Domino [3+3] annulation/ring-cleavage reactions of 1,3- bis(trimethylsilyloxy)-1,3-butadienes with 5-aryl- and 5-vinyl-3-acyl-4,5- dihydrofurans: Efficient synthesis of 5-(4-chlorobut-2-en-1-yl)- and 5-(2-aryl-2-chloroethyl)salicylates

Article abstract of DOI:10.1002/ejoc.201000158

The domino "[3+3] cyclization-ring-opening" reactions of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with 3-acetyl-5vinyl-4, 5-dihydrofurans afforded 5-(4-halobut-2-en-1-yl)salicylates. The reactions of 1,3-bis(trimethylsilyloxy)-1,3butadienes with 3-acetyl

Full text of DOI:10.1002/ejoc.201000158

FULL PAPER
DOI: 10.1002/ejoc.201000158
Domino [3+3] Annulation/Ring-Cleavage Reactions of
1,3-Bis(trimethylsilyloxy)-1,3-butadienes with 5-Aryl- and 5-Vinyl-3-acyl-
4,5-dihydrofurans: Efficient Synthesis of 5-(4-Chlorobut-2-en-1-yl)- and
5-(2-Aryl-2-chloroethyl)salicylates
Matthias Lau,[a] Muhammad Sher,[a,b,c] Alexander Villinger,[a] Christine Fischer,[b] and
Peter Langer*[a,b]
Dedicated to Professor Dr. Uwe Rosenthal on the occasion of his 60th birthday
Keywords: Arenes / Regioselectivity / Annulation / Ring cleavage / Silyl enol ethers
The domino “[3+3] cyclization–ring-opening” reactions of
1,3-bis(trimethylsilyloxy)-1,3-butadienes with 3-acetyl-5-
vinyl-4,5-dihydrofurans afforded 5-(4-halobut-2-en-1-yl)-
salicylates. The reactions of 1,3-bis(trimethylsilyloxy)-1,3-
butadienes with 3-acetyl-5-aryl-4,5-dihydrofurans gave 5-(2-
aryl-2-chloroethyl)salicylates.
Introduction
Results and Discussion
1,3-Bis(trimethylsilyloxy)-1,3-butadienes represent useful
synthetic building blocks.[1,2] They have been employed in
the synthesis of butenolides,[3a] arenes,[3b] nitrogen hetero-
cycles,[3c] biaryl lactones, azaxanthones and benzophe-
nones,[3d] organofluorine compounds[3e] and tetrahydro-
furan derivatives.[3f] Some years ago we reported[4] the syn-
thesis of 5-(2-chloroethyl)salicylates by TiCl4-mediated
domino “[3+3] cyclization–cyclopropane-opening” reac-
tions of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with 1,1-
diacylcyclopropanes. Recently we reported[5] the cyclization
of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with 3-acetyl-5-
aryl-4,5-dihydrofurans. Herein, we report full details of
these studies. With regard to our preliminary studies,[5] we
have greatly extended the scope of this method, which pro-
vides a convenient approach to a variety of 5-(2-aryl-2-
haloethyl)salicylates.
In addition, we report for the first time the synthesis of
5-(4-chlorobut-2-en-1-yl)salicylates by the domino “[3+3]
cyclization–ring-opening” reactions of 1,3-bis(trimethyl-
silyloxy)-1,3-butadienes with 3-acetyl-5-vinyl-4,5-dihy-
drofurans. None of the products reported herein, which are
highly functionalized arenes, are readily available by any
other method.
1,1-Diacetyl-2-vinylcyclopropane (1) was prepared, fol-
lowing a known procedure,[6] by K2CO3-mediated cycliza-
tion of acetylacetone with 1,4-dibromobut-2-ene
(Scheme 1).
Scheme 1. Synthesis of 1. Reagents and conditions: i) K2CO3, ace-
tone, 14 h, reflux.
1,3-Bis(trimethylsilyloxy)-1,3-butadienes 2a–k are readily
available in two steps from the corresponding β-keto es-
ters.[7,8] The TiCl4-mediated cyclization of 1,3-bis(silyloxy)-
1,3-butadiene 2a with 1 afforded salicylate 3a (Scheme 2).
The formation of 3a can be explained by TiCl4-mediated
attack of the terminal carbon atom of 2a on 1 to give inter-
mediate A, cyclization to intermediate B, attack of the
TiCl4-derived chloride ion on the vinylcyclopropyl double
bond and cleavage of the spirocyclopropane moiety.
The best yield was obtained when 2 equiv. of TiCl4 and
1.5 equiv. of diene 2a were employed. In contrast to our
original protocol for the reaction of 2a with 1,1-diacetylcy-
clopropane, it proved advantageous to carry out the reac-
tion in a highly concentrated solution [c(1) = 0.2 ]. The
yield decreased to 23% when the reaction was carried out
in a more dilute solution [c(1) = 0.02 ].
[a] Institut für Chemie der Universität Rostock,
Albert-Einstein-Straße 3a, 18059 Rostock, Germany
Fax: +49-381-498-6411
E-mail: peter.langer@uni-rostock.de
[b] Leibniz Institut für Katalyse e.V. an der Universität Rostock,
Albert-Einstein-Straße 29a, 18059 Rostock, Germany
[c] Department of Chemistry, Allama Iqbal Open University,
Islamabad, Pakistan
Eur. J. Org. Chem. 2010, 3743–3753
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3743

M. Lau, M. Sher, A. Villinger, C. Fischer, P. Langer
FULL PAPER
Scheme 2. Possible mechanism for the formation of 3a.
Scheme 4. Possible mechanism for the cyclization of 2a with 4.
1,1-Diacetyl-2-vinylcyclopropane (1) has previously been
transformed[6] into 3-acetyl-5-vinyl-4,5-dihydrofuran 4 by a
[Ni(cod)2]-mediated reaction (Scheme 3). Compound 4 is
also formed during the synthesis of 1 from 1,4-dibromobut-
2-ene. We separated fractions of pure product 4 and used it
in reactions with dienes 2.
Scheme 5. Synthesis of 3a–e.
Table 1. Synthesis of 3a–e (see also Scheme 5).
Scheme 3. Synthesis of 4. Reagents and conditions: i) [Ni(cod)2],
2,2Ј-bipyridyl, acetonitrile, 15 min, 20 °C.
2,3
R1
R2
Yield [%][a]
a
b
c
d
e
H
H
Me
OMe
H
OMe
OEt
OMe
OMe
Me
77
52
51
31
30
The reaction of diene 2a with 4 afforded salicylate 3a in
77% yield (Scheme 4). It is important to note that the yield
is much higher than the yield of the same product prepared
from 2a and 1 (see Scheme 2). During the optimization it
was found to be important to carry out the reaction in a
relatively dilute solution [c(4) = 0.02 ]. The yield decreased
to 48% when the reaction was carried out in a more con-
centrated solution [c(4) = 0.2 ]. The formation of 3a can
be explained by the conjugate addition of the terminal car-
bon atom of 2a to 4 to give intermediate C, cyclization to
intermediate D and aromatization (before or during the
aqueous work-up).
[a] Yields of isolated products.
a known procedure[9] afforded products 7a–i (Scheme 6,
Table 2). The synthesis of 7a–c and 7f has been previously
reported.[9]
The reactions of 4 with dienes 2b–e following our opti-
mized procedure afforded products 3b–e (Scheme 5,
Table 1). The best yields were obtained for the reactions of
the C4-unsubstituted dienes 2a and 2b. The yield of product
3e was relatively low (compared to products 3a,b), which
can be explained by the lower reactivity of 1,3-diketone-
derived diene 2e relative to the β-keto ester derived dienes
2a–d.
The reactions of 1,3-diketones 5a,b with styrenes 6a–h,
mediated by ceric ammonium nitrate (CAN) and following conditions: i) 6a–h (4.4 equiv.), CAN (2.0 equiv.), 20 °C, 0.5–2 h.
Scheme 6. Synthesis of 5-aryl-4,5-dihydrofurans 7a–i. Reagents and
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 3743–3753

Synthesis of Chlorobutenyl- and Chloroethylsalicylates
Table 2. Synthesis of dihydrofurans 7a–i (see also Scheme 6).
5
6
7
R1
R2
R3
R4
R5 Yield of 7 [%][a]
a
a
a
a
a
a
a
a
b
a
b
c
d
e
f
g
h
a
a
b
c
d
e
f
g
h
i
Me
Me
Me
Me
Me
Me
Me
Me
Et
H
H
H
H
H
H
Cl
Cl
H
H
H
H
H
H
Cl
H
H
H
H
Me
Cl
Br
F
H
H
H
H
H
H
H
H
H
Cl
H
69[b]
63[b]
74[b]
54
43
47[b]
65
H
H
28
30
[a] Yields of isolated compounds. [b] Known compound (see ref.[9]).
The dihydrofurans 7 are rather unstable and can be
stored only for a few days at –20 °C. However, we were able
to grow crystals of 7h. The crystal structure is shown in
Figure 1.[10]
Scheme 7. Possible mechanism for the formation of 8a.
Figure 1. Crystal structure of 7h.
The reaction of diene 2a with 7a in the presence of
TiCl4 afforded the 5-(2-phenyl-2-chloroethyl)salicylate 8a
(Scheme 7). The best yields of 8a were obtained when
1.0 equiv. of 7a, 1.7 equiv. of 2a and 2.0 equiv. of TiCl4 were
employed. The low concentration [c(7a) = 0.017 ] and the
Scheme 8. Reaction of 5-aryl-4,5-dihydrofurans 7a–i with 1,3-
bis(silyloxy)-1,3-butadienes 2a–c and 2f–i. Reagents and condi-
tions: i) TiCl4 (2.0 equiv.), CH2Cl2, –78Ǟ20 °C.
use of hydrochloric acid (10%) for the aqueous work-up tend to be slightly higher than those of the other products.
also played an important role. The yield of 8a decreased to This can be explained by the electron-withdrawing effect of
37% when an aqueous solution of NaOH was employed (c the halogen atoms, which results in activation of the dihy-
= 1 mol/L). The employment of BF3·Et2O instead of TiCl4 drofuran moiety.
resulted in the formation of a complex mixture from which
The structure of 8r was independently confirmed by X-
only the starting material 7a could be isolated in 28% yield. ray crystal structure analysis (Figure 2).[10]
The formation of 8a can be explained by attack of the ter-
Stilbenes are present in various plants,[11] including, for
minal carbon atom of 2a on 7a to give intermediate E, ring example, in the phytoestrogen rhaponthicin[12] or the phyto-
cleavage, cyclization to give intermediate F, aromatization alexin resveratrol, which is found in grapes and possesses
and formation of the final product 8a after aqueous work- anti-mutagenic and possibly anticarcinogenic properties.[13]
up.
In addition, cytostatic activities have been reported.[14]
The TiCl4-mediated cyclization reactions of 1,3-bis- Stilbene derivatives are also used as dyes and fluorescence
(silyloxy)-1,3-butadienes 2a–c and 2f–i with 3-acetyl-5-aryl- dyes. Hence their synthesis is of considerable interest.
4,5-dihydrofurans 7a–i afforded the 5-(2-aryl-2-chloro-
ethyl)salicylates 8a–z (Scheme 8, Table 3).
The thermal elimination of hydrogen chloride from sali-
cylate 8a afforded stilbene 10a (Scheme 9, Table 4). Initially,
In the reactions of dihydrofurans 7g and 7h, the alcohols the reactions were carried out without the addition of base.
9a–c were isolated. Their formation can be explained by The best results with regard to E diastereoselectivity and
hydrolysis of the chloride moiety. The yields of the products yield (60%) were obtained when the reaction was carried
derived from halogenated 3-acetyl-5-aryl-4,5-dihydrofurans out at 150 °C for 3 h. Both the yield and E diastereoselectiv-
Eur. J. Org. Chem. 2010, 3743–3753
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3745

M. Lau, M. Sher, A. Villinger, C. Fischer, P. Langer
FULL PAPER
Table 3. Synthesis of 8a–x and 9a–c (see also Scheme 8).
7
2
8
9
X
R1
R2
R3
R4
R5
R6
R7
Yield of 8
[%][a]
a
a
a
a
a
a
a
b
c
f
g
h
a
b
c
d
e
f
Cl
Cl
Cl
Cl
Cl
Cl
H
H
Me
Et
H
nPr
OMe
OEt
OMe
OMe
OiPr
OMe
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
46
44
36
51
56
52
b
a
g
Cl
H
OMe
H
H
Me
H
Me
35
c
c
c
c
a
b
c
f
h
i
Cl
Cl
Cl
Cl
H
H
Me
Et
OMe
OEt
OMe
OMe
H
H
H
H
H
H
H
H
Cl
Cl
Cl
Cl
H
H
H
H
Me
Me
Me
Me
38
74
47
56
j
k
d
d
d
d
d
a
c
f
g
i
l
Cl
Cl
Cl
Cl
Cl
H
Me
Et
OMe
OMe
OMe
OiPr
OMe
H
H
H
H
H
H
H
H
H
H
Br
Br
Br
Br
Br
H
H
H
H
H
Me
Me
Me
Me
Me
53
62
45
65
32
m
n
o
p
H
Cl(CH2)3
e
e
e
a
c
f
q
r
s
Cl
Cl
Cl
H
Me
Et
OMe
OMe
OMe
H
H
H
H
H
H
F
F
F
H
H
H
Me
Me
Me
45
51
22
f
a
c
f
a
c
a
a
c
t
u
v
w
x
Cl
Cl
Cl
H
Me
Et
H
Me
H
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
H
H
H
Cl
Cl
Cl
H
H
Cl
Cl
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
H
H
Me
Me
Me
Me
Me
Et
46
38
33
f
f
g
g
h
i
a
b
c
Cl (OH)[b]
Cl (OH)[b]
Cl (OH)[b]
Cl
15 (36)[c]
14 (47)[c]
0 (49)[c]
39
y
z
H
Me
Et
Et
i
Cl
70
[a] Yields of isolated products. [b] Substitutes in parentheses refer to 9a–c. [c] Yields in brackets refer to 9a–c.
ity decreased when the reaction time was prolonged or
when the temperature was increased. Dramatic improve-
ments in the yield and E diastereoselectivity were observed
when the reactions were carried out in the presence of so-
dium hydride in DMF at 20 °C.
Table 4. Optimization of the synthesis of 10a (see also Scheme 9).
Entry
T [°C]
t [h]
E/Z[a]
Yield [%][b]
1
2
3
200
150
150
3
3
7
4:1
11:1
6:1
38
60
45
1
[a] By H NMR spectroscopy. [b] Yields of isolated products.
Figure 2. Crystal structure of 8r.
Scheme 10. Synthesis of 10b. Reagents and conditions: i) NaH
(3.0 equiv.), TBAI (3.6 equiv.), DMF, 20 °C, 20 h.
Scheme 9. Synthesis of stilbene 10a.
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Eur. J. Org. Chem. 2010, 3743–3753

Synthesis of Chlorobutenyl- and Chloroethylsalicylates
7.1 Hz, 3 H, OCH2CH3), 2.25 (s, 3 H, CH3), 2.43 (s, 3 H, CH3),
3.32–3.39 (m, 3J = 5.4 Hz, 2 H, CHCH2), 3.96–4.03 (m, 3J =
7.0 Hz, 2 H, CHCH2), 4.42 (q, 3J = 7.1 Hz, 2 H, OCH2CH3), 5.30–
Treatment of 8p with NaH and TBAI (tetrabutylammo-
nium iodide) afforded, following a known procedure,[8b] the
chromane 10b in 76% yield as the pure E diastereomer
(Scheme 10). The product was formed by base-mediated eli-
mination and intramolecular Williamson reaction.
3
5.48 (m, 3Jtrans = 15.2, JCHCH2 = 7.0 Hz, 1 H, CHCH2), 5.77–5.92
3
3
(m, Jtrans = 15.2, JCHCH2 = 5.4 Hz, 1 H, CHCH2), 6.70 (s, 1 H,
Ar), 10.68 (s, 1 H, OH) ppm. 13C NMR (62.9 MHz, CDCl3): δ =
14.2, 18.6, 20.9 (CH3), 31.7, 45.0, 61.5 (CH2), 116.9 (CHAr), 126.4,
132.7 (CHOlefin), 111.9, 128.0, 138.9, 144.1, 159.9 (CAr), 171.5 (CO-
Conclusions
OCH CH ) ppm. IR (KBr): ν = 2981 (m), 1658 (s), 1603 (m), 1574
˜
2
3
(m), 1467 (m), 1373 (m), 1243 (s), 1155 (m), 1016 (w), 861 (m) cm–1.
MS (EI, 70 eV): m/z (%) = 284 (26) [M]+ (37Cl), 282 (75) [M]+
(35Cl), 247 (63), 236 (100), 201 (71). HRMS (EI): calcd. for
C15H19ClO3 [M]+ (35Cl) 282.10165; found 282.10172.
We have reported an efficient synthesis of 5-(4-halobut-
2-en-1-yl)salicylates by domino “[3+3] cyclization–ring-
opening” reactions of 1,3-bis(trimethylsilyloxy)-1,3-butadi-
enes with 3-acetyl-5-vinyl-4,5-dihydrofurans. The domino
reactions of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with
3-acetyl-5-aryl-4,5-dihydrofurans gave 5-(2-aryl-2-chloro-
ethyl)salicylates. The highly functionalized products re-
ported are not readily available by other methods.
Methyl 5-[(E)-4-Chlorobut-2-enyl]-3,4,6-trimethylsalicylate (3c):
Starting with 1 (0.135 g, 0.89 mmol), 2c (0.365 g, 1.33 mmol) and
TiCl4 (0.20 mL, 1.77 mmol), 3c was isolated by chromatography
(heptane/EtOAc, 20:1) as a colourless solid (0.129 g, 51%); m.p.
54–57 °C; Rf = 0.82 (heptane/EtOAc, 1:1). 1H NMR (250 MHz,
CDCl3): δ = 2.19 (s, 3 H, CH3), 2.21 (s, 3 H, CH3), 2.39 (s, 3 H,
CH3), 3.38–3.43 (m, 3J = 5.3 Hz, 2 H, CHCH2), 3.93 (s, 3 H,
OCH3), 3.97–4.03 (m, 3J = 7.1 Hz, 2 H, CHCH2), 5.30–5.46 (m,
3Jtrans = 15.2, 3JCHCH2 = 7.1 Hz, 1 H, CHCH2), 5.81–5.94 (m, 3Jtrans
= 15.2, 3JCHCH2 = 5.3 Hz, 1 H, CHCH2), 10.87 (s, 1 H, OH) ppm.
13C NMR (62.9 MHz, CDCl3): δ = 12.2, 16.8, 18.6 (CH3), 32.2,
45.1 (CH2), 52.0 (OCH3), 126.5, 135.4 (CHOlefin), 111.2, 122.6,
127.6, 135.6, 142.5, 157.5 (CAr), 172.6 (COOCH3) ppm. IR (ATR):
Experimental Section
General: All solvents were dried by standard methods and all reac-
tions were carried out under an inert atmosphere. For H and 13C
1
NMR spectra the deuteriated solvents indicated were used. Mass
spectrometric data (MS) were obtained by electron ionization (EI,
70 eV), chemical ionization (CI, isobutane) or electrospray ioniza-
tion (ESI). For preparative-scale chromatography, silica gel 60
(0.063–0.200 mm, 70–230 mesh) was used.
ν = 2953 (w), 1652 (s), 1596 (m), 1437 (m), 1349 (m), 1313 (m),
˜
1248 (s), 1205 (s), 1178 (s), 1097 (m) cm–1. MS (EI, 70 eV): m/z (%)
= 284 (11) [M]+ (37Cl), 282 (33) [M]+ (35Cl), 250 (100), 222 (13),
215 (95). C15H19ClO3 (282.76): calcd. C 63.71, H 6.77; found C
63.41, H 6.86.
General Procedure for the Synthesis of 3a–e, 8a–z and 9a–c: Diene
2 (1.5–1.7 equiv.) was added to a dichloromethane solution (50 mL)
of 1, 4 or 7 (1.0 equiv.) was added at –78 °C under argon. TiCl4
(2.0 equiv.) was added to the mixture. The temperature of the solu-
tion was allowed to warm to 20 °C over 16 h with stirring. Hydro-
chloric acid (10%, 50 mL) was added to the mixture. The mixture
was stirred for 10 min and was subsequently extracted with dichlo-
romethane (3ϫ50 mL). The combined organic layers were dried
(Na2SO4), filtered and the filtrate was concentrated in vacuo. The
residue was purified by chromatography (silica gel, heptanes/
EtOAc).
Methyl 5-[(E)-4-Chlorobut-2-enyl]-3-methoxy-4,6-dimethylsalicylate
(3d): Starting with 1 (0.170 g, 1.12 mmol), 2d (0.487 g, 1.68 mmol)
and TiCl4 (0.25 mL, 2.24 mmol), 3d was isolated by chromatog-
raphy (heptane/EtOAc, 10:1) as a slightly yellow solid (0.104 g,
31%); m.p. 43–45 °C; Rf = 0.57 (heptane/EtOAc, 1:1). 1H NMR
(250 MHz, CDCl3): δ = 2.23 (s, 3 H, CH3), 2.35 (s, 3 H, CH3),
3.34–3.40 (m, 3J = 5.4 Hz, 2 H, CHCH2), 3.79 (s, 3 H, OCH3), 3.94
(s, 3 H, OCH3), 3.96–4.03 (m, 3J = 7.1 Hz, 2 H, CHCH2), 5.31–
3
5.47 (m, 3Jtrans = 15.3, JCHCH2 = 7.1 Hz, 1 H, CHCH2), 5.77–5.90
3
3
(m, Jtrans = 15.3, JCHCH2 = 5.4 Hz, 1 H, CHCH2), 10.20 (s, 1 H,
OH) ppm. 13C NMR (62.9 MHz, CDCl3): δ = 12.8, 18.0 (CH3),
32.1, 45.0 (CH2), 52.2, 60.2 (OCH3), 126.5, 132.5 (CHOlefin), 113.4,
128.1, 133.0, 136.2, 144.6, 152.5 (CAr), 171.7 (COOCH3) ppm. IR
Methyl 5-[(E)-4-Chlorobut-2-enyl]-4,6-dimethylsalicylate (3a): Start-
ing with 1 (see Scheme 2; 0.150 g, 0.97 mmol), 2a (0.385 g,
1.48 mmol) and TiCl4 (0.22 mL, 1.97 mmol), 3a was isolated by
chromatography (heptane/EtOAc, 10:1) as a slightly yellow solid
1
(KBr): ν = 2954 (m), 1654 (s), 1598 (w), 1438 (s), 1414 (m), 1359
˜
(0.205 g, 77%); m.p. 55–57 °C; Rf = 0.62 (heptane/EtOAc, 1:1). H
(m), 1321 (s), 1217 (m), 1071 (m), 968 (m) cm–1. MS (EI, 70 eV):
m/z (%) = 300 (8) [M]+ (37Cl), 298 (24) [M]+ (35Cl), 266 (70), 238
(12), 231 (100). C15H19ClO4 (298.77): calcd. C 60.30, H 6.41; found
C 60.10, H 6.52.
NMR (300 MHz, CDCl3): δ = 2.25 (s, 3 H, CH3), 2.41 (s, 3 H,
CH3), 3.36 (d, 3J = 5.3 Hz, 2 H, CHCH2), 3.94 (s, 3 H, OCH3),
4.00 (d, 3J = 7.0 Hz, 2 H, CHCH2), 5.38 (dt, 3Jtrans = 15.2, 3JCH,CH2
= 7.0 Hz, 1 H, CH2CH), 5.84 (dt, 3Jtrans = 15.2, 3JCH,CH2 = 5.3 Hz,
1 H, CH2CH), 6.70 (s, 1 H, Ar), 10.64 (s, 1 H, OH) ppm. 13C NMR
(62.9 MHz, CDCl3): δ = 18.5, 20.9 (CH3), 31.6, 45.0 (CH2), 52.0
(OCH3), 111.8, 128.1, 138.9, 144.3, 159.9 (CAr), 116.9 (CHAr),
5-[(E)-4-Chlorobut-2-enyl]-4,6-dimethylacetophenone (3e): Starting
with 1 (0.155 g, 1.02 mmol), 2e (0.373 g, 1.53 mmol) and TiCl4
(0.22 mL, 2.04 mmol), 3e was isolated by chromatography (hep-
tane/EtOAc, 10:1) as a slightly yellow solid (0.077 g, 30%); m.p.
47–50 °C; Rf = 0.57 (heptane/EtOAc, 1:1). 1H NMR (250 MHz,
CDCl3): δ = 2.25 (s, 3 H, CH3), 2.40 (s, 3 H, CH3), 2.58 (s, 3 H,
126.4, 132.6 (CHOlefin), 171.9 (COOCH ) ppm. IR (ATR): ν = 2984
˜
3
(w), 1650 (m), 1600 (m), 1574 (m), 1441 (m), 1246 (m), 1211 (m),
1071 (m), 1033 (m), 920 (w) cm–1. MS (EI, 70 eV): m/z (%) = 270
(11) [M]+ (37Cl), 268 (31) [M]+ (35Cl), 238 (35), 236 (100), 201 (29).
C14H17ClO3 (268.74): calcd. C 62.57, H 6.38; found C 62.67, H 6.69.
3
3
CH3), 3.32–3.39 (m, J = 5.4 Hz, 2 H, CHCH2), 3.96–4.03 (m, J
3
3
= 7.0 Hz, 2 H, CHCH2), 5.32–5.47 (m, Jtrans = 15.2, JCHCH2
7.0 Hz, 1 H, CHCH2), 5.78–5.91 (m, Jtrans = 15.2, JCHCH2
=
=
3
3
Ethyl 5-[(E)-4-Chlorobut-2-enyl]-2,4-dimethylsalicylate (3b): Start-
ing with 1 (0.180 g, 1.18 mmol), 2b (0.487 g, 1.77 mmol) and TiCl4 5.4 Hz, 1 H, CHCH2), 6.68 (s, 1 H, Ar), 10.90 (s, 1 H, OH) ppm.
(0.26 mL, 2.37 mmol), 3b was isolated by chromatography (hep-
tane/EtOAc, 10:1) as a yellow oil (0.174 g, 52%). Rf = 0.58 (hep-
tane/EtOAc, 1:1). H NMR (250 MHz, CDCl3): δ = 1.41 (t, J =
13C NMR (62.9 MHz, CDCl3): δ = 19.5, 20.7, 32.8 (CH3), 31.5,
44.9 (CH2), 117.3 (CHAr), 126.5, 132.3 (CHOlefin), 122.6, 128.1,
136.9, 144.4, 158.4 (CAr), 206.3 (CO) ppm. IR (KBr): ν = 2966 (w),
˜
1
3
Eur. J. Org. Chem. 2010, 3743–3753
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3747

M. Lau, M. Sher, A. Villinger, C. Fischer, P. Langer
FULL PAPER
1625 (s), 1559 (m), 1450 (m), 1442 (s), 1205 (s), 1058 (m), 1025 (m), (35Cl), 221 (22), 141 (24), 43 (100). HRMS (EI): calcd. for
979 (m), 839 (w) cm–1. MS (EI, 70 eV): m/z (%) = 254 (6) [M]+
(37Cl), 252 (17) [M]+ (35Cl), 237 (23), 217 (100), 175 (16). HRMS
(EI): calcd. for C14H17ClO2 [M]+ (35Cl) 252.09116; found
252.091036.
C13H13ClO2 [M]+ (35Cl) 236.06002; found 236.05986.
1-[5-(2,6-Dichlorophenyl)-2-methyl-4,5-dihydrofuran-3-yl]ethanone
(7h): Starting with 5a (0.62 mL, 5.99 mmol), 6h (3.60 mL,
26.37 mmol) and CAN (6.571 g, 11.99 mmol) in acetonitrile
(100 mL), 7h was isolated by chromatography (heptane/EtOAc,
20:1) as a colourless solid (0.450 g, 28%); m.p. 61–62 °C; Rf = 0.45
General Procedure for the Synthesis of Dihydrofurans 7a–i: Ceric
ammonium nitrate (CAN; 2.0 equiv.) was dissolved in acetonitrile.
1
(heptane/EtOAc, 1:1). H NMR (300 MHz, CDCl3): δ = 2.28 (s, 3
An acetonitrile solution (10 mL) of 5a,b (1.0 equiv.) and
6
H, CH3), 2.31–2-34 (m, 3 H, CH3), 3.13–3.40 (m, 2 H, Ha, Hb),
6.28–6.41 (m, 1 H, Hx), 7.21–7.32 (m, 1 H, Ar), 7.35–7.42 (m, 2 H,
Ar) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 14.7, 29.5 (CH3), 36.0
(CH2), 79.4 (CHCH2), 112.6, 134.1, 135.4, 167.4 (CAr,Olefin), 129.3,
(4.4 equiv.) was added to the mixture and the solution was stirred
at 20 °C until the reaction was complete (TLC control). Water
(250 mL) was added to the mixture and the mixture was extracted
with diethyl ether (3ϫ100 mL). The combined organic layers were
washed with water (300 mL), dried (Na2SO4) and filtered. The sol-
vent of the filtrate was removed in vacuo. The residue was purified
by chromatography (silica gel, heptanes/EtOAc). Compounds 7a–c
and 7f have been previously reported.[9]
129.9 (CHAr), 194.4 (CO) ppm. IR (ATR): ν = 2873 (w), 1668 (m),
˜
1586 (s), 1435 (m), 1358 (m), 1330 (m), 1223 (s), 1135 (m), 1068
(m), 932 (s) cm–1. MS (EI, 70 eV): m/z (%) = 272 (53) [M]+ (35Cl,
37Cl), 270 (87) [M]+ (35Cl, 35Cl), 255 (25), 111 (50). HRMS (EI):
calcd. for C13H12Cl2O2 [M]+ (35Cl, 35Cl) 270.02074; found
270.02089.
1-[5-(4-Bromophenyl)-2-methyl-4,5-dihydrofuran-3-yl]ethanone (7d):
Starting with 5a (0.51 mL, 4.99 mmol), 6d (2.87 mL, 21.97 mmol)
and CAN (5.476 g, 9.99 mmol) in acetonitrile (100 mL), 7d was
isolated by chromatography (heptane/EtOAc, 15:1) to give 7d as a
yellow oil (0.763 g, 54%). Rf = 0.17 (heptane/EtOAc, 1:1). 1H
NMR (300 MHz, CDCl3): δ = 2.20 (s, 3 H, CH3), 2.26–2-32 (m, 3
H, CH3), 2.83–2.97 (m, 1 H, Ha), 3.31–3.45 (m, 1 H, Hb), 5.47–
1-(2-Ethyl-5-phenyl-4,5-dihydrofuran-3-yl)propan-1-one (7i): Start-
ing with 5b (0.63 mL, 4.68 mmol), 6a (2.37 mL, 20.60 mmol) and
CAN (5.133 g, 9.36 mmol) in acetonitrile (100 mL), 7i was isolated
by chromatography (heptane/EtOAc, 20:1) as a yellow oil (0.327 g,
30%). Rf = 0.62 (heptane/EtOAc, 1:1). 1H NMR (250 MHz,
CDCl3): δ = 1.08 (t, 3J = 7.3 Hz, 3 H, CH2CH3), 1.20 (t, 3J =
3
5.60 (m, 1 H, Hx), 7.14–7.23 (m, J = 8.4 Hz, 2 H, Ar), 7.44–7.55
3
7.5 Hz, 3 H, CH2CH3), 2.36–2.50 (m, J = 7.3 Hz, 2 H, CH2CH3),
3
(m, J = 8.4 Hz, 2 H, Ar) ppm. 13C NMR (75.5 MHz, CDCl3): δ
2.68–2.84 (m, 3J = 7.3 Hz, 2 H, CH2CH3), 2.88–3.02 (m, 1 H, Ha),
3.32–3.47 (m, 1 H, Hb), 5.53–5.64 (m, 1 H, Hx), 7.24–7.44 (m, 5 H,
Ph) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 7.9, 11.1 (CH3), 22.0,
34.7, 38.8 (CH2), 82.9 (CHCH2), 109.6, 141.7, 172.0 (CPh,Olefin),
= 14.9, 29.4 (CH3), 38.7 (CH2), 82.4 (CHCH2), 111.9, 122.1, 140.3,
167.3 (CAr,Olefin), 127.3, 131.9 (CHAr), 194.3 (CO) ppm. IR (ATR):
ν = 2921 (w), 2866 (w), 1591 (s), 1487 (m), 1381 (m), 1360 (m),
˜
1216 (s), 1068 (m), 1010 (m), 930 (m) cm–1. MS (EI, 70 eV): m/z
(%) = 282 (81) [M]+ (81Br), 280 (82) [M]+ (79Br), 263 (17), 186 (52),
115 (36). HRMS (EI): calcd. for C13H13BrO2 [M]+ (79Br)
280.00896; found 280.00934.
125.5, 128.1, 128.7 (CHPh), 197.4 (CO) ppm. IR (ATR): ν = 2978
˜
(w), 2940 (w), 1703 (br), 1589 (m), 1596 (m), 1450 (m), 1377 (m),
1207 (m), 903 (m), 757 (m) cm–1. MS (EI, 70 eV): m/z (%) = 230
(52) [M]+, 201 (24), 131 (35), 105 (57), 57 (100). HRMS (EI): calcd.
for C15H18O2 [M]+ 230.13026; found 230.13013.
1-[5-(4-Fluorophenyl)-2-methyl-4,5-dihydrofuran-3-yl]ethanone (7e):
Starting with 5a (0.62 mL, 5.99 mmol), 6e (3.15 mL, 26.37 mmol)
and CAN (6.571 g, 11.99 mmol) in acetonitrile (100 mL), 7e was
isolated by chromatography (heptane/EtOAc, 15:1) as a yellow oil
Methyl
5-(2-Chloro-2-phenylethyl)-4,6-dimethylsalicylate
(8a):
Starting with 7a (0.198 g, 0.98 mmol), 2a (0.383 g, 1.47 mmol) and
TiCl4 (0.21 mL, 1.96 mmol), 8a was isolated by chromatography
(heptane/EtOAc, 20:1) as a colourless solid (0.143 g, 46%); m.p.
79–80 °C; Rf = 0.62 (heptane/EtOAc, 1:1). 1H NMR (250 MHz,
(0.563 g, 43%). Rf
=
0.44 (heptane/EtOAc, 1:1). 1H NMR
(250 MHz, CDCl3): δ = 2.21 (s, 3 H, CH3), 2.26–2.31 (m, 3 H,
CH3), 2.85–3.00 (m, 1 H, Ha), 3.29–3.45 (m, 1 H, Hb), 5.48–5.64
(m, 1 H, Hx), 6.94–7.15 (m, 2 H, Ar), 7.22–7.39 (m, 2 H, Ar) ppm.
13C NMR (75.5 MHz, CDCl3): δ = 15.0, 29.4 (CH3), 38.8 (CH2),
82.5 (CHCH2), 112.0, 167.3 (COlefin), 115.6 (d, 2J = 21.8 Hz, CHAr),
2
CDCl3): δ = 2.12, 2.41 (s, 3 H, CH3), 3.26 (dd, JHa,Hb = 14.8,
2
3
3JHa,Hx = 7.3 Hz, 1 H, Ha), 3.49 (dd, JHa,Hb = 14.8, JHb,Hx
=
3
7.3 Hz, 1 H, Hb), 3.94 (s, 3 H, OCH3), 4.95 (t, JHx,Hab = 7.3 Hz,
1 H, CHCl), 6.64 (s, 1 H, Ar), 7.30 (s, 5 H, Ph), 10.70 (s, 1 H,
OH) ppm. 13C NMR (62.9 MHz, CDCl3): δ = 19.0, 21.4 (CH3),
40.3 (CH2CHCl), 52.1 (OCH3), 63.2 (CHCl), 111.9, 127.2, 139.4,
141.1, 144.9, 160.2 (CPh,Ar), 117.2, 126.9, 128.3, 128.4 (CHPh,Ar),
4
127.5 (d, 3J = 8.3 Hz, CHAr), 137.0 (d, J = 3.2 Hz, CAr), 162.5 (d,
1J = 246.9 Hz, CAr), 194.4 (CO) ppm. IR (ATR): ν = 1712 (br),
˜
1599 (m), 1510 (s), 1372 (m), 1222 (s), 1157 (m), 1099 (m), 1126
(m), 1014 (m), 835 (s) cm–1. MS (EI, 70 eV): m/z (%) = 220 (68)
[M]+, 201 (18), 159 (27), 133 (26). HRMS (EI): calcd. for
C13H13FO2 [M]+ 220.08987; found 220.08941.
171.9 (COOCH ) ppm. IR (ATR): ν = 2991 (w), 1661 (s), 1569 (m),
˜
3
1442 (m), 1202 (m), 1154 (m), 1072 (m), 1055 (w), 915 (m), 820
(m) cm–1. MS (EI, 70 eV): m/z (%) = 320 (3) [M]+ (37Cl), 318 (9)
[M]+ (35Cl), 193 (93), 178 (11), 161 (100). HRMS (EI): calcd. for
C18H19ClO3 [M]+ (35Cl) 318.10153; found 318.10172. C18H19ClO3
(318.79): calcd. C 67.82, H 6.01; found C 67.47, H 5.91.
1-[5-(2-Chlorophenyl)-2-methyl-4,5-dihydrofuran-3-yl]ethanone (7g):
Starting with 5a (0.62 mL, 5.99 mmol), 6g (3.35 mL, 26.37 mmol)
and CAN (6.571 g, 11.99 mmol) in acetonitrile (100 mL), 7g was
isolated by chromatography (heptane/EtOAc, 20:1) as a yellow oil
Ethyl 5-(2-Chloro-2-phenylethyl)-4,6-dimethylsalicylate (8b): Start-
ing with 7a (0.167 g, 0.83 mmol), 2b (0.340 g, 1.5 mmol) and TiCl4
(0.18 mL, 1.65 mmol), 8b was isolated by chromatography (hep-
tane/EtOAc, 50:1) as a colourless solid (0.120 g, 44%); m.p. 66–
(0.918 g, 65%). Rf
=
0.35 (heptane/EtOAc, 1:1). 1H NMR
(300 MHz, CDCl3): δ = 2.18 (s, 3 H, CH3), 2.33–2.37 (m, 3 H,
CH3), 2.72–2.84 (m, 1 H, Ha), 3.48–3.61 (m, 1 H, Hb), 5.82–5.95
(m, 1 H, Hx), 7.22–7.41 (m, 4 H, Ar) ppm. 13C NMR (75.5 MHz, 68 °C; Rf = 0.67 (heptane/EtOAc, 1:1). 1H NMR (250 MHz,
3
CDCl3): δ = 14.8, 29.5 (CH3), 38.3 (CH2), 80.0 (CHCH2), 111.6, CDCl3): δ = 1.42 (t, J = 7.1 Hz, 3 H, CH2CH3), 2.12, 2.42 (s, 3
131.2, 139.3, 167.2 (CAr,Olefin), 125.9, 127.1, 129.0, 129.6 (CHAr),
2
H, CH3), 3.26 (dd, JHa,Hb = 14.8, 3JHa,Hx = 7.3 Hz, 1 H, Ha), 3.50
2
3
194.5 (CO) ppm. IR (ATR): ν = 2922 (w), 2867 (w), 1602 (s), 1476
(dd, JHa,Hb = 14.8, JHb,Hx = 7.3 Hz, 1 H, Hb), 4.41 (q, 3J =
˜
(m), 1383 (m), 1360 (m), 1219 (s), 1130 (s), 922 (m), 752 (s) cm–1. 7.1 Hz, 2 H, CH2CH3), 4.96 (t, JHx,Hab = 7.3 Hz, 1 H, CHCl),
3
MS (EI, 70 eV): m/z (%) = 238 (44) [M]+ (37Cl), 236 (91) [M]+
6.64 (s, 1 H, Ar), 7.30 (s, 5 H, Ph), 10.78 (s, 1 H, OH) ppm. 13C
3748
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 3743–3753

Synthesis of Chlorobutenyl- and Chloroethylsalicylates
NMR (62.9 MHz, CDCl3): δ = 14.2 (OCH2CH3), 19.1, 21.4 (CH3), (3) [M]+ (35Cl), 250 (34), 221 (77), 161 (100). HRMS (EI): calcd. for
40.3 (CH2CHCl), 61.6 (OCH2CH3), 63.2 (CHCl), 112.0, 127.1,
139.4, 141.2, 144.8, 160.2 (CPh,Ar), 117.2, 126.9, 128.3, 128.4 (346.13): calcd. C 69.26, H 6.68; found C 68.84, H 6.77.
C20H23ClO3 [M]+ (35Cl) 346.13344; found 346.13302. C20H23ClO3
(CHPh,Ar), 171.5 (COOCH CH ) ppm. IR (ATR): ν = 2977 (w),
˜
2
3
Methyl 5-(2-Chloro-2-phenylethyl)-4,6-dimethyl-3-propylsalicylate
(8f): Starting with 7a (0.167 g, 0.83 mmol), 2h (0.375 g, 1.24 mmol)
and TiCl4 (0.18 mL, 1.65 mmol), 8f was isolated by chromatog-
raphy (heptane/EtOAc, 50:1) as a colourless solid (0.154 g, 52%);
1650 (w), 1468 (m), 1373 (m), 1313 (m), 1246 (s), 1232 (s), 1161
(m), 1072 (m), 920 (w) cm–1. MS (EI, 70 eV): m/z (%) = 334 (0.8)
[M]+ (37Cl), 268 (2) [M]+ (35Cl), 250 (7), 207 (65), 161 (100).
C19H21ClO3 (332.82): calcd. C 68.57, H 6.36; found C 68.67, H
6.36.
m.p. 67–68 °C; Rf
=
0.71 (heptane/EtOAc, 1:1). 1H NMR
3
(250 MHz, CDCl3): δ = 0.95 (t, J = 7.3 Hz, 3 H, CH3CH2), 1.36–
1.53 (m, 2 H, CH2), 2.09, 2.35 (s, 3 H, CH3), 2.56–2.68 (m, 2 H,
Methyl 5-(2-Chloro-2-phenylethyl)-3,4,6-trimethylsalicylate (8c):
Starting with 7a (0.160 g, 0.79 mmol), 2c (0.366 g, 1.35 mmol) and
TiCl4 (0.17 mL, 1.58 mmol), 8c was isolated by chromatography
(heptane/EtOAc, 50:1) as a slightly yellow solid (0.098 g, 36%);
2
3
CH2), 3.32 (dd, JHa,Hb = 14.9, JHa,Hx = 7.5 Hz, 1 H, Ha), 3.56
2
3
3
(dd, JHa,Hb = 14.9, JHb,Hx = 7.0 Hz, 1 H, Hb), 4.93 (“t”, JHx,Ha
3
= 7.5, JHx,Hb = 7.0 Hz, 1 H, CHCl), 7.28 (s, 5 H, Ar), 10.85 (s, 1
H, OH) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 14.3, 16.8, 19.1
(CH3), 22.2, 28.7, 40.6 (CH2), 52.1 (OCH3), 63.5 (CHCl), 111.5,
126.9, 127.5, 136.0, 141.1, 142.6, 158.1 (CAr), 127.0, 128.2, 128.4
m.p. 78–79 °C; Rf
=
0.62 (heptane/EtOAc, 1:1). 1H NMR
(250 MHz, CDCl3): δ = 2.12, 2.15, 2.34 (s, 3 H, CH3), 3.32 (dd,
2JHa,Hb = 15.0, 3JHa,Hx = 7.2 Hz, 1 H, Ha), 3.56 (dd, 2JHa,Hb = 15.0,
3
3JHb,Hx = 7.3 Hz, 1 H, Hb), 3.92 (s, 3 H, OCH3), 4.94 (“t”, JHx,Ha
3
(CHAr), 172.6 (COOCH ) ppm. IR (ATR): ν = 2949 (m), 2866 (m),
˜
3
1651 (s), 1586 (m), 1437 (s), 1402 (m), 1321 (s), 1169 (s), 1110 (s),
1039 (m) cm–1. MS (EI, 70 eV): m/z (%) = 362 (1) [M]+ (37Cl), 360
(2) [M]+ (35Cl), 264 (36), 235 (87), 203 (100). HRMS (EI): calcd.
for C21H25ClO3 [M]+ (35Cl) 360.14919; found 360.14867.
= 7.2, JHx,Hb = 7.3 Hz, 1 H, CHCl), 7.29 (s, 5 H, Ar), 10.90 (s, 1
H, OH) ppm. 13C NMR (62.9 MHz, CDCl3): δ = 12.3, 17.4, 19.1
(CH3), 40.5 (CH2CHCl), 52.1 (OCH3), 63.6 (CHCl), 111.4, 122.8,
126.7, 135.9, 141.2, 143.0, 158.0 (CAr), 127.0, 128.2, 128.4 (CHAr),
172.6 (COOCH ) ppm. IR (ATR): ν = 3033 (w), 2958 (w), 1646
˜
3
Methyl 5-[2-Chloro-2-(p-tolyl)ethyl]-4,6-dimethylsalicylate (8g):
Starting with 7b (0.121 g, 0.56 mmol), 2a (0.248 g, 0.95 mmol) and
TiCl4 (0.12 mL, 1.12 mmol), 8g was isolated by chromatography
(heptane/EtOAc, 50:1) as a yellow oil (0.065 g, 35%). Rf = 0.43
(heptane/EtOAc, 1:1). 1H NMR (250 MHz, CDCl3): δ = 2.14, 2.34,
2.43 (s, 3 H, CH3), 3.25 (dd, 2JHa,Hb = 14.8, 3JHa,Hx = 7.0 Hz, 1 H,
Ha), 3.49 (dd, JHa,Hb = 14.8, JHb,Hx = 7.5 Hz, 1 H, Hb), 3.94 (s,
3 H, OCH3), 4.94 (“t”, 3JHx,Ha = 7.0, 3JHx,Hb = 7.5 Hz, 1 H, CHCl),
6.65 (s, 1 H, Ar), 7.07–7.24 (m, 4 H, Ar), 10.68 (s, 1 H, OH) ppm.
13C NMR (62.9 MHz, CDCl3): δ = 19.1, 21.1, 21.5 (CH3), 40.2
(CH2CHCl), 52.1 (OCH3), 63.3 (CHCl), 111.9, 127.3, 138.1, 138.3,
139.4, 144.9, 160.1 (CAr), 117.2, 126.8, 129.1 (CHAr), 171.9 (CO-
(s), 1435 (m), 1350 (m), 1264 (s), 1205 (s), 1174 (s), 1009 (m), 951
(m) cm–1. MS (EI, 70 eV): m/z (%) = 334 (1) [M]+ (37Cl), 332 (3)
[M]+ (35Cl), 264 (4), 207 (58), 175 (100). HRMS (EI): calcd. for
C19H21ClO [M]+ (35Cl) 332.11817; found 332.11737. C19H21ClO3
(332.12): calcd. C 68.57, H 6.36; found C 68.33, H 6.41.
2
3
Methyl
5-(2-Chloro-2-phenylethyl)-3-ethyl-4,6-dimethylsalicylate
(8d): Starting with 7a (0.167 g, 0.83 mmol), 2f (0.405 g, 1.40 mmol)
and TiCl4 (0.18 mL, 1.65 mmol), 8d was isolated by chromatog-
raphy (heptane/EtOAc, 50:1) as a colourless solid (0.147 g, 51%);
m.p. 72–73 °C; Rf
=
0.70 (heptane/EtOAc, 1:1). 1H NMR
3
(250 MHz, CDCl3): δ = 1.05 (t, J = 7.5 Hz, 3 H, CH3CH2), 2.10,
OCH ) ppm. IR (ATR): ν = 2952 (w), 2860 (w), 1658 (s), 1572 (m),
˜
2.35 (s, 3 H, CH3), 2.60–2.76 (m, 3J = 7.5 Hz, 2 H, CH3CH2), 3.32
3
1437 (m), 1347 (m), 1312 (m), 1235 (s), 1207 (s), 1072 (m) cm–1.
MS (EI, 70 eV): m/z (%) = 334 (1) [M]+ (37Cl), 332 (3) [M]+ (35Cl),
264 (18), 193 (78), 161 (100). HRMS (EI): calcd. for C19H21ClO3
[M]+ (35Cl) 332.11765; found 332.11737.
2
3
2
(dd, JHa,Hb = 14.9, JHa,Hx = 7.4 Hz, 1 H, Ha), 3.56 (dd, JHa,Hb
3
= 14.9, JHb,Hx = 7.1 Hz, 1 H, Hb), 3.93 (s, 3 H, OCH3), 4.94 (“t”,
3
3JHx,Ha = 7.4, JHx,Hb = 7.1 Hz, 1 H, CHCl), 7.28 (s, 5 H, Ph),
10.85 (s, 1 H, OH) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 13.2
16.5, 19.0 (CH3), 19.9 (CH3CH2) 40.6 (CH2CHCl), 52.1 (OCH3),
63.5 (CHCl), 111.6, 128.9, 136.0, 141.2, 142.3, 157.9 (CPh,Ar), 127.0,
Methyl 5-[2-Chloro-2-(4-chlorophenyl)ethyl]-4,6-dimethylsalicylate
(8h): Starting with 7c (0.170 g, 0.72 mmol), 2a (0.318 g, 1.22 mmol)
and TiCl4 (0.16 mL, 1.44 mmol), 8h was isolated by chromatog-
raphy (heptane/EtOAc, 50:1) as a colourless solid (0.146 g, 38%);
128.2, 128.4 (CHPh,Ar), 172.5 (COOCH ) ppm. IR (ATR): ν = 2962
˜
3
(w), 2871 (w), 1648 (s), 1436 (m), 1357 (m), 1205 (s), 1171 (m),
1032 (m), 952 (m), 807 (m) cm–1. MS (EI, 70 eV): m/z (%) = 348
(5) [M]+ (37Cl), 346 (14) [M]+ (35Cl), 315 (9), 221 (99), 189 (100).
HRMS (EI): calcd. for C20H23ClO3 [M]+ (35Cl) 346.13267; found
346.13302.
m.p. 91–93 °C; Rf
=
0.65 (heptane/EtOAc, 1:1). 1H NMR
2
(250 MHz, CDCl3): δ = 2.11, 2.37 (s, 3 H, CH3), 3.23 (dd, JHa,Hb
= 14.8, 3JHa,Hx = 7.7 Hz, 1 H, Ha), 3.46 (dd, 2JHa,Hb = 14.8, 3JHb,Hx
3
= 7.0 Hz, 1 H, Hb), 3.94 (s, 3 H, OCH3), 4.91 (“t”, JHx,Ha = 7.7,
3JHx,Hb = 7.0 Hz, 1 H, CHCl), 6.65 (s, 1 H, Ar), 7.18–7.30 (m, 4
H, Ar), 10.68 (s, 1 H, OH) ppm. 13C NMR (75.5 MHz, CDCl3): δ
= 19.0, 21.4 (CH3), 40.3 (CH2CHCl), 52.1 (OCH3), 62.2 (CHCl),
111.9, 126.8, 134.0, 139.3, 139.6, 144.8, 160.2 (CAr), 117.3, 128.4,
Isopropyl 5-(2-Chloro-2-phenylethyl)-4,6-dimethylsalicylate (8e):
Starting with 7a (0.200 g, 0.99 mmol), 2g (0.428 g, 1.48 mmol) and
TiCl4 (0.22 mL, 1.98 mmol), 8e was isolated by chromatography
(heptane/EtOAc, 50:1) as a yellow solid (0.192 g, 56%); m.p. 73–
74 °C; Rf = 0.63 (heptane/EtOAc, 1:1). 1H NMR (300 MHz,
CDCl3): δ = 1.36–1.43 (m, 3J = 6.3 Hz, 3 H, CH3CHCH3), 2.12,
2.40 (s, 3 H, CH3), 3.26 (dd, 2JHa,Hb = 14.8, 3JHa,Hx = 7.3 Hz, 1 H,
Ha), 3.49 (dd, 2JHa,Hb = 14.8, 3JHb,Hx = 7.2 Hz, 1 H, Hb), 4.96 (“t”,
128.6 (CHAr), 171.8 (COOCH ) ppm. IR (ATR): ν = 3026 (w),
˜
3
2980 (w), 1661 (s), 1568 (m), 1432 (br), 1312 (s), 1202 (br), 1150
(m), 1072 (m), 825 (m) cm–1. MS (EI, 70 eV): m/z (%) = 354 (2)
[M]+ (37Cl, 35Cl), 252 (3) [M]+ (35Cl, 35Cl), 284 (6), 193 (92), 161
(100). HRMS (EI): calcd. for C18H18Cl2O3 [M]+ (35Cl, 35Cl)
352.06352; found 352.06275. C18H18Cl2O3 (353.24): calcd. C 61.20,
H 5.14; found C 61.29, H 5.30.
3
3JHx,Ha = 7.3, JHx,Hb = 7.2 Hz, 1 H, CHCl), 5.31 (sept., 3J =
6.3 Hz, 1 H, CH3CHCH3), 6.64 (s, 1 H, Ar), 7.30 (br. s, 5 H, Ph),
10.78 (s, 1 H, OH) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 19.1,
21.4, 21.9 (CH3), 40.4 (CH2CHCl), 63.3, 69.7 (CH), 112.4, 127.1,
Ethyl
5-[2-Chloro-2-(4-chlorophenyl)ethyl]-4,6-dimethylsalicylate
139.4, 141.2, 144.6, 160.1 (CPh,Ar), 117.2, 126.9, 128.2, 128.4 (8i): Starting with 7c (0.179 g, 0.76 mmol), 2b (0.353 g, 1.29 mmol)
(CHPh,Ar), 171.0 (COO) ppm. IR (ATR): ν = 2980 (w), 2935 (w), and TiCl4 (0.17 mL, 1.51 mmol), 8i was isolated by chromatog-
˜
1650 (s), 1595 (m), 1455 (m), 1367 (s), 1303 (m), 1243 (s), 1102 (s), raphy (heptane/EtOAc, 50:1) as a slightly yellow solid (0.205 g,
912 (m) cm–1. MS (EI, 70 eV): m/z (%) = 348 (1) [M]+ (37Cl), 346 74%); m.p. 93–94 °C; Rf = 0.76 (heptane/EtOAc, 1:1). 1H NMR
Eur. J. Org. Chem. 2010, 3743–3753
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3749

M. Lau, M. Sher, A. Villinger, C. Fischer, P. Langer
FULL PAPER
3
(250 MHz, CDCl3): δ = 1.41 (t, J = 7.1 Hz, 3 H, CH3CH2), 2.12,
H, Ar), 7.38–7.46 (m, 2 H, Ar), 10.68 (s, 1 H, OH) ppm. 13C NMR
(62.9 MHz, CDCl3): δ = 19.1, 21.4 (CH3), 40.2 (CH2CHCl), 52.2
(OCH3), 62.2 (CHCl), 112.0, 122.2, 126.7, 139.4, 140.1, 144.8,
160.3 (CAr), 117.3, 128.7, 131.6 (CHAr), 171.8 (COOCH3) ppm. IR
2.37 (s, 3 H, CH3), 3.23 (dd, 2JHa,Hb = 14.8, 3JHa,Hx = 7.7 Hz, 1 H,
2
3
Ha), 3.46 (dd, JHa,Hb = 14.8, JHb,Hx = 6.9 Hz, 1 H, Hb), 4.41 (q,
3J = 7.1 Hz, 2 H, CH3CH2), 4.91 (“t”, JHx,Ha = 7.7, JHx,Hb
=
3
3
6.9 Hz, 1 H, CHCl), 6.45 (s, 1 H, Ar), 7.17–7.30 (m, 4 H, Ar), 10.75 (ATR): ν = 2977 (w), 2951 (w), 1666 (s), 1568 (m), 1464 (m), 1315
˜
(s, 1 H, OH) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 14.2 19.1,
(s), 1192 (s), 1152 (s), 1071 (s), 911 (m) cm–1. MS (EI, 70 eV): m/z
21.4 (CH3), 40.3 (CH2CHCl), 61.6 (OCH2CH3), 62.2 (CHCl), (%) = 398 (1) [M]+ (37Cl/79Br, 35Cl/81Br), 193 (90), 178 (6), 161
112.1, 126.7, 134.0, 139.4, 139.6, 144.6, 160.3 (CAr), 117.3, 128.4, (100). HRMS (EI): calcd. for C18H18BrClO3 [M]+ (35Cl, 79Br)
128.6 (CHAr), 171.4 (COOCH CH ) ppm. IR (ATR): ν = 2989 (w), 396.01201; found 396.01224. C18H18BrClO3 (396.01): calcd. C
˜
2
3
2935 (w), 1656 (s), 1570 (m), 1470 (m), 1309 (s), 1197 (s), 1014 (s),
914 (m), 831 (m) cm–1. MS (EI, 70 eV): m/z (%) = 368 (3) [M]+
(37Cl, 35Cl), 366 (4) [M]+ (35Cl, 35Cl), 321 (9), 207 (100), 161 (99).
HRMS (ESI): calcd. for C19H20Cl2NaO3 [M + Na]+ (35Cl, 35Cl)
389.06817; found 389.06729. C19H20Cl2O3 (367.27): calcd. C 62.14,
H 5.49; found C 62.07, H 5.47.
54.36, H 4.56; found C 54.28, H 4.63.
Methyl 5-[2-(4-Bromophenyl)-2-chlorethyl]-3,4,6-trimethylsalicylate
(8m): Starting with 7d (0.147 g, 0.52 mmol), 2c (0.242 g,
0.89 mmol) and TiCl4 (0.11 mL, 1.05 mmol), 8m was isolated by
chromatography (heptane/EtOAc, 50:1) as
(0.133 g, 62%); m.p. 105–107 °C; Rf = 0.63 (heptane/EtOAc, 1:1).
a colourless solid
Methyl 5-[2-Chloro-2-(4-chlorophenyl)ethyl]-3,4,6-trimethylsalicyl- 1H NMR (250 MHz, CDCl3): δ = 2.12, 2.15, 2.29 (s, 3 H, CH3),
ate (8j): Starting with 7c (0.151 g, 0.64 mmol), 2c (0.296 g,
1.09 mmol) and TiCl4 (0.14 mL, 1.28 mmol), 8j was isolated by
2
3
3.29 (dd, JHa,Hb = 14.9, JHa,Hx = 7.6 Hz, 1 H, Ha), 3.52 (dd,
2JHa,Hb = 14.9, JHb,Hx = 7.0 Hz, 1 H, Hb), 3.93 (s, 3 H, OCH3),
3
3
3
chromatography (heptane/EtOAc, 40:1) as
a
colourless solid
4.87 (“t”, JHx,Ha = 7.6, JHx,Hb = 7.0 Hz, 1 H, CHCl), 7.11–7.19
(m, 2 H, Ar), 7.37–7.46 (m, 2 H, Ar), 10.90 (s, 1 H, OH) ppm.
(0.109 g, 47%); m.p. 100–101 °C; Rf = 0.73 (heptane/EtOAc, 1:1).
1H NMR (250 MHz, CDCl3): δ = 2.12, 2.15, 2.30 (s, 3 H, CH3), 13C NMR (62.9 MHz, CDCl3): δ = 12.3, 17.4, 19.1 (CH3), 40.4
2
3
3.29 (dd, JHa,Hb = 15.0, JHa,Hx = 7.6 Hz, 1 H, Ha), 3.53 (dd,
(CH2CHCl), 52.1 (OCH3), 62.6 (CHCl), 111.5, 122.1, 123.0, 126.2,
2JHa,Hb = 15.0, JHb,Hx = 7.0 Hz, 1 H, Hb), 3.93 (s, 3 H, OCH3), 135.9, 140.1, 142.8, 158.1 (CAr), 128.7, 131.5 (CHAr), 172.5 (CO-
3
3
3
4.89 (“t”, JHx,Ha = 7.6, JHx,Hb = 7.0 Hz, 1 H, CHCl), 7.16–7.32
OCH ) ppm. IR (ATR): ν = 2996 (w), 2948 (w), 1662 (s), 1588 (m),
˜
3
(m, 4 H, Ar), 10.90 (s, 1 H, OH) ppm. 13C NMR (62.9 MHz,
1436 (m), 1313 (s), 1256 (s), 1166 (s), 1008 (s), 918 (m) cm–1. MS
CDCl3): δ = 12.3, 17.4, 19.1 (CH3), 40.5 (CH2CHCl), 52.1 (OCH3), (EI, 70 eV): m/z (%) = 412 (5) [M]+ (37Cl/79Br, 35Cl/81Br), 344 (4),
62.6 (CHCl), 111.4, 122.9, 126.2, 134.0, 135.9, 139.6, 142.8, 158.1 207 (100), 175 (95). C19H20BrClO3 (411.72): calcd. C 55.43, H 4.90;
(CAr), 128.4, 128.5 (CHAr), 172.5 (COOCH ) ppm. IR (ATR): ν = found C 55.58, H 4.90.
˜
3
2992 (w), 2945 (w), 1660 (s), 1588 (m), 1437 (m), 1314 (s), 1166 (s),
Methyl 5-[2-(4-Bromophenyl)-2-chloroethyl]-3-ethyl-4,6-dimethyl-
salicylate (8n): Starting with 7d (0.152 g, 0.54 mmol), 2f (0.265 g,
0.92 mmol) and TiCl4 (0.12 mL, 1.08 mmol), 8n was isolated by
1089 (s), 1114 (m), 919 (m) cm–1. MS (EI, 70 eV): m/z (%) = 368
(6) [M]+ (35Cl, 37Cl), 366 (9) [M]+ (35Cl, 35Cl), 207 (100), 175 (98).
HRMS (EI): calcd. for C19H20Cl2O3 [M]+ (35Cl, 35Cl) 366.07804;
found 366.07840. C19H20Cl2O3 (366.08): calcd. C 62.14, H 5.49;
found C 62.01, H 5.38.
chromatography (heptane/EtOAc, 50:1) as
a colourless solid
(0.104 g, 45%); m.p. 102–103 °C; Rf = 0.53 (heptane/EtOAc, 1:1).
1H NMR (300 MHz, CDCl3): δ = 1.05 (t, 3J = 7.5 Hz, 3 H,
Methyl 5-[2-Chloro-2-(4-chlorophenyl)ethyl]-3-ethyl-4,6-dimethyl- CH3CH2), 2.11, 2.31 (s, 3 H, CH3), 2.60–2.75 (m, 3J = 7.5 Hz, 2
salicylate (8k): Starting with 7c (0.146 g, 0.62 mmol), 2f (0.303 g,
1.05 mmol) and TiCl4 (0.14 mL, 1.23 mmol), 8k was isolated by
3
H, CH3CH2), 3.28 (dd, 2JHa,Hb = 14.9, JHa,Hx = 7.8 Hz, 1 H, Ha),
2
3
3.52 (dd, JHa,Hb = 14.9, JHb,Hx = 6.8 Hz, 1 H, Hb), 3.93 (s, 3 H,
3
3
chromatography (heptane/EtOAc, 50:1) as
a
colourless solid
OCH3), 4.87 (“t”, JHx,Ha = 7.8, JHx,Hb = 6.8 Hz, 1 H, CHCl),
7.09–7.17 (m, 2 H, Ar), 7.37–7.45 (m, 2 H, Ar), 10.84 (s, 1 H,
1
(0.131 g, 56%); m.p. 98–99 °C; Rf = 0.71 (heptane/EtOAc, 1:1). H
NMR (250 MHz, CDCl3): δ = 1.05 (t, 3J = 7.5 Hz, 3 H, CH3CH2), OH) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 13.2, 16.5, 19.1
2.10, 2.31 (s, 3 H, CH3), 2.59–2.76 (m, 3J = 7.5 Hz, 2 H, CH3CH2),
(CH3), 19.9 (CH3CH2), 40.5 (CH2CHCl), 52.1 (OCH3), 62.5
(CHCl), 111.7, 122.1, 126.5, 129.1, 136.0, 140.1, 142.1, 158.0 (CAr),
2
3
3.29 (dd, JHa,Hb = 14.9, JHa,Hx = 7.7 Hz, 1 H, Ha), 3.52 (dd,
2JHa,Hb = 14.9, JHb,Hx = 6.8 Hz, 1 H, Hb), 3.93 (s, 3 H, OCH3), 128.7, 131.5 (CHAr), 172.5 (COOCH ) ppm. IR (ATR): ν = 2949
3
˜
3
3
3
4.89 (“t”, JHx,Ha = 7.7, JHx,Hb = 6.8 Hz, 1 H, CHCl), 7.15–7.30
(w), 2870 (w), 1660 (m), 1588 (m), 1436 (s), 1317 (s), 1202 (s), 1152
(s), 1103 (s), 919 (m) cm–1. MS (EI, 70 eV): m/z (%) = 426 (3)
[M]+ (37Cl/79Br, 35Cl/81Br), 358 (3), 221 (93), 189 (100).
C20H22BrClO3 (424.04): calcd. C 56.42, H 5.21; found C 56.40, H
5.26.
(m, 4 H, Ar), 10.84 (s, 1 H, OH) ppm. 13C NMR (62.9 MHz,
CDCl3):
δ = 13.2, 16.5, 19.1 (CH3), 19.9 (CH3CH2), 40.6
(CH2CHCl), 52.1 (OCH3), 62.4 (CHCl), 111.6, 126.5, 129.1, 134.0,
136.0, 139.6, 142.1, 158.0 (CAr), 128.4, 128.5 (CHAr), 172.5 (CO-
OCH ) ppm. IR (ATR): ν = 2965 (w), 2930 (w), 1651 (s), 1587 (m),
˜
3
Isopropyl 5-[2-(4-Bromophenyl)-2-chloroethyl]-4,6-dimethylsalicylate
(8o): Starting with 7d (0.195 g, 0.69 mmol), 2g (0.340 g, 1.18 mmol)
and TiCl4 (0.15 mL, 1.34 mmol), 8o was isolated by chromatog-
raphy (heptane/EtOAc, 50:1) as a colourless solid (0.192 g, 65%);
m.p. 101–102 °C; Rf = 0.74 (heptane/EtOAc, 1:1). 1H NMR
1441 (s), 1319 (s), 1202 (s), 1168 (s), 1034 (m), 821 (m) cm–1. MS
(EI, 70 eV): m/z (%) = 380 (1) [M]+ (35Cl) 35, 278 (4), 221 (91), 189
(100), 161 (27). HRMS (EI): calcd. for C20H22Cl2O3 [M]+ (35Cl,
35Cl) 380.09330; found 380.09405.
Methyl 5-[2-(4-Bromophenyl)-2-chloroethyl]-4,6-dimethylsalicylate (250 MHz, CDCl3): δ = 1.39 (d, 3J = 6.2 Hz, 6 H, CH3CHCH3),
(8l): Starting with 7d (0.155 g, 0.51 mmol), 2a (0.244 g, 0.94 mmol)
und TiCl4 (0.12 mL, 1.10 mmol), 8l was isolated by chromatog-
2.12, 2.33 (s, 3 H, CH3), 3.22 (dd, 2JHa,Hb = 14.8, 3JHa,Hx = 7.7 Hz,
1 H, Ha), 3.45 (dd, 2JHa,Hb = 14.8, 3JHb,Hx = 6.9 Hz, 1 H, Hb), 4.88
raphy (heptane/EtOAc, 50:1) as a colourless solid (0.116 g, 53%); (“t”, 3JHx,Ha = 7.7, JHx,Hb = 6.9 Hz, 1 H, CHCl), 5.30 (sept., J =
3
3
m.p. 94–95 °C; Rf
=
0.56 (heptane/EtOAc, 1:1). 1H NMR
6.2 Hz, 1 H, CH3CHCH3), 6.65 (s, 1 H, Ar), 7.10–7.19 (m, 2 H,
Ar), 7.37–7.47 (m, 2 H, Ar), 10.78 (s, 1 H, OH) ppm. 13C NMR
(75.5 MHz, CDCl3): δ = 19.1, 21.3, 21.9, 21.9 (CH3), 40.3
(CH2CHCl), 62.2 (CHCl), 69.7 (CH3CHCH3), 112.4, 122.1, 126.6,
2
(250 MHz, CDCl3): δ = 2.11, 2.37 (s, 3 H, CH3), 3.23 (dd, JHa,Hb
= 14.8, 3JHa,Hx = 7.6 Hz, 1 H, Ha), 3.46 (dd, 2JHa,Hb = 14.8, 3JHb,Hx
3
= 7.0 Hz, 1 H, Hb), 3.94 (s, 3 H, OCH3), 4.89 (“t”, JHx,Ha = 7.6,
3JHx,Hb = 7.0 Hz, 1 H, CHCl), 6.65 (s, 1 H, Ar), 7.11–7.19 (m, 2 139.3, 140.1, 144.4, 160.2 (CAr), 117.3, 128.7, 131.5 (CHAr), 170.9
3750
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 3743–3753

Synthesis of Chlorobutenyl- and Chloroethylsalicylates
(COOiPr) ppm. IR (ATR): ν = 2981 (w), 2932 (w), 1650 (s), 1569
Methyl
5-[2-Chloro-2-(4-fluorophenyl)ethyl]-3-ethyl-4,6-dimethyl-
˜
(m), 1467 (m), 1363 (s), 1224 (m), 1203 (s), 1103 (s), 914 (m) cm–1. salicylate (8s): Starting with 7e (0.132 g, 0.60 mmol), 2f (0.294 g,
MS (EI, 70 eV): m/z (%) = 426 (3) [M]+ (37Cl/79Br, 35Cl/81Br), 221
(95), 179 (83), 161 (100). C20H22BrClO3 (411.72): calcd. C 56.42,
H 5.21; found C 56.40, H 5.32.
1.02 mmol) and TiCl4 (0.13 mL, 1.20 mmol), 8s was isolated by
chromatography (heptane/EtOAc, 50:1) as a colourless solid (0.048 g,
22%); m.p. 68–69 °C; Rf = 0.73 (heptane/EtOAc, 1:1). 1H NMR
3
(300 MHz, CDCl3): δ = 1.05 (t, J = 7.5 Hz, 3 H, CH3CH2), 2.10,
Methyl 5-[2-(4-Bromophenyl)-2-chloroethyl]-3-(3-chloropropyl)-4,6-
dimethylsalicylate (8p): Starting with 7d (0.198 g, 0.70 mmol), 2i
(0.403 g, 1.20 mmol) and TiCl4 (0.15 mL, 1.41 mmol), 8p was iso-
lated by chromatography (heptane/EtOAc, 100:1) as a colourless
solid (0.106 g, 32%); m.p. 101–102 °C; Rf = 0.47 (heptane/EtOAc,
3
2.32 (s, 3 H, CH3), 2.57–2.77 (m, J = 7.5 Hz, 3 H, CH3CH2), 3.29
2
3
2
(dd, JHa,Hb = 14.9, JHa,Hx = 7.8 Hz, 1 H, Ha), 3.53 (dd, JHa,Hb
=
3
14.9, JHb,Hx = 6.8 Hz, 1 H, Hb), 3.93 (s, 3 H, OCH3), 4.91 (“t”,
3JHx,Ha = 7.8, 3JHx,Hb = 6.8 Hz, 1 H, CHCl), 6.90–7.03 (m, 2 H, Ar),
7.17–7.29 (m, 2 H, Ar), 10.85 (s, 1 H, OH) ppm. 13C NMR
(75.5 MHz, CDCl3): δ = 13.2, 16.5, 19.0 (CH3), 19.9 (CH3CH2), 40.7
(CH2CHCl), 52.1 (OCH3), 62.6 (CHCl), 111.6, 126.6, 129.0, 136.0,
142.1, 158.0 (CAr), 136.9 (d, 4J = 3.3 Hz, CAr), 162.4 (d, 1J =
247.3 Hz, CAr), 115.2 (d, 2J = 21.0 Hz, CHAr), 128.7 (d, 3J = 8.3 Hz,
CHAr), 172.5 (COOCH3) ppm. 19F NMR (282 MHz, CDCl3): δ =
1
1:1). H NMR (300 MHz, CDCl3): δ = 1.84–1.97 (m, 2 H, CH2),
2.13, 2.33 (s, 3 H, CH3), 2.72–2.88 (m, 2 H, CH2), 3.20–3.65 (m, 4
H, CH2, Ha, Hb), 3.94 (s, OCH3), 4.80–4.93 (m, 1 H, Hx), 7.09–
7.17 (m, 3J = 8.4 Hz, 2 H, Ar), 7.38–7.45 (m, 3J = 8.4 Hz, 2 H,
CH2), 10.92 (s, OH) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 16.9,
19.2 (CH3), 24.2, 31.9, 40.5, 45.1 (CH2), 52.2 (OCH3), 62.4 (CHCl),
111.7, 122.2, 126.0, 126.7, 136.7, 140.1, 142.5, 158.3 (CAr), 128.7,
–113.7 (CF) ppm. IR (ATR): ν = 2960 (w), 2870 (w), 1659 (s), 1589
˜
(m), 1506 (s), 1436 (s), 1317 (s), 1200 (s), 1103 (s), 917 (m) cm–1. MS
(EI, 70 eV): m/z (%) = 364 (2) [M]+ (35Cl), 296 (24), 221 (52), 189
(100). HRMS (EI): calcd. for C20H22ClFO3 [M]+ (35Cl) 364.12359;
found 364.12360. C20H22ClFO3 (364.12): calcd. C 65.84, H 6.08;
found C 66.09, H 6.42.
131.5 (CHAr), 172.4 (COOCH ) ppm. IR (ATR): ν = 2949 (w),
˜
3
1650 (m), 1587 (m), 1485 (m), 1435 (s), 1317 (s), 1192 (s), 1165 (s),
1142 (s), 1009 (s) cm–1. MS (EI, 70 eV): m/z (%) = 474 (2) [M]+
(35Cl/35Cl/81Br), 371 (3), 269 (87), 237 (100). HRMS (EI): calcd. for
C21H23BrCl2O3 [M]+ (35Cl, 35Cl, 81Br) 474.01817; found 474.01733.
5-[2-Chloro-2-(3-chlorophenyl)ethyl]-4,6-dimethylsalicylate
(8t):
Methyl 5-[2-Chloro-2-(4-fluorophenyl)ethyl]-4,6-dimethylsalicylate
(8q): Starting with 7e (0.161 g, 0.73 mmol), 2a (0.324 g, 1.24 mmol)
and TiCl4 (0.16 mL, 1.46 mmol), 8q was isolated by chromatog-
raphy (heptane/EtOAc, 50:1) as a colourless solid (0.111 g, 45%);
m.p. 120–121 °C; Rf = 0.59 (heptane/EtOAc, 1:1). 1H NMR
Starting with 7f (0.159 g, 0.67 mmol), 2a (0.297 g, 1.14 mmol) and
TiCl4 (0.15 mL, 1.34 mmol), 8t was isolated by chromatography
(heptane/EtOAc, 50:1) as a colourless solid (0.110 g, 46%); m.p.
76–77 °C; Rf = 0.64 (heptane/EtOAc, 1:1). 1H NMR (250 MHz,
2
2
CDCl3): δ = 2.15, 2.39 (s, 3 H, CH3), 3.23 (dd, JHa,Hb = 14.9,
(250 MHz, CDCl3): δ = 2.11, 2.38 (s, 3 H, CH3), 3.24 (dd, JHa,Hb
2
3
3JHa,Hx = 7.2 Hz, 1 H, Ha), 3.46 (dd, JHa,Hb = 14.9, JHb,Hx
=
= 14.8, 3JHa,Hx = 7.7 Hz, 1 H, Ha), 3.47 (dd, 2JHa,Hb = 14.8, 3JHb,Hx
3
3
7.4 Hz, 1 H, Hb), 3.94 (s, 3 H, OCH3), 4.89 (“t”, JHx,Ha = 7.2,
3JHx,Hb = 7.4 Hz, 1 H, CHCl), 6.66 (s, 1 H, Ar), 7.07–7.15 (m, 1
H, Ar), 7.17–7.30 (m, 2 H, Ar), 7.33–7.38 (m, 1 H, Ar), 10.71 (s, 1
H, OH) ppm. 13C NMR (62.9 MHz, CDCl3): δ = 19.0, 21.4 (CH3),
40.1 (CH2CHCl), 51.1 (OCH3), 62.1 (CHCl), 111.9, 126.7, 134.4,
139.3, 143.1, 144.8, 160.3 (CAr), 117.3, 125.1, 127.1, 128.4, 129.7
= 6.9 Hz, 1 H, Hb), 3.94 (s, 3 H, OCH3), 4.93 (“t”, JHx,Ha = 7.7,
3JHx,Hb = 6.9 Hz, 1 H, CHCl), 6.65 (s, 1 H, Ar), 6.91–7.05 (m, 2
H, Ar), 7.19–7.32 (m, 2 H, Ar), 10.69 (s, 1 H, OH) ppm. 13C NMR
(62.9 MHz, CDCl3): δ = 19.9, 21.4 (CH3), 40.5 (CH2CHCl), 52.2
(OCH3), 62.3 (CHCl), 111.9, 126.9, 139.4, 144.8, 160.3 (CAr), 137.0
4
1
2
(d, J = 3.3 Hz, CAr), 162.4 (d, J = 247.5 Hz, CAr), 115.3 (d, J =
3
(CHAr), 171.8 (COOCH ) ppm. IR (ATR): ν = 2989 (w), 2949 (w),
˜
3
22.0 Hz, CHAr), 117.3 (CHAr), 128.7 (d, J = 8.3 Hz, CHAr), 171.9
(COOCH3) ppm. 19F NMR (235 MHz, CDCl3):
δ = 113.5
1660 (s), 1571 (m), 1441 (m), 1333 (m), 1315 (m), 1206 (s), 1073
(m), 916 (m) cm–1. MS (EI, 70 eV): m/z (%) = (1) [M]+ (35Cl, 35Cl),
284 (7), 193 (58), 161 (100). HRMS (EI): calcd. for C18H18Cl2O3
[M]+ (35Cl) 352.06334; found 352.06275. C18H18Cl2O3 (352.06):
calcd. C 61.20, H 5.14; found C 61.48, H 5.15.
(CF) ppm. IR (ATR): ν = 2991 (w), 2950 (w), 1661 (s), 1601 (m),
˜
1506 (m), 1442 (s), 1335 (s), 1201 (s), 1071 (m), 914 (m) cm–1. MS
(EI, 70 eV): m/z (%) = 336 (1) [M]+ (35Cl), 300 (7), 193 (60), 161
(100). HRMS (EI): calcd. for C18H18ClFO3 [M]+ (35Cl) 336.09215;
found 336.09230. C18H18ClFO3 (336.09): calcd. C 64.19, H 5.39;
found C 64.20, H 5.66.
Methyl 5-[2-Chloro-2-(3-chlorophenyl)ethyl]-3,4,6-trimethylsalicyl-
ate (8u): Starting with 7f (0.151 g, 0.64 mmol), 2c (0.296 g,
1.09 mmol) and TiCl4 (0.14 mL, 1.28 mmol), 8u was isolated by
Methyl 5-[2-Chloro-2-(4-fluorophenyl)ethyl]-3,4,6-trimethylsalicyl-
ate (8r): Starting with 7e (0.152 g, 0.69 mmol), 2c (0.320 g,
1.17 mmol) and TiCl4 (0.15 mL, 1.38 mmol), 8r was isolated by
chromatography (heptane/EtOAc, 50:1) as
a colourless solid
1
(0.088 g, 38%); m.p. 65–66 °C; Rf = 0.73 (heptane/EtOAc, 1:1). H
NMR (300 MHz, CDCl3): δ = 2.13, 2.16, 2.33 (s, 3 H, CH3), 3.29
chromatography (heptane/EtOAc, 50:1) as
a colourless solid
2
3
2
(dd, JHa,Hb = 15.0, JHa,Hx = 7.2 Hz, 1 H, Ha), 3.53 (dd, JHa,Hb
(0.098 g, 51%); m.p. 103–104 °C; Rf = 0.69 (heptane/EtOAc, 1:1).
3
1H NMR (300 MHz, CDCl3): δ = 2.11, 2.15, 2.30 (s, 3 H, CH3),
= 15.0, JHb,Hx = 7.3 Hz, 1 H, Hb), 3.93 (s, 3 H, OCH3), 4.87 (“t”,
3JHx,Ha = 7.2, JHx,Hb = 7.3 Hz, 1 H, CHCl), 7.08–7.14 (m, 1 H,
3
2
3
3.30 (dd, JHa,Hb = 14.9, JHa,Hx = 7.7 Hz, 1 H, Ha), 3.54 (dd,
2JHa,Hb = 14.9, JHb,Hx = 6.9 Hz, 1 H, Hb), 3.92 (s, 3 H, OCH3),
3
Ar), 7.17–7.30 (m, 2 H, Ar), 7.32–7.36 (m, 1 H, Ar), 10.91 (s, 1 H,
OH) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 12.3, 17.4, 19.1
(CH3), 40.3 (CH2CHCl), 52.1 (OCH3), 62.5 (CHCl), 111.5, 123.0,
126.2, 134.3, 135.9, 142.8, 143.1, 158.1 (CAr), 125.2, 127.2, 128.4,
3
3
4.91 (“t”, JHx,Ha = 7.7, JHx,Hb = 6.9 Hz, 1 H, CHCl), 6.92–7.02
(m, 2 H, Ar), 7.20–7.30 (m, 2 H, Ar), 10.90 (s, 1 H, OH) ppm.
13C NMR (75.5 MHz, CDCl3): δ = 12.3, 17.4, 19.0 (CH3), 40.7
(CH2CHCl), 52.1 (OCH3), 62.7 (CHCl), 111.4, 122.9, 126.4, 135.9,
142.8, 158.1 (CAr), 137.0 (d, 4J = 3.3 Hz, CAr), 162.4 (d, 1J =
247.7 Hz, CAr), 115.3 (d, 2J = 21.6 Hz, CHAr), 128.7 (d, 3J =
8.2 Hz, CHAr), 172.5 (COOCH3) ppm. 19F NMR (282 MHz,
129.6 (CHAr), 172.5 (COOCH ) ppm. IR (ATR): ν = 2958 (w),
˜
3
2924 (w), 1651 (s), 1595 (m), 1432 (s), 1351 (m), 1312 (s), 1203 (s),
1094 (m), 952 (m) cm–1. MS (EI, 70 eV): m/z (%) = 368 (1) [M]+
(35Cl, 37Cl), 366 (2) [M]+ (35Cl, 35Cl), 330 (3), 207 (53), 175 (100).
HRMS (EI): calcd. for C19H20Cl2O3 [M]+ (35Cl) 366.07927; found
366.07840. C19H20Cl2O3 (366.08): calcd. C 62.14, H 5.49; found C
61.87, H 5.48.
CDCl ): δ = –113.7 (CF) ppm. IR (ATR): ν = 2997 (w), 2949 (w),
˜
3
1651 (s), 1603 (m), 1508 (m), 1439 (m), 1345 (m), 1303 (m), 1204
(s), 1097 (m) cm–1. MS (EI, 70 eV): m/z (%) = 352 (1) [M]+ (37Cl),
350 (3) [M]+ (35Cl), 282 (36), 207 (53), 175 (100). HRMS (EI): Methyl 5-[2-Chloro-2-(3-chlorophenyl)ethyl]-3-ethyl-4,6-dimethyl-
calcd. for C19H20ClFO3 [M]+ (35Cl) 350.10876; found 350.10795.
salicylate (8v): Starting with 7f (0.150 g, 0.63 mmol), 2f (0.311 g,
Eur. J. Org. Chem. 2010, 3743–3753
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3751

M. Lau, M. Sher, A. Villinger, C. Fischer, P. Langer
FULL PAPER
2
3
1.08 mmol) and TiCl4 (0.14 mL, 1.27 mmol), 8v was isolated by CH3), 2.98 (dd, JHa,Hb = 14.6, JHa,Hx = 9.5 Hz, 1 H, Ha), 3.10
2
3
chromatography (heptane/EtOAc, 50:1) as a colourless oil (0.080 g,
(dd, JHa,Hb = 14.6, JHb,Hx = 4.5 Hz, 1 H, Hb), 3.95 (s, 3 H,
33%); Rf = 0.74 (heptane/EtOAc, 1:1). 1H NMR (250 MHz,
OCH3), 5.29 (dd, 3JHx,Ha = 9.5, 3JHx,Hb = 4.5 Hz, 1 H, CHCl), 6.72
3
CDCl3): δ = 1.05 (t, J = 7.5 Hz, 3 H, CH3CH2), 2.11, 2.35 (s, 3 (s, 1 H, Ar), 7.16–7.40 (m, 3 H, Ar), 7.65–7.77 (m, 1 H, Ar), 10.62
H, CH3), 2.59–2.77 (m, 3J = 7.5 Hz, 2 H, CH3CH2), 3.28 (dd, (s, 1 H, OH) ppm. 13C NMR (62.9 MHz, CDCl3): δ = 19.2, 21.8
2JHa,Hb = 15.0, 3JHa,Hx = 7.4 Hz, 1 H, Ha), 3.53 (dd, 2JHa,Hb = 15.0,
(CH3), 37.3 (CH2CHOH), 52.1 (OCH3), 70.3 (CHOH), 112.0,
126.9, 131.6, 140.0, 141.8, 145.6, 160.0 (CAr), 117.2, 127.2, 127.3,
3JHb,Hx = 7.1 Hz, 1 H, Hb), 3.93 (s, 3 H, OCH3), 4.87 (“t”, JHx,Ha
3
= 7.4, 3JHx,Hb = 7.1 Hz, 1 H, CHCl), 7.06–7.13 (m, 1 H, Ar), 7.16–
7.29 (m, 2 H, Ar), 7.31–7.36 (m, 1 H, Ar), 10.87 (s, 1 H, OH) ppm.
13C NMR (62.9 MHz, CDCl3): δ = 13.2, 16.5, 19.1 (CH3), 19.9
128.6, 129.3 (CHAr), 172.0 (COOCH ) ppm. IR (ATR): ν = 3479
˜
3
(w), 2956 (w), 1657 (m), 1573 (m), 1440 (m), 1348 (m), 1306 (m),
1236 (m), 1209 (s), 1028 (m) cm–1. MS (EI, 70 eV): m/z (%) = 334
(CH3CH2), 40.4 (CH2CHCl), 52.1 (OCH3), 62.4 (CHCl), 111.6, (1) [M]+ (35Cl), 194 (41), 161 (100). HRMS (EI): calcd. for
126.4, 129.1, 134.3, 136.0, 142.1, 143.1, 152.0 (CAr), 125.2, 127.2, C18H19ClO4 [M]+ (35Cl) 334.09680; found 334.09664.
128.3, 129.6 (CHAr), 172.5 (COOCH ) ppm. IR (ATR): ν = 2953
˜
3
Methyl 5-[2-(2-Chlorophenyl)-2-hydroxyethyl]-3,4,6-trimethylsalicyl-
ate (9b): Starting with 7g (0.175 g, 0.74 mmol), 2c (0.304 g,
1.11 mmol) and TiCl4 (0.16 mL, 1.48 mmol), 9b was isolated by
chromatography (heptane/EtOAc, 100:1) as a colourless solid
(w), 2872 (w), 1653 (s), 1573 (m), 1435 (m), 1348 (m), 1316 (m),
1268 (s), 1201 (s), 1034 (m) cm–1. MS (EI, 70 eV): m/z (%) = 382
(1) [M]+ (35Cl, 37Cl), 380 (2) [M]+ (35Cl, 35Cl), 312 (7), 221 (83),
189 (100). HRMS (EI): calcd. for C20H22Cl2O3 [M]+ (35Cl)
380.09446; found 380.09405. C20H22Cl2O3 (380.09): calcd. C 63.00,
H 5.82; found C 62.79, H 5.33.
1
(0.120 g, 47%); m.p. 86–88 °C; Rf = 0.50 (heptane/EtOAc, 1:1). H
NMR (250 MHz, CDCl3): δ = 1.25 (s, 1 H, OH), 2.21, 2.36, 2.55
(s, 3 H, CH3), 3.05 (dd, 2JHa,Hb = 14.8, 3JHa,Hx = 9.5 Hz, 1 H, Ha),
2
3
Methyl 5-[2-Chloro-2-(2-chlorophenyl)ethyl]-4,6-dimethylsalicylate 3.15 (dd, JHa,Hb = 14.8, JHb,Hx = 4.6 Hz, 1 H, Hb), 3.95 (s, 3 H,
3
3
(8w): Starting with 7g (0.165 g, 0.70 mmol), 2a (0.272 g, 1.05 mmol)
and TiCl4 (0.15 mL, 1.39 mmol), 8w was isolated by chromatog-
raphy (heptane/EtOAc, 50:1) as a colourless solid (0.037 g, 15%);
m.p. 119–120 °C; Rf = 0.71 (heptane/EtOAc, 1:1). 1H NMR
OCH3), 5.28 (dd, JHx,Ha = 9.5, JHx,Hb = 4.6 Hz, 1 H, CHOH),
7.17–7.39 (m, 3 H, Ar), 7.66–7.76 (m, 1 H, Ar), 10.82 (s, 1 H,
OH) ppm. 13C NMR (62.9 MHz, CDCl3): δ = 12.3, 17.6, 19.3
(CH3), 37.5 (CH2CHOH), 52.1 (OCH3), 70.5 (CHOH), 111.6,
122.9, 126.3, 131.6, 136.5, 141.9, 143.7, 157.9 (CAr), 127.2, 127.3,
2
(250 MHz, CDCl3): δ = 2.26, 2.49 (s, 3 H, CH3), 3.27 (dd, JHa,Hb
= 14.9, 3JHa,Hx = 6.3 Hz, 1 H, Ha), 3.47 (dd, 2JHa,Hb = 14.9, 3JHb,Hx
128.5, 129.3 (CHAr), 172.6 (COOCH ) ppm. IR (ATR): ν = 2952
˜
3
3
= 8.5 Hz, 1 H, Hb), 3.94 (s, 3 H, OCH3), 5.60 (dd, JHx,Ha = 6.3,
(w), 2925 (w), 1593 (br. m), 1438 (m), 1381 (m), 1358 (m), 1211
3JHx,Hb = 8.5 Hz, 1 H, CHCl), 6.67 (s, 1 H, Ar), 7.17–7.40 (m, 3 (m), 1222 (s), 1030 (m), 753 (s) cm–1. MS (EI, 70 eV): m/z (%) =
H, Ar), 7.74–7.82 (m, 1 H, Ar), 10.87 (s, 1 H, OH) ppm. 13C NMR
350 (2) [M]+ (37Cl), 348 (5) [M]+ (35Cl), 317 (6), 207 (90), 175 (100).
(62.9 MHz, CDCl3): δ = 19.2, 21.6 (CH3), 38.9 (CH2CHCl), 52.1 HRMS (EI): calcd. for C19H21ClO4 [M]+ (35Cl) 348.11224; found
(OCH3), 58.6 (CHCl), 111.9, 126.6, 132.4, 139.1, 139.7, 145.0,
160.3 (CAr), 117.2, 127.4, 129.2, 129.4, 129.4 (CHAr), 172.0 (CO-
348.11229. C19H21ClO4 (348.11): calcd. C 65.42, H 6.07; found C
65.34, H 6.11.
OCH ) ppm. IR (ATR): ν = 2961 (w), 2928 (w), 1665 (m), 1566
˜
3
Methyl 5-[2-(2,6-Dichlorophenyl)-2-hydroxyethyl]-4,6-diethylsalicyl-
ate (9c): Starting with 7h (0.152 g, 0.56 mmol), 2a (0.219 g,
0.84 mmol) and TiCl4 (0.12 mL, 1.12 mmol), 9c was isolated by
chromatography (heptane/EtOAc, 100:1) as a colourless solid
(0.102 g, 49%); m.p. 149–150 °C; Rf = 0.29 (heptane/EtOAc, 1:1).
(m), 1438 (m), 1315 (m), 1260 (m), 1190 (m), 1070 (m), 911
(m) cm–1. MS (EI, 70 eV): m/z (%) = 354 (2) [M]+ (35Cl, 37Cl), 352
(3) [M]+ (35Cl, 35Cl), 193 (99), 161 (100). HRMS (EI): calcd. for
C18H18Cl2O3 [M]+ (35Cl, 35Cl) 352.06306; found 352.06275.
Methyl 5-[2-Chloro-2-(2-chlorophenyl)ethyl]-3,4,6-trimethylsalicyl- 1H NMR (300 MHz, CDCl3): δ = 2.29, 2.51 (s, 3 H, CH3), 3.19
ate (8x): Starting with 7g (0.175 g, 0.74 mmol), 2c (0.304 g, (dd, JHa,Hb = 14.5, JHa,Hx = 6.5 Hz, 1 H, Ha), 3.53 (dd, JHa,Hb
1.11 mmol) and TiCl4 (0.16 mL, 1.48 mmol), 8x was isolated by
chromatography (heptane/EtOAc, 100:1) as a colourless solid
2
3
2
3
= 14.5, JHb,Hx = 8.2 Hz, 1 H, Hb), 3.93 (s, 3 H, OCH3), 5.55 (dd,
3
3JHx,Ha = 6.5, JHx,Hb = 8.2 Hz, 1 H, CHCl), 6.67 (s, 1 H, Ar),
(0.038 g, 14%); m.p. 132–133 °C; Rf = 0.65 (heptane/EtOAc, 1:1). 7.09–7.18 (m, 1 H, Ar), 7.23–7.32 (m, 2 H, Ar), 10.63 (s, 1 H,
1H NMR (250 MHz, CDCl3): δ = 2.17, 2.25, 2.45 (s, 3 H, CH3), OH) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 19.2, 21.6 (CH3),
2
3
3.32 (dd, JHa,Hb = 15.1, JHa,Hx = 6.1 Hz, 1 H, Ha), 3.56 (dd,
34.6 (CH2CHOH), 52.1 (OCH3), 71.9 (CHOH), 111.9, 126.7,
2JHa,Hb = 15.1, JHb,Hx = 8.6 Hz, 1 H, Hb), 3.93 (s, 3 H, OCH3), 134.5, 137.2, 139.8, 145.2, 160.0 (CAr), 117.1, 129.1, 129.4 (CHAr),
3
5.58 (dd, 3JHx,Ha = 6.1, 3JHx,Hb = 8.6 Hz, 1 H, CHCl), 7.177.40 (m,
3 H, Ar), 7.73–7.82 (m, 1 H, Ar), 10.91 (s, 1 H, OH) ppm. 13C
172.0 (COOCH ) ppm. IR (ATR): ν = 3500 (w), 2921 (w), 1651
˜
3
(s), 1573 (m), 1433 (s), 1352 (s), 1241 (s), 1194 (m), 1072 (s), 767
NMR (62.9 MHz, CDCl3): δ = 12.3, 17.6, 19.3 (CH3), 39.1 (s) cm–1. MS (EI, 70 eV): m/z (%) = 370 (4) [M]+ (35Cl, 37Cl), 368
(CH2CHCl), 52.1 (OCH3), 59.0 (CHCl), 111.4, 122.8, 126.1, 132.4,
136.2, 139.2, 143.1, 158.2 (CAr), 127.4, 129.3, 129.3, 129.5 (CHAr),
(7) [M]+ (35Cl, 35Cl), 337 (13), 194 (100), 162 (81). HRMS (EI):
calcd. for C18H18Cl2O4 [M]+ (35Cl, 35Cl) 368.05825; found
172.6 (COOCH ) ppm. IR (ATR): ν = 2961 (w), 1660 (m), 1658 368.05767. C18H18Cl2O4 (368.06): calcd. C 58.55, H 4.91; found C
˜
3
(s), 1587 (w), 1435 (m), 1375 (w), 1310 (m), 1257 (s), 1092 (s), 1009
(s) cm–1. MS (EI, 70 eV): m/z (%) = 368 (1) [M]+ (35Cl, 37Cl), 366
(2) [M]+ (35Cl, 35Cl), 298 (7), 207 (52), 175 (100). HRMS (EI):
calcd. for C19H20Cl2O3 [M]+ (35Cl, 35Cl) 366.07917; found
366.07840.
58.52, H 5.24.
Methyl 5-(2-Chloro-2-phenylethyl)-4,6-diethylsalicylate (8y): Start-
ing with 7i (0.165 g, 0.72 mmol), 2a (0.280 g, 1.08 mmol) and TiCl4
(0.16 mL, 1.43 mmol), 8y was isolated by chromatography (hept-
ane/EtOAc, 50:1) as a colourless solid (0.096 g, 39%); m.p. 72–
73 °C; Rf = 0.60 (heptane/EtOAc, 1:1). 1H NMR (250 MHz,
Methyl 5-[2-(2-Chlorophenyl)-2-hydroxyethyl]-4,6-dimethylsalicylate
(9a): Starting with 7g (0.165 g, 0.70 mmol), 2a (0.272 g, 1.05 mmol) CDCl3): δ = 1.09 (t, 3J = 7.3 Hz, 3 H, CH3CH2), 1.12 (t, 3J =
and TiCl4 (0.15 mL, 1.39 mmol), 9a was isolated by chromatog-
raphy (heptane/EtOAc, 50:1) as a colourless solid (0.085 g, 36%);
m.p. 116–117 °C; Rf = 0.53 (heptane/EtOAc, 1:1). 1H NMR
(250 MHz, CDCl3): δ = 1.82 (br. s, 1 H, OH), 2.37, 2.58 (s, 3 H,
7.5 Hz, 3 H, CH3CH2), 2.34–2.58 (m, 2 H, CH3CH2), 2.72–3.03
2
3
(m, 2 H, CH3CH2), 3.25 (dd, JHa,Hb = 14.9, JHa,Hx = 7.3 Hz, 1
2
3
H, Ha), 3.48 (dd, JHa,Hb = 14.9, JHb,Hx = 7.2 Hz, 1 H, Hb), 3.94
3
3
(s, 3 H, OCH3), 4.94 (“t”, JHx,Ha = 7.3, JHx,Hb = 7.2 Hz, 1 H,
3752
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 3743–3753

Synthesis of Chlorobutenyl- and Chloroethylsalicylates
CHCl), 6.70 (s, 1 H, Ar), 7.29 (s, 5 H, Ar), 10.58 (s, 1 H, OH) ppm. isolated by chromatography (heptane/EtOAc, 150:1) as a colourless
1
13C NMR (62.9 MHz, CDCl3): δ = 14.5, 15.8 (CH3), 24.1, 26.5,
oil (0.24 g, 60%, E/Z = 11:1); Rf = 0.73 (heptane/EtOAc, 1:1). H
38.8 (CH2), 52.2 (OCH3), 64.2 (CHCl), 111.1, 125.7, 141.1, 145.8, NMR (300 MHz, CDCl3): δ = 2.30, 2.53 (s, 3 H, CH3), 3.96 (s, 3
3
150.9, 160.4 (CPh/Ar), 115.5, 126.9, 128.3, 128.4 (CHPh/Ar), 171.7 H, OCH3), 6.46 (d, Jtrans = 16.6 Hz, 1 H, CHOlefin), 6.76 (s, 1 H,
3
(COOCH ) ppm. IR (ATR): ν = 2965 (w), 2872 (w), 1658 (s), 1572
Ar), 7.00 (d, Jtrans = 16.6 Hz, 1 H, CHOlefin), 7.23–7.43 (m, 3 H,
˜
3
(m), 1435 (m), 1346 (m), 1309 (m), 1242 (s), 1206 (s), 1081 Ph), 7.45–7.55 (m, 2 H, Ph), 10.91 (s, 1 H, OH) ppm. 13C NMR
(m) cm–1. MS (EI, 70 eV): m/z (%) = 348 (1) [M]+ (37Cl), 346 (3)
(62.9 MHz, CDCl3): δ = 20.6, 21.8 (CH3), 52.1 (OCH3), 111.2,
[M]+ (35Cl), 278 (100), 221 (69), 189 (83). HRMS (EI): calcd. for 130.6, 137.3, 138.7, 144.1, 160.6 (CPh,Ar), 116.6, 126.2, 127.6, 128.7
C20H23ClO3 [M]+ (35Cl) 346.13247; found 346.13302. C20H23ClO3
(346.13): calcd. C 69.26, H 6.68; found C 68.73, H 6.46.
(CHPh,Ar), 126.8, 134.8 (CHOlefin), 172.1 (COOCH3) ppm. IR
(ATR): ν = 3024 (w), 2952 (w), 1657 (s), 1571 (m), 1438 (m), 1348
˜
(m), 1310 (m), 1216 (s), 1156 (m), 1073 (m) cm–1. MS (EI, 70 eV):
m/z (%) = 282 (58) [M]+, 250 (100), 235 (37), 178 (29). HRMS (EI):
calcd. for C18H18O3 [M]+ 282.12537; found 282.12505. C18H18O3
(282.13): calcd. C 76.57, H 6.43; found C 76.67, H 6.45.
Methyl
5-(2-Chloro-2-phenylethyl)-4,6-diethyl-3-methylsalicylate
(8z): Starting with 7i (0.165 g, 0.72 mmol), 2c (0.295 g, 1.08 mmol)
and TiCl4 (0.16 mL, 1.43 mmol), 8z was isolated by chromatog-
raphy (heptane/EtOAc, 100:1) as a yellow solid (0.180 g, 70%); m.p.
83–84 °C; Rf = 0.71 (heptane/EtOAc, 1:1). 1H NMR (250 MHz,
CDCl3): δ = 1.04 (t, 3J = 7.5 Hz, 3 H, CH3CH2), 1.07 (t, 3J =
7.3 Hz, 3 H, CH3CH2), 2.36–2.99 (m, 4 H, CH3CH2), 3.10 (dd,
2JHa,Hb = 15.0, 3JHa,Hx = 7.1 Hz, 1 H, Ha), 3.49 (dd, 2JHa,Hb = 15.0,
Acknowledgments
Financial support by the State of Mecklenburg-Vorpommern is
gratefully acknowledged.
3
3JHb,Hx = 7.3 Hz, 1 H, Hb), 3.93 (s, 3 H, OCH3), 4.95 (“t”, JHx,Ha
3
= 7.1, JHx,Hb = 7.3 Hz, 1 H, CHCl), 7.30 (s, 5 H, Ar), 10.81 (s, 1
H, OH) ppm. 13C NMR (62.9 MHz, CDCl3): δ = 11.7, 13.9, 15.9
(CH3), 23.5, 24.1, 39.1 (CH2), 52.2 (OCH3), 64.7 (CHCl), 110.8,
122.5, 125.0, 141.2, 142.7, 149.0, 158.5 (CPh/Ar), 126.9, 128.2, 128.4
[1] For reviews of domino reactions, see: a) L. F. Tietze, U. Beifuss,
Angew. Chem. 1993, 105, 137; Angew. Chem. Int. Ed. Engl.
1993, 32, 131; b) L. F. Tietze, Chem. Rev. 1996, 96, 115.
[2] For a review on 1,3-bis(silyl enol ethers) in general, see: P.
Langer, Synthesis 2002, 441.
[3] a) For a review, see: P. Langer, Synlett 2006, 3369; b) for a
review, see: H. Feist, P. Langer, Synthesis 2007, 327; c) for a
review, see: P. Langer, Eur. J. Org. Chem. 2007, 2233; d) for a
review, see: P. Langer, Synlett 2007, 1016; e) for a review, see:
P. Langer, Synlett 2009, 2205; f) for a review, see: E. Bellur, H.
Feist, P. Langer, Tetrahedron 2007, 63, 10865.
[4] a) P. Langer, G. Bose, Angew. Chem. Int. Ed. 2003, 42, 4033;
b) G. Bose, V. T. H. Nguyen, E. Ullah, S. Lahiri, H. Görls, P.
Langer, J. Org. Chem. 2004, 69, 9128.
[5] M. Lau, P. Langer, Tetrahedron Lett. 2008, 49, 5618.
[6] R. K. Bowman, S. J. Johnson, Org. Lett. 2006, 8, 573, and ref-
erences therein.
[7] a) T.-H. Chan, P. Brownbridge, J. Am. Chem. Soc. 1980, 102,
3534; b) P. Brownbridge, T.-H. Chan, M. A. Brook, G. J. Kang,
Can. J. Chem. 1983, 61, 688; c) G. A. Molander, K. O. Cam-
eron, J. Am. Chem. Soc. 1993, 115, 830.
[8] a) V. T. H. Nguyen, E. Bellur, B. Appel, Synthesis 2006, 2865;
b) V. T. H. Nguyen, B. Appel, P. Langer, Tetrahedron 2006, 62,
7674.
[9] E. Baciocchi, R. Ruzziconi, J. Org. Chem. 1991, 56, 4773.
[10] CCDC-769303 (for 7h) and -769302 (for 8r) contain the supple-
mentary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[11] B. Fugmann (Ed.), Römpp-Lexikon Naturstoffe, Georg Thieme,
Stuttgart, New York, 1997.
(CHPh), 172.3 (COOCH ) ppm. IR (ATR): ν = 2948 (w), 2871 (w),
˜
3
1651 (s), 1597 (m), 1434 (m), 1405 (m), 1308 (s), 1201 (s), 1173 (s),
952 (m) cm–1. MS (EI, 70 eV): m/z (%) = 360 (2) [M]+ (35Cl), 292
(25), 235 (49), 203 (100), 175 (7). HRMS (EI): calcd. for
C21H25ClO3 [M]+ (35Cl) 360.14902; found 360.14876. C21H25ClO3
(360.15): calcd. C 69.89, H 6.98; found C 69.82, H 7.24.
Methyl
6-[(E)-2-(4-Bromophenyl)vinyl]-5,7-dimethylchromane-8-
carboxylate (10b): To a DMF solution (20 mL per 1 mmol of 8p)
of 8p (1.0 equiv.) was added TBAI (2.2 equiv.) under argon. The
mixture was cooled to –78 °C and NaH (60% dispersion in mineral
oil, 1.5 equiv.) was added at 0 °C. After stirring for 20 h at 20 °C,
ethyl acetate (5 mL) and ice-cold water (5 mL) were added and the
mixture was subsequently neutralized by addition of hydrochloric
acid (10%). The mixture was extracted with EtOAc (3ϫ20 mL).
The combined organic layers were dried (Na2SO4), filtered and the
filtrate was concentrated in vacuo. The residue was purified by
chromatography. Starting with 8p (0.050 g, 0.11 mmol), sodium hy-
dride (0.013 g, 0.32 mmol) and TBAI (0.140 g, 0.38 mmol), 10b was
isolated by chromatography (heptane/EtOAc, 50:1) as a colourless
solid (0.032 g, 76%); m.p. 145–147 °C; Rf = 0.75 (heptane/EtOAc,
1
3
1:1). H NMR (300 MHz, CDCl3): δ = 1.99–2.09 (m, J = 6.6 Hz,
2 H, CH2), 2.18 (br. s, 6 H, 2 CH3), 2.64 (t, 3J = 6.6 Hz, 2 H, CH2),
3.89 (s, 3 H, OCH3), 4.10–4.18 (m, 2 H, CH2), 6.36 (d, 3J =
3
16.6 Hz, 1 H, CH), 7.00 (d, J = 16.6 Hz, 1 H, CH), 7.29–7.38 (m,
3J = 8.4 Hz, 2 H, Ar), 7.42–7.52 (m, J = 8.4 Hz, 2 H, Ar) ppm.
3
[12] P. Cos, T. De Bruyne, S. Apers, D. van den Berghe, L. Pieters,
A. J. Vlietinck, Planta Med. 2003, 69, 58.
[13] M. Jang, L. Cai, G. U. Udeani, K. V. Slowing, C. F. Thomas,
C. W. W. Beecher, H. H. S. Fong, N. R. Farnsworth, A. D.
Kinghorn, R. G. Mehta, R. C. Moon, J. M. Pezzuto, Science
1997, 275, 218.
13C NMR (75.5 MHz, CDCl3): δ = 16.6, 17.7 (CH3), 22.3, 23.0,
66.1 (CH2), 52.1 (OCH3), 119.1, 121.3, 121.6, 129.6, 131.3, 136.3,
136.9, 150.6 (CAr), 127.7, 131.7 (CHAr), 127.7, 133.4 (CHOlefin),
169.4 (COOCH ) ppm. IR (ATR): ν = 2947 (w), 2872 (w), 1728
˜
3
(s), 1574 (m), 1486 (m), 1436 (m), 1274 (s), 1191 (m), 1114 (s), 937
(w) cm–1. MS (EI, 70 eV): m/z (%) = 402 (99) [M]+ (81Br), 400 (100)
[M]+ (79Br), 369 (25), 342 (39), 306 (36). HRMS (EI): calcd. for
C23H19BrO3 [M]+ (79Br) 400.06686; found 400.06657.
[14] S. H. Inayat-Hussain, N. F. Thomas, Expert Opin. Ther. Pat.
2004, 14, 819.
Received: February 3, 2010
Published Online: May 19, 2010
Methyl 4,6-Dimethyl-5-[(E)-styryl]salicylate (10a): Heating of neat
8a (0.045 g, 0.14 mmol) at 150 °C for 3 h afforded 10a, which was
After publication in Early View, erroneous Scheme 3 was replaced
by the correct version.
Eur. J. Org. Chem. 2010, 3743–3753
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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