One-pot synthesis of 6-(thien-2-yl)- and 6-(fur-2-yl)salicylates based on regioselective [3 + 3] cyclocondensations of 1,3-bis(trimethylsilyloxy)-1,3- butadienes

Article abstract of DOI:10.1039/b803472a

6-(Thien-2-yl) and 6-(fur-2-yl)salicylates are prepared by TiCl ₄-mediated [3 + 3] cyclocondensations of 1,3-bis(trimethylsilyloxy)- 1,3-butadienes with 3-(thien-2-yl)- and 3-(fur-2-yl)-3-silyloxy-2-en-1-ones, respectively. The regioselectivity

Full text of DOI:10.1039/b803472a

View Article Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
One-pot synthesis of 6-(thien-2-yl)- and 6-(fur-2-yl)salicylates based on
regioselective [3 + 3] cyclocondensations of 1,3-bis(trimethylsilyloxy)-
1,3-butadienes†
Ibrar Hussain,a Abdolmajid Riahi,a Mirza Arfan Yawer,a Alexander Villinger,a Christine Fischer,a,b
Helmar Go¨rlsc and Peter Langer*a,b
Received 28th February 2008, Accepted 28th May 2008
First published as an Advance Article on the web 16th July 2008
DOI: 10.1039/b803472a
6-(Thien-2-yl) and 6-(fur-2-yl)salicylates are prepared by TiCl4-mediated [3 + 3] cyclocondensations of
1,3-bis(trimethylsilyloxy)-1,3-butadienes with 3-(thien-2-yl)- and 3-(fur-2-yl)-3-silyloxy-2-en-1-ones,
respectively. The regioselectivity of the cyclization depends on the substitution pattern of the
3-silyloxy-2-en-1-one.
alkyl- and CF3-substituted substrates proceeded with different
regioselectivity, which can be explained by electronic factors.
Heterocyclic biaryls are of considerable pharmacological rele-
Introduction
vance and represent important lead structures in medicinal chemi-
Results and discussion
stry.1 In this context, highly functionalized 2-(thien-2-yl)benzene
derivatives are of special interest. For example, 6-(thien-2-
yl)salicylates have been reported to show in vitro inhibitory activity
on guinea-pig detrusor muscle contraction on electrical field
stimulation.2 2-(Thien-2-yl)benzoates are CAAX peptidomimetics
and represent potent inhibitors of farnesyltransferase (Ftase).3 2-
(Thien-2-yl)benzoates have been prepared by the Grignard reac-
tion of 1-bromo-2-(thien-2-yl)benzene with carbon dioxide4 and
by Stille5 or Suzuki reactions6 of 2-halobenzoates, or related tran-
sition metal catalyzed cross-coupling reactions. The scope of these
methods is often limited by the fact that sterically encumbered sub-
strates often fail to undergo transition metal catalyzed reactions
or the yields are low. Besides, the synthesis of highly substituted
and functionalized starting materials is often a difficult task.
Some years ago, Chan and Brownbridge developed7 an elegant
approach to functionalized arenes based on formal [3 + 3] cycliza-
tions of 1,3-bis(silyl enol ethers).8,9 Herein, we report the applica-
tion of this methodology to the synthesis of arenes containing an
electron-rich heterocyclic moiety. From a preparative viewpoint,
the chemistry reported offers a convenient and regioselective
approach to functionalized and sterically encumbered 6-(thien-
2-yl)- and 6-(fur-2-yl)salicylates that are not readily available by
other methods and have only scarcely been reported so far.10 Due
to the considerable importance of the trifluoromethyl group in
organic and medicinal chemistry,11 this group was included in the
present studies.‡ The cyclization of 1,3-bis(silyl enol ethers) with
The 3-(thien-2-yl)- and 3-(fur-2-yl)-1,3-diones 3a–d were prepared
by the LDA-mediated reaction of ketones 1a–c with (thien-2-
yl)- and (fur-2-yl)carboxylic acid chloride (2a,b) (Table 1). The
silylation of 3a–d afforded the silyl enol ethers 4a–d. The TiCl4-
mediated [3 + 3] cyclization of 4a–d with 1,3-bis(silyl enol ethers)
5a–e, prepared from the corresponding 1,3-dicarbonyl compounds
in two steps,12 afforded the 6-(thien-2-yl)salicylates 6a–m and the 6-
(fur-2-yl)salicylates 6n,o. All products were formed with very good
regioselectivity. During the optimization of this reaction, the (high)
concentration and the temperature played an important role. The
relatively low yields (30–47%) can be explained by hydrolysis and
TiCl4 mediated oxidative dimerization of dienes 5.
The cyclocondensation of 4a with 5a and the regioselectivity
can be explained by formation of intermediate A, attack of the
terminal carbon atom of 5 onto the carbon located next to
ꢀ
the methyl group to give intermediate B, cyclization by an SN
mechanism with displacement of the Cl3TiO-group (intermediate
C), and subsequent aromatization (Scheme 1). Alternatively, the
cyclization might proceed by isomerization of intermediate A
into intermediate D and subsequent cyclocondensation by a
mechanism similar to the one described above.
The structures of all the products were elucidated by spectro-
scopic methods (2D NMR). The structure of 6b was independently
confirmed by X-ray crystal structure analysis (Fig. 1).13 The thienyl
and the phenyl moiety are in plane. An intramolecular hydrogen
bond is observed although the ester group is slightly twisted out
of plane.
aInstitut fu¨r Chemie, Universita¨t Rostock, Albert-Einstein-Str. 3a, 18059
Rostock, Germany. E-mail: peter.langer@uni-rostock.de; Fax: 00 49 381
49864112; Tel: 0049 381 4986410
1-Propanoyl-1-(thien-2-oyl)cyclopropane (8) was prepared by
the reaction of 3b with 1,2-dibromoethane (Table 2). The TiCl4-
mediated reaction of 1,3-bis(silyloxy)-1,3-butadienes 5a–d with
bLeibniz-Institut fu¨r Katalyse e. V. an der Universita¨t Rostock, Albert-
Einstein-Str. 29a, 18059 Rostock, Germany
cInstitut fu¨r Anorganische und Analytische Chemie, Universita¨t Jena, August-
Bebel-Str. 2, 07740 Jena, Germany
† Electronic Supplementary Information (ESI) available: Details of the
X-ray structure analyses. CCDC reference numbers 664610, 664611 and
675254. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/b803472a
‡ While the sizes of the methyl and trifluoromethyl groups are comparable,
the latter possesses a highly electron-withdrawing effect. Therefore, the
replacement of a CH3- by a CF3-group in a molecule results in a great
change in its electronic properties and reactivity. The trifluoromethyl
group in drugs plays an important role in drug–receptor interactions and
in their in vivo transport. In addition, the high chemical and biological
stability of the CF3-group allows the avoidance of unwanted metabolic
transformations.
3542 | Org. Biomol. Chem., 2008, 6, 3542–3551
This journal is
The Royal Society of Chemistry 2008
©

View Article Online
Table 1 Synthesis of 6a–o
Reagents and conditions: i: LDA (1.5 equiv.), THF; ii: NEt3 (1.6 equiv.),
Me3SiCl (1.8 equiv.), C6H6, 20 ◦C, 3 d; iii: TiCl4, CH2Cl2, −78 → 20 ◦C.
4
5
6
X
R1
R2
R3
% (6)a
a
a
a
a
a
b
b
b
b
c
a
b
c
d
e
a
b
c
d
a
b
c
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
S
S
S
S
S
S
S
S
S
S
S
S
S
O
O
Me
Me
Me
Me
Me
Et
Et
Et
Et
nPr
nPr
nPr
nPr
Et
H
Me
Et
nHex
nOct
H
Me
Et
nHex
H
Me
Et
Me
Me
Et
Me
Me
Me
Me
Et
Me
Me
Me
Et
Me
Me
Me
32
33
35
30
34
35
34
30
30
40
47
42
35
32
30
c
c
c
d
d
d
a
b
nHex
H
Me
Scheme 1 Possible mechanism of the formation of 6a. Reagents and
conditions: i: TiCl4, CH2Cl2, −78 → 20 ◦C.
Et
a Yields of isolated products.
8 afforded the 6-(thien-2-yl)salicylates 9a–d containing a remote
chloride group (Table 2). The products are formed by a domino
‘[3 + 3]-cyclization–homo-Michael’ reaction.14 It is noteworthy
that the regioselectivity decreased with increasing steric hindrance
of the 1,3-bis(silyl enol ether).
The trifluoromethyl-substituted silyl enol ethers 4e,f were
prepared by silylation of the corresponding 1,3-diketones 3e,f.
The TiCl4-mediated cyclization of 4e,f with 1,3-bis(silyloxy)-
1,3-butadienes 5a–e afforded the novel 4-hetaryl-6-(trifluo-
romethyl)salicylates 10a–j with very good regioselectivity
(Scheme 2, Table 3). The cyclization and the regioselectivity can
be explained by a mechanism similar to the one discussed above
for the synthesis of 6a.
It is noteworthy that the cyclizations of 1,3-bis(silyl enol ethers)
5 with alkyl- and CF3-substituted silyl enol ethers 4a–d and 4e,f
proceed with different regioselectivity. This might be explained
by comparison of the resonance structures of the cations formed
by reaction of TiCl4 with silyl enol ethers 4a and 4e (Fig. 2). In
the case of the CH3-substituted silyl enol ethers 4a–d, it can be
expected that resonance structure A1 is predominant over A2 due
to the r-donating effect of the methyl group. The hetaryl moiety
is expected to be twisted out of plane. In contrast, E2 is expected
to be more stable than E1 due to the cation-destabilizing effect of
the CF3-group. The reactions presumably proceed, under kinetic
reaction control, by attack of the terminal carbon atom of 5 onto
the cationic intermediate that is predominantly present.
Fig. 1 Crystal structure of 6b.
The structures of the products were elucidated by spectroscopic
methods (2D NMR). The structures of 10a and 10f were indepen-
dently confirmed by X-ray crystal structure analyses (Fig. 3 and
ESI†).13 Similarly to 6b, the thienyl and the phenyl moiety are in
plane. An intramolecular hydrogen bond is present although the
ester group is slightly twisted out of plane.
Conclusions
In conclusion, a variety of sterically encumbered 6-(thien-2-yl)-
and 6-(fur-2-yl)salicylates were regioselectively prepared by the
Lewis acid mediated [3 + 3] cyclizations of 1,3-bis(silyl enol
ethers) with novel 3-(thien-2-yl)- and 3-(fur-2-yl)-3-silyloxy-2-
en-1-ones and with 1-alkanoyl-1-(thien-2-oyl)cyclopropanes. The
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 3542–3551 | 3543
©

View Article Online
Table 2 Synthesis of 9a–d
Table 3 Synthesis of 10a–j
Reagents and conditions: i: NEt3 (1.6 equiv.), Me3SiCl (1.8 equiv.), C6H6,
20 ◦C, 3 d; ii: TiCl4, CH2Cl2, −78 → 20 ◦C.
4
5
10
X
R1
R2
% (10)a
e
e
e
e
e
f
a
b
c
d
e
a
b
c
d
e
a
b
c
d
e
f
S
S
S
S
H
Me
Et
nHex
nOct
H
Me
Et
Me
Me
Et
Me
Me
Me
Me
Et
35
45
44
34
37
40
41
35
30
35
Reagents and conditions: i: K2CO3 (4.0 equiv.), DMSO; ii: TiCl4, CH2Cl2,
−78 → 20 ◦C, 20 h.
S
O
O
O
O
O
5
9
R1
R2
% (9)a
Regioisomeric ratio
f
g
h
i
f
a
b
c
a
b
c
H
Me
Et
Me
Me
Et
42
40
34
32
100 : 0
95 : 5
80 : 20
66 : 33
f
nHex
nOct
Me
Me
f
j
a Yields of isolated products.
d
d
nHex
Me
a Yields of isolated products.
Scheme 2 Possible mechanism of the formation of 10a. Reagents and
conditions: i: TiCl4, CH2Cl2, −78 → 20 ◦C.
Fig. 2 Possible explanation for the different regioselectivity of formation
of 6a and 10a.
3544 | Org. Biomol. Chem., 2008, 6, 3542–3551
This journal is
The Royal Society of Chemistry 2008
©

View Article Online
2.60 (q, 3J = 7.6 Hz, 2 H, CH2CH3), 6.22 (s, 1 H, CH), 7.31–7.33
(m, 1 H, CHHetar), 7.78 (dd, 3J = 4.9 Hz, 4J = 1.1 Hz, 1 H, CHHetar),
7.88–7.90 (m, 1 H, CHHetar), 15.89 (s, 1 H, OH). 13C NMR (75 MHz,
CDCl3): d = 10.5 (CH2CH3), 31.0 (CH2CH3), 95.3 (CH), 128.5,
130.4, 132.6 (CHHetar), 142.1 (CHetar), 182.1 (COH), 186.1 (CO).
GC-MS (EI, 70 eV): m/z (%) = 182 ([M+], 62), 153 (86), 126 (26),
111 (100), 97 (7), 83 (8), 69 (56), 56 (17), 53 (7), 45 (8), 39 (17),
29 (8). HRMS (EI): calcd for C9H10O2S [M+]: 182.03960; found:
182.03933.
1-Hydroxy-1-(2-thienyl)-1-hexen-3-one (3c). Starting with
THF (62.5 mL), LDA (75.0 mmol), 2-pentanone (1c) (4.306 g,
50.0 mmol) and 2-thiophenecarboxylic acid chloride (2) (8.796 g,
60.0 mmol), 3c was isolated as a yellowish oil (2.750 g, 28%).
Fig. 3 Crystal structure of 10a.
cyclizations of 1,3-bis(silyl enol ethers) with alkyl- and CF3-
substituted substrates proceeded with different regioselectivity.
The products are not readily available by other methods.
3
1H NMR (300 MHz, CDCl3): d = 0.86 (t, J = 7.4 Hz, 3 H,
3
CH2CH2CH3), 1.53–1.61 (m, 2 H, CH2CH2CH3), 2.21 (t, J =
7.2 Hz, 2 H, CH2CH2CH3), 5.91 (s, 1 H, CH), 6.97–7.00 (m, 1
3
4
H, CHHetar), 7.46 (dd, J = 4.4 Hz, J = 0.9 Hz, 1 H, CHHetar),
7.56–7.57 (m, 1 H, CHHetar), 15.62 (s, 1 H, OH). 13C NMR
(75 MHz, CDCl3): d = 12.6 (CH2CH2CH3), 18.4 (CH2CH2CH3),
38.2 (CH2CH2CH3), 94.8 (CH), 126.6, 129.1, 131.9 (CHHetar), 142.6
(CHetar), 181.0 (COH), 189.1 (CO). GC-MS (EI, 70 eV): m/z (%) =
196 ([M+], 47), 181 (3), 168 (14), 153 (100), 135 (4), 126 (34), 111
(90), 97 (7), 85 (7), 69 (53), 53 (5), 39 (18). HRMS (EI): calcd for
C10H12O2S [M+]: 196.05525; found: 196.05469.
Experimental section
General Comments. All solvents were dried by standard
methods and all reactions were carried out under an inert
atmosphere. For 1H and 13C NMR spectra the deuterated solvents
indicated were used. Mass spectrometric data (MS) were obtained
by electron ionization (EI, 70 eV), chemical ionization (CI,
H2O) or electrospray ionization (ESI). For preparative scale
chromatography, silica gel (60–200 mesh) was used. Melting points
are uncorrected.
General procedure for the synthesis of silyl enol ethers 4. To
a stirred benzene solution (2.5 mL per 1.0 mmol of 3) of 3
(10.0 mmol) was added triethylamine (16.0 mmol). After the so-
lution had been stirred for 2 h, trimethylchlorosilane (18.0 mmol)
was added. After the solution had been stirred for 72 h, the solvent
was removed in vacuo and hexane (25 mL) was added to the
residue to give a suspension. The latter was filtered under an argon
atmosphere. The filtrate was concentrated in vacuo to give silyl enol
ethers 4.
General procedure for the synthesis of 1,3-dicarbonyl compounds
3. To a stirred solution of LDA (75.0 mmol) in THF (1.2 mL
per 1.0 mmol of LDA) was added ketone 1 (50.0 mmol) at
◦
−78 C. After the solution was stirred for 1 h, the acid chloride
2a,b (60.0 mmol) was added. The temperature of the solution was
allowed to rise to 20 ◦C over 12 h. A saturated solution of NH4Cl
was added, the layers were separated, and the aqueous layer was
extracted with EtOAc (3 × 50 mL). The combined organic layers
were dried (Na2SO4) and filtered, and the solvent was removed
in vacuo. The residue was purified by chromatography (silica gel,
n-heptane–EtOAc = 30 : 1 → 20 : 1) to give 3. Compounds 1a–c
and 3e,f are commercially available.
4-(2-Thienyl)-4-[(trimethylsilyl)oxy]-3-buten-2-one (4a). Start-
ing with benzene (41.0 mL), 3a (2.757 g, 16.4 mmol), triethy-
lamine (3.205 g, 26.2 mmol) and trimethylchlorosilane (3.205 g,
1
29.5 mmol), 4a was isolated as a reddish oil (3.464 g, 88%). H
NMR (300 MHz, CDCl3): d = 0.19 (m, 9 H, Si(CH3)3), 2.21 (s, 3
H, CH3), 5.18 (s, 1 H, CH), 6.90–6.96 (m, 1 H, CHHetar), 7.34–7.38
(m, 1 H, CHHetar), 7.39–7.42 (m, 1 H, CHHetar).
4-Hydroxy-4-(2-thienyl)-3-buten-2-one (3a). Starting with
THF (4.8 mL), LDA (6 mmol), acetone 1a (0.232 g, 4.0 mmol)
and 2-thiophenecarbonyl chloride 2 (0.704 g, 4.8 mmol), 3a was
1
1-(2-Thienyl)-1-[(trimethylsilyl)oxy]-1-penten-3-one
(4b).
isolated as a yellowish oil (0.235 g, 34%). H NMR (300 MHz,
Starting with benzene (30.0 mL), 3b (1.821 g, 10.0 mmol),
triethylamine (1.619 g, 16.0 mmol) and trimethylchlorosilane
(1.738 g, 18.0 mmol), 4b was isolated as a reddish oil (2.162 g,
85%). 1H NMR (300 MHz, CDCl3): d = 0.20 (m, 9 H, Si(CH3)3),
CDCl3): d = 2.02 (s, 3 H, CH3), 5.90 (s, 1 H, CH), 6.97 (m, 1
3
4
H, CHHetar), 7.45 (dd, J = 4.9 Hz, J = 1.1 Hz, 1 H, CHHetar),
7.54–7.56 (m, 1 H, CHHetar), 15.59 (s, 1 H, OH). 13C NMR
(75 MHz, CDCl3): d = 22.70 (CH3), 95.4 (CH), 126.7, 129.9, 132.6
(CHHetar), 140.5 (CHetar), 180.7 (COH), 186.1 (CO). IR (KBr, cm−1):
m˜ = 3435 (br, m), 3085 (m), 2963 (w), 1629 (s), 1519 (m), 1408 (s),
1275 (s), 1078 (m), 937 (m), 797 (m), 779 (s), 723 (s). GC-MS (EI,
70 eV): m/z (%) = 168 ([M+], 87), 153 (45), 135 (21), 126 (18),
111 (100), 97 (7), 84 (15), 69 (53), 43 (23). HRMS (EI): calcd for
C8H8O2S [M+]: 168.02395; found: 168.02385.
3
3
0.98 (t, J = 7.4 Hz, 3 H, CH2CH3), 2.68 (q, J = 7.6 Hz, 2
H, CH2CH3), 5.96 (s, 1 H, CH), 6.93–6.95 (m, 1 H, CHHetar),
7.36–7.38 (m, 1 H, CHHetar), 7.42–7.44 (m, 1 H, CHHetar).
1-(2-Thienyl)-1-[(trimethylsilyl)oxy]-1-hexen-3-one (4c). Start-
ing with benzene (73.0 mL), 3c (4.799 g, 24.5 mmol), triethy-
lamine (3.960 g, 39.1 mmol) and trimethylchlorosilane (4.780 g,
44.0 mmol), 4c was isolated as a yellowish oil (6.018 g, 92%). 1H
NMR (300 MHz, CDCl3): d = 0.27 (m, 9 H, Si(CH3)3), 0.90 (t,
3J = 7.2 Hz, 3 H, CH2CH2CH3), 1.53 (m, 2 H, CH2CH2CH3), 2.74
(t, 3J = 6.1 Hz, 2 H, CH2CH2CH3), 6.08 (s, 1 H, CH), 6.97–7.01
(m, 1 H, CHHetar), 7.43–7.45 (m, 1 H, CHHetar), 7.49–7.51 (m, 1 H,
1-Hydroxy-1-(2-thienyl)-1-penten-3-one (3b). Starting with
THF (62.5 mL), LDA (75 mmol), 2-butanone 1b (3.606 g,
50.0 mmol) and 2-thiophenecarbonyl chloride 2 (8.796 g,
60.0 mmol), 3b was isolated as a yellowish oil (2.720 g, 30%). 1H
NMR (300 MHz, CDCl3): d = 1.41 (t, 3J = 6.6 Hz, 3 H, CH2CH3),
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 3542–3551 | 3545
©

View Article Online
CHHetar). 13C NMR (75 MHz, CDCl3): d = 0.3 (Si(CH3)3), 12.8
(CH2CH2CH3), 18.4 (CH2CH2CH3), 35.3 (CH2CH2CH3), 103.8
(CH), 127.5, 128.8, 132.0 (CHHetar), 147.3 (CHetar), 174.8 (C), 181.7
(CO).
d = 2.13 (s, 3 H, CH3), 2.22 (s, 3 H, CH3), 3.51 (s, 3 H, OCH3),
6.69 (m, 1 H, CHAr), 6.79 (m, 1 H, CHHetar), 6.92 (dd, 3J = 5.1 Hz,
4J = 1.7 Hz, 1 H, CHHetar), 7.19 (dd, J = 5.1 Hz, J = 1.1 Hz,
1 H, CHHetar), 10.88 (s, 1 H, OH). 13C NMR (75 MHz, CDCl3):
d = 12.0, 20.7 (CH3), 52.2 (OCH3), 110.3 (CCOOCH3Ar), 125.1
(CHAr), 125.3 (CAr), 125.5, 125.9, 126.8 (CHHetar), 133.5, 143.2
(CAr), 144.5 (CHetar), 159.8 (COHAr), 172.0 (CO). IR (neat, cm−1):
m˜= 2948 (w), 2854 (w), 1668 (s), 1600 (m), 1562 (w), 1433 (s), 1332
(w), 1258 (s), 1150 (s), 1089 (s), 1057 (m), 842 (s), 798 (s), 711 (s).
GC-MS (EI, 70 eV): m/z (%) = 262 ([M+], 63), 230 (100), 215 (4),
202 (58), 187 (26), 173 (17), 159 (6), 141 (3), 129 (6), 115 (12), 91
(3), 77 (3), 63 (3), 45 (4). HRMS (EI): calcd for C14H14O3S [M+]:
262.06582; found: 262.06563.
3
4
1-(2-Furyl)-1-[(trimethylsilyl)oxy]-1-penten-3-one (4d). Start-
ing with benzene (30.0 mL), 3d (1.660 g, 10.0 mmol), triethy-
lamine (1.619 g, 16.0 mmol) and trimethylchlorosilane (1.738 g,
18.0 mmol), 4d was isolated as a yellowish oil (2.028 g, 84%). 1H
NMR (250 MHz, CDCl3): d = 0.27 (m, 9 H, Si(CH3)3), 1.05 (t,
3J = 7.6 Hz, 3 H, CH2CH3), 2.76 (q, 3J = 7.4 Hz, 2 H, CH2CH3),
6.09 (s,1 H, CH), 6.43 (m, 1 H, CHHetar), 7.01 (m, 1 H, CHHetar),
7.44 (m, 1 H, CHHetar).
1,1,1-Trifluoro-4-(2-thienyl)-4-[(trimethylsilyl)oxy]-3-buten-2-
one (4e). Starting with benzene (45.0 mL), 3e (3.330 g,
15.0 mmol), triethylamine (2.429 g, 24.0 mmol) and trimethyl-
chlorosilane (2.917 g, 27.0 mmol), 4e was isolated as a reddish oil
Ethyl 3-ethyl-2-hydroxy-4-methyl-6-(2-thienyl)-benzoate (6c).
Starting with 4a (0.360 g, 1.5 mmol), 5c (0.495 g, 1.6 mmol) and
TiCl4 (0.18 mL, 1.6 mmol), 6c was isolated as a reddish viscous
oil (0.152 g, 35%). 1H NMR (300 MHz, CDCl3): d = 0.72 (t, 3J =
1
(3.175 g, 72%). H NMR (250 MHz, CDCl3): d = 0.24 (m, 9 H,
3
7.2 Hz, 3 H, CH2CH3), 0.97 (t, J = 7.4 Hz, 3 H, OCH2CH3),
Si(CH3)3), 6.53 (m, 1 H, CH), 7.04 (m, 1 H, CHHeter), 7.56–7.62 (m,
2 H, CHHeter).
3
2.13 (s, 3 H, CH3), 2.56 (q, J = 7.4 Hz, 2 H, CH2CH3), 3.87
3
(q, J = 7.2 Hz, 2 H, OCH2CH3), 6.56 (s, 1 H, CHAr), 6.67 (m,
3
4
1,1,1-Trifluoro-4-(2-furyl)-4-[(trimethylsilyl)oxy]-3-buten-2-one
(4f). Starting with benzene (45.0 mL), 3f (3.09 g, 15.0 mmol),
triethylamine (2.429 g, 24.0 mmol) and trimethylchlorosilane
(2.917 g, 27.0 mmol), 4f was isolated as a reddish oil (3.169 g,
76%). 1H NMR (300 MHz, CDCl3): d = 0.27 (m, 9 H, Si(CH3)3),
6.44 (m, 1 H, CH), 6.59 (m, 1 H, CHHeter), 7.12–7.19 (m, 1 H,
CHHeter), 7.49–7.54 (m, 1 H, CHHeter).
1 H, CHHetar), 6.79 (dd, J = 5.1 Hz, J = 1.7 Hz, 1 H, CHHetar),
3
4
7.07 (dd, J = 5.1 Hz, J = 1.1 Hz, 1 H, CHHetar), 10.89 (s, 1
H, OH). 13C NMR (75 MHz, CDCl3): d = 14.1 (CH2CH3), 14.2
(OCH2CH3), 20.6 (CH2CH3), 27.7 (CH3), 62.2 (OCH2CH3), 112.3
(CCOOCH2CH3Ar), 126.3 (CHAr), 127.2, 127.3, 128.2 (CHHetar),
132.8, 135.2 (CAr), 143.7 (CHetar), 146.1 (CAr), 161.4 (COHAr), 173.1
(CO). IR (neat, cm−1): m˜ = 2928 (m), 2872 (w), 1658 (s), 1606 (m),
1455 (m), 1389 (s), 1275 (s), 1226 (s), 1176 (m), 1104 (m), 1037 (w),
810 (w), 693 (m). GC-MS (EI, 70 eV): m/z (%) = 290 ([M+], 78),
244 (100), 229 (60), 216 (69), 201 (34), 187 (8), 171 (16), 158 (5),
128 (10), 115 (10), 77 (5), 45 (4). HRMS (EI): calcd for C16H18O3S
[M+]: 290.09712; found: 290.09704.
General procedure for the synthesis of salicylates 6. To a
CH2Cl2 solution (2 mL per 1.0 mmol of 4) of 4 (1.0 mmol)
was added 5 (1.1 mmol) and, subsequently, TiCl4 (1.1 mmol) at
−78 ◦C. The temperature of the solution was allowed to warm
to 20 ◦C over 14 h with stirring. To the solution was added
hydrochloric acid (10%, 20 mL) and the organic and the aqueous
layer were separated. The latter was extracted with CH2Cl2 (3 ×
20 mL). The combined organic layers were dried (Na2SO4), filtered
and the filtrate was concentrated in vacuo. The residue was purified
by chromatography (silica gel, n-heptane–EtOAc) to give 6.
Methyl 3-hexyl-2-hydroxy-4-methyl-6-(2-thienyl)-benzoate (6d).
Starting with 4a (0.360 g, 1.5 mmol), 5d (0.563 g, 1.6 mmol) and
TiCl4 (0.18 mL, 1.6 mmol), 6d was isolated as a reddish viscous oil
(0.134 g, 30%). 1H NMR (300 MHz, CDCl3): d = 0.70 (t(br), 3J =
6.6 Hz, 3 H, CH2(CH2)4CH3), 1.08 (m, 8 H, CH2(CH2)4CH3), 2.13
(s, 3 H, CH3), 2.53 (t, 3J = 7.2 Hz, 2 H, CH2(CH2)4CH3), 3.40 (s,
3 H, OCH3), 6.56 (m, 1 H, CHAr), 6.68–6.70 (m, 1 H, CHHetar),
Methyl 2-hydroxy-4-methyl-6-(2-thienyl)-benzoate (6a). Start-
ing with 4a (0.361 g, 1.5 mmol), 5a (0.426 g, 1.6 mmol) and TiCl4
(0.18 mL, 1.6 mmol), 6a was isolated as a reddish viscous oil
3
6.80 (m, 1 H, CHHetar), 7.08 (d, J = 5.9 Hz, 1 H, CHHetar), 10.71
(s, 1 H, OH). 13C NMR (75 MHz, CDCl3): d = 15.2 ((CH2)5CH3),
20.9 (CH3), 23.7, 27.5, 29.9, 30.7, 32.8 ((CH2)5CH3), 53.0 (OCH3),
111.3 (CCOOCH3Ar), 125.9 (CHAr), 126.6, 126.7, 127.6 (CHHetar),
131.0, 134.4 (CAr), 143.4 (CHetar), 145.3 (CAr), 160.6 (COHAr), 172.8
(CO). IR (neat, cm−1): m˜ = 2925 (s), 2855 (s), 1663 (s), 1607 (m),
1440 (s), 1391 (m), 1268 (s), 1226 (s), 1197 (m), 1162 (m), 1122 (w),
849 (w), 693 (m). GC-MS (EI, 70 eV): m/z (%) = 332 ([M+], 56),
300 (24), 285 (43), 271 (3), 243 (11), 230 (100), 215 (4), 202 (20),
187 (5), 171 (11), 128 (8), 41 (4). HRMS (EI): calcd for C19H24O3S
[M+]: 332.14407; found: 332.14436.
1
(0.119 g, 32%); H NMR (300 MHz, CDCl3): d = 2.24 (s, 3 H,
CH3), 3.50 (s, 3 H, OCH3), 6.77 (m, 1 H, CHAr), 6.74 (m, 1 H,
3
4
CHAr), 6.80–6.82 (m, 1 H, CHHetar), 6.91 (dd, J = 4.9 Hz, J =
3
4
1.5 Hz, 1 H, CHHetar), 7.20 (dd, J = 4.5 Hz, J = 1.8 Hz, 1 H,
CHHetar), 10.55 (s, 1 H, OH). 13C NMR (75 MHz, CDCl3): d = 21.9
(CH3), 52.2 (OCH3), 110.7 (CCOOCH3Ar), 118.2 (CHAr), 125.4 (2
CHHetar), 126.1 (CHHetar), 126.9 (CHAr), 136.8, 144.0 (CAr), 145.1
(CHetar), 161.9 (COHAr), 171.5 (CO). IR (neat, cm−1): m˜ = 2921 (w),
2851 (w), 1660 (m), 1611 (m), 1569 (m), 1432 (m), 1333 (m), 1261
(m), 1222 (m), 1089 (m), 848 (w), 795 (m), 702 (m). GC-MS (EI,
70 eV): m/z (%) = 248 ([M+], 53), 216 (100), 188 (52), 160 (11),
145 (3), 128 (5), 115 (16), 77 (3). HRMS (EI): calcd for C13H12O3S
[M+]: 248.04948; found: 248.04961.
Methyl 2-hydroxy-4-methyl-3-octyl-6-(2-thienyl)-benzoate (6e).
Starting with 4a (0.360 g, 1.5 mmol), 5e (0.609 g, 1.6 mmol) and
TiCl4 (0.18 mL, 1.6 mmol), 6e was isolated as a reddish viscous oil
(0.180 g, 34%). 1H NMR (300 MHz, CDCl3): d = 0.70 (t(br), 3J =
6.2 Hz, 3 H, CH2(CH2)6CH3), 1.09 (m, 12 H, CH2(CH2)6CH3),
Methyl 2-hydroxy-3,4-dimethyl-6-(2-thienyl)-benzoate (6b).
Starting with 4a (0.240 g, 1.0 mmol), 5b (0.190 g, 1.1 mmol) and
TiCl4 (0.12 mL, 1.1 mmol), 6b was isolated as a reddish solid.
3
2.13 (s, 3 H, CH3), 2.50 (t, J = 7.4 Hz, 2 H, CH2(CH2)6CH3),
◦
1
(0.086 g, 33%), mp = 75–81 C. H NMR (300 MHz, CDCl3):
3.53 (s, 3 H, OCH3), 6.57 (m, 1 H, CHAr), 6.69 (m, 1 H, CHHetar),
3546 | Org. Biomol. Chem., 2008, 6, 3542–3551
This journal is
The Royal Society of Chemistry 2008
©

View Article Online
6.80–6.82 (m, 1 H, CHHetar), 7.07–7.09 (m, 1 H, CHHetar), 10.71 (s,
1 H, OH). 13C NMR (75 MHz, CDCl3): d = 15.2 ((CH2)7CH3),
20.9 (CH3), 23.8, 27.5, 28.3, 29.9, 30.5, 31.2, 33.0 (CH2), 53.0
(OCH3), 111.3 (CCOOCH3Ar), 125.9 (CHAr), 126.6 (2 CHHetar),
127.6 (CHHetar), 131.0, 134.3 (CAr), 143.3 (CHetar), 145.3 (CAr), 160.7
(COHAr), 172.8 (CO). IR (neat, cm−1): m˜ = 2925 (s), 2855 (m), 1663
(s), 1607 (m), 1439 (m), 1360 (w), 1260 (m), 1226 (s), 1162 (m),
1025 (w), 844 (m), 693 (m). GC-MS (EI, 70 eV): m/z (%) = 360
([M+], 51), 328 (24), 313 (41), 230 (100), 202 (18), 171 (9), 128 (6),
41 (5). HRMS (EI): calcd for C21H28O3S [M+]: 360.17537; found:
360.17496.
(CH2CH3), 16.6 (OCH2CH3), 19.5 (CH2CH3), 26.4 (CH2CH3),
61.3 (OCH2CH3), 110.8 (CCOOCH2CH3Ar), 124.2 (CHAr), 125.9,
126.1, 127.1 (CHHetar), 134.0, 139.7 (CAr), 144.8 (CHetar), 148.1 (CAr),
160.4 (COHAr), 171.6 (CO). IR (neat, cm−1): m˜ = 2968 (s), 2874 (m),
1657 (s), 1606 (m), 1559 (m), 1463 (m), 1394 (s), 1322 (m), 1274
(s), 1242 (m), 1220 (s), 1175 (s), 1109 (m), 1030 (m), 870 (w), 812
(m), 694 (s). MS (EI, 70 eV): m/z (%) = 304 ([M+], 47), 258 (100),
229 (31), 215 (52), 201 (6), 187 (7), 171 (13), 153 (6), 97 (11), 81(9),
69 (14), 55 (13), 41 (11). HRMS (EI): calcd for C17H20O3S [M+]:
304.11277; found: 304.11299.
Methyl 4-ethyl-3-hexyl-2-hydroxy-6-(2-thienyl)-benzoate (6i).
Starting with 4b (0.425 g, 1.7 mmol), 5d (0.628 g, 1.8 mmol) and
TiCl4 (0.20 mL, 1.8 mmol), 6i was isolated as a reddish viscous oil
(0.156 g, 30%). 1H NMR (300 MHz, CDCl3): d = 0.71 (t(br), 3J =
7.0 Hz, 3 H, CH2(CH2)4CH3), 1.03 (t, 3J = 7.6 Hz, 3 H, CH2CH3),
Methyl 4-ethyl-2-hydroxy-6-(2-thienyl)-benzoate (6f). Starting
with 4b (0.448 g, 2.0 mmol), 5a (0.567 g, 2.2 mmol) and TiCl4
(0.24 mL, 2.2 mmol), 6f was isolated as a reddish viscous oil
1
3
(0.184 g, 35%). H NMR (300 MHz, CDCl3): d = 1.15 (t, J =
3
3
7.4 Hz, 3 H, CH2CH3), 2.53 (q, J = 7.4 Hz, 2 H, CH2CH3),
1.08–1.14 (m, 8 H, CH2(CH2)4CH3), 2.46 (q, J = 7.2 Hz, 2 H,
3
3.50 (s, 3 H, OCH3), 6.69 (s, 1 H, CHAr), 6.77 (s, 1 H, CHAr),
CH2CH3), 2.48 (q, J = 8.1 Hz, 2 H, CH2(CH2)4CH3), 3.41 (s,
3
4
6.81 (m, 1 H, CHHetar), 6.91 (dd, J = 5.1 Hz, J = 1.7 Hz, 1 H,
CHHetar), 7.21 (dd, 3J = 4.9 Hz, 4J = 1.3 Hz, 1 H, CHHetar), 10.55
(s, 1 H, OH). 13C NMR (75 MHz, CDCl3): d = 13.6 (CH2CH3),
27.7 (CH2CH3), 50.8 (OCH3), 109.0 (CCOOCH3Ar), 115.5 (CHAr),
122.8, 123.9 (CHHetar), 124.7 (CHAr), 125.4 (CHHetar), 135.5, 142.7
(CAr), 149.7 (CHetar), 160.5 (COHAr), 170.0 (CO). IR (neat, cm−1):
m˜ = 2967 (s), 2872 (w), 1734 (w), 1664 (s), 1610 (s), 1568 (s), 1440
(s), 1360 (s), 1265 (s), 1160 (m), 1098 (s), 1014 (m), 932 (m), 808
(m), 791 (m), 697 (s). GC-MS (EI, 70 eV): m/z (%) = 262 ([M+],
43), 230 (100), 202 (26), 187 (24), 173 (7), 115 (10). HRMS (EI):
calcd for C14H14O3S [M+]: 262.0582; found: 262.06562.
3 H, OCH3), 6.59 (m, 1 H, CHAr), 6.70 (m, 1 H, CHHetar), 6.82
3
4
(dd, J = 6.4 Hz, J = 1.7 Hz, 1 H, CHHetar), 7.07–7.09 (m, 1 H,
CHHetar), 10.71 (s, 1 H, OH). 13C NMR (75 MHz, CDCl3): d = 15.2
((CH2)5CH3), 20.9 (CH2CH3), 23.8, 27.2, 30.4, 30.7, 31.0, 33.1
(CH2), 53.0 (OCH3), 111.2 (CCOOCH3Ar), 124.9 (CHAr), 125.9,
126.6, 127.6 (CHHetar), 130.4, 134.6 (CAr), 145.8 (CHetar), 149.3 (CAr),
160.8 (COHAr), 172.8 (CO). IR (neat, cm−1): m˜ = 2925 (s), 2854 (m),
1661 (s), 1606 (m), 1559 (m), 1439 (s), 1396 (s), 1324 (m), 1263 (s),
1220 (s), 1197 (m), 1162 (m), 1125 (w), 849 (m), 813 (w), 649 (m).
GC-MS (EI, 70 eV): m/z (%) = 346 ([M+], 43), 314 (8), 285 (100),
271 (5), 257 (8), 244 (55), 215 (13), 187 (4), 171 (12), 153 (4), 85 (8),
71 (11), 57 (15), 43 (13). HRMS (EI): calcd for C20H26O3S [M+]:
346.15972; found: 346.15989.
Methyl 4-ethyl-2-hydroxy-3-methyl-6-(2-thienyl)-benzoate (6g).
Starting with 4b (0.448 g, 2.0 mmol), 5b (0.598 g, 2.2 mmol) and
TiCl4 (0.24 mL, 2.2 mmol), 6g was isolated as a reddish viscous
oil. (0.180 g, 34%). 1H NMR (300 MHz, CDCl3): d = 1.09 (t, 3J =
7.6 Hz, 3 H, CH2CH3), 2.13 (s, 3 H, CH3), 2.54 (q, 3J = 7.4 Hz, 2 H,
CH2CH3), 3.48 (s, 3 H, OCH3), 6.67 (s, 1 H, CHAr), 6.77–6.79 (m, 1
H, CHHetar), 6.90 (dd, 3J = 4.9 Hz, 4J = 1.5 Hz, 1 H, CHHetar), 7.16
(dd, 3J = 5.1 Hz, 4J = 1.1 Hz, 1 H, CHHetar), 10.87 (s, 1 H, OH).
13C NMR (75 MHz, CDCl3): d = 11.0 (CH2CH3), 14.0 (CH3),
26.8 (CH2CH3), 51.7 (OCH3), 109.0 (CCOOCH3Ar), 123.1 (CHAr),
123.5, 124.6, 126.3 (CHHetar), 133.3, 139.7 (CAr), 144.4 (CHetar), 148.4
(CAr), 159.6 (COHAr), 171.6 (CO). IR (Nujol, cm−1): m˜ = 1663 (s),
1607 (m), 1561 (m), 1261 (s), 1220 (m), 1196 (m), 1160 (m), 1102
(w), 1043 (m), 1007 (m), 848 (m), 806 (m), 766 (w), 649 (s). MS
(EI, 70 eV): m/z (%) = 276 ([M+], 98), 244 (100), 216 (91), 201
(41), 187 (23), 173 (25), 115 (15), 97 (8), 69 (10), 55 (8), 43 (8).
HRMS (CI, positive): calcd for C15H17O3S ([M + 1]+): 277.08929;
found: 277.08890.
Methyl 2-hydroxy-4-propyl-6-(2-thienyl)-benzoate (6j). Start-
ing with 4c (0.536 g, 2.0 mmol), 5a (0.568 g, 2.2 mmol) and
TiCl4 (0.24 mL, 2.2 mmol), 6j was isolated as a reddish viscous
oil (0.214 g, 40%). 1H NMR (300 MHz, CDCl3): d = 0.81 (t, 3J =
7.4 Hz, 3 H, CH2CH2CH3), 1.45–1.58 (m, 2 H, CH2CH2CH3), 2.42
(t, 3J = 7.8 Hz, 2 H, CH2CH2CH3), 3.46 (s, 3 H, OCH3), 6.62 (s, 1
H, CHAr), 6.70 (s, 1 H, CHAr), 6.77 (m, 1 H, CHHetar), 6.86 (m, 1 H,
CHHetar), 7.15 (d, 3J = 6.3 Hz, 1 H, CHHetar), 10.57 (s, 1 H, OHAr). 13C
NMR (75 MHz, CDCl3): d = 13.7 (CH3), 23.6, 37.7 (CH2), 51.7
(OCH3), 110.2 (CCOOMeAr), 117.1, 124.3 (CHAr), 124.9, 125.6,
126.4 (CHHetar), 136.7, 143.7 (CAr), 149.2 (CHetar), 161.4 (COHAr),
171.0 (CO). IR (KBr, cm−1): m˜ = 3012 (w), 2844 (w), 1662 (s), 1499
(m), 1459 (s), 1378 (s), 1239 (s), 1106 (m), 1074 (m), 1025 (m), 806
(m). MS (EI, 70 eV): m/z (%) = 276 ([M+], 60), 244 (100), 229
(5), 216 (97), 187 (24), 160 (10), 115 (20). HRMS (EI): calcd for
C15H16SO3 [M+]: 276.08147; found: 276.08178.
Ethyl 3,4-diethyl-2-hydroxy-6-(2-thienyl)-benzoate (6h). Start-
ing with 4b (0.448 g, 2.0 mmol), 5c (0.659 g, 2.2 mmol) and TiCl4
(0.24 mL, 2.2 mmol), 6h was isolated as a reddish viscous oil
Methyl 2-hydroxy-3-methyl-4-propyl-6-(2-thienyl)-benzoate
(6k). Starting with 4c (0.537 g, 2.0 mmol), 5b (0.604 g, 2.2 mmol)
and TiCl4 (0.24 mL, 2.2 mmol), 6k was isolated as a reddish
1
3
1
(0.186 g, 30%). H NMR (300 MHz, CDCl3): d = 0.82 (t, J =
viscous oil (0.274 g, 47%). H NMR (300 MHz, CDCl3): d =
3
3
7.0 Hz, 3 H, CH2CH3), 1.09 (t, J = 7.4 Hz, 3 H, CH2CH3),
0.88 (t, J = 7.4 Hz, 3 H, CH2CH2CH3), 1.46–1.49 (m, 2 H,
3
3
3
1.12 (t, J = 7.6 Hz, 3 H, OCH2CH3), 2.56 (q, J = 7.4 Hz, 2
H, CH2CH3), 2.64 (q, 3J = 7.4 Hz, 2 H, CH2CH3), 3.96 (q, 3J =
7.0 Hz, 2 H, OCH2CH3), 6.67 (s, 1 H, CHAr), 6.76–6.78 (m, 1
CH2CH2CH3), 2.14 (s, 3 H, CH3), 2.49 (t, J = 7.8 Hz, 2 H,
CH2CH2CH3), 3.49 (s, 3 H, OCH3), 6.66 (s, 1 H, CHAr), 6.78–6.79
(m, 1 H, CHHetar), 6.90 (dd, 3J = 5.1 Hz, 4J = 1.5 Hz, 1 H, CHHetar),
3
4
3
4
H, CHHetar), 6.90 (dd, J = 5.1 Hz, J = 1.5 Hz, 1 H, CHHetar),
7.17 (dd, J = 5.1 Hz, J = 1.1 Hz, 1 H, CHHetar), 10.88 (s, 1 H,
OH). 13C NMR (75 MHz, CDCl3): d = 11.7 (CH2CH2CH3), 14.7
(CH3), 23.1 (CH2CH2CH3), 36.3 (CH2CH2CH3), 52.2 (OCH3),
3
4
7.17 (dd, J = 5.1 Hz, J = 1.1 Hz, 1 H, CHHetar), 10.99 (s, 1
H, OH). 13C NMR (75 MHz, CDCl3): d = 13.5 (CH2CH3), 14.4
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 3542–3551 | 3547
©

View Article Online
110.2 (CCOOMeAr), 124.8 (CHAr), 125.9, 126.8, 127.5 (CHHetar),
133.5, 140.0 (CAr), 144.6 (CHetar), 147.5 (CAr), 160.1 (COHAr), 172.1
(CO). IR (neat, cm−1): m˜ = 2957 (s), 2871 (m), 1662 (s), 1607 (m),
1562 (m), 1438 (s), 1397 (s), 1312 (m), 1266 (s), 1198 (m), 1161
(m), 1011 (w), 849 (w), 807 (m), 747 (w), 697 (m). MS (EI, 70
eV): m/z (%) = 290 ([M+], 72), 258 (100), 229 (18), 215 (25), 202
(55), 187 (13), 171 (13), 158 (4), 128 (9), 115 (10), 89 (3), 77 (4),
45 (3). HRMS (EI): calcd for C16H18O3S [M+]: 290.09712; found:
290.09699.
NMR (75 MHz, CDCl3): d = 15.0 (CH2CH3), 29.0 (CH2CH3),
52.6 (OCH3), 107.2 (CHAr), 109.4 (CCOOCH3Ar), 111.1 (CHAr),
116.8, 122.1 (CHHetar), 132.6 (CAr), 142.1 (CHHetar), 151.1 (CAr),
154.1 (CHeter), 161.2 (COHAr), 170.8 (CO). MS (EI, 70 eV): m/z
(%) = 246 ([M+], 36), 214 (100), 186 (28), 171 (19), 128 (7), 115
(12). HRMS (EI): calcd for C14H14O4 [M+]: 246.08866; found:
246.08807.
Methyl 4-ethyl-6-(2-furyl)-2-hydroxy-3-methyl-benzoate (6o).
Starting with 4d (0.261 g, 1.1 mmol), 5b (0.190 g, 1.1 mmol)
and TiCl4 (0.12 mL, 1.1 mmol), 6o was isolated as a yellowish
Ethyl 3-ethyl-2-hydroxy-4-propyl-6-(2-thienyl)-benzoate (6l).
Starting with 4c (0.537 g, 2.0 mmol), 5c (0.659 g, 2.2 mmol) and
TiCl4 (0.24 mL, 2.2 mmol), 6l was isolated as a reddish viscous
1
viscous oil (0.085 g, 30%). H NMR (250 MHz, CDCl3): d =
3
1.12 (t, J = 7.2 Hz, 3 H, CH2CH3), 2.16 (s, 3 H, CH3), 2.58 (q,
3J = 7.4 Hz, 2 H, CH2CH3), 3.41 (s, 3 H, OCH3), 6.28–6.30 (m,
1 H, CHHetar), 6.36–6.39 (m, 1 H, CHHetar), 6.73 (s, 1 H, CHAr),
7.36 (m, 1 H, CHHetar), 10.72 (s, 1 H, OH). 13C NMR (75 MHz,
CDCl3): d = 11.2 (CH2CH3), 14.3 (CH3), 29.8 (CH2CH3), 52.6
(OCH3), 106.8, 109.1 (CHHetar), 113.3 (CCOOCH3Ar), 122.2 (CAr),
124.9, 129.9 (CAr) 142.0 (CHHetar), 149.0 (CAr), 154.7 (CHetar), 159.6
(COHAr), 170.6 (CO). GC-MS (EI, 70 eV): m/z (%) = 260 ([M+],
43), 228 (100), 200 (49), 185 (12), 171 (7), 157 (13), 128 (16), 115
(11). HRMS (EI): calcd for C15H16O4 [M+]: 260.104319; found:
260.10424.
1
oil (0.245 g, 42%). H NMR (300 MHz, CDCl3): d = 0.81 (t,
3J = 7.0 Hz, 3 H, CH2CH2CH3), 0.89 (t, 3J = 7.2 Hz, 3 H,
3
CH2CH3), 1.09 (t, J = 7.4 Hz, 3 H, OCH2CH3), 1.49–1.56 (m,
3
2 H, CH2CH2CH3), 2.50 (t, J = 7.8 Hz, 2 H, CH2CH2CH3),
3
3
2.64 (q, J = 7.4 Hz, 2 H, CH2CH3), 3.96 (q, J = 7.0 Hz, 2
H, OCH2CH3), 6.66 (s, 1 H, CHAr), 6.76–6.77 (m, 1 H, CHHetar),
6.88 (dd, 3J = 5.1 Hz, 4J = 1.5 Hz, 1 H, CHHetar), 7.16 (dd,
4
3J = 5.1 Hz, J = 1.1 Hz, 1 H, CHHetar), 10.99 (s, 1 H, OH). 13C
NMR (75 MHz, CDCl3): d = 13.5 (CH2CH2CH3), 14.3 (CH2CH3),
14.6 (OCH2CH3), 19.6 (CH2CH2CH3), 24.5 (CH2CH2CH3), 35.5
(CH2CH3), 61.3 (OCH2CH3), 110.8 (CCOOCH2CH3Ar), 124.8
(CHAr), 125.0, 125.9, 126.7 (CHHetar), 131.0, 133.7 (CAr), 142.6
(CHetar), 144.8 (CAr), 160.2 (COHAr), 171.6 (CO). GC-MS (EI, 70
eV): m/z (%) = 318 ([M+], 62), 272 (100), 257 (64), 244 (18), 229
(45), 216 (7), 201 (7), 187 (5), 171 (14), 153 (4), 115 (7), 97 (3),
77 (3). HRMS (EI): calcd for C18H22O3S [M+]: 318.12842; found:
318.12842.
General procedure for the synthesis of 8. To a stirred dimethyl-
sulfoxide solution (1 mL per 1.0 mmol of 3) of 3 (10.0 mmol) was
added potassium carbonate (40.0 mmol) at room temperature.
After the solution had been stirred for 30 min, 1,2-dibromoethane
(20.0 mmol) was added at 20 ◦C. After the solution had been stirred
for 12 h, an excess amount of water was added to remove dimethyl-
sulfoxide and the mixture was extracted with dichloromethane.
The combined organic layers were dried (Na2SO4) and filtered.
The filtrate was concentrated in vacuo. The residue was purified by
chromatography (silica gel, n-heptane–EtOAc = 30 : 1 → 20 : 1)
to give 8.
Methyl 3-hexyl-2-hydroxy-4-propyl-6-(2-thienyl)-benzoate (6m).
Starting with 4c (0.537 g, 2.0 mmol), 5d (0.812 g, 2.2 mmol) and
TiCl4 (0.24 mL, 2.2 mmol), 6m was isolated as a reddish viscous
oil (0.273 g, 35%). 1H NMR (300 MHz, CDCl3): d = 0.71 (t(br),
3
3J = 4.7 Hz, 3 H, CH2(CH2)4CH3), 0.81 (t, J = 7.2 Hz, 3 H,
1-[1-(2-Thienylcarbonyl)cyclopropyl]-1-ethanone (8a). Starting
with dimethysulfoxide (17.8 mL), 3b (3.250 g, 17.840 mmol),
K2CO3 (9.863 g, 71.4 mmol) and 1,2-dibromoethane (6.704 g,
CH2CH2CH3), 1.08 (m, 8 H, CH2(CH2)4CH3), 1.39–1.47 (m, 2 H,
3
CH2CH2CH3), 2.41 (t, J = 7.8 Hz, 2 H, CH2CH2CH3), 2.49 (t,
3J = 7.4 Hz, 2 H, CH2(CH2)4CH3), 3.41 (s, 3 H, OCH3), 6.57 (m,
1
35.7 mmol), 8a was isolated as a reddish oil (3.417 g, 91%). H
3
NMR (300 MHz, CDCl3): d = 0.90 (t, 3J = 7.1 Hz, 3 H, CH2CH3),
1.34 (t, 3J = 3.1 Hz, 2 H, CH2), 1.43 (t, 3J = 3.2 Hz, 2 H, CH2),
2.42 (q, 3J = 7.3 Hz, 2 H, CH2CH3), 7.05 (dd, 3J = 4.9 Hz, 4J =
1.1 Hz, 1 H, CHHetar), 7.56–7.58 (m, 1 H, CHHetar), 7.60–7.62 (m,
1 H, CHHetar). 13C NMR (75 MHz, CDCl3): d = 7.4 (CH2CH3),
16.1 (2 CH2), 35.2 (CH2CH3), 41.6 (COCCO), 128.2, 133.6, 134.2
(CHHetar), 143.4 (CHetar), 188.7, 206.0 (CO). IR (neat, cm−1): m˜ =
2977 (w), 1700 (m), 1647 (s), 1512 (w), 1409 (s), 1315 (m), 1233
(m), 1052 (m), 972 (w), 794 (w), 721 (s), 657 (w). GC-MS (EI, 70
eV): m/z (%) = 208 ([M+], 16), 193 (10), 179 (22), 151 (9), 111
(100), 83 (8), 57 (13), 39 (13). HRMS (EI): calcd for C11H12O2S
[M+]: 208.05507; found: 208.05475.
1 H, CHAr), 6.69–6.71 (m, 1 H, CHHetar), 6.81 (dd, J = 4.9 Hz,
4J = 1.5 Hz, 1 H, CHHetar), 7.10 (dd, 3J = 5.1 Hz, 4J = 1.1 Hz, 1
H, CHHetar), 10.71 (s, 1 H, OH). 13C NMR (75 MHz, CDCl3): d =
13.1 ((CH2)5CH3), 13.2 (CH2CH2CH3), 21.6, 23.0, 25.0, 28.5, 28.6,
30.7, 34.2 (CH2), 50.8 (OCH3), 108.9 (CCOOCH3Ar), 123.5 (CHAr),
123.6, 124.4, 125.4 (CHHetar), 128.5, 132.1 (CAr), 143.3 (CHetar), 145.7
(CAr), 158.7 (COHAr), 170.6 (CO). IR (neat, cm−1): m˜ = 2927 (s),
2870 (m), 1663 (s), 1605 (m), 1559 (m), 1437 (s), 1396 (s), 1268 (s),
1161 (s), 1114 (w), 1015 (w), 810 (m), 693 (s). MS (EI, 70 eV): m/z
(%) = 360 ([M+], 79), 328 (35), 311 (21), 285 (100), 271 (13), 258
(73), 243 (28), 201 (11), 171 (11), 97 (6), 83 (6), 57 (11). HRMS
(CI, positive): calcd for C21H29O3S ([M + 1]+): 361.18319; found:
361.18305.
General procedure for the synthesis of salicylates 9. To a
CH2Cl2 solution (50 mL per 1.0 mmol of 8) of 8 (1.0 mmol)
was added 5 (1.1 mmol) and, subsequently, TiCl4 (1.1 mmol) at
−78 ◦C. The temperature of the solution was allowed to warm
to 20 ◦C over 14 h with stirring. To the solution was added
hydrochloric acid (10%, 20 mL) and the organic and the aqueous
layer were separated. The latter was extracted with CH2Cl2 (3 ×
20 mL). The combined organic layers were dried (Na2SO4), filtered
Methyl 4-ethyl-2-(2-furyl)-6-hydroxy-benzoate (6n). Starting
with 4d (0.380 g, 1.6 mmol), 5a (0.426 g, 1.6 mmol) and TiCl4
(0.18 mL, 1.6 mmol), 6n was isolated as a yellow oil (0.125 g,
1
3
32%). H NMR (250 MHz, CDCl3): d = 1.25 (t, J = 7.6 Hz,
3
3 H, CH2CH3), 2.63 (q, J = 7.5 Hz, 2 H, CH2CH3), 3.71 (s, 3
H, OCH3), 6.39 (m, 1 H, CHHetar), 6.45 (m, 1 H, CHHetar), 6.82
(s, 1 H, CHAr), 7.46 (m, 1 H, CHHetar), 10.43 (s, 1 H, OH). 13C
3548 | Org. Biomol. Chem., 2008, 6, 3542–3551
This journal is
The Royal Society of Chemistry 2008
©

View Article Online
and the filtrate was concentrated in vacuo. The residue was purified
by chromatography (silica gel, n-heptane–EtOAc) to give 9.
(CAr), 140.8 (CHetar), 157.1 (COHAr), 170.5 (CO). IR (neat, cm−1):
m˜ = 2963 (w), 1651 (s), 1589 (w), 1446 (w), 1396 (m), 1371 (s),
1277 (s), 1194 (s), 1121 (m), 1018 (m), 814 (w), 693 (s). MS (EI,
70 eV): m/z (%) = 368 ([M+], 37Cl, 18), 366 ([M+], 35Cl, 55), 341
(15), 344 (56), 322 (37Cl, 38), 320 (35Cl, 100), 287 (34), 271 (23), 257
(61), 243 (19), 228 (10), 213 (5), 177 (94), 161 (60), 149 (40), 129
(22). HRMS (EI): calcd for C19H23ClO3S ([M]+, 35Cl): 366.10509;
found: 366.10404.
Methyl 5-(2-chloroethyl)-4-ethyl-2-hydroxy-6-(2-thienyl)-ben-
zoate (9a). Starting with 8a (0.312 g, 1.2 mmol), 5a (0.429 g,
1.6 mmol) and TiCl4 (0.570 mL, 3.0 mmol), 9a was isolated as
reddish viscous oil (0.204 g, 42%). 1H NMR (250 MHz, CDCl3):
3
3
d = 1.15 (t, J = 7.4 Hz, 3 H, CH2CH3), 2.92 (q, J = 7.4 Hz,
3
2 H, CH2CH3), 3.08 (t, J = 7.5 Hz, 2 H, CH2CH2Cl), 3.36 (t,
3J = 8.1 Hz, 2 H, CH2CH2Cl), 3.92 (s, 3 H, OCH3), 6.95 (s, 1 H,
CHAr), 6.96 (s, 1 H, CHHetar), 7.03 (d, 3J = 5.1 Hz, 1 H, CHHetar),
Methyl 5-(2-chloroethyl)-4-ethyl-3-hexyl-2-hydroxy-6-(2-
thienyl)-benzoate (9d). Starting with 8a (0.312 g, 1.2 mmol), 5d
(0.587 g, 1.6 mmol) and TiCl4 (0.570 mL, 3.0 mmol), 9d was
3
4
7.32 (dd, J = 5.1 Hz, J = 1.2 Hz, 1 H, CHHetar), 10.42 (s, 1
H, OH). 13C NMR (62 MHz, CDCl3): d = 15.9 (CH2CH3), 26.6
(CH2CH3), 32.9 (CH2CH2Cl), 43.4 (CH2CH2Cl), 52.5 (OCH3),
112.6 (CCOOCH3Ar), 118.2 (CHAr), 126.1 (CHHetar), 126.8 (CAr),
126.9, 127.0 (CHHetar), 141.1, 141.3 (CAr), 145.8 (CHetar), 159.4
(COHAr), 170.2 (CO). IR (neat, cm−1): m˜ = 2923 (w), 1661 (s),
1597 (w), 1569 (m), 1434 (s), 1337 (m), 1234 (s), 1203 (s), 1142
(m), 1080 (m), 939 (w), 807 (m), 788 (m), 692 (s). MS (EI, 70 eV):
m/z (%) = 326 ([M+], 37Cl, 8), 324 ([M+], 35Cl, 21), 294 (37Cl, 17),
292 (35Cl, 49), 275 (6), 245 (37Cl, 5), 243 (35Cl, 100), 215 (4), 187
(5), 171 (6), 119 (9), 97 (11), 83 (11), 69 (24), 57 (19). HRMS (EI):
calcd for C16H17ClO3S ([M]+, 35Cl): 324.05796; found: 324.05780.
1
isolated as a colourless oil (0.186 g, 32%). H NMR (250 MHz,
CDCl3): d = 0.75 (t (br), 3J = 7.0 Hz, 3 H, CH2(CH2)4CH3), 1.10 (t,
3J = 7.3 Hz, 3 H, CH2CH3), 1.14–1.16 (m, 8 H, CH2(CH2)4CH3),
3
1.29–1.32 (m, 2 H, CH2(CH2)4CH3), 2.27 (q, J = 6.1 Hz, 2 H,
3
3
CH2CH3), 2.85 (t, J = 6.2 Hz, 2 H, CH2CH2Cl), 3.34 (t, J =
5.5 Hz, 2 H, CH2CH2Cl), 3.91 (s, 3 H, OCH3), 6.75–6.77 (m, 1
3
4
H, CHHetar), 7.03 (dd, J = 5.2 Hz, J = 1.7 Hz, 1 H, CHHetar),
7.33 (d, 3J = 6.3 Hz, 1 H, CHHetar), 10.61 (s, 1 H, OH). 13C NMR
(62 MHz, CDCl3): d = 14.0 (CH2)5CH3), 16.0, (CH2CH3), 22.4,
23.1, 28.3, 29.8, 29.9, 31.3, 33.9, 43.9 (8 CH2), 52.4 (OCH3), 112.3
(CCOOC2H5Ar), 122.7 (CAr), 125.3, 125.8, 126.0 (CHHetar), 130.2,
138.7, 139.4 (CAr), 140.8 (CHetar), 157.0 (COHAr), 170.9 (CO). IR
(neat, cm−1): m˜ = 2925 (w), 16582 (m), 1590 (w), 1432 (m), 1316
(m), 1202 (m), 1124 (m), 1070 (w), 833 (w), 817 (w), 693 (m). GC–
MS (EI, 70 eV): m/z (%) = 410 ([M+], 37Cl, 27), 408 ([M+], 35Cl,
74), 378 (37Cl, 36), 376 (35Cl, 100), 359 (27), 313 (42), 285 (12), 243
(48), 227 (8), 184 (7), 112 (4). HRMS (EI): calcd for C22H29ClO3S
([M]+, 35Cl): 408.15204; found: 408.15396.
Methyl 5-(2-chloroethyl)-4-ethyl-2-hydroxy-3-methyl-6-(2-
thienyl)-benzoate (9b). Starting with 8a (0.312 g, 1.2 mmol), 5b
(0.452 g, 1.7 mmol) and TiCl4 (0.570 mL, 3.0 mmol), 9b was
isolated as a colourless viscous oil (0.200 g, 40%). 1H NMR
(250 MHz, CDCl3): d = 1.13 (t, 3J = 7.4 Hz, 3 H, CH2CH3), 1.88 (s,
3 H, CH3), 2.86 (q, 3J = 7.5 Hz, 2 H, CH2CH3), 2.89 (t, 3J = 7.3 Hz,
2 H, CH2CH2Cl), 3.42 (t, 3J = 6.5 Hz, 2 H, CH2CH2Cl), 3.92 (s, 3
H, OCH3), 6.74–6.76 (m, 1 H, CHHetar), 7.05 (dd, 3J = 5.2 Hz, 4J =
1.7 Hz, 1 H, CHHetar), 7.36 (d, 3J = 6.2 Hz, 1 H, CHHetar), 10.71 (s,
1 H, OH). 13C NMR (62 MHz, CDCl3): d = 12.7 (CH2CH3), 15.7
(CH3), 23.3 (CH2CH3), 32.8 (CH2CH2Cl), 42.8 (CH2CH2Cl), 51.5
(OCH3), 112.0 (CCOOCH3Ar), 124.8, 125.7, 126.1 (CHHetar), 126.7,
139.1, 139.9, 140.8 (CAr), 140.8 (CHetar), 157.1 (COHAr), 170.9 (CO).
IR (neat, cm−1): m˜ = 2953 (w), 1642 (s), 1567 (w), 1434 (m), 1325
(m), 1236 (s), 1209 (s), 1122 (s), 1035 (m), 814 (s), 716 (s), 666 (m),
554 (m). MS (EI, 70 eV): m/z (%) = 340 ([M+], 37Cl, 17), 338 ([M+],
35Cl, 36), 308 (37Cl, 33), 306 (35Cl, 100), 289 (7), 271 (7), 257 (68),
243 (51), 229 (7), 214 (5), 177 (10), 161 (7), 135 (6), 111 (8), 97
(12), 83 (13), 69 (21), 57 (24). HRMS (EI): calcd for C17H19ClO3S
([M]+, 35Cl): 338.07361; found: 338.07354.
General procedure for the synthesis of salicylates 10. To a
CH2Cl2 solution (2 mL per 1 mmol of 4) of 4 (1.0 mmol) was added
5 (1.1 mmol) and, subsequently, TiCl4 (1.1 mmol) at −78 ◦C. The
temperature of the solution was allowed to warm to 20 ◦C
over 14 h with stirring. To the solution was added hydrochloric
acid (10%, 20 mL) and the organic and the aqueous layer were
separated. The latter was extracted with CH2Cl2 (3 × 20 mL).
The combined organic layers were dried (Na2SO4), filtered and
the filtrate was concentrated in vacuo. The residue was purified by
chromatography (silica gel, n-heptane–EtOAc) to give 10.
Methyl 2-hydroxy-4-(2-thienyl)-6-(trifluoromethyl)-benzoate
(10a). Starting with 4e (0.442 g, 1.5 mmol), 5a (0.430 g, 1.6 mmol)
and TiCl4 (0.18 mL, 1.6 mmol), 10a was isolated as a colourless
Ethyl 5-(2-chloroethyl)-3,4-diethyl-2-hydroxy-6-(2-thienyl)-
benzoate (9c). Starting with 8a (0.312 g, 1.2 mmol), 5c (0.499 g,
1.6 mmol) and TiCl4 (0.570 mL, 3.0 mmol), 9c was isolated as a
colourless oil (0.194 g, 34%).1H NMR (250 MHz, CDCl3): d =
◦
solid (0.160 g, 35%), mp = 126–128 C.1H NMR (250 MHz,
3
4
CDCl3): d = 3.92 (s, 3 H, OCH3), 7.05 (dd, J = 5.1 Hz, J =
1.4 Hz, 1 H, CHHeter), 7.33–7.35 (m, 2 H, CHHeter), 7.37–7.39 (m,
1 H, CHAr), 7.47 (m, 1 H, CHAr), 10.86 (s, 1 H, OH). 13C NMR
(62 MHz, CDCl3): d = 52.8 (OCH3), 109.2 (CCOOCH3Ar), 116.6
(d, 3JF, C = 6.8 Hz, CHAr), 117.8 (CHAr), 123.1 (d, 1JF, C = 269.7 Hz,
3
3
0.95 (t, J = 7.4 Hz, 3 H, CH2CH3), 1.15 (t, J = 7.2 Hz, 3 H,
3
3
CH2CH3), 1.38 (t, J = 7.1 Hz, 3 H, OCH2CH3), 2.32 (q, J =
3
7.5 Hz, 2 H, CH2CH3), 2.67 (t, J = 7.5 Hz, 2 H, CH2CH2Cl),
3
3
2
2.88 (q, J = 7.4 Hz, 2 H, CH2CH3), 3.34 (t, J = 5.0 Hz, 2
CF3), 125.7, 127.5, 128.5 (CHHeter), 130.5 (d, JF, C = 31.6 Hz,
3
H, CH2CH2Cl), 4.40 (q, J = 7.1 Hz, 2 H, OCH2CH3), 6.77 (d,
CCF3Ar), 139.7 (CHeter), 141.2 (CAr), 162.4 (COHAr), 169.3 (CO).
19F NMR (235 MHz, CDCl3): d = −59.0 (CF3). IR (neat, cm−1):
m˜ = 2964 (w), 2857 (w), 1672 (m), 1614 (w), 1440 (m), 1422 (m),
1326 (m), 1228 (w), 1127 (m), 1030 (m), 923 (m), 869 (m), 717 (m).
GC-MS (EI, 70 eV): m/z (%) = 302 ([M+], 81), 270 (100), 242 (41),
223 (9), 214 (40), 194 (4), 169 (4), 145 (16), 121 (13). HRMS (EI):
calcd for C13H9O3F3S: 302.02190; found: 302.02202.
3J = 4.6 Hz, 1 H, CHHetar), 7.04 (dd, J = 5.1 Hz, J = 1.7 Hz,
3
4
3
1 H, CHHetar), 7.33 (d, J = 6.2 Hz, 1 H, CHHetar), 10.75 (s, 1 H,
OH). 13C NMR (62 MHz, CDCl3): d = 13.0, 13.3, (CH2CH3), 15.1
(OCH2CH3), 18.3 (CH2CH3), 23.3 (CH2CH2Cl), 32.9 (CH2CH3),
42.9 (CH2CH2Cl), 60.9 (OCH2CH3), 112.5 (CCOOC2H5Ar), 124.6
(CHHetar), 125.3 (CAr), 125.9, 126.8 (CHHetar), 130.9, 138.8, 139.1
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 3542–3551 | 3549
©

View Article Online
Methyl 2-hydroxy-3-methyl-4-(2-thienyl)-6-(trifluoromethyl)-
benzoate (10b). Starting with 4e (0.442 g, 1.5 mmol), 5b (0.452 g,
1.6 mmol) and TiCl4 (0.18 mL, 1.6 mmol), 10b was isolated as
a colourless solid (0.215 g, 45%), mp = 72–74 ◦C. 1H NMR
1.6 mmol) and TiCl4 (0.18 mL, 1.6 mmol), 10e was isolated
◦
1
as a colourless viscous oil (0.231 g, 37%), mp = 49–50 C. H
3
NMR (250 MHz, CDCl3): d = 0.58 (t(br), J = 6.9 Hz, 3 H,
CH2(CH2)6CH3), 0.95–1.26 (m, 12 H, CH2(CH2)6CH3), 2.47 (t,
3J = 8.1 Hz, 2 H, CH2(CH2)6CH3), 3.70 (s, 3 H, OCH3), 6.80 (m,
1 H, CHAr), 6.83 (m, 1 H, CHHeter), 7.04 (m, 1 H, CHHeter), 7.13 (dd,
(250 MHz, CDCl3): d = 2.30 (s, 3 H, CH3), 3.92 (s, 3 H, OCH3),
4
7.04 (d, J
= 2.2 Hz, 1 H, CHAr), 7.07 (m, 1 H, CHHeter),
H, F
4
7.30 (m, 1 H, CHHeter), 7.36 (m, 1 H, CHHeter), 11.16 (s, 1 H,
3J = 6.3 Hz, J = 1.3 Hz, 1 H, CHHeter), 10.82 (s, 1 H, OH). 13C
OH). 13C NMR (62 MHz, CDCl3): d = 12.8 (CH3), 51.8 (OCH3),
NMR (75 MHz, CDCl3): d = 14.0 (CH3), 22.6, 27.6, 29.1, 29.2,
29.4, 29.7, 31.8 (CH2), 52.8 (OCH3), 109.2 (CCOOCH3Ar), 121.3
(q, 3JF, C = 6.7 Hz, CHAr), 123.3 (d, 1JF, C = 271.5 Hz, CF3), 126.5
(d, 2JF, C = 31.5 Hz, CCF3Ar), 126.6, 127.2, 127.4 (CHHeter), 135.0,
139.1 (CAr), 140.5 (CHeter), 160.5 (COHAr), 170.1 (CO). 19F NMR
(235 MHz, CDCl3): d = −58.7 (CF3). IR (neat, cm−1): m˜ = 2915
(w), 2848 (w), 1669 (m), 1604 (w), 1440 (m), 1338 (m), 1286 (m),
1197 (m), 1125 (s), 1048 (w), 946 (m), 852 (w), 698 (s). GC-MS (EI,
70 eV): m/z (%) = 414 ([M+], 100), 382 (30), 365 (12), 297 (16),
284 (33), 283 (63), 269 (74), 256 (48), 235 (7), 207 (24), 158 (12).
HRMS (EI): calcd for C21H25O3F3S: 414.14710; found: 414.14684.
3
107.7 (CCOOCH3Ar), 119.8 (d, JF, C = 6.8 Hz, CHAr), 122.3 (d,
1JF, C = 271.5 Hz, CF3), 125.8 (CHHeter), 126.0 (d, 2JF, C = 31.5 Hz,
CCF3Ar), 126.3, 126.9 (CHHeter), 128.8, 138.3 (CAr), 139.6 (CHeter),
159.7 (COHAr), 169.0 (CO). 19F NMR (235 MHz, CDCl3): d =
−58.6 (CF3). IR (neat, cm−1): m˜ = 2962 (w), 2853 (w), 1683 (m),
1606 (w), 1436 (m), 1315 (m), 1275 (s), 1112 (s), 1013 (m), 937 (m),
882 (m), 687 (s). GC-MS (EI, 70 eV): m/z (%) = 316 ([M+], 66),
284 (29), 256 (100), 237 (5), 207 (11), 187 (10), 159 (8), 134 (4),
115 (6). HRMS (EI): calcd for C14H11O3F3S: 316.03755; found:
316.03784.
Ethyl 3-ethyl-2-hydroxy-4-(2-thienyl)-6-(trifluoromethyl)-ben-
zoate (10c). Starting with 4e (0.442 g, 1.5 mmol), 5c (0.499 g,
1.6 mmol) and TiCl4 (0.18 mL, 1.6 mmol), 10c was isolated as a
yellow oil (0.230 g, 44%). 1H NMR (250 MHz, CDCl3): d = 1.12 (t,
3J = 7.4 Hz, 3 H, CH2CH3), 1.34 (t, 3J = 7.1 Hz, 3 H, OCH2CH3),
Methyl 2-hydroxy-4-(2-furanyl)-6-(trifluoromethyl)-benzoate
(10f). Starting with 4f (0.556 g, 2.0 mmol), 5a (0.567 g, 2.2 mmol)
and TiCl4 (0.24 mL, 2.2 mmol), 10f w◦as isolated as a colourless
1
solid (0.231 g, 40%), mp = 116–118 C. H NMR (250 MHz,
4
CDCl3): d = 3.91 (s, 3 H, OCH3), 6.45 (q, JH, F = 1.7 Hz, 1 H,
3
3
2.74 (q, J = 7.4 Hz, 2 H, CH2CH3), 4.38 (q, J = 7.1 Hz, 3 H,
CHAr), 6.78 (dd, 3J = 4.1 Hz, 4J = 0.6 Hz, 1 H, CHHeter), 7.37 (m,
1 H, CHHeter), 7.47 (m, 1 H, CHAr), 7.52 (m, 1 H, CHHeter), 10.84 (s,
1 H, OH). 13C NMR (75 MHz, CDCl3): d = 52.8 (OCH3), 108.9,
112.2 (CHHeter), 114.7 (q, 3JF, C = 6.7 Hz, CHAr), 115.6 (CHAr), 117.7
OCH2CH3), 7.03 (m, 1 H, CHHeter), 7.04 (d, 4J
= 1.4 Hz, 1 H,
H, F
CHAr), 7.26 (m, 1 H, CHHeter), 7.33–7.35 (m, 1 H, CHHeter), 11.19 (s,
1 H, OH). 13C NMR (75 MHz, CDCl3): d = 14.1, 14.2 (CH3), 21.0
(CH2CH3), 62.5 (OCH2CH3), 109.5 (CCOOCH2CH3Ar), 121.2 (d,
(CCOOCH3Ar), 123.1 (d, 1JF, C = 271.5 Hz, CF3), 131.0 (d, 2JF, C
=
1
3JF, C = 7.5 Hz, CHAr), 123.3 (d, JF, C = 271.5 Hz, CF3), 126.6
32.2 Hz, CCF3Ar), 135.6 (CAr), 144.0 (CHHeter), 151.2 (CHeter), 162.4
(COHAr), 169.4 (CO). 19F NMR (235 MHz, CDCl3): d = −59.0
(CF3). IR (neat, cm−1): m˜ = 2921 (w), 2852 (w), 1660 (m), 1621 (w),
1440 (m), 1335 (m), 1290 (m), 1212 (m), 1126 (m), 1016 (m), 904
(m), 802 (m), 760 (m). GC-MS (EI, 70 eV): m/z (%) = 286 ([M+],
81), 254 (100), 226 (69), 207 (10), 198 (23), 169 (16), 151 (21), 129
(4), 113 (8), 75 (5). HRMS (EI): calcd for C13H9O4F3: 286.04474;
found: 286.04447.
(CHHeter), 127.0 (d, 2JF, C = 31.5 Hz, CCF3Ar), 127.3, 127.4 (CHHeter),
136.0, 138.8 (CAr), 140.5 (CHeter), 160.6 (COHAr), 169.6 (CO). IR
(neat, cm−1): m˜ = 2930 (w), 2874 (w), 1666 (m), 1608 (w), 1463 (w),
1372 (m), 1288 (s), 1231 (m), 1137 (s), 1013 (m), 932 (m), 883 (w),
696 (s). GC-MS (EI, 70 eV): m/z (%) = 344 ([M+], 45), 298 (15),
270 (100), 255 (4), 222 (4), 207 (6), 171 (5).
Methyl 3-hexyl-2-hydroxy-4-(2-thienyl)-6-(trifluoromethyl)-ben-
zoate (10d). Starting with 4e (0.442 g, 1.5 mmol), 5d (0.568 g,
1.6 mmol) and TiCl4 (0.18 mL, 1.6 mmol), 10d was isolated as a
colourless viscous oil (0.196 g, 34%). 1H NMR (250 MHz, CDCl3):
d = 0.79 (t(br), 3J = 6.6 Hz, 3 H, CH2(CH2)4CH3), 1.18–1.51 (m,
8 H, CH2(CH2)4CH3), 2.69 (t, 3J = 8.2 Hz, 2 H, CH2(CH2)4CH3),
3.92 (s, 3 H, OCH3), 7.02 (m, 1 H, CHAr), 7.04–7.06 (m, 1 H,
CHHeter), 7.26 (m, 1 H, CHHeter), 7.35 (dd, 3J = 4.8 Hz, 4J = 1.3 Hz,
1 H, CHHeter), 11.05 (s, 1 H, OH). 13C NMR (62 MHz, CDCl3):
d = 13.0 (CH3), 21.5, 26.6, 28.3, 28.4, 30.4 (CH2), 51.8 (OCH3),
Methyl 4-(2-furanyl)-2-hydroxy-3-methyl-6-(trifluoromethyl)-
benzoate (10g). Starting with 4f (0.4176 g, 1.5 mmol), 5b (0.452 g,
1.6 mmol) and TiCl4 (0.18 mL, 2.2 mmol), 10g was isolated as a
◦
1
red solid (0.186 g, 41%), mp = 79–82 C. H NMR (300 MHz,
CDCl3): d = 2.38 (s, 3 H, CH3), 3.91 (s, 3 H, OCH3), 6.48 (dd, 3J =
4
5.2 Hz, J = 1.8 Hz, 1 H, CHHeter), 6.65–6.67 (m, 1 H, CHHeter),
7.50 (m, 1 H, CHAr), 7.60 (m, 1 H, CHHeter), 11.21 (s, 1 H, OH).
13C NMR (62 MHz, CDCl3): d = 12.5 (CH3), 51.8 (OCH3), 107.1
3
(CCOOCH3Ar), 110.8, 110.9 (CHHeter), 116.4 (q, JF, C = 6.8 Hz,
3
1
108.2 (CCOOCH3Ar), 120.2 (q, JF, C = 8.2 Hz, CHAr), 122.4 (d,
CHAr), 122.4 (d, JF, C = 271.5 Hz, CF3), 124.6 (CAr), 126.4 (d,
1JF, C = 250.4 Hz, CF3), 125.7(CAr), 125.6, 126.2, 126.4 (CHHeter),
134.0, 138.1 (CAr), 139.5 (CHeter), 159.5 (COHAr), 169.1 (CO). 19F
NMR (235 MHz, CDCl3): d = −58.7 (CF3). IR (neat, cm−1): m˜ =
2928 (w), 2849 (w), 1672 (m), 1601 (w), 1439 (m), 1356 (m), 1298
(s), 1198 (m), 1124 (s), 1047 (w), 940 (m), 810 (m), 701 (s). GC-MS
(EI, 70 eV): m/z (%) = 386 ([M+], 100), 354 (25), 337 (11), 326
(94), 315 (8), 297 (14), 283 (59), 256 (54), 235 (7), 207 (28), 187 (7),
158 (14). HRMS (EI): calcd for C19H21O3F3S: 386.11580; found:
386.11536.
2JF, C = 32.2 Hz, CCF3Ar), 133.6 (CAr), 142.1 (CHHeter), 150.3 (CHeter),
159.8 (COHAr), 169.1 (CO). 19F NMR (235 MHz, CDCl3): d =
−58.8 (CF3). IR (neat, cm−1): m˜ = 2921 (w), 2850 (w), 1798 (m),
1658 (m), 1438 (m), 1338 (m), 1282 (s), 1120 (s), 1018 (m), 936 (m),
804 (m), 754 (m). GC-MS (EI, 70 eV): m/z (%) = 300 ([M+], 100),
268 (78), 248 (80), 219 (9), 192 (10), 164 (26), 133 (11), 115 (21).
HRMS (EI): calcd for C14H11O4F3: 300.06039; found: 300.05967.
Ethyl 3-ethyl-4-(2-furanyl)-2-hydroxy-6-(trifluoromethyl)-ben-
zoate (10h). Starting with 4f (0.556 g, 2.0 mmol), 5c (0.652 g,
2.2 mmol) and TiCl4 (0.24 mL, 2.2 mmol), 10h was isolated as
Methyl 2-hydroxy-3-octyl-4-(2-thienyl)-6-(trifluoromethyl)-ben-
zoate (10e). Starting with 4e (0.442 g, 1.5 mmol), 5e (0.614 g,
1
a red viscous oil (0.226 g, 35%). H NMR (300 MHz, CDCl3):
3550 | Org. Biomol. Chem., 2008, 6, 3542–3551
This journal is
The Royal Society of Chemistry 2008
©

View Article Online
3
3
d = 1.18 (t, J = 7.4 Hz, 3 H, CH2CH3), 1.34 (t, J = 7.2 Hz,
(w), 739 (w). GC-MS (EI, 70 eV): m/z (%) = 398 ([M+], 100), 366
3
3 H, OCH2CH3), 2.87 (q, J = 7.2 Hz, 2 H, CH2CH3), 4.38 (q,
(42), 338 (8), 267 (76), 219 (37), 183 (12), 133 (11).
3J = 7.2 Hz, 2 H, OCH2CH3), 6.47 (q, JH, F = 5.1 Hz, 1 H,
3
CHAr), 6.63 (m, 1 H, CHHeter), 7.50 (m, 1 H, CHHeter), 7.54 (m, 1 H,
CHHeter), 11.27 (s, 1 H, OH). 13C NMR (62 MHz, CDCl3): d = 12.0
(CH2CH3), 12.5 (OCH2CH3), 19.6 (CH2CH3), 61.5 (OCH2CH3),
Acknowledgements
Financial support by the state of Pakistan (HEC scholarships for
I. H. and for M. A. Y.) is gratefully acknowledged.
107.8 (CCOOCH2CH3Ar), 109.9, 110.8 (CHHeter), 117.0 (q, 3JF, C
6.8 Hz, CHAr), 122.4 (d, 1JF, C = 269.1 Hz, CF3), 126.4 (d, 2JF, C
=
=
32.2 Hz, CCF3Ar), 132.7, 133.0 (CAr), 142.2 (CHHeter), 150.3 (CHeter),
159.9 (COHAr), 168.7 (CO). 19F NMR (235 MHz, CDCl3): d =
−58.1 (CF3). IR (neat, cm−1): m˜ = 2924 (w), 2853 (w), 1671 (m),
1439 (m), 1336 (m), 1282 (s), 1200 (m), 1131 (s), 1047 (m), 954
(w), 886 (w), 770 (w), 701 (s). GC-MS (EI, 70 eV): m/z (%) =
328 ([M+], 61), 282 (29), 254 (100), 234 (7), 207 (7), 177 (7),
128 (7). HRMS (EI): calcd for C16H15O4F3: 328.09170; found:
328.09162.
Notes and references
1 W. Steglich, B. Fugmann and S. Lang-Fugmann, Ro¨mpp Lexikon
Naturstoffe, Thieme, Stuttgart, 1997.
2 K. Take, K. Okumura, K. Takimoto, M. Kato, M. Ohtsuka and Y.
Shiokawa, Chem. Pharm. Bull., 1991, 39, 2915.
3 H. Storflor and J. Skramstad, Acta Chem. Scand., Ser. B, 1986, 40, 178.
4 T. R. Bailey, Tetrahedron Lett., 1986, 27, 4407.
5 Y. Qian, J. J. Marugan, R. D. Fossum, A. Vogt, S. M. Sebti and A. D.
Hamilton, Bioorg. Med. Chem., 1999, 7, 3011.
6 (a) A. Salimbeni, R. Canevotti, F. Paleari, F. Bonaccorsi, A. R. Renzetti,
L. Belvisi, G. Bravi and C. Scolastico, J. Med. Chem., 1994, 37, 3928;
(b) A. Pelter, I. Jenkins and D. E. Jones, Tetrahedron, 1997, 53, 10357.
7 T.-H. Chan and P. Brownbridge, J. Am. Chem. Soc., 1980, 102, 3534.
8 For a review of 1,3-bis(silyl enol ethers) in general, see: P. Langer,
Synthesis, 2002, 441.
9 (a) For a review of [3 + 3] cyclizations of 1,3-bis(silyl enol ethers), see:
H. Feist and P. Langer, Synthesis, 2007, 327; for the recent work of
our group, see: (b) M. Sher, Z. Ahmed, M. A. Rashid, C. Fischer and
P. Langer, J. Org. Chem., 2007, 72, 6284; (c) C. Mamat, S. Bu¨ttner,
T. Trabhardt, C. Fischer and P. Langer, J. Org. Chem., 2007, 72, 6273;
(d) I. Hussain, V. T. H. Nguyen, M. A. Yawer, T. T. Dang, C. Fischer, H.
Reinke and P. Langer, J. Org. Chem., 2007, 72, 6255; (e) M. A. Yawer, I.
Hussain, S. Reim, Z. Ahmed, E. Ullah, I. Iqbal, C. Fischer, H. Reinke,
H. Go¨rls and P. Langer, Tetrahedron, 2007, 63, 12562; (f) C. Mamat,
T. Pundt, T. H. T. Dang, R. Klassen, H. Reinke, M. Ko¨ckerling and
P. Langer, Eur. J. Org. Chem., 2008, 492; (g) I. Hussain, M. A. Yawer,
M. Lau, T. Pundt, C. Fischer, H. Reinke, H. Go¨rls and P. Langer,
Eur. J. Org. Chem., 2008, 503; (h) M. A. Yawer, A. Riahi, M. Adeel, I.
Hussain, C. Fischer and P. Langer, Synthesis, 2008, 1276.
10 (a) V. Prelog, O. Metzler and O. Jeger, Helv. Chim. Acta, 1947, 30,
675; (b) G. N. Dorofeenko, A. V. Koblik and K. F. Suzdalev, J. Org.
Chem. USSR (Engl. Transl.), 1981, 17, 927; Zh. Org. Khim., 1981, 17,
1050; (c) G. A. M. Nawwar, B. M. Haggag and E.-S. M. A. Z. Yakout,
Z. Naturforsch., B, 1992, 47, 1639.
11 (a) Fluorine in Bioorganic Chemistry, ed. R. Filler, Y. Kobayasi and
L. M. Yagupolskii, Elsevier, Amsterdam, 1993; (b) R. Filler, Fluorine
Containing Drugs in Organofluorine Chemicals and their Industrial
Application, Pergamon, New York, 1979, chapter 6; (c) M. Hudlicky,
Chemistry of Organic Compounds, Ellis Horwood, Chichester, 1992;
see also: (d) T. Ryckmanns, L. Balancon, O. Berton, C. Genicot, Y.
Lamberty, B. Lallemand, P. Passau, N. Pirlot, L. Que´re´ and P. Talaga,
Bioorg. Med. Chem. Lett., 2002, 12, 261; (e) M. S. Malamas, J. Sredy, C.
Moxham, A. Katz, W. Xu, R. McDevitt, F. O. Adebayo, D. R. Sawicki,
L. Seestaller, D. Sullivan and J. R. Taylor, J. Med. Chem., 2000, 43,
1293; (f) A. J. Ciha and P. G. Ruminski, J. Agric. Food Chem., 1991, 39,
2072.
Methyl 4-(2-furanyl)-3-hexyl-2-hydroxy-6-(trifluoromethyl)-
benzoate (10i). Starting with 4f (0.556 g, 2.0 mmol), 5d (0.751 g,
2.2 mmol) and TiCl4 (0.24 mL, 2.2 mmol), 10i was isolated as
1
a viscous oil (0.222 g, 30%). H NMR (250 MHz, CDCl3): d =
3
0.84 (t, J = 6.8 Hz, 3 H, CH2(CH2)4CH3), 1.23–1.54 (m, 8 H,
CH2(CH2)4CH3), 2.80 (t, 3J = 7.6 Hz, 2 H, CH2(CH2)4CH3), 3.89
(s, 3 H, OCH3), 6.46 (q, 4JH, F = 1.8 Hz, 1 H, CHAr), 6.58 (m, 1 H,
CHHeter), 7.48 (m, 1 H, CHHeter), 7.53 (m, 1 H, CHHeter), 11.14 (s, 1
H, OH). 13C NMR (62 MHz, CDCl3): d = 13.0 (CH3), 21.6, 26.2,
27.5, 28.6, 30.5 (CH2), 51.7 (OCH3), 107.4 (CCOOCH3Ar), 109.9,
110.8 (CHHeter), 177.0 (q, 3JF, C = 6.8 Hz, CHAr), 122.4 (d, 1JF, C
=
2
269.1 Hz, CF3), 126.3 (d, JF, C = 31.6 Hz, CCF3Ar), 131.7, 133.3
(CAr), 142.1 (CHHeter), 150.3 (CHeter), 159.8 (COHAr), 169.1 (CO).
19F NMR (235 MHz, CDCl3): d = −59.0 (CF3). IR (neat, cm−1):
m˜ = 2917 (w), 2849 (w), 1672 (m), 1439 (m), 1336 (m), 1282 (s),
1202 (m), 1133 (s), 948 (w), 880 (w), 739 (w). GC-MS (EI, 70
eV): m/z (%) = 370 ([M+], 100), 338 (24), 321 (11), 310 (42), 281
(32), 267 (68), 240 (28), 219 (31), 211 (6), 183 (14), 164 (11), 133
(15), 115 (8). HRMS (EI): calcd for C19H21O4F3: 370.13865; found:
370.13811.
Methyl 4-(2-furanyl)-3-octyl-2-hydroxy-6-(trifluoromethyl)-ben-
zoate (10j). Starting with 4f (0.556 g, 2.0 mmol), 5e (0.812 g,
2.2 mmol) and TiCl4 (0.24 mL, 2.2 mmol), 10j was isolated as a
colourless viscous oil (0.280 g, 35%). 1H NMR (300 MHz, CDCl3):
d = 0.79 (t, 3J = 6.8 Hz, 3 H, CH2(CH2)6CH3), 1.46–1.54 (m, 12
3
H, CH2(CH2)6CH3), 2.80 (t, J = 7.6 Hz, 2 H, CH2(CH2)6CH3),
3.89 (s, 3 H, OCH3), 6.44 (q,4JH, F = 4.1 Hz, 1 H, CHAr), 6.57 (dd,
3J = 4.1 Hz, 4J = 0.8 Hz, 1 H, CHHeter), 7.47 (m, 1 H, CHHeter), 7.52
(m, 1 H, CHHeter), 11.12 (s, 1 H, OH). 13C NMR (62 MHz, CDCl3):
d = 14.0 (CH3), 22.6, 27.2, 28.6, 29.2, 29.3, 29.9, 31.8 (CH2), 52.7
(OCH3), 108.4 (CCOOCH3Ar), 110.9, 111.8 (CHHeter), 118.1 (q,
3JF, C = 6.8 Hz, CHAr), 123.4 (d, 1JF, C = 269.0 Hz, CF3), 127.4 (q,
2JF, C = 31.0 Hz, CCF3Ar), 132.8, 134.3 (CAr), 143.1 (CHHeter), 151.4
(CHeter), 160.9 (COHAr), 170.1 (CO). 19F NMR (235 MHz, CDCl3):
d = −58.8 (CF3). IR (neat, cm−1): m˜ = 2917 (w), 2849 (w), 1672
(m), 1439 (m), 1336 (m), 1282 (s), 1202 (m), 1133 (s), 948 (w), 880
12 G. A. Molander and K. O. Cameron, J. Am. Chem. Soc., 1993, 115,
830.
13 CCDC-675254 (6b), CCDC-664611 (10a), and CCDC-664610 (10f)
contain all the crystallographic details of this publication and are
available free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html,
or can be ordered from the following address: Cambridge Crystallo-
graphic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK; Fax:
(+44)1223-336-033; or deposit@ccdc.cam.ac.uk.
14 G. Bose, V. T. H. Nguyen, E. Ullah, S. Lahiri, H. Go¨rls and P. Langer,
J. Org. Chem., 2004, 69, 9128.
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 3542–3551 | 3551
©