 (t, 3J¼7.0 Hz, CH2CH3). 13C NMR (CDCl3, 75 MHz):
d¼195.4
EtOAc 1:1). 1H NMR (CDCl3, 250 MHz):
d
¼10.13 (s, 1H, OH), 6.78 (s, 1H,
(C]O), 165.1 (OeC]O), 157.2 (SeCeS), 135.2 (C), 61.5 (CH2), 30.0
CH), 2.84 (s, 3H, CH3), 2.44 (s, 3H, CH3), 2.28 (s, 6H, 2ꢂ CH3). 13C NMR
(COCH3), 18.5 (SCH3), 14.0 (CH2CH3). IR (ATR, cmꢁ1):
n¼2981 (w), 2925
(63 MHz, CDCl3):
d¼206.7 (C]O), 156.8 (CeO), 143.8, 135.7, 133.2, 125.2
(w), 1698 (s), 1663 (m), 1524 (m), 1488 (m), 1419 (m), 1390 (w), 1354
(m), 1248 (s), 1199 (s). MS (EI, 70 eV): m/z (%)¼234 (Mþ, 19), 219 (100),
191 (13), 189 (14), 173 (26), 147 (23). Anal. Calcd for C9H14O3S2 (234.34):
C, 46.13; H, 6.02. Found: C, 45.93; H, 6.09.
(C), 119.3 (CH), 32.5 (COCH3), 21.7, 20.6, 16.6 (CH3). IR (ATR, cmꢁ1):
n
¼3220 (br, m), 2978 (m), 2950 (w), 2922 (w),1670 (s), 1591 (s), 1454 (s).
MS (EI, 70 eV): m/z (%)¼210 (Mþ, 30), 195 (100), 192 (43), 180 (18), 177
(16),161 (15). Anal. Calcd for C11H14O2S (210.29): C, 62.83; H, 6.71. Found:
C, 62.70; H, 6.97.
3.2.3. Benzyl 2-acetyl-3,3-bis(methylthio)acrylate (2t). Starting with
benzyl acetoacetate (1.923 g, 10.0 mmol), sodium hydride (60%,
800 mg, 20.0 mmol), carbon disulfide (0.62 mL, 10.0 mmol) and
iodomethane (1.25 mL, 20.0 mmol) in THF (30 mL), 2t was isolated
as a yellow oil (1.812 g, 62%); Rf 0.71 (heptanes/EtOAc 1:1). 1H NMR
3.3.3. Methyl 6-hydroxy-3,4-dimethyl-2-methylthio-benzoate (5c). Starting
with 2b (176 mg, 1.0 mmol), 4g (521 mg, 2.0 mmol) and titanium tetra-
chloride (0.11mL,1.0mmol) inCH2Cl2 (2 mL), 5c was isolated as a colourless
solid (185 mg, 82%); mp¼88e90 ꢀC; Rf 0.36 (heptanes/EtOAc 1:1). 1H NMR
(CDCl3, 300 MHz):
d
¼7.40e7.31 (m, 5H, Ph), 5.26 (s, 2H, OCH2), 2.41
(CDCl3, 250 MHz):
d
¼9.06 (s, 1H, OH), 6.78 (s, 1H, CH), 3.97 (s, 3H, OCH3),
(s, 6H, 2ꢂ SCH3), 2.29 (s, 3H, COCH3). 13C NMR (CDCl3, 63 MHz):
2.43 (s, 3H, CH3), 2.28 (s, 3H, CH3), 2.27 (s, 3H, CH3). 13C NMR (63 MHz,
CDCl3):
¼170.6 (C]O), 156.7 (CeO), 143.4, 136.1, 133.3 (C), 118.6 (CH), 116.9
d¼195.2 (C]O), 164.9 (OeC]O), 158.0 (SeCeS), 135.2, 134.7 (C),
d

M. Lubbe et al. / Tetrahedron 69 (2013) 5998e6007
6003
(C), 52.3 (OCH3), 21.6, 20.0, 17.0 (CH3). IR (ATR, cmꢁ1):
(m), 2952 (w), 2917 (w), 1699 (s), 1580 (s), 1430 (s). MS (EI, 70 eV): m/z (%)¼
226 (Mþ, 45), 195 (21), 194 (100), 179 (15), 166 (35), 151 (58). Anal. Calcd for
C11H14O3S (226.29): C, 58.38; H, 6.24. Found: C, 58.49; H, 6.52.
n
¼3336 (br, m), 2978
2.0 mmol) and titanium tetrachloride (0.11 mL, 1.0 mmol) in
CH2Cl2 (2 mL), 5h was isolated as a colourless solid (201 mg, 79%);
mp¼102e104 ꢀC; Rf 0.40 (heptanes/EtOAc 1:1). 1H NMR (CDCl3,
250 MHz):
d
¼9.21 (s, 1H, OH), 6.77 (s, 1H, CH), 3.98 (s, 3H, OCH3),
2.84 (t, 3J¼8.1 Hz, 2H, ArCH2), 2.31 (s, 6H, 2ꢂ CH3), 1.57e1.41 (m,
3.3.4. Methyl4-ethyl-2-hydroxy-5-methyl-6-methylthio-benzoate(5d). Star-
ting with 2c (191 mg, 1.0 mmol), 4g (521 mg, 2.0 mmol) and titanium
tetrachloride (0.11 mL, 1.0 mmol) in CH2Cl2 (2 mL), 5d was isolated as
a colourless solid (216 mg, 90%); mp¼86e89 ꢀC; Rf 0.48 (heptanes/EtOAc
2H, CH2CH3), 1.01 (t, 3J¼7.3 Hz, 3H, CH2CH3). 13C NMR (63 MHz,
CDCl3):
d
¼170.6 (C]O), 157.4 (CeO), 142.9, 138.0, 136.2 (C), 119.1
(CH), 116.4 (C), 52.4 (OCH3), 32.9 (CH2) 23.8 (CH2), 21.0, 20.9, 14.4
(CH3). IR (ATR, cmꢁ1):
n
¼3279 (br, m), 2952 (m), 2924 (w), 2866
1:1). 1H NMR (CDCl3, 250 MHz):
d
¼9.04 (s, 1H, OH), 6.80 (s, 1H, ArH), 3.97
(w), 1702 (s), 1586 (s), 1433 (s). MS (EI, 70 eV): m/z (%)¼254 (Mþ,
38), 223 (11), 222 (50), 207 (8), 194 (13), 193 (100). HRMS (EI,
70 eV): calcd for C13H18O3S (Mþ) 254.09712, found 254.097158.
(s, 3H, OCH3), 2.63 (q, 3J¼7.4 Hz, 2H, ArCH2), 2.47 (s, 3H, CH3), 2.29 (s, 3H,
CH3), 1.20 (t, 3J¼7.4 Hz, 3H, CH2CH3). 13C NMR (63 MHz, CDCl3):
¼170.6
d
(C]O), 157.0 (CeO), 149.0, 136.4, 132.6, 116.9 (C), 116.8 (CH), 52.3 (OCH3),
27.6 (ArCH2), 20.0, 16.3, 13.8 (CH3). IR (ATR, cmꢁ1):
n
¼3305 (br, m), 2962
3.3.9. 2-Methoxyethyl
6-hydroxy-4-methyl-2-methylthio-3-(n-pro-
(m), 2924 (w), 2871 (w), 1704 (s), 1587 (s), 1403 (s). MS (EI, 70 eV): m/z (%)¼
240 (Mþ, 48), 209 (20), 208 (100),193 (10),180 (28),165 (43). Anal. Calcd for
C12H16O3S (240.32): C, 59.97; H, 6.71. Found: C, 59.63; H, 6.91.
pyl)-benzoate (5i). Starting with 2e (205 mg, 1.0 mmol), 4k (609 mg,
2.0 mmol) and titanium tetrachloride (0.11 mL, 1.0 mmol) in CH2Cl2
(2 mL), 5i was isolated as a colourless solid (237 mg, 80%);
mp¼46e49 ꢀC; Rf 0.34 (heptanes/EtOAc 1:1). 1H NMR (CDCl3,
3.3.5. Ethyl 4-ethyl-6-hydroxy-3-methyl-2-methylthio-benzoate (5e). Star-
ting with 2c (191 mg, 1.0 mmol), 4d (549 mg, 2.0 mmol) and titanium
tetrachloride (0.11 mL, 1.0 mmol) in CH2Cl2 (2 mL), 5e was isolated as
a colourless solid (227 mg, 89%); mp¼120e121 ꢀC; Rf 0.39 (heptanes/
250 MHz):
d
¼8.63 (s, 1H, OH), 6.77 (s, 1H, CH), 4.55 (t, 3J¼4.7 Hz, 2H,
OCH2), 3.74 (t, 3J¼4.7 Hz, 2H, OCH2), 3.43 (s, 3H, OCH3), 2.84 (t,
3J¼8.1 Hz, 2H, ArCH2), 2.35 (s, 3H, CH3), 2.31 (s, 3H, CH3), 1.55e1.41
(m, 2H, CH2CH3), 1.01 (t, 3J¼7.6 Hz, 3H, CH2CH3). 13C NMR (63 MHz,
EtOAc 3:1). 1H NMR (CDCl3, 250 MHz):
d
¼9.08 (s, 1H, OH), 6.80 (s, 1H,
CDCl3):
d
¼168.8 (C]O), 155.8 (CeO), 142.3, 138.2, 135.3 (C), 119.5
CH), 4.45 (q, 3J¼7.1 Hz, 2H, OCH2), 2.62 (q, 3J¼7.5 Hz, 2H, ArCH2), 2.47 (s,
(CH), 118.8 (C), 69.8 (OCH2), 63.9 (OCH2), 58.8 (OCH3), 32.9 (CH2)
3H, CH3), 2.30 (s, 3H, CH3), 1.43 (t, 3J¼7.1 Hz, 3H, OCH2CH3), 1.20 (t,
23.9 (CH2), 21.2, 20.8, 14.5 (CH3). IR (ATR, cmꢁ1):
n¼3340 (br, m),
3J¼7.5 Hz, 3H, ArCH2CH3). 13C NMR (75 MHz, CDCl3):
d¼170.2 (C]O),
2951 (m), 2922 (w), 2866 (w), 1699 (s), 1588 (s), 1407 (s). MS (EI,
70 eV): m/z (%)¼298 (Mþ, 32), 223 (18), 222 (70), 194 (13), 193 (100).
HRMS (EI, 70 eV): calcd for C15H22O4S (Mþ) 298.12333, found
298.122574.
156.9 (CeO), 148.8, 136.2, 132.7, 117.3 (C), 116.9 (CH), 61.8 (OCH2), 27.6
(ArCH2), 20.0, 16.2, 14.0, 13.8 (CH3). IR (ATR, cmꢁ1):
n
¼3299 (br, m), 2963
(m), 2923 (w), 2871 (w), 1699 (s), 1587 (s), 1404 (s). MS (EI, 70 eV): m/z
(%)¼254 (Mþ, 39), 209 (21), 208 (100), 193 (8), 180 (27), 165 (32).
Anal. Calcd for C13H18O3S (254.10): C, 61.39; H, 7.13. Found: C, 61.35; H,
7.27.
3.3.10. 4-(tert-Butyl)-2-hydroxy-6-methylthio-acetophenone
(5k). Starting with 2f (205 mg, 1.0 mmol), 4a (489 mg, 2.0 mmol)
and titanium tetrachloride (0.11 mL, 1.0 mmol) in CH2Cl2 (2 mL), 5k
was isolated as a colourless solid (119 mg, 50%); mp¼77e79 ꢀC; Rf
3.3.6. Ethyl 3-ethyl-6-hydroxy-4-methyl-2-methylthio-benzoate (5f). Star-
ting with 2d (191 mg, 1.0 mmol), 4d (549 mg, 2.0 mmol) and titanium
tetrachloride (0.11 mL, 1.0 mmol) in CH2Cl2 (2 mL), 5f was isolated as
a colourless solid (227 mg, 89%); mp¼106e108 ꢀC; Rf 0.50 (heptanes/
0.64 (heptanes/EtOAc 1:1). 1H NMR (CDCl3, 250 MHz):
d
¼12.73 (s,
1H, OH), 6.81e6.78 (m, 2H, 2ꢂ CH), 2.84 (s, 3H, CH3), 2.55 (s, 3H,
CH3), 1.30 (s, 9H, t-Bu). 13C NMR (63 MHz, CDCl3):
¼204.9 (C]O),
163.7 (CeO), 158.3, 141.4, 118.1 (C), 115.3, 112.5 (CH), 35.4 (C(CH3)3),
33.6 (CH3), 30.6 (C(CH3)3), 17.6 (CH3). IR (ATR, cmꢁ1):
d
EtOAc 3:1). 1H NMR (CDCl3, 300 MHz):
d
¼9.23 (s, 1H, OH), 6.78 (s, 1H,
ArH), 4.46 (q, 3J¼7.2 Hz, 2H, OCH2), 2.93 (q, 3J¼7.4 Hz, 2H, ArCH2), 2.34 (s,
3H, CH3), 2.33 (s, 3H, CH3), 1.44 (t, 3J¼7.2 Hz, 3H, OCH2CH3), 1.13 (t,
n
¼2964 (m),
2919 (m), 2867 (w), 1582 (s), 1553 (s), 1538 (s). MS (EI, 70 eV): m/z
(%)¼238 (Mþ, 25), 224 (14), 223 (100), 220 (17), 208 (12), 205 (13).
HRMS (EI, 70 eV): calcd for C13H18O2S (Mþ) 238.10220, found
238.102061.
3J¼7.4 Hz, 3H, ArCH2CH3). 13C NMR (75 MHz, CDCl3):
¼170.2 (C]O),
d
157.3 (CeO), 142.6, 139.6, 135.6 (C), 119.4 (CH), 117.2 (C), 61.9 (OCH2), 23.9
(ArCH2), 21.2, 20.7, 14.7, 14.0 (CH3). IR (ATR, cmꢁ1):
n
¼3323 (br, m), 2963
(m), 2919 (w), 2868 (w), 1698 (s), 1588 (s), 1404 (s). MS (EI, 70 eV): m/z
(%)¼254 (Mþ, 48), 209 (22), 208 (100), 193 (96), 180 (10), 165 (21).
Anal. Calcd for C13H18O3S (254.10): C, 61.39; H, 7.13. Found: C, 61.36; H,
7.32.
3.3.11. Methyl4-cyclohexyl-2-hydroxy-6-methylthio-benzoate(5l). Starting
with 2g (230 mg, 1.0 mmol), 4g (521 mg, 2.0 mmol) and titanium tetra-
chloride (0.118 mL, 1.0 mmol) in CH2Cl2 (2.0 mL), 5l was isolated as
a colourless solid (40 mg, 14%); mp 52e53 ꢀC. 1H NMR (CDCl3, 300 MHz):
3.3.7. 2-Methoxyethyl
3-ethyl-6-hydroxy-4-methyl-2-methylthio-
d
¼11.34 (s, 1H, OH), 6.61 (d, 4J¼1.5 Hz, 1H, CHAr), 6.52 (d, 4J¼1.5 Hz, 1H,
benzoate (5g). Starting with 2d (191 mg, 1.0 mmol), 4k (609 mg,
2.0 mmol) and titanium tetrachloride (0.11 mL, 1.0 mmol) in CH2Cl2
(2 mL), 5g was isolated as a colourless solid (215 mg, 76%);
mp¼79e81 ꢀC; Rf 0.30 (heptanes/EtOAc 1:1). 1H NMR (CDCl3,
CHAr), 3.98 (s, 3H, OCH3), 3.05e2.95 (m, 1H, ArCH), 2.43 (s, 3H, SCH3)
1.87e1.25 (m, 10H, 5ꢂ CH2). 13C NMR (CDCl3, 75 MHz):
¼169.8 (C]O),
d
162.6 (CeO),154.0,142.3 (C),113.7,110.7 (CHAr),107.0 (C), 50.9 (OCH3), 44.0
(ArCH), 32.7, 25.6, 25.0 (CH2), 15.4 (SCH3). IR (ATR, cmꢁ1):
n¼2917 (s), 1849
300 MHz):
d
¼8.62 (s,1H, OH), 6.77 (s,1H, CH), 4.55 (t, 3J¼4.8 Hz, 2H,
(s), 1655 (s) 1605 (s), 1563 (s). MS (EI, 70 eV): m/z (%)¼280 (Mþ, 64), 249
(21), 248 (100),193 (55),180 (57). HRMS (ESI): calcd for C16H22NaO4S (Mþ)
303.10254, found 303.10182.
OCH2), 3.74 (t, 3J¼4.8 Hz, 2H, OCH2), 3.43 (s, 3H, OCH3), 2.93 (q,
3J¼7.4 Hz, 2H, ArCH2), 2.37 (s, 3H, CH3), 2.32 (s, 3H, CH3), 1.12 (t,
3J¼7.4 Hz, 3H, ArCH2CH3). 13C NMR (63 MHz, CDCl3):
¼168.7 (C]
d
O), 155.8 (CeO), 142.1, 139.5, 134.9 (C), 119.7 (CH), 119.0 (C), 69.8,
3.3.12. Methyl
4-cyclohexyl-2-hydroxy-3-methoxy-6-methylthio-
63.9 (OCH2), 58.8 (OCH3), 23.8 (ArCH2), 21.2, 20.6, 14.7 (CH3). IR
benzoate (5m). Starting with 2g (400 mg, 1.6 mmol), 4c (930 mg,
3.2 mmol) and titanium tetrachloride (0.18 mL, 1.6 mmol) in CH2Cl2
(3.5 mL), 5m was isolated as a slightly yellow solid (75 mg,15%); mp
(ATR, cmꢁ1):
n
¼3202 (br, m), 2967 (m), 2929 (m), 2873 (w),1725 (s),
1587 (s), 1404 (s). MS (EI, 70 eV): m/z (%)¼284 (Mþ, 37), 209 (25),
208 (100), 193 (69), 180 (7), 165 (15). Anal. Calcd for C14H20O4S
(284.37): C, 59.13; H, 7.09. Found: C, 59.13; H, 7.26.
106e107 ꢀC. 1H NMR (CDCl3, 250 MHz):
d
¼11.48 (s, 1H, OH), 6.52 (s,
1H, CHAr), 3.99 (s, 3H, OCH3), 3.84 (s, 3H, OCH3), 3.05e2.95 (m, 1H,
ArCH), 2.43 (s, 3H, SCH3) 1.86e1.28 (m, 10H, 5ꢂ CH2). 13C NMR
3.3.8. Methyl 6-hydroxy-4-methyl-2-methylthio-3-(n-propyl)-benzo-
ate (5h). Starting with 2e (205 mg, 1.0 mmol), 4g (521 mg,
(CDCl3, 75 MHz):
d
¼170.0 (C]O), 155.7 (CeO), 145.6, 141.6, 136.0
(C), 112.2 (CHAr), 118.1 (C), 59.8, 51.0 (OCH3), 36.9 (ArCH), 32.4, 25.7,

6004
M. Lubbe et al. / Tetrahedron 69 (2013) 5998e6007
25.1 (CH2), 15.5 (SCH3). IR (ATR, cmꢁ1):
n
¼3000 (m), 2923 (s), 2844
(18), 206 (10), 205 (9). HRMS (EI, 70 eV): calcd for C14H18O3S (Mþ)
266.09712, found 266.097242.
(m), 1657 (s) 1599 (m), 1553 (m). MS (EI, 70 eV): m/z (%)¼310 (Mþ,
37), 295 (100), 269 (50), 191 (85), 163 (38). HRMS (EI, 70 eV): calcd
for C16H22O4S (Mþ) 310.12333, found 310.122947.
3.3.17. Ethyl 3-hydroxy-1-methylthio-6,7,8,9-tetrahydro-5H-benzo-
cyclohepten-2-carboxylate (5r). Starting with 2k (217 mg,
1.0 mmol), 4d (549 mg, 2.0 mmol) and titanium tetrachloride
(0.11 mL, 1.0 mmol) in CH2Cl2 (2 mL), 5r was isolated as a colourless
solid (149 mg, 69%); mp¼128e130 ꢀC; Rf 0.52 (heptanes/EtOAc 1:1).
3.3.13. Ethyl 6-hydroxy-4-methylthio-indan-5-carboxylate
(5n). Starting with 2h (189 mg, 1.0 mmol), 4d (549 mg,
2.0 mmol) and titanium tetrachloride (0.11 mL, 1.0 mmol) in CH2Cl2
(2 mL), 5n was isolated as a slightly yellow oil (125 mg, 50%). 1H
1H NMR (CDCl3, 250 MHz):
d
¼8.93 (s, 1H, OH), 6.75 (s, 1H, ArH),
NMR (CDCl3, 250 MHz):
d
¼10.16 (s,1H, OH), 6.80 (s,1H, CH), 4.46 (q,
4.45 (q, 3J¼7.1 Hz, 2H, OCH2), 3.21 (t, 3J¼5.4 Hz, 2H, ArCH2), 2.77 (t,
3J¼5.4 Hz, 2H, ArCH2), 2.29 (s, 3H, SCH3), 1.86e1.76 (m, 2H, CH2),
1.67e1.59 (m, 4H, 2ꢂ CH2), 1.43 (t, 3J¼7.1 Hz, 3H, CH2CH3). 13C NMR
3J¼7.1 Hz, 2H, OCH2), 3.01e2.88 (m, 4H, 2ꢂ ArCH2), 2.35 (s, 3H,
SCH3), 2.10e1.99 (m, 2H, CH2CH2CH2), 1.45 (t, 3J¼7.1 Hz, 3H,
OCH2CH3). 13C NMR (75 MHz, CDCl3):
d
¼170.6 (C]O), 160.3 (CeO),
(63 MHz, CDCl3):
d
¼170.3 (C]O), 156.5 (CeO), 150.0, 140.4, 134.6
150.9, 140.7, 133.8, 114.1 (C), 113.0 (CH), 61.8 (OCH2), 33.9, 33.1, 24.8
(CAr), 118.4 (CHAr), 117.8 (CAr), 61.8 (OCH2), 37.1, 32.0, 31.2, 28.2, 27.9
(CH2), 19.4, 14.0 (CH3). IR (ATR, cmꢁ1):
n
¼3292 (br, m), 2948 (m),
(CH2), 21.0 (SCH3), 14.1 (CH2CH3). IR (ATR, cmꢁ1):
n
¼3353 (br, m),
2922 (w), 2861 (w), 1694 (s), 1589 (s), 1424 (s). MS (EI, 70 eV): m/z
(%)¼252 (Mþ, 36), 207 (19), 206 (100), 191 (9), 178 (21), 163 (14).
Anal. Calcd for C13H16O3S (252.33): C, 61.88; H, 6.39. Found: C,
61.88; H, 6.40.
2913 (m), 2842 (m), 1696 (s), 1586 (s), 1413 (s). MS (EI, 70 eV): m/z
(%)¼280 (Mþ, 41), 235 (21), 234 (100), 219 (16), 206 (10), 205 (9).
HRMS (EI, 70 eV): calcd for C15H20O3S (Mþ) 280.11277, found
280.113342.
3.3.14. Ethyl 3-hydroxy-1-methylthio-5,6,7,8-tetrahydronaphthalen-
2-carboxylate (5o). Starting with 2i (203 mg, 1.0 mmol), 4d (549 mg,
2.0 mmol) and titanium tetrachloride (0.11 mL, 1.0 mmol) in CH2Cl2
(2 mL), 5o was isolated as a colourless solid (146 mg, 55%);
mp¼130e134 ꢀC; Rf 0.54 (heptanes/EtOAc 1:1). 1H NMR (CDCl3,
3.3.18. Methyl 3-hydroxy-1-methylthio-5,6,7,8,9,10-hexahydro-ben-
zocycloocten-2-carboxylate (5s). Starting with 2l (231 mg,
1.0 mmol), 4g (521 mg, 2.0 mmol) and titanium tetrachloride
(0.11 mL, 1.0 mmol) in CH2Cl2 (2 mL), 5s was isolated as a colourless
solid (262 mg, 66%); mp¼97e99 ꢀC; Rf 0.44 (heptanes/EtOAc 1:1).
250 MHz):
d
¼9.06 (s, 1H, OH), 6.69 (s, 1H, ArH), 4.45 (q, 3J¼7.2 Hz,
1H NMR (CDCl3, 250 MHz):
d
¼9.16 (s, 1H, OH), 6.75 (s, 1H, CH), 3.99
2H, OCH2), 2.92 (t, 3J¼6.1 Hz, 2H, ArCH2), 2.74 (t, 3J¼6.1 Hz, 2H,
ArCH2), 2.31 (s, 3H, SCH3), 1.84e1.68 (m, 4H, 2ꢂ CH2), 1.44 (t,
(s, 3H, OCH3), 3.08 (t, 3J¼6.1 Hz, 2H, ArCH2), 2.75 (t, 3J¼6.0 Hz, 2H,
ArCH2), 2.32 (s, 3H, SCH3), 1.74e1.63 (m, 4H, 2ꢂ CH2) 1.50e1.26 (m,
3J¼7.2 Hz, 3H, CH2CH3). 13C NMR (63 MHz, CDCl3):
d
¼170.1 (C]O),
4H, 2ꢂ CH2). 13C NMR (63 MHz, CDCl3):
¼170.6 (C]O), 157.5
d
156.6 (CeO), 143.9, 136.4, 133.8 (C), 117.4 (CH),117.3 (C), 61.8 (OCH2),
30.5, 27.7, 23.4, 22.3 (CH2), 19.8 (SCH3), 14.0 (CH2CH3). IR (ATR,
(CeO), 148.8, 137.4, 135.7 (C), 118.2 (CH), 117.0 (C), 52.4 (OCH3), 34.5,
32.2, 31.0, 28.3, 26.5, 25.7 (CH2), 21.1 (SCH3). IR (ATR, cmꢁ1):
cmꢁ1):
n¼3304 (br, m), 2919 (m), 2875 (m), 2853 (m), 1694 (s), 1586
n
¼3290 (br, m), 2923 (m), 2849 (m), 1703 (s), 1588 (s), 1408 (s). MS
(s), 1414 (s). MS (EI, 70 eV): m/z (%)¼266 (Mþ, 41), 221 (21), 220
(100), 205 (26), 192 (19), 164 (24). HRMS (EI, 70 eV): calcd for
C14H18O3S (Mþ) 266.09712, found 266.097639.
(EI, 70 eV): m/z (%)¼280 (Mþ, 50), 249 (20), 248 (100), 233 (11), 206
(17). HRMS (EI, 70 eV): calcd for C15H20O3S (Mþ) 280.11277, found
280.113078.
3.3.15. 2-Methoxyethyl 3-hydroxy-1-methylthio-5,6,7,8-
tetrahydronaphthalen-2-carboxylate (5p). Starting with 2i (203 mg,
1.0 mmol), 4k (609 mg, 2.0 mmol) and titanium tetrachloride
(0.11 mL,1.0 mmol) in CH2Cl2 (2 mL), 5p was isolated as a colourless
solid (117 mg, 40%); mp¼71e73 ꢀC; Rf 0.30 (heptanes/EtOAc 1:1).
3.3.19. Ethyl 3-hydroxy-1-methylthio-5,6,7,8,9,10-hexahydro-benzo-
cycloocten-2-carboxylate (5t). Starting with 2l (231 mg, 1.0 mmol),
4d (549 mg, 2.0 mmol) and titanium tetrachloride (0.11 mL,
1.0 mmol) in CH2Cl2 (2 mL), 5t was isolated as a colourless solid
(170 mg, 58%); mp¼134e136 ꢀC; Rf 0.50 (heptanes/EtOAc 1:1). 1H
1H NMR (CDCl3, 250 MHz):
d
¼8.53 (s, 1H, OH), 6.69 (s, 1H, CH), 4.54
NMR (CDCl3, 250 MHz):
d
¼9.21 (s, 1H, OH), 6.76 (s, 1H, ArH), 4.46 (t,
(t, 3J¼4.8 Hz, 2H, OCH2), 3.74 (t, 3J¼4.8 Hz, 2H, OCH2), 3.42 (s, 3H,
OCH3), 2.92 (t, 3J¼6.1 Hz, 2H, ArCH2), 2.74 (t, 3J¼6.1 Hz, 2H, ArCH2),
2.33 (s, 3H, SCH3), 1.84e1.70 (m, 4H, 2ꢂ CH2). 13C NMR (63 MHz,
3J¼7.1 Hz, 2H, OCH2), 3.09 (t, 3J¼6.2 Hz, 2H, ArCH2), 2.75 (t,
3J¼6.1 Hz, 2H, ArCH2), 2.34 (s, 3H, SCH3), 1.74e1.63 (m, 4H, CH2,
CH2), 1.45 (t, 3J¼7.1 Hz, 3H, CH2CH3), 1.48e1.22 (m, 4H, 2ꢂ CH2). 13
C
CDCl3):
d
¼168.8 (C]O), 155.3 (CeO), 143.5, 135.7, 133.8, 118.8 (C),
NMR (63 MHz, CDCl3):
d
¼170.2 (C]O), 157.5 (CeO), 148.7, 137.6,
117.7 (CH), 69.8, 63.9 (OCH2), 58.8 (OCH3), 30.4, 27.6, 23.4, 22.4
135.5 (C), 118.3 (CH), 117.6 (C), 61.9 (OCH2), 36.4, 32.2, 31.0, 28.3,
(CH2), 19.7 (SCH3). IR (ATR, cmꢁ1):
n
¼3339 (br, m), 2930 (m), 2900
26.6, 25.7 (CH2), 21.3 (SCH3), 14.0 (CH2CH3). IR (ATR, cmꢁ1):
n
¼3281
(m), 2853 (w), 1693 (s), 1585 (s), 1414 (s). MS (EI, 70 eV): m/z (%)¼
296 (Mþ, 23), 221 (25), 220 (100), 207 (18), 205 (20), 192 (18).
Anal. Calcd for C15H20O4S (296.38): C, 60.79; H, 6.80. Found: C,
60.83; H, 7.02.
(br, m), 2990 (m), 2920 (m), 2850 (m), 1695 (s), 1588 (s), 1408 (s).
MS (EI, 70 eV): m/z (%)¼294 (Mþ, 43), 249 (21), 248 (100), 233 (11),
220 (9), 206 (17). HRMS (EI, 70 eV): calcd for C16H22O3S (Mþ)
294.12842, found 294.127982.
3.3.16. Methyl 3-hydroxy-1-methylthio-6,7,8,9-tetrahydro-5H-ben-
zocyclohepten-2-carboxylate (5q). Starting with 2k (217 mg,
1.0 mmol), 4g (521 mg, 2.0 mmol) and titanium tetrachloride
(0.11 mL, 1.0 mmol) in CH2Cl2 (2 mL), 5q was isolated as a colour-
less solid (165 mg, 62%); mp¼134e136 ꢀC; Rf 0.40 (heptanes/EtOAc
3.3.20. 2-Hydroxy-6-methylthio-4-(b-naphthyl)-acetophenone
(5u). Starting with 2m (274 mg, 1.0 mmol), 4a (489 mg, 2.0 mmol)
and titanium tetrachloride (0.11 mL, 1.0 mmol) in CH2Cl2 (2 mL), 5u
was isolated as a yellow solid (134 mg, 44%); mp 123e124 ꢀC. 1H
NMR (CDCl3, 500 MHz):
d
¼12.79 (s, 1H, OH), 8.07 (s, 1H, CH),
1:1). 1H NMR (CDCl3, 250 MHz):
d
¼8.88 (s, 1H, OH), 6.75 (s, 1H,
7.95e7.87 (m, 3H, 3ꢂ CH), 7.73e7.71 (m, 1H, CH), 7.56e7.51 (m, 2H,
CH), 3.97 (s, 3H, OCH3), 3.21 (t, 3J¼5.4 Hz, 2H, ArCH2), 2.77 (t,
3J¼5.4 Hz, 2H, ArCH2), 2.28 (s, 3H, SCH3), 1.85e1.76 (m, 2H, CH2)
2ꢂ CH), 7.13 (d, 4J¼1.9 Hz, 1H, CH), 7.10 (d, 4J¼1.6 Hz, 1H, CH), 2.91
(s, 3H, CH3), 2.64 (s, 3H, CH3). 13C NMR (CDCl3, 126 MHz):
d
¼205.1
1.68e1.58 (m, 4H, 2ꢂ CH2). 13C NMR (63 MHz, CDCl3):
d
¼170.6
(C]O), 164.0 (CeO), 146.9, 142.8, 136.6, 133.4, 133.3 (C), 128.8,
(C]O), 156,5 (CeO), 150.2, 140.3, 134.7 (C), 118.3 (CH),117.4 (C),
128.4, 127.7, 126.7, 126.6, 126.5, 124.9 (CH), 119.3 (C), 116.4, 113.9
52.3 (OCH3), 37.1, 32.0, 31.2, 28.2, 27.9 (CH2), 20.9 (SCH3). IR (ATR,
(CH), 33.8 (COCH3), 17.6 (SCH3). IR (ATR, cmꢁ1):
n
¼3055 (m), 2986
cmꢁ1):
n
¼3358 (br, m), 2930 (m), 2837 (m), 1690 (s), 1589 (s), 1411
(m), 2922 (w), 2851 (w), 1609 (s) 1552 (m), 1504 (m). MS (EI,
(s). MS (EI, 70 eV): m/z (%)¼266 (Mþ, 46), 235 (20), 234 (100), 219
70 eV): m/z (%)¼308 (Mþ, 40), 293 (100), 292 (28), 69 (28), 43 (27).

M. Lubbe et al. / Tetrahedron 69 (2013) 5998e6007
6005
HRMS (EI, 70 eV): calcd for C19H16O2S (Mþ) 308.08655, found
308.085815.
307 (18), 279 (33), 261 (17). HRMS (EI, 70 eV): calcd for C20H18O4S
(Mþ) 354.09203, found 354.091884.
3.3.21. Ethyl
2-hydroxy-6-methylthio-4-(
b
-naphthyl)-benzoate
3.3.25. Methyl 2-chloro-40-fluoro-5-hydroxy-3-methylthio-biphenyl-
4-carboxylate (5z). Starting with 2n (277 mg, 1.0 mmol), 4g
(521 mg, 2.0 mmol) and titanium tetrachloride (190 mg,
1.0 mmol) in CH2Cl2 (2 mL), 5z was isolated as a slightly yellow
solid (288 mg, 88%); mp 96e97 ꢀC; Rf 0.38 (heptanes/EtOAc 1:1).
(5v). Starting with 2m (274 mg, 1.0 mmol), 4d (549 mg,
2.0 mmol) and titanium tetrachloride (0.11 mL, 1.0 mmol) in
CH2Cl2 (2 mL), 5v was isolated as a slightly brownish solid
(124 mg, 37%); mp 121e122 ꢀC. 1H NMR (CDCl3, 250 MHz):
d
¼11.58 (s, 1H, OH), 8.06 (s, 1H, CH), 7.94e7.87 (m, 3H, 3ꢂ CH),
1H NMR (CDCl3, 250 MHz):
d
¼9.20 (s, 1H, OH), 7.36 (d,
7.72 (m, 1H, CH), 7.55e7.50 (m, 2H, 2ꢂ CH), 7.01 (d, 4J¼1.6 Hz, 1H,
CH), 7.00 (d, 4J¼1.6 Hz, 1H, CH), 4.53 (q, 3J¼7.3 Hz, 2H, OCH2), 2.53
(s, 3H, SCH3), 1.51 (t, 3J¼7.3 Hz, 3H, CH2CH3). 13C NMR (CDCl3,
3J¼8.8 Hz, 2H, H-20), 7.12 (d, J¼8.8 Hz, 2H, H-30), 6.93 (s, 1H, H-
3
6), 4.03 (s, 3H, OCH3), 2.47 (s, 3H, SCH3). 13C NMR (CDCl3,
75 MHz):
d
¼169.5 (OeC]O), 162.6 (d, JC,F¼248 Hz, C-40) 156.9
75 MHz):
d
¼169.5 (C]O), 162.7 (CeO), 145.6, 143.6, 136.1, 132.4,
(C-5), 145.2, 137.2, 135.0 (C), 130.9 (d, JC,F¼8 Hz, C-20), 129.7 (C),
132.2 (C), 127.7, 127.4, 126.7, 125.6, 125.4, 124.1, 113.5, 111.4 (CH),
119.9 (C-6), 119.6 (C), 115.1 (d, JC,F¼22 Hz, C-30), 52.8 (OCH3), 19.6
108.2 (C), 61.2 (OCH2), 15.6, 13.3 (CH3). IR (ATR, cmꢁ1):
n
¼3053
(SCH3). 19F NMR (CDCl3, 235 MHz):
d
¼ꢁ113.4 (CF). IR (KBr,
(m), 2985 (m), 2913 (w), 1650 (s) 1593 (m), 1553 (s), 1504 (m). MS
(EI, 70 eV): m/z (%)¼338 (Mþ, 50), 293 (21), 292 (100), 264 (23),
221 (9). HRMS (EI, 70 eV): calcd for C20H18O3S (Mþ) 338.09712,
found 338.097141.
cmꢁ1):
n
¼3265 (br, m), 2958 (w), 2925 (w), 2848 (w), 1703 (s),
1590 (m) 1508 (s). MS (EI, 70 eV): m/z (%)¼328 (Mþ, 37Cl, 18),
326 (Mþ, 35Cl, 45), 296 (38), 294 (100), 266 (27), 251 (42). HRMS
(EI, 70 eV): calcd for C15H12O3ClFS (Mþ, 35Cl) 326.01742, found
326.017066.
3.3.22. Methyl
2-hydroxy-3-methyl-6-methylthio-4-(b-naphthyl)-
benzoate (5w). Starting with 2m (274 mg, 1.0 mmol), 4l (549 mg,
2.0 mmol) and titanium tetrachloride (0.11 mL, 1.0 mmol) in CH2Cl2
(2 mL), 5w was isolated as a slightly yellow solid (144 mg, 43%); mp
3.3.26. Methyl 2-chloro-40-fluoro-5-hydroxy-6-methyl-3-
methylthio-biphenyl-4-carboxylate
(5aa). Starting
with
2n
(277 mg, 1.0 mmol), 4l (549 mg, 2.0 mmol) and titanium tetra-
chloride (190 mg, 1.0 mmol) in CH2Cl2 (2 mL), 5aa was isolated as
a slightly yellow solid (210 mg, 62%); mp 101e102 ꢀC; Rf 0.40 (n-
86e87 ꢀC. 1H NMR (CDCl3, 250 MHz):
d
¼11.90 (s,1H, OH), 7.92e7.87
(m, 3H, 3ꢂ CH), 7.78 (s, 1H, CH), 7.56e7.52 (m, 2H, 2ꢂ CH), 7.45 (m,
1H, CH), 6.66 (s, 1H, CH), 4.05 (s, 3H, OCH3), 2.41 (s, 3H, CH3), 2.16 (s,
heptanes/EtOAc 1:1). 1H NMR (CDCl3, 250 MHz):
d
¼9.41 (s, 1H, OH),
3H, CH3). 13C NMR (CDCl3, 63 MHz):
d¼171.5 (C]O), 162.2 (CeO),
7.19e7.07 (m, 4H, 4ꢂ ArH), 4.03 (s, 3H, OCH3), 2.43 (s, 3H, SCH3),
147.6, 139.8, 138.6, 133.1, 132.6 (C), 128.1, 127.8, 127.7, 127.6, 127.1,
126.4, 126.3 (CH), 120.5 (C), 116.7 (CH), 108.5 (C), 52.1 (OCH3), 16.4,
1.96 (s, 3H, ArCH3). 13C NMR (CDCl3, 75 MHz):
d
¼170.2 (C]O), 162.1
(d, JC,F¼247 Hz, C-40) 155.7 (C-5), 144.9, 134.8, 132.7, 131.0 (C), 130.5
13.0 (CH3). IR (ATR, cmꢁ1):
n
¼3050 (m), 3024 (m), 2915 (m), 2859
(d, JC,F¼8 Hz, C-20), 127.7, 119.0 (C), 115.5 (d, JC,F¼22 Hz, C-30), 52.8
(w), 1722 (s) 1659 (s), 1593 (s), 1549 (s), 1503 (m). MS (EI, 70 eV): m/
z (%)¼338 (Mþ, 84), 306 (100), 305 (78), 245 (41), 202 (40).
Anal. Calcd for C20H18O3S (338.42): C, 70.98; H, 5.36. Found: C,
70.84; H, 5.39.
(OCH3), 19.5, 14.3 (CH3). 19F NMR (CDCl3, 235 MHz):
d¼ꢁ114.1 (CF).
IR (ATR, cmꢁ1):
n
¼3307 (m), 3068 (w), 2958 (w), 1711 (s), 1601 (w),
1550 (w) 1509 (s). MS (EI, 70 eV): m/z (%)¼342 (Mþ, 37Cl, 20), 340
(Mþ, 35Cl, 52), 296 (38), 309 (35), 307 (100), 265 (17). HRMS (EI,
70 eV): calcd for C16H14O3ClFS (Mþ, 35Cl) 340.03307, found
340.032738.
3.3.23. Methyl 3-ethyl-2-hydroxy-6-methylthio-4-(b-naphthyl)-ben-
zoate (5x). Starting with 2m (274 mg, 1.0 mmol), 4b (577 mg,
2.0 mmol) and titanium tetrachloride (0.11 mL, 1.0 mmol) in CH2Cl2
(2 mL), 5x was isolated as a slightly yellow solid (129 mg, 37%); mp
3.3.27. Ethyl 2-chloro-40-fluoro-5-hydroxy-6-ethyl-3-methylthio-bi-
phenyl-4-carboxylate (5ab). Starting with 2n (277 mg,1.0 mmol), 4f
(606 mg, 2.0 mmol) and titanium tetrachloride (190 mg, 1.0 mmol)
in CH2Cl2 (2 mL), 5ab was isolated as a slightly yellow solid
(226 mg, 63%); mp 111e112 ꢀC; Rf 0.65 (n-heptanes/EtOAc 1:1). 1H
163e165 ꢀC. 1H NMR (CDCl3, 500 MHz):
d¼11.84 (s, 1H, OH),
7.91e7.87 (m, 3H, 3ꢂ CH), 7.77 (s, 1H, CH), 7.54 (m, 2H, 2ꢂ CH), 7.43
(m, 1H, CH), 6.60 (s, 1H, CH), 4.05 (s, 3H, OCH3), 2.59 (q, 3J¼7.3 Hz,
2H, CH2), 2.38 (s, 3H, SCH3), 1.08 (t, 3J¼7.3 Hz, CH2CH3). 13C NMR
NMR (CDCl3, 250 MHz):
d
¼9.41 (s, 1H, OH), 7.19e7.08 (m, 4H, 4ꢂ
(CDCl3, 75 MHz):
d
¼170.5 (C]O), 161.0 (CeO), 146.5, 138.8, 137.7,
CH), 4.50 (q, 3J¼7.1 Hz, 2H, OCH2), 2.45 (s, 3H, SCH3), 2.39 (q,
132.1, 131.5 (C), 127.1, 126.7, 126.7, 126.3, 125.9 (CH), 125.7 (C), 125.4,
125.2 (CH), 115.8, 107.8 (C), 51.0 (OCH3), 19.3 (CH2), 15.4, 13.1 (CH3).
3J¼7.1 Hz, 2H, ArCH2), 1.47 (t, 3J¼7.1 Hz, 3H, OCH2CH3), 0.97 (t,
3J¼7.1 Hz, 3H, ArCH2CH3). 13C NMR (CDCl3, 75 MHz):
d
¼169.8
IR (ATR, cmꢁ1):
n
¼3050 (m), 3024 (m), 2961 (m), 2933 (w), 2916 (s),
(OeC]O), 162.3 (d, JC,F¼247 Hz, C-40) 155.5 (C-5), 144.4, 134.6,
133.7, 132.5, 131.4 (C), 130.4 (d, JC,F¼8 Hz, C-20), 119.8 (C), 115.4 (d,
JC,F¼22 Hz, C-30), 62.4 (OCH2), 21.7 (ArCH2), 19.5, 14.0, 13.6 (CH3). 19F
2873 (s), 1731 (s) 1659 (s), 1591 (s), 1548 (s), 1504 (m). MS (EI,
70 eV): m/z (%)¼352 (Mþ, 37), 320 (100), 305 (14), 277 (21), 259
(30). Anal. Calcd for C21H20O3S (352.48): C, 71.56; H, 5.72. Found: C,
71.52; H, 5.59.
NMR (CDCl3, 235 MHz):
d
¼ꢁ114.9 (CF). IR (ATR, cmꢁ1):
¼3276 (br,
n
m), 2977 (w), 2933 (w), 2878 (w), 1703 (s), 1602 (m), 1509 (s). MS
(EI, 70 eV): m/z (%)¼370 (Mþ, 37Cl, 22), 368 (Mþ, 35Cl, 56), 323 (57),
321 (100), 259 (22), 183 (20). HRMS (EI, 70 eV): calcd for
C18H18O3ClFS (Mþ, 35Cl) 368.06437, found 368.064283.
3.3.24. Methyl 2-hydroxy-3-methoxy-6-methylthio-4-(b-naphthyl)-
benzoate (5y). Starting with 2m (274 mg, 1.0 mmol), 4c (581 mg,
2.0 mmol) and titanium tetrachloride (0.11 mL, 1.0 mmol) in CH2Cl2
(2 mL), 5y was isolated as a slightly yellow solid (121 mg, 35%); mp
3.3.28. 3-Chloro-6-hydroxy-4-methyl-2-methylthio-acetophenone
(5ag). Starting with 2q (197 mg, 1.0 mmol), 4a (489 mg, 2.0 mmol)
and titanium tetrachloride (0.11 mL, 1.0 mmol) in CH2Cl2 (2 mL),
5ag was isolated as a colourless solid (100 mg, 43%); mp¼85e87 ꢀC.
110e112 ꢀC. 1H NMR (CDCl3, 500 MHz):
d
¼11.51 (s, 1H, OH), 9.03 (s,
1H, CH), 7.92e7.88 (m, 3H, 3ꢂ CH), 7.72 (dd, 3J¼6.9 Hz, 1H, CH),
7.55e7.51 (m, 2H, 2ꢂ CH), 6.74 (s, 1H, CH), 4.05 (s, 3H, OCH3), 3.61
(s, 3H, OCH3), 2.46 (s, 3H, SCH3). 13C NMR (CDCl3, 126 MHz):
1H NMR (CDCl3, 250 MHz):
d
¼10.31 (s, 1H, OH), 6.87 (s, 1H, CH),
d
¼170.9 (C]O), 157.2 (CeO), 142.9, 139.9, 137.5, 134.9, 133.2, 132.9
(C), 128.3, 128.1, 127.8, 127.7, 127.0, 126.5, 126.3, 116.7 (CH), 110.7 (C),
60.5, 52.2 (OCH3), 19.3 (CH2), 16.6 (SCH3). IR (ATR, cmꢁ1):
2.85 (s, 3H, CH3), 2.46 (s, 3H, CH3), 2.39 (s, 3H, CH3). 13C NMR
(75 MHz, CDCl3):
¼205.8 (C]O), 157.3 (CeO), 143.3, 135.2, 131.9,
126.0 (C), 120.4 (CH), 32.3 (COCH3), 21.9, 19.9 (CH3). IR (ATR, cmꢁ1):
d
n
¼3049
(m), 3023 (m), 2957 (m), 2930 (w), 2847 (m), 1660 (s) 1602 (m),
n
¼3182 (br, m), 2924 (m), 1677 (s), 1587 (s), 1379 (s). MS (EI, 70 eV):
1553 (s), 1504 (m). MS (EI, 70 eV): m/z (%)¼354 (Mþ, 91), 322 (100),
m/z (%)¼232 (Mþ 37Cl, 11), 230 (Mþ 35Cl, 28), 217 (38), 215 (100),

6006
M. Lubbe et al. / Tetrahedron 69 (2013) 5998e6007
212 (39), 180 (49). HRMS (EI, 70 eV): calcd for C10H11ClO2S (Mþ,
35Cl) 230.01628, found 230.015977.
(CDCl3, 63 MHz):
d
¼170.2, 168.7 (C]O), 161.6 (CeO), 141.4, 135.1,
134.5 (C), 119.7 (CH), 114.6 (C), 52.6, 52.2 (OCH3), 21.3, 19.8 (CH3). IR
(ATR, cmꢁ1):
n
¼3228 (br, m), 2955 (m), 2923 (m), 2852 (w), 1734
3.3.29. Methyl 3-chloro-6-hydroxy-4-methyl-2-methylthio-benzoate
(5ah). Starting with 2q (197 mg, 1.0 mmol), 4g (521 mg, 2.0 mmol)
and titanium tetrachloride (0.11 mL, 1.0 mmol) in CH2Cl2 (2 mL),
5ah was isolated as a colourless solid (202 mg, 82%); mp¼76e78 ꢀC.
(s), 1690 (s), 1589 (s) 1433 (s). MS (EI, 70 eV): m/z (%)¼270 (Mþ, 75),
240 (15), 239 (100), 223 (12), 207 (97), 206 (86). Anal. Calcd for
C12H14O5S (270.30): C, 53.32; H, 5.22. Found: C, 53.08; H, 5.30.
1H NMR (CDCl3, 250 MHz):
d
¼9.35 (s, 1H, OH), 6.86 (s, 1H, CH), 3.99
3.3.34. Ethyl methyl 2-hydroxy-3-methyl-6-methylthio-isophthalate
(5an). Starting with 2s (235 mg, 1.0 mmol), 4g (521 mg, 2.0 mmol)
and titanium tetrachloride (190 mg, 1.0 mmol) in CH2Cl2 (2 mL),
5an was isolated as a slightly yellow solid (199 mg, 70%); mp
112e114 ꢀC; Rf 0.44 (heptanes/EtOAc 1:1). 1H NMR (CDCl3,
(s, 3H, OCH3), 2.41 (s, 3H, CH3), 2.39 (s, 3H, CH3). 13C NMR (75 MHz,
CDCl3):
¼169.8 (C]O), 157.4 (CeO), 142.9, 136.2, 131.7 (C), 119.5
(CH), 117.7 (C), 52.6 (OCH3), 21.9, 19.5 (CH3). IR (ATR, cmꢁ1):
d
n
¼3407
(br, m), 2952 (m), 2925 (w), 1709 (s), 1594 (s), 1429 (s). MS (EI,
70 eV): m/z (%)¼248 (Mþ 37Cl, 17) 246 (Mþ 35Cl, 45), 216 (40), 214
(100), 188 (14), 186 (37), 173 (19), 171 (47). HRMS (EI, 70 eV): calcd
for C10H11ClO3S (Mþ, 35Cl) 246.01119, found 246.011702.
300 MHz):
d
¼11.47 (s, 1H, OH), 6.83 (s, 1H, CH), 4.40 (q, 3J¼7.2 Hz,
2H, OCH2), 4.00 (s, 3H, OCH3), 2.38 (s, 3H, CH3), 2.27 (s, 3H, CH3),
1.39 (t, 3J¼7.2 Hz, 3H, CH2CH3). 13C NMR (CDCl3, 63 MHz):
¼170.3,
d
168.1 (C]O), 161.6 (CeO), 141.3, 135.4, 135.2 (C), 119.7 (CH), 114.6
3.3.30. Ethyl 3-chloro-6-hydroxy-4-methyl-2-methylthio-benzoate
(5ai). Starting with 2q (197 mg, 1.0 mmol), 4d (549 mg, 2.0 mmol)
and titanium tetrachloride (0.11 mL, 1.0 mmol) in CH2Cl2 (2 mL), 5ai
was isolated as a colourless solid (197 mg, 75%); mp¼90e92 ꢀC. 1H
(C), 61.3 (OCH2), 52.6 (OCH3), 21.3, 19.7, 14.1 (CH3). IR (ATR, cmꢁ1):
n
¼3225 (br, m), 2985 (w), 2953 (w), 2924 (w), 1733 (s), 1682 (s),
1589 (s) 1435 (m). MS (EI, 70 eV): m/z (%)¼284 (Mþ, 66), 253 (11),
252 (32), 241 (16), 240 (12), 239 (95), 209 (16), 208 (19), 207 (100),
206 (93). HRMS (EI, 70 eV): calcd for C13H16O5S (Mþ) 284.07130,
found 284.071230.
NMR (CDCl3, 250 MHz):
d
¼9.38 (s, 1H, OH), 6.86 (s, 1H, CH), 4.46 (q,
3J¼7.1 Hz, 2H, OCH2), 2.42 (s, 3H, CH3), 2.38 (s, 3H, CH3), 1.44 (t,
3J¼7.1 Hz, 3H, OCH2CH3). 13C NMR (75 MHz, CDCl3):
¼169.4 (C]O),
d
157.4 (CeO),142.8,136.0,131.9 (C),119.5 (CH),118.1 (C), 62.2 (OCH2),
3.3.35. Benzyl
methyl
2-hydroxy-3-methyl-6-methylthio-iso-
21.9, 19.5 (CH3), 14.0 (OCH2CH3). IR (ATR, cmꢁ1):
n
¼3271 (br, m),
phthalate (5ao). Starting with 2t (297 mg, 1.0 mmol), 4g (521 mg,
2.0 mmol) and titanium tetrachloride (190 mg, 1.0 mmol) in CH2Cl2
(2 mL), 5ao was isolated as a slightly yellow oil (201 mg, 58%); Rf
2981 (m), 2924 (w), 1695 (s), 1582 (s), 1372 (s). MS (EI, 70 eV): m/z
(%)¼262 (Mþ 37Cl, 14), 260 (Mþ 35Cl, 37), 216 (40), 214 (100), 188
(14), 186 (37), 173 (13), 171 (36). HRMS (EI, 70 eV): calcd for
C11H13ClO3S (Mþ, 35Cl) 260.02684, found 260.026474.
0.35 (heptanes/EtOAc 1:1). 1H NMR (CDCl3, 300 MHz):
d
¼10.53 (s,
1H, OH), 7.47e7.33 (m, 5H, Phenyl), 6.82 (s, 1H, CH), 5.36 (s, 2H,
OCH2), 4.00 (s, 3H, OCH3), 2.32 (s, 3H, CH3), 2.22 (s, 3H, CH3). 13
NMR (CDCl3, 63 MHz):
¼170.3, 168.0 (C]O), 161.8 (CeO), 141.5,
135.4, 135.1, 134.5 (C), 128.8, 128.5, 128.4, 119.7 (CH), 114.5 (C), 67.3
(OCH2), 52.6 (OCH3), 21.3, 19.7 (CH3). IR (ATR, cmꢁ1):
C
3.3.31. Methyl 5-chloro-2-hydroxy-3,4-dimethyl-6-methylthio-ben-
zoate (5ak). Starting with 2q (197 mg, 1.0 mmol), 4l (549 mg,
2.0 mmol) and titanium tetrachloride (0.11 mL, 1.0 mmol) in CH2Cl2
(2 mL), 5ak was isolated as a colourless solid (132 mg, 51%);
d
n
¼3339 (br,
m), 2951 (m), 2925 (m), 1724 (s), 1664 (s), 1592 (s) 1440 (m). MS (EI,
70 eV): m/z (%)¼346 (Mþ, 25), 314 (5), 281 (5), 255 (23), 239 (33),
207 (54), 193 (28), 91 (100). HRMS (EI, 70 eV): calcd for C18H18O5S
(Mþ) 346.08695, found 346.087527.
mp¼61e63 ꢀC. 1H NMR (CDCl3, 250 MHz):
¼9.50 (s, 1H, OH), 3.98
d
(s, 3H, OCH3), 2.40 (s, 6H, 2ꢂ CH3), 2.23 (s, 3H, CH3). 13C NMR
(75 MHz, CDCl3):
d
¼170.6 (C]O), 155.5 (CeO), 141.1, 132.3, 132.1,
126.9, 117.3 (C), 52.5 (OCH3), 19.6, 18.5, 12.9 (CH3). IR (ATR, cmꢁ1):
n
¼3153 (br, m), 2958 (m), 2918 (w), 1738 (s), 1699 (s), 1585 (m),
3.3.36. Ethyl
methyl
2-hydroxy-6-methylthio-3-(n-propyl)-iso-
1553 (m). MS (EI, 70 eV): m/z (%)¼262 (Mþ 37Cl, 23), 260 (Mþ 35Cl,
59), 230 (39), 228 (100), 187 (12), 185 (33), 165 (53). HRMS (EI,
70 eV): calcd for C11H13ClO3S (Mþ, 35Cl) 260.02684, found
260.026363.
phthalate (5ap). Starting with 2u (263 mg, 1.0 mmol), 4g (521 mg,
2.0 mmol) and titanium tetrachloride (190 mg, 1.0 mmol) in CH2Cl2
(2 mL), 5ap was isolated as a slightly yellow oil (155 mg, 50%); Rf
0.65 (heptanes/EtOAc 1:1). 1H NMR (CDCl3, 300 MHz):
d¼10.41 (s,
1H, OH), 6.85 (s, 1H, CH), 4.39 (q, 3J¼7.2 Hz, 2H, OCH2), 4.00 (s, 3H,
OCH3), 2.50 (t, 3J¼7.8 Hz, 2H, ArCH2), 2.38 (s, 3H, SCH3), 1.71e1.56
(m, 2H, CH2CH2CH3), 1.38 (t, 3J¼7.2 Hz, 3H, OCH2CH3), 0.94 (t,
3.3.32. Methyl
5-chloro-2-hydroxy-4-methyl-6-methylthio-3-(n-
propyl)-benzoate (5al). Starting with 2q (197 mg, 1.0 mmol), 4e
(605 mg, 2.0 mmol) and titanium tetrachloride (0.11 mL, 1.0 mmol)
in CH2Cl2 (2 mL), 5al was isolated as a colourless solid (210 mg,
3J¼7.4 Hz, 3H, (CH2)2CH3). 13C NMR (CDCl3, 63 MHz):
¼170.2, 168.1
d
(C]O), 161.5 (CeO), 145.8, 135.3, 134.2 (C), 118.7 (CH), 114.9 (C), 61.3
(OCH2), 52.6 (OCH3), 36.7 (ArCH2), 23.4 (CH2CH2CH3), 21.4,14.1,13.9
73%); mp¼78e80 ꢀC. 1H NMR (CDCl3, 250 MHz):
¼9.45 (s, 1H, OH),
d
3.98 (s, 3H, OCH3), 2.69 (t, 3J¼7.9 Hz, 2H, CH2), 2.41 (s, 3H, CH3), 2.40
(CH3). IR (ATR, cmꢁ1):
n
¼3368 (br, m), 2959 (m), 2929 (m), 2972
(s, 3H, CH3), 1.56e1.47 (m, 2H, CH2), 0.99 (t, 3J¼7.3 Hz, 3H, CH2CH3).
(m), 1723 (s), 1665 (s), 1592 (s) 1436 (m). MS (EI, 70 eV): m/z (%)¼
312 (Mþ, 67), 280 (25), 267 (100), 235 (75), 219 (30), 206 (23).
HRMS (EI, 70 eV): calcd for C15H20O5S (Mþ) 312.10260, found
312.102764.
13C NMR (75 MHz, CDCl3):
d
¼170.6 (C]O), 155.5 (CeO), 140.8,
132.4, 132.4, 131.5, 117.3 (CAr), 52.5 (OCH3), 29.3, 22.1 (CH2), 19.5,
18.1, 14.2 (CH3). IR (ATR, cmꢁ1):
n
¼3306 (br, m), 2956 (m), 2925 (m),
1666 (s), 1580 (s), 1548 (m), 1438 (m). MS (EI, 70 eV): m/z (%)¼290
(Mþ 37Cl, 31), 288 (Mþ 35Cl, 80), 258 (27), 256 (67), 243 (32), 241
(93), 229 (41), 228 (42), 227 (100). HRMS (EI, 70 eV): calcd for
C13H17ClO3S (Mþ, 35Cl) 288.05814, found 288.058368.
3.4. Procedure for the synthesis of 4-bromo-5-methylthio-
salicylates 5aq and 5ar
To
a solution of 1,1-bis(methylthio)-but-1-en-3-one (2a)
3.3.33. Dimethyl
2-hydroxy-3-methyl-6-methylthio-isophthalate
(1.0 equiv) in CH2Cl2 (5 mL/mmol) was added N-bromosuccinimide
at 20 ꢀC (1.2 equiv) and the solution was stirred for 1.5 h. Sub-
sequently, 1,3-bis(trimethylsilyloxy)-1,3-butadiene 3 (2.0 equiv)
and titanium tetrachloride (1.0 equiv) were added at ꢁ78 ꢀC under
argon atmosphere. The mixture was allowed to slowly warm to
20 ꢀC and the mixture was stirred for 12 h. To the mixture was
added hydrochloric acid (10%) and the organic layer was separated.
(5am). Starting with 2r (221 mg, 1.0 mmol), 4g (521 mg, 2.0 mmol)
and titanium tetrachloride (190 mg, 1.0 mmol) in CH2Cl2 (2 mL),
5am was isolated as a slightly yellow solid (128 mg, 48%); mp
103e105 ꢀC; Rf 0.45 (heptanes/EtOAc 1:1). 1H NMR (CDCl3,
300 MHz):
d
¼10.49 (s, 1H, OH), 6.83 (s, 1H, CH), 4.00 (s, 3H, OCH3),
3.91 (s, 3H, OCH3), 2.38 (s, 3H, CH3), 2.56 (s, 3H, CH3). 13C NMR

M. Lubbe et al. / Tetrahedron 69 (2013) 5998e6007
6007
Die aqueous layer was extracted with dichloromethane and the
combined organic layers were dried (Na2SO4), filtered and the fil-
trate was concentrated in vacuo. The residue was purified by
chromatography (silica gel, heptanes/EtOAc¼20:1).
diisopropylamine (0.97 mL, 6.9 mmol), 2,4-pentanedione (0.33 mL,
3.0 mmol) and 2m (0.315 g, 1.4 mmol) in THF (18 mL), 7b was
isolated as a colourless solid (0.278 g, 90%); mp 126e127 ꢀC. 1H
NMR (CDCl3, 300 MHz):
d
¼12.44 (s, 1H, OH), 7.92e7.86 (m, 3H, 3ꢂ
CH), 7.81 (s, 1H, CH), 7.58e7.52 (m, 2H, 2ꢂ CH), 7.50e7.43 (m, 1H,
3.4.1. Ethyl
3-bromo-6-hydroxy-4-methyl-2-methylthio-benzoate
CH), 6.82 (d, 4J¼2.0 Hz, 1H, CH), 6.74 (d, 4J¼2.0 Hz, 1H, CH), 2.51 (s,
(5aq). Starting with 2a (162 mg, 1.0 mmol), N-bromosuccinimide
(214 mg, 1.2 mmol), 4d (549 mg, 2.0 mmol) and titanium tetra-
chloride (0.11 mL, 1.0 mmol) in CH2Cl2 (5 mL), 5aq was isolated as
a colourless solid (222 mg, 73%); mp¼109e111 ꢀC. 1H NMR (CDCl3,
3H, SCH3), 1.80 (s, 3H, COCH3). 13C NMR (CDCl3, 75 MHz):
d¼204.8
(C]O), 161.5 (CeO), 146.8, 143.9, 138.3, 132.2, 131.8 (C), 127.4, 127.1,
126.8, 126.7, 125.9, 125.8, 125.7, 118.8 (CH), 116.6 (C), 111.1 (CH),
30.7 (COCH3), 13.5 (SCH3). IR (ATR, cmꢁ1):
n
¼3049 (w), 3013 (w),
250 MHz):
d
¼9.25 (s,1H, OH), 6.87 (s,1H, CH), 4.46 (q, 3J¼7.1 Hz, 2H,
2978 (w), 2912 (m), 1615 (s), 1588 (s), 1538 (s), 1502 (m). MS (EI,
70 eV): m/z (%)¼308 (Mþ, 100), 293 (65), 260 (17), 246 (25), 189
(28). HRMS (EI, 70 eV): calcd for C19H17O2S (Mþ) 309.09438, found
309.09406.
OCH2), 2.44 (s, 3H, CH3), 2.42 (s, 3H, CH3), 1.44 (t, 3J¼7.2 Hz, 3H,
OCH2CH3). 13C NMR (75 MHz, CDCl3):
d
¼169.3 (C]O), 157.8 (CeO),
144.6, 137.8, 125.0 (C), 119.4 (CH), 118.7 (C), 62.3 (OCH2), 25.2, 20.0
(CH3), 14.0 (OCH2CH3). IR (ATR, cmꢁ1):
n¼3257 (br, m), 2981 (m),
2922 (w), 1694 (s), 1575 (s), 1443 (m), 1370 (s). MS (EI, 70 eV): m/z
(%)¼306 (Mþ 81Br, 36), 304 (Mþ 79Br, 38), 260 (100), 258 (92), 232
(33), 230 (26), 217 (28), 215 (24). HRMS (EI, 70 eV): calcd for
C11H13BrO3S (Mþ, 79Br) 303.97633, found 303.976581.
3.5.3. 2-Hydroxy-3-methyl-4-methylthio-6-(b-naphthyl)-propiophe-
none (7c). Starting with n-BuLi (2.5 M in n-hexane, 2.76 mL,
6.9 mmol), diisopropylamine (0.97 mL, 6.9 mmol), 3,5-
heptanedione (0.40 mL, 3.0 mmol) and 2m (0.315 g, 1.4 mmol)
in THF (18 mL), 7c was isolated as a yellow oil (0.247 g, 74%). 1H
3.4.2. Methyl 5-bromo-2-hydroxy-3,4-dimethyl-6-methylthio-ben-
zoate (5ar). Starting with 2a (162 mg, 1.0 mmol), N-bromosucci-
nimide (214 mg, 1.2 mmol), 4l (549 mg, 2.0 mmol) and titanium
tetrachloride (0.11 mL, 1.0 mmol) in CH2Cl2 (5 mL), 5ar was isolated
as a colourless solid (188 mg, 62%); mp¼66e68 ꢀC. 1H NMR (CDCl3,
NMR (CDCl3, 300 MHz):
d
¼12.20 (s, 1H, OH), 7.93e7.85 (m, 3H,
3ꢂ CH), 7.81 (s, 1H, CH), 7.60e7.52 (m, 2H, 2ꢂ CH), 7.48e7.45 (m,
1H, CH), 6.67 (s, 1H, CH), 2.50 (s, 3H, SCH3), 2.31 (s, 3H, ArCH3),
2.06 (q, 3J¼7.2 Hz, 2H, COCH2), 0.80 (t, 3J¼7.2 Hz, 3H, CH2CH3). 13
C
NMR (CDCl3, 75 MHz):
138.9, 132.2, 131.7 (C), 127.4, 127.1, 126.8, 126.6, 126.1, 125.8, 125.5
d
¼209.2 (C]O), 157.5 (CeO), 144.5, 140.5,
250 MHz):
d
¼9.35 (s, 1H, OH), 3.98 (s, 3H, OCH3), 2.47 (s, 3H, CH3),
2.41 (s, 3H, CH3), 2.26 (s, 3H, CH3). 13C NMR (75 MHz, CDCl3):
¼170.5 (C]O), 155.8 (CeO), 142.8, 134.1, 126.9, 125.8, 118.0 (C),
52.6 (OCH3), 22.0, 20.2, 13.3 (CH3). IR (ATR, cmꢁ1):
(CH), 121.0, 116.3 (C), 116.0 (CH), 35.6 (COCH2), 13.8, 10.8, 8.4
d
(CH3). IR (ATR, cmꢁ1):
n
¼3051 (w), 2975 (w), 2920 (m), 2874 (w),
n
¼3152 (br, m),
1611 (s), 1581 (s), 1534 (s), 1504 (m). MS (EI, 70 eV): m/z (%)¼
336 (Mþ, 90), 308 (31), 307 (100), 260 (27), 202 (18). HRMS
(EI, 70 eV): calcd for C21H20O2S (Mþ) 336.11785, found
336.117291.
2988 (m), 2917 (w), 1737 (s), 1699 (s), 1583 (m), 1546 (m), 1441 (s).
MS (EI, 70 eV): m/z (%)¼306 (Mþ 81Br, 54), 304 (Mþ 79Br, 53), 274
(94), 272 (91), 231 (23), 229 (24), 165 (100). HRMS (EI, 70 eV): calcd
for C11H13BrO3S (Mþ, 79Br) 303.97633, found 303.976462.
3.5. Procedure for the synthesis of 7aec
Acknowledgements
To a solution of diisoproylamine (6.9 equiv) in THF was added n-
butyllithium (6.9 equiv) at 0 ꢀC and the mixture was stirred for
30 min. 1,3-Diketone 6 (3.0 equiv) was added at 0 ꢀC and the so-
lution was stirred for 1 h. To the solution was added 2 (1.0 equiv) at
Financial support by the State of Mecklenburg-Vorpommern
(scholarship for F.B.) is gratefully acknowledged.
0
ꢀC. The mixture was allowed to slowly warm to 20 ꢀC and the
References and notes
mixture was stirred for 14 h. To the mixture was added hydro-
chloric acid (10%) and the organic layer was separated. Die aqueous
layer was extracted with dichloromethane and the combined or-
ganic layers were dried (Na2SO4), filtered and the filtrate was
concentrated in vacuo. The residue was purified by chromatogra-
phy (silica gel, heptanes/EtOAc¼20:1).
1. (a) Campiani, G.; Nacci, V.; Bechelli, S.; Ciani, S. M.; Garofalo, A.; Fiorini, I.;
€
Wikstrom, H.; de Boer, P.; Liao, Y.; Tepper, P. G.; Cagnotto, A.; Mennini, T. J. Med.
Chem. 1998, 41, 3763; (b) Cabiddu, M. G.; Cabiddu, S.; Cadoni, E.; Demontis, S.;
Fattuoni, C.; Melis, S. Tetrahedron 2002, 58, 4529; (c) Ritchie, C. D.; Hofelich, T.
C. J. Am. Chem. Soc. 1980, 102, 7039; (d) Ohkata, K.; Takee, K.; Akiba, K.-y Bull.
Chem. Soc. Jpn. 1985, 58, 1946; (e) Cabiddu, M. G.; Cabiddu, S.; Cadoni, E.;
Demontis, S.; Fattuoni, C.; Melis, S.; Usai, M. Synthesis 2002, 7, 875; (f) Mu-
kherjee, C.; Kamila, S.; De, A. Tetrahedron 2003, 59, 4767; (g) Mukherjee, C.; De,
A. Synlett 2002, 325; (h) Pradhan, T. K.; De, A. Tetrahedron Lett. 2005, 46, 1493;
(i) Weber, R. J. Heterocycl. Chem. 1978, 15, 865; (j) Dhareshwar, G. P.; Chhaya, P.
N.; Hosangadi, B. D. Indian J. Chem., Sect. B 1980, 19, 831; (k) Uchida, Y.; Kozuka,
S. Bull. Chem. Soc. Jpn. 1982, 55, 1183; (l) Grohe, K.; Heitzer, H. Liebigs Ann.
Chem. 1987, 29; (m) Luxen, A. J.; Christiaens, L. E. E.; Renson, M. J. J. Organomet.
Chem. 1985, 287, 81.
2. (a) Ila, H.; Junjappa, H. J. Org. Chem. 1990, 55, 5589; (b) Cipollina, J. A.; Ruediger,
E. H.; New, J. S.; Wire, M. E.; Shepherd, T. A.; Smith, D. W.; Yevich, J. P. J. Med.
Chem. 1991, 34, 3316; (c) Cabiddu, S.; Maccioni, A.; Piras, P. P.; Plumitallo, A. Gazz.
Chim. Ital. 1981, 111, 123; (d) Bi, X.; Dong, D.; Liu, Q.; Pan, W.; Zhao, L.; Li, B. J. Am.
Chem. Soc. 2005, 127, 4578.
3.5.1. 2-Hydroxy-4-methylthio-6-phenyl-acetophenone
(7a). Starting with n-BuLi (2.5 M in n-hexane, 3.96 mL, 9.9 mmol),
diisopropylamine (1.00 g, 9.9 mmol), 2,4-pentanedione (0.431 g,
4.3 mmol) and 2p (0.315 g, 1.4 mmol) in THF (25 mL), 7a was iso-
lated as a slightly yellow solid (0.252 g, 70%); mp 72e73 ꢀC; Rf 0.13
(heptanes/EtOAc 1:1). 1H NMR (CDCl3, 250 MHz):
d
¼12.40 (s, 1H,
OH), 7.45e7.39 (m, 3H, 3ꢂ CH), 7.34e7.30 (m, 2H, 2ꢂ CH), 6.77 (s,
1H, CH), 6.64 (s, 1H, CH), 2.50 (s, 3H, SCH3), 1.80 (s, 3H, COCH3). 13
NMR (CDCl3, 75 MHz):
¼205.8 (C]O), 162.4 (CeO), 147.6, 145.0,
141.8 (C), 128.8, 128.6, 128.3, 119.4 (CH), 117.5 (C), 112.0 (CH), 31.5
(SCH3), 14.4 (COCH3). IR (ATR, cmꢁ1):
C
d
3. For a review of [3þ3] cyclocondensations of 1,3-bis(silyl enol ethers) with 1,3-
dielectrophiles, see: Feist, H.; Langer, P. Synthesis 2007, 327.
n
¼3053 (w), 3022 (w), 2973
4. Lubbe, M.; Klassen, R.; Trabhardt, T.; Villinger, A.; Langer, P. Synlett 2008, 2331.
5. (a) Iaroshenko, V. O.; Bunescu, A.; Domke, L.; Spannenberg, A.; Sevenard, D.;
Villinger, A.; Sosnovskikh, V. Y.; Langer, P. J. Fluorine Chem. 2011, 132, 441; (b)
Imran, M.; Iqbal, I.; Rasool, N.; Fischer, C.; Langer, P. Tetrahedron 2009, 65,
8794; (c) Bendrath, F.; Villinger, A.; Langer, P. J. Organomet. Chem. 2011, 696,
1388.
(w), 2921 (m), 1708 (m), 1610 (s), 1587 (s), 1541 (s), 1494 (m), 1436
(m). MS (EI, 70 eV): m/z (%)¼258 (Mþ, 100), 257 (68), 244 (14), 243
(91), 228 (10), 210 (14), 197 (11), 196 (41). HRMS (EI, 70 eV): calcd
for C15H14O2S (Mþ) 258.07090, found 258.070216.
6. Potts, K. T.; Winslow, P. A. Synthesis 1987, 839.
7. (a) Chan, T. H.; Brownbridge, P. J. Am. Chem. Soc. 1980, 102, 3534; (b) Molander,
G. A.; Cameron, K. O. J. Am. Chem. Soc. 1993, 115, 830; (c) Nguyen, V. T. H.; Bellur,
E.; Appel, B. Synthesis 2006, 2865.
3.5.2. 2-Hydroxy-4-methylthio-6-(
(7b). Starting with n-BuLi (2.5 M in n-hexane, 2.76 mL, 6.9 mmol),
b-naphthyl)-acetophenone