Synthesis of 3-alkyl- and 3-chloroalkyl-2-hydroxybenzoates based on [3+3] cyclizations of 4-alkyl- and 4-chloroalkyl-1,3-bis(trimethylsilyloxy)buta-1,3- dienes

Article abstract of DOI:10.1055/s-2006-926381

The TiCl₄-mediated [3+3] cyclization of 4-alkyl- and 4-chloroalkyl-1,3-bis(trimethylsilyloxy)buta-1,3-dienes with 3-silylalk-2-en-1-ones afforded 3-alkyl- and 3-chloroalkyl-2-hydroxybenzoates, respectively; the latter containing a remote chlori

Full text of DOI:10.1055/s-2006-926381

PAPER
1103
Synthesis of 3-Alkyl- and 3-Chloroalkyl-2-hydroxybenzoates Based on [3+3]
Cyclizations of 4-Alkyl- and 4-Chloroalkyl-1,3-bis(trimethylsilyloxy)buta-
1,3-dienes
S
ynthesis of 3-Alk
a
yl- and 3-C
n
hloroalkyl-2-hydro
T
xybenzoates hi Hong Nguyen,a Esen Bellur,a Bettina Appel,a Peter Langer*b,c
a
Institut für Chemie und Biochemie, Universität Greifswald, Soldmannstr. 16, 17487 Greifswald, Germany
Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
Fax +381 4986412; E-mail: peter.langer@uni-rostock.de
b
c
Leibniz-Institut für Katalyse e. V. an der Universität Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
Received 29 August 2005; revised 7 November 2005
OH
Abstract: The TiCl4-mediated [3+3] cyclization of 4-alkyl- and 4-
chloroalkyl-1,3-bis(trimethylsilyloxy)buta-1,3-dienes with 3-silyl-
alk-2-en-1-ones afforded 3-alkyl- and 3-chloroalkyl-2-hydroxyben-
zoates, respectively; the latter containing a remote chloride
functionality. The TiCl4- and TiBr4-mediated [3+3] cyclization of
1,3-bis(trimethylsilyloxy)-4-chloroalkylbuta-1,3-dienes with 1,1-
diacetylcyclopropane afforded salicylates containing two remote
halide functionalities.
MeO
OMe
Figure 2 Hierridin B
For reasons of comparison, the 3-unsubstituted 2-hydroxy-
benzoates 3a–c were prepared, according to the procedure
reported by Chan,4 by TiCl4-mediated [3+3] cyclization of
1,3-bis(silyl) enol ethers 1a,b6 with 3-silyloxyalk-2-en-1-
ones 2a,b. The cyclization of 2a–c with 1,3-bis(silyl) enol
ethers 1c–h7,8 afforded 3-alkyl-2-hydroxybenzoates 3d–k
(Scheme 1, Table 1). In fact, comparable yields were ob-
tained for the synthesis of 3-unsubstituted and 3-alkyl-2-
hydroxybenzoates by [3+3] cyclizations.
Key words: arenes, cyclizations, domino reactions, silyl enol
ethers
Polyalkylated phenols and salicylates occur in a number
of natural products.1 For example, 3-undecyl-1,2-dihy-
droxybenzene has been isolated from Schistochila appen-
diculata. Other natural products include, for example,
bhilawanol, 5-chlorflexirubin, belamcandol A, amorfrutin
B (Figure 1), and hierridin B (Figure 2).2 Chan and co-
workers developed an elegant approach to salicylates
based on cyclization reactions of 1,3-bis(silyl) enol ethers
Me3SiO
R1O
OSiMe3
O
OH
R2
R2
R1O
1a–h
– electroneutral 1,3-dicarbonyl dianion equivalents3,4
–
TiCl4
O
OSiMe3
with 3-silyloxyalk-2-en-1-ones. In a recent communica-
tion, we have reported the synthesis of benzopyrans by
sequential [3+3] cyclizations/Williamson reactions of
1,3-bis(trimethylsilyloxy)-7-chloro-1-ethoxyhepta-1,3-di-
ene.5a We have also reported the synthesis of 3-alkyl-5-(2-
chloroethyl)-2-hydroxybenzoates by [3+3] cyclization of
1,3-bis(silyl) enol ethers with 1,1-diacylcyclopropanes.5b
Functionalized dibenzo[b,d]pyran-6-ones were prepared
by sequential ‘[3+3] cyclization–Suzuki cross-coupling’
reactions of 1,3-bis(silyl) enol ethers.5c Herein, we report
the synthesis of 3-alkyl- and 3-chloroalkyl-2-hydroxyben-
zoates based on [3+3] cyclizations of 4-alkyl- and 4-chlo-
roalkyl-1,3-bis(trimethylsilyloxy)buta-1,3-dienes.
+
CH2Cl2
R3
R3
2a–c
3a–k
Scheme 1 Synthesis of 3-alkyl-2-hydroxybenzoates 3a–k
The condensation of the dianion9,10 of ethyl acetoacetate
with 3-chloro-1-iodopropane (4a) afforded, according to a
known procedure,11 ethyl 7-chloro-3-oxoheptanoate (5a).
The attack of the dianion occurred regioselectively at the
carbon atom attached to the iodide (Scheme 2, Table 2).
Likewise, the condensation of the dianion of ethyl ace-
toacetate with 3-chloro-1-iodo-2-methylpropane (4b), 5-
chloro-1-iodopentane (4c) and 6-chloro-1-iodohexane
(4d) afforded ethyl 7-chloro-6-methyl-3-oxoheptanoate
(5b), ethyl 9-chloro-3-oxononanoate (5c) and ethyl 10-
chloro-3-oxodecanoate (5d), respectively. Treatment of
b-keto esters 5a–d with Me3SiCl/Et3N gave the silyl enol
ethers 6a–d. Deprotonation of the latter and subsequent
addition of Me3SiCl afforded the chloro-substituted 1,3-
bis(silyl) enol ethers 7a–d. Cyclization of 1,3-bis(trimeth-
ylsilyloxy)-7-chlorohepta-1,3-diene (7a) with 2a afforded
3-(3-chloropropyl)-2-hydroxybenzoate (8a). Likewise, 3-
O
OH
HO
Ph
OMe
Figure 1 Amorfrutin B
SYNTHESIS 2006, No. 7, pp 1103–1110
x
x
.
x
x
.2
0
0
6
Advanced online publication: 08.03.2006
DOI: 10.1055/s-2006-926381; Art ID: T11605SS
© Georg Thieme Verlag Stuttgart · New York

1104
V. T. H. Nguyen et al.
PAPER
O
O
Table 1 Compounds 3 Prepared
O
O
i
OEt
I
R1
Me
Me
Et
Et
Et
Et
Et
Et
Et
Et
Et
R2
R3
Product Yield (%)a
OEt
1
a
a
b
c
d
e
e
f
2
a
b
b
a
a
c
()
n Cl
()n
Cl
+
H
Me
Et
3a
3b
3c
3d
3e
3f
51
44
46
44
46
42
33
42
40
39
39
R1
R1
4a–d
H
5a–d
H
Et
ii
n-Pr
n-Bu
n-Hex
n-Hex
Me
Me
H
Me3SiO
O
Me3SiO
OSiMe3
OEt
iii
OEt
()n
()n
Cl
Cl
R1
6a–d
R1
a
a
c
Me
3g
3h
3i
7a–d
n-Hept Me
iv
O
OSiMe3
f
n-Hept
n-Oct
H
H
H
O
OH
g
h
c
3j
R2
2a,c
()n
EtO
Cl
c
n-Non
3k
R1
a Yield of isolated products.
R2
8a–d
(3-chloro-2-methylpropyl)-2-hydroxybenzoate (8b) was
prepared by cyclization of 2a with 1,3-bis(trimethylsilyl-
Scheme 2 Synthesis of 3-chloroalkyl-2-hydroxybenzoates 8a–d.
Reagents and conditions: i) 1. LDA (2.5 equiv), THF, 0 °C, 1 h, 2.
oxy)-7-chloro-6-methylhepta-1,3-diene (7b). 3-(5-Chlo- 4a–d, –78 → 20 °C; ii) Me3SiCl, Et3N, toluene, 20 °C, 24 h; iii) 1.
LDA, THF, –78 °C, 1 h, 2. Me3SiCl, 20 °C, –78 → 20 °C; iv) TiCl4,
CH2Cl2, –78 → 20 °C.
ropentyl)-2-hydroxybenzoate (8c) and 3-(6-chlorohexyl)-
2-hydroxybenzoate (8d) were prepared by cyclization of
2c with 1,3-bis(trimethylsilyloxy)-9-chloronona-1,3-di-
ene (7c) and 1,3-bis(trimethylsilyloxy)-10-chlorodeca-
1,3-diene (7d), respectively. The synthesis of 7a,d and
8a,d has been previously reported by us.5a Comparable
yields were obtained for the synthesis of 3-alkyl- and 3-
chloroalkyl-2-hydroxybenzoates.
O
O
Cl
OH
O
Me3SiO
OSiMe3
OEt
OEt
9
Cl
TiX4
CH2Cl2
The TiCl4-mediated cyclization of 7a with 1,1-diacetylcy-
clopropane (9) afforded 5-(2-chloroethyl)-3-(3-chloro-
propyl)-2-hydroxybenzoate (10a)5a which was formed by
a domino [3+3] cyclization-homo-Michael reaction5b
(Scheme 3). Likewise, the cyclization of 7a with 9, in the
presence of TiBr4, afforded 5-(2-bromoethyl-3-(3-chloro-
propyl)-2-hydroxybenzoate (10b).
X
7a
10a (X = Cl, 53%)
10b (X = Br, 35%)
Scheme 3 Synthesis of 2-hydroxybenzoates 10a,b
All solvents were dried by standard methods and all reactions were
In summary, we have reported the synthesis of polyalkyl-
ated 2-hydroxybenzoates, some of them containing a re-
mote halide function, based on [3+3] cyclizations of 4-
alkyl- and 4-chloroalkyl-1,3-bis(trimethylsilyloxy)buta-
1,3-dienes.
1
carried out under an inert atmosphere. For H and 13C NMR, the
deuterated solvents indicated were used. Mass spectrometric data
(MS) were obtained by electron ionization (70 eV), chemical ion-
ization (CI, H2O) or electrospray ionization (ESI). For preparative
scale chromatography, silica gel (60–200 mesh) was used. Melting
points are uncorrected.
Table 2 Compounds 5–8 Prepared
5–8
a
n
1
1
3
4
R1
H
R2
Me
Me
H
Yield (%) 5a
Yield (%) 6a
Yield (%) 7a
Yield (%) 8a
55
92
56
88
95
93
96
95
98
93
87
96
52
44
50
55
b
Me
H
c
d
H
H
a Yield of isolated products.
Synthesis 2006, No. 7, 1103–1110 © Thieme Stuttgart · New York

PAPER
Synthesis of 3-Alkyl- and 3-Chloroalkyl-2-hydroxybenzoates
1105
b-Keto Esters 5a–d; General Procedure
lution in n-hexane) and 5-chloro-1-iodopentane (4c; 6.00 g, 25.0
mmol) in THF (200 mL), product 5c was isolated after chromato-
graphy (silica gel, n-hexane–EtOAc, 100:1 → 10:1) as a yellowish
oil (2.745 g, 56%, keto/enol = 87:13).
A THF solution of LDA (2.5 equiv) was prepared by addition of n-
BuLi (15% or 2.5 M solution in n-hexane) to a solution of diisopro-
pylamine (2.5 equiv) in THF (2.5 mL/mmol of LDA). To this solu-
tion ethyl acetoacetate (1.0 equiv) was added at 0 °C. The deep
yellow, clear solution was stirred at 0 °C for 1 h. To this mixture,
the alkyl halide (1.2 equiv) was added at –78 °C. The temperature
was allowed to rise to r.t. within 14 h and the mixture was stirred at
r.t. for 2 h. After the addition of aq 10% HCl (200 mL), the mixture
was extracted with Et2O (4 × 250 mL). The combined organic lay-
ers were dried (Na2SO4), filtered and the solvent removed in vacuo.
The residue was purified by chromatography (silica gel, n-hexane–
EtOAc) to give 5a–d.
IR (neat): 2982 (w), 2934 (s), 2857 (m), 1745 (s), 1710 (s), 1645
(m), 1624 (m), 1449 (m), 1415 (m), 1370 (m), 1318 (m), 1305 (m),
1238 (s), 1182 (m), 1153 (m), 1096 (w), 1033 (m), 1012 (w), 1007
(w), 937 (w), 842 (w), 805 (w), 736 (w), 652 cm–1 (w).
1H NMR (CDCl3, 300 MHz): d = 1.18 (t, J = 7.2 Hz, 3 H, CH3),
1.14–1.33 (m, 2 H, CH2), 1.59–1.80 (m, 6 H, 3 × CH2), 2.40–2.46
(m, 2 H, CH2), 3.47 (s, 2 H, CH2), 3.50–3.55 (m, 2 H, CH2Cl), 4.08
(q, J = 7.2 Hz, 2 H, OCH2), 4.85 (s, 1 H, CH=C of enol), 12.05 (s, 1
H, OH of enol).
13C NMR (CDCl3, 75 MHz): d = 13.8 (CH3), 25.2 (2 C), 25.5, 27.9
(2 C, CH2), 44.6 (CH2Cl), 47.0 (CH2), 60.9 (OCH2), 86.6 (CH=C of
enol), 167.1 (O=CO), 205.5 (C=O).
MS (EI, 70 eV): m/z (%) = 236 (M+ [37Cl], 2), 234 (M+ [35Cl], 15),
199 (35), 162 (6), 148 (9), 146 (33), 143 (26), 130 (42), 126 (14),
119 (6), 114 (24), 110 (10), 97 (10), 87 (21), 83 (68), 72 (14), 70
(27), 59 (23), 55 (100).
Ethyl 7-Chloro-3-oxoheptanoate (5a)
Starting with ethyl acetoacetate (9.1 mL, 71.9 mmol), diisopropyl-
amine (25.3 mL, 180 mmol), n-BuLi (72 mL, 180 mmol, 2.5 M in
n-hexane) and 1-chloro-3-iodopropane (4a; 18.0 g, 86.3 mmol) in
THF (350 mL), product 5a was isolated after chromatography (sili-
ca gel, n-hexane–EtOAc, 100:1 → 10:1) as a yellowish oil (8.160 g,
55%; 8% of enol form).
IR (neat): 2985 (m), 2971 (m), 2876 (w), 1744 (s), 1716 (s), 1647
(m), 1448 (m), 1411 (m), 1369 (m), 1318 (m), 1258 (m), 1244 (m),
1177 (m), 1160 (m), 1096 (m), 1029 (m), 939 (w), 856 (w), 804 (w),
727 (w), 650 cm–1 (w).
1H NMR (CDCl3, 300 MHz): d = 1.29 (t, J = 7.2 Hz, 3 H, CH3),
1.73–1.82 (m, 4 H, 2 × CH2), 2.60 (t, J = 6.9 Hz, 2 H, CH2), 3.44 (s,
2 H, CH2), 3.55 (t, J = 6.9 Hz, 2 H, CH2Cl), 4.21 (q, J = 7.2 Hz, 2
H, OCH2), 4.99 (s, 1 H, CH=C of enol), 12.10 (s, 1 H, OH of enol).
13C NMR (CDCl3, 75 MHz): d = 13.7 (CH3), 20.3, 31.3, 41.6 (CH2),
44.3 (CH2Cl), 48.9 (CH2), 61.0 (OCH2), 166.8 (O=CO), 202.0
(C=O).
MS (EI, 70 eV): m/z (%) = 208 (M+ [37Cl], 2), 206 (M+ [35Cl], 6),
172 (3), 171 (31), 170 (26), 163 (3), 161 (9), 151 (3), 143 (21), 130
(34), 125 (11), 121 (19), 119 (62), 114 (49), 93 (15), 91 (44), 87
(49), 83 (17), 70 (42), 55 (100).
HRMS (EI, 70 eV): The exact molecular mass for C11H19ClO3
m/z = 234.1023 2 ppm [M+].
Ethyl 10-Chloro-3-oxodecanoate (5d)
Starting with ethyl acetoacetate (0.98 mL, 7.8 mmol), diisopropyl-
amine (2.8 mL, 19.5 mmol), n-BuLi (7.8 mL, 19.5 mmol, 2.5 M in
n-hexane) and 1-chloro-6-iodohexane (4d; 2.4 g, 9.3 mmol) in THF
(100 mL), product 5d was isolated after chromatography (silica gel,
n-hexane–EtOAc, 100:1 → 20:1) as a slightly yellowish oil
(1.704 g, 88%; 7% of enol-form).
IR (neat): 2984 (w), 2936 (s), 2860 (w), 1744 (s), 1716 (s), 1646
(w), 1463 (w), 1448 (w), 1411 (w), 1369 (w), 1314 (m), 1238 (m),
1178 (m), 1157 (m), 1098 (w), 1073 (w), 1032 (m), 650 cm–1 (w).
1H NMR (CDCl3, 300 MHz): d = 1.29 (t, J = 7.2 Hz, 3 H, CH3),
1.30–1.38 (m, 4 H, 2 × CH2), 1.39–1.46 (m, 2 H, CH2), 1.56–1.63
(m, 2 H, CH2), 1.76 (quint, J = 6.9 Hz, 2 H, CH2), 2.54 (t, J = 7.2
Hz, 2 H, CH2), 3.43 (s, 2 H, CH2), 3.53 (t, J = 6.9 Hz, 2 H, CH2Cl),
4.20 (q, J = 7.2 Hz, 2 H, OCH2), 4.97 (s, 1 H, CH=C of enol), 12.11
(s, 1 H, OH of enol).
Anal. Calcd for C9H15ClO3 (206.67): C, 52.31; H, 7.32. Found: C,
52.58; H, 7.31.
Ethyl 7-Chloro-6-methyl-3-oxoheptanoate (5b)
13C NMR (CDCl3, 75 MHz): d = 13.8 (CH3), 22.9, 26.3, 28.2, 28.4,
32.2, 42.5, 44.7 (CH2), 48.9 (CH2Cl), 60.9 (OCH2), 88.7 (CH=C of
enol), 166.9 (O=CO), 172.4 (O=CO of enol), 178.4 (OC=CH of
enol), 202.5 (C=O).
MS (EI, 70 eV): m/z (%) = 248 (M+ [35Cl], 1), 213 (3), 163 (6), 161
(29), 143 (14), 130 (86), 114 (17), 97 (36), 93 (1), 91 (4), 88 (26),
84 (24), 70 (36), 55 (100).
Starting with ethyl acetoacetate (6.3 mL, 50.0 mmol), diisopropyl-
amine (17.6 mL, 125.0 mmol), n-BuLi (50 mL, 125.0 mmol, 2.5 M
solution in n-hexane) and 1-bromo-3-chloro-2-methylpropane (4b;
7.0 mL, 60.0 mmol) in THF (200 mL), product 5b was isolated after
chromatography (silica gel, n-hexane–EtOAc, 100:1 → 10:1) as a
yellowish oil (10.2 g, 92%).
IR (neat): 2969 (s), 1743 (s), 1717 (s), 1647 (m), 1457 (m), 1413
(m), 1373 (m), 1316 (m), 1241 (m), 1180 (m), 1031 cm–1 (m).
1H NMR (CDCl3, 300 MHz): d = 1.05 (d, J = 6.5 Hz, 3 H, CH3),
1.31 (t, J = 7.2 Hz, 3 H, CH3), 1.56 (m, 1 H, CH), 1.77–1.87 (m, 2
H, CH2), 2.57–2.62 (t, J = 7.0 Hz, 2 H, CH2), 3.44 (d, J = 7.2 Hz, 2
H, CH2), 3.46 (s, 2 H, CH2), 4.19 (q, J = 7.1 Hz, 2 H, CH2).
13C NMR (CDCl3, 75 MHz): d = 14.1, 17.6 (CH3), 27.3 (CH2), 34.6
(CH), 40.3, 49.2, 50.5, 61.4 (CH2), 167.2, 202.3 (C).
MS (EI, 70 eV): m/z (%) = 184 ([M – Cl]+, 19), 143 (18), 133 (39),
96 (64), 70 (100), 43 (51, 29 (54).
HRMS (EI, 70 eV): The exact molecular mass for C12H21ClO3
m/z = 248.1179 2 ppm [M+].
Silyl Enol Ethers 6a–d; General Procedure
To a benzene solution of b-keto esters 5a–d (1.0 equiv) Et3N (1.5
equiv) was added. After stirring for 1 h at 20 °C, TMSCl (1.5 equiv)
was added dropwise at 20 °C. After stirring for 48 h, the precipitat-
ed salts were filtered off and the filtrate was concentrated in vacuo
to give silyl enol ethers 6a–d.
UV-Vis (MeCN): lmax (log e) = 245 nm (2.94).
7-Chloro-1-ethoxy-3-(trimethylsilyloxy)hept-2-en-1-one (6a)
Starting with 5a (3.651 g, 17.7 mmol), Et3N (3.9 mL, 28 mmol) and
TMSCl (4.0 mL, 32 mmol) in benzene (70 mL), product 6a was iso-
lated without further purification as a yellowish oil (4.689 g, 95%).
Anal. Calcd for C10H17ClO3 (220.69): C, 54.42; H, 7.76. Found: C,
54.33; H, 8.21.
Ethyl 9-Chloro-3-oxononanoate (5c)
Starting with ethyl acetoacetate (2.64 mL, 20.9 mmol), diisopropyl-
1H NMR (CDCl3, 300 MHz): d = 0.29 [s, 9 H, Si(CH3)3], 1.27 (dt,
J = 2.1, 7.2 Hz, 3 H, CH3), 1.66–1.73 (m, 2 H, CH2), 1.77–1.84 (m,
amine (7.3 mL, 52.2 mmol), n-BuLi (21 mL, 52.2 mmol, 2.5 M so-
Synthesis 2006, No. 7, 1103–1110 © Thieme Stuttgart · New York

1106
V. T. H. Nguyen et al.
PAPER
2 H, CH2), 2.75 (t, J = 7.2 Hz, 2 H, CH2), 3.56 (t, J = 6.6 Hz, 2 H,
CH2Cl), 4.12 (dq, J = 2.1, 7.2 Hz, 2 H, OCH2), 5.09 (s, 1 H, CH).
13C NMR (CDCl3, 150 MHz): d = 0.3 [Si(CH3)3], 14.6 (CH3), 24.3,
32.1, 32.3 (CH2), 45.0 (CH2Cl), 59.5 (OCH2), 99.4 (CH=C), 167.8
(O=CO), 172.5 (OC=CH).
1H NMR (CDCl3, 300 MHz): d = 0.16 [s, 9 H, Si(CH3)3], 0.27 [s, 9
H, Si(CH3)3], 1.28 (t, J = 7.2 Hz, 3 H, CH3), 1.85 (m, 2 H, CH2),
2.22 (m, 2 H, CH2), 3.54 (t, J = 7.3 Hz, 2 H, CH2), 3.75 (q, J = 7.1
Hz, 2 H, OCH2), 4.83 (t, J = 7.1 Hz, 1 H, CH=C), 5.13 (s, 1 H,
CH=C).
1,3-Bis(trimethylsilyloxy)-7-chloro-1-ethoxy-6-methylhepta-
1,3-diene (7b)
Starting with 6b (11.87 g, 40.0 mmol), diisopropylamine (8.43 mL,
60.0 mmol), n-BuLi (24 mL, 60.0 mmol, 2.5 M in n-hexane) and
TMSCl (7.58 mL, 60.0 mmol) in THF (200 mL), product 7b was
isolated without further purification as a yellowish oil (13.50 g,
93%).
1H NMR (CDCl3, 300 MHz): d = 0.14 [s, 9 H, Si(CH3)3], 0.25 [s, 9
H, Si(CH3)3], 0.78 (d, J = 6.5 Hz, 3 H, CH3), 1.12 (t, J = 7.2 Hz, 3
H, CH3), 1.21 (m, 1 H, CH), 1.75 (m, 1 H, CH2), 2.05 (m, 1 H, CH2),
3.19 (m, 1 H, CH2), 3.45 (m, 1 H, CH2), 4.12 (q, J = 7.1 Hz, 2 H,
OCH2), 4.84 (t, J = 7.1 Hz, 1 H, CH=C), 5.11 (s, 1 H, CH=C).
7-Chloro-1-ethoxy-6-methyl-3-(trimethylsilyloxy)hept-2-en-1-
one (6b)
Starting with 5b (9.95 g, 45.0 mmol), Et3N (9.36 mL, 67.5 mmol)
and TMSCl (8.53 mL, 67.5 mmol) in benzene (200 mL), product 6b
was isolated without further purifications as a yellowish oil
(12.47 g, 93%).
1H NMR (CDCl3, 300 MHz): d = 0.01 [s, 9 H, Si(CH3)3], 0.75 (d,
J = 6.5 Hz, 3 H, CH3), 0.97 (t, J = 7.2 Hz, 3 H, CH3), 1.17 (m, 1 H,
CH), 1.43–1.59 (m, 2 H, CH2), 2.44–2.52 (t, J = 7.0 Hz, 2 H, CH2),
3.12–3.23 (m, J = 7.2 Hz, 2 H, CH2), 3.83 (q, J = 7.1 Hz, 2 H,
OCH2), 4.80 (s, 1 H, CH=C).
9-Chloro-1-ethoxy-3-(trimethylsilyloxy)non-2-en-1-one (6c)
Starting with 5c (2.474 g, 10.5 mmol), Et3N (2.4 mL, 17.0 mmol)
and TMSCl (2.4 mL, 19.0 mmol) in benzene (50 mL), product 6c
was isolated without further purification as a yellowish oil (3.093 g,
96%).
1H NMR (CDCl3, 300 MHz): d = 0.27 [s, 9 H, Si(CH3)3], 1.27 (dt,
J = 2.1, 7.2 Hz, 3 H, CH3), 1.29–1.45 (m, 6 H, 3 × CH2), 1.57–1.87
(m, 4 H, 2 × CH2), 3.51 (t, J = 6.6 Hz, 2 H, CH2Cl), 4.12 (dq,
J = 2.1, 7.2 Hz, 2 H, OCH2), 4.95 (s, 1 H, CH).
1,3-Bis(trimethylsilyloxy)-9-chloro-1-ethoxynona-1,3-diene (7c)
Starting with 6c (2.64 g, 8.5 mmol), diisopropylamine (1.8 mL, 12.7
mmol), n-BuLi (5.1 mL, 12.7 mmol, 2.5 M solution in n-hexane)
and TMSCl (1.61 mL, 12.7 mmol) in THF (50 mL), product 7c was
isolated without further purification as a yellowish oil (2.8 g, 87%).
1H NMR (CDCl3, 300 MHz): d = 0.17 [s, 9 H, Si(CH3)3], 0.21 [s, 9
H, Si(CH3)3], 1.24 (t, J = 7.2 Hz, 3 H, CH3), 1.36 (m, 2 H, CH2),
1.61–1.82 (m, 4 H, 2 × CH2), 2.25 (m, 2 H, CH2), 3.52 (m, 2 H,
CH2), 4.10 (q, J = 7.1 Hz, 2 H, OCH2), 4.65 (t, J = 7.1 Hz, 1 H,
CH=C), 4.91 (s, 1 H, CH=C).
13C NMR (CDCl3, 150 MHz): d = 0.3 [Si(CH3)3], 14.6 (CH3), 26.16
(2 C), 26.21, 29.8 (2 C, CH2), 40.5 (CH2Cl), 59.4 (OCH2), 97.3
(CH=C), 167.8 (O=CO), 177.4 (OC=CH).
1,3-Bis(trimethylsilyloxy)-10-chloro-1-ethoxydeca-1,3-diene
(7d)
Starting with 6d (0.963 g, 3.0 mmol), diisopropylamine (0.63 mL,
4.5 mmol), n-BuLi (1.8 mL, 4.5 mmol, 2.5 M in n-hexane) and
TMSCl (0.55 mL, 4.5 mmol) in THF (70 mL), product 7d was iso-
lated without further purification as a brownish oil (1.123 g, 96%).
10-Chloro-1-ethoxy-3-(trimethylsilyloxy)dec-2-en-1-one (6d)
Starting with 5d (0.9 g, 3.62 mmol), Et3N (0.75 mL, 5.43 mmol),
TMSCl (0.69 mL, 5.43 mmol) in benzene (50 mL), product 6d was
isolated without further purification as a yellowish oil (1.1 g, 95%).
1H NMR (CDCl3, 300 MHz): d = 0.29 [s, 9 H, Si(CH3)3], 1.26 (dt,
J = 1.5, 7.2 Hz, 3 H, CH3), 1.32–1.37 (m, 6 H, 3 × CH2), 1.39–1.47
(m, 2 H, CH2), 1.48–1.58 (m, 2 H, CH2), 1.77 (quint, J = 7.5 Hz, 2
H, CH2), 2.70 (t, J = 7.5 Hz, 2 H, CH2), 3.53 (t, J = 6.9 Hz, 2 H,
CH2Cl), 4.12 (dq, J = 2.1, 7.2 Hz, 2 H, OCH2), 5.06 (s, 1 H, CH).
1H NMR (CDCl3, 300 MHz): d = 0.18 [s, 9 H, Si(CH3)3], 0.25 [s, 9
H, Si(CH3)3], 1.26–1.49 (m, 7 H, CH3, 2 × CH2), 1.78 (quint,
J = 7.5 Hz, 2 H, CH2), 2.01–2.12 (m, 2 H, CH2), 3.53 (t, J = 6.8 Hz,
2 H, CH2Cl), 3.95 (q, J = 7.2 Hz, 2 H, OCH2), 4.86 (t, J = 7.2 Hz, 1
H, CH=C), 5.06, 5.11 (ds, 1 H, CH=C).
13C NMR (CDCl3, 150 MHz): d = 0.8 [Si(CH3)3], 14.6 (CH3), 26.9,
28.8, 28.9, 32.7, 33.2, 38.3 (CH2), 45.2 (CH2Cl), 59.4 (OCH2), 99.9
(CH=C), 165.8 (O=CO), 173.4 (OC=CH).
13C NMR (CDCl3, 75 MHz): d = 0.8 [3 C, Si(CH3)3], 1.9 [3 C,
Si(CH3)3], 14.3 (CH3), 25.6, 26.8, 28.7, 29.9, 32.6, 45.1 (CH2), 59.2
(OCH2), 98.9, 108.1 (CH=C), 144.6, 156.1 (C).
1,3-Bis(silyl) Enol Ethers 7a–d; General Procedure
2-Hydroxybenzoates 3a–k and 8a–d; General Procedure
To a CH2Cl2 solution of 2a–c (1.0 equiv) and 1a–h or 7a–d (1.0
equiv), was added dropwise TiCl4 (1.0 equiv) at –78 °C under ar-
gon. The mixture was stirred at –78 °C for 30 min and then allowed
to warm to 20 °C during 18 h. A sat. aq solution of NaHCO3 was
added, the organic layer was separated and the aqueous layer was
repeatedly extracted with CH2Cl2. The combined organic extracts
were dried (Na2SO4) and filtered. The filtrate was concentrated in
vacuo and the residue was purified by chromatography (silica gel,
n-hexane–EtOAc, 20:1).
To a THF solution of LDA, prepared by addition of n-BuLi (1.5
equiv, 15% or 2.5 M solution in n-hexane) to a THF solution of di-
isopropylamine (1.5 equiv) at 0 °C and stirring for 20 min, a THF
solution of silyl enol ethers 6a–d (1.0 equiv) was added at –78 °C.
After stirring for 1 h at –78 °C, TMSCl (1.5 equiv) was added. The
temperature of the solution was allowed to rise to r.t. during 2 h and
the solution was stirred for 1 h at 20 °C. The solvent was removed
in vacuo and n-hexane was added to the residue. The precipitated
LiCl was removed by filtration under inert atmosphere and the sol-
vent was removed in vacuo to give 1,3-bis-silyl enol ethers 7a–d.
The product was stored at –20 °C under inert atmosphere and was
used without further purification.
Methyl 2-Hydroxy-4,5,6-trimethylbenzoate (3a)
Starting with 1a (1.04 g, 4.0 mmol), 2a (0.744 g, 4.0 mmol) and
TiCl4 (0.76 g, 4.0 mmol) in CH2Cl2 (8 mL), product 3a was isolated
after chromatography (silica gel, n-hexane–EtOAc, 20:1) as a col-
orless solid (0.395 g, 51%); mp 66 °C.
1,3-Bis(trimethylsilyloxy)-7-chloro-1-ethoxyhepta-1,3-diene
(7a)
Starting with 6a (14.14 g, 50 mmol), diisopropylamine (10.54 mL,
75 mmol), n-BuLi (30 mL, 75 mmol, 2.5 M in n-hexane) and
TMSCl (9.5 mL, 75 mmol) in THF (220 mL), product 7a was iso-
lated without further purification as a yellowish oil (17.2 g, 98%).
IR (KBr): 3240 (w), 3002 (w), 2956 (s), 1657 (s), 1209 (s), 1236 (s),
1156 (s), 1065 (s), 805 cm–1 (w).
Synthesis 2006, No. 7, 1103–1110 © Thieme Stuttgart · New York

PAPER
Synthesis of 3-Alkyl- and 3-Chloroalkyl-2-hydroxybenzoates
1107
1H NMR (CDCl3, 300 MHz): d = 2.13 (s, 3 H, CH3), 2.27 (s, 3 H,
CH3), 2.44 (s, 3 H, CH3), 3.94 (s, 3 H, CH3), 6.69 (s, 1 H, CH), 10.84
(s, 1 H, OH).
13C NMR (CDCl3, 75 MHz): d = 15.2, 18.8, 21.5, 51.5 (CH3), 111.3
(C), 116.2 (CH), 127.2, 138.1, 143.8, 159.0, 171.9 (C=O).
MS (EI, 70 eV): m/z (%) = 193 (M+, 35), 162 (100), 134 (34), 28
(16).
chromatography (silica gel, n-hexane–EtOAc, 20:1) as a yellowish
solid (0.545 g, 44%).
IR (KBr): 2961 (s), 2932 (s), 1636 (s), 1403 (s), 1312 (s), 1196 (s),
1044 (s), 805 cm–1 (m).
1H NMR (CDCl3, 300 MHz): d = 0.99 (t, J = 7.2 Hz, 3 H, CH3),
1.43 (t, J = 7.2 Hz, 3 H, CH3), 1.40–1.52 (sext, J = 7.7 Hz, 2 H,
CH2), 2.15 (s, 3 H, CH3), 2.25 (s, 3 H, CH3), 2.42 (s, 3 H, CH3),
2.67–2.72 (m, 2 H, CH2), 4.42 (q, J = 7.1 Hz, 2 H, CH2), 10.71 (s,
1 H, OH).
13C NMR (CDCl3, 75 MHz): d = 14.2, 14.4, 16.1, 19.2, 22.6 (CH3),
22.6, 28.6), 61.3 (CH2), 111.3, 126.7, 134.8, 141.6, 157.1 (C), 172.2
(C=O).
HRMS (EI, 70 eV): The exact molecular mass for C11H14O3 m/z =
194.0913 2 ppm [M+].
UV-Vis (MeCN): lmax (log e) = 214 (4.38), 252 (3.88), 314 nm
(3.58).
Anal. Calcd for C11H14O3 (194.23): C, 68.02; H, 7.27. Found: C,
68.13; H, 8.21.
MS (EI, 70 eV): m/z (%) = 250 (M+, 50), 204 (100), 176 (93), 146
(32), 91 (39), 29 (25).
Methyl 5-Ethyl-2-hydroxy-4,6-dimethylbenzoate (3b)
Starting with 1a (0.52 g, 2.0 mmol), 2b (0.4 g, 2.0 mmol) and TiCl4
(0.38 g, 2.0 mmol) in CH2Cl2 (5 mL), product 3b was isolated after
chromatography (silica gel, n-hexane–EtOAc, 20:1) as a colorless
solid (0.185 g, 44%).
HRMS (EI, 70 eV): The exact molecular mass C15H22O3 m/z =
250.1569 2 ppm [M+].
UV-Vis (MeCN): lmax (log e) = 217 (4.26), 257 (3.78), 323 nm
(3.34).
Anal. Calcd for C15H22O3 (250.33): C, 72.00; H, 8.85. Found: C,
72.57; H, 8.15.
IR (KBr): 3022 (m), 2969 (s), 1661 (s), 1445 (s), 1354 (s), 1228 (s),
1156 (s), 1074 cm–1 (s).
1H NMR (CDCl3, 300 MHz): d = 1.07 (t, J = 7.2 Hz, 3 H, CH3),
2.47 (s, 3 H, CH3), 2.61 (s, 3 H, CH3), 2.63 (q, J = 7.1 Hz, 2 H, CH2),
3.94 (s, 3 H, OCH3), 6.68 (s, 1 H, CH), 10.54 (s, 1 H, OH).
13C NMR (CDCl3, 75 MHz): d = 13.7, 18.1, 20.7 (CH3), 22.9, 22.3
(CH2), 51.9 (CH3), 111.6, 116.8, 133.3, 137.8, 143.6, 159.3, 172.1
(C=O).
Ethyl 3-Butyl-2-hydroxy-4,5,6-trimethylbenzoate (3e)
Starting with 1d (1.32 g, 4.0 mmol), 2a (0.744 g, 4 mmol) and TiCl4
(0.76 g, 4.0 mmol) in CH2Cl2 (8 mL), product 3e was isolated after
chromatography (silica gel, n-hexane–EtOAc, 20:1) as a yellowish
solid (0.488 g, 46%).
IR (KBr): 2959 (s), 2932 (s), 1654 (s), 1313 (s), 1195 (s), 1043
cm–1 (m).
1H NMR (CDCl3, 300 MHz): d = 0.92 (t, J = 7.2 Hz, 3 H, CH3),
1.22–1.29 (m, 4 H, 2 × CH2), 1.41 (t, J = 7.1 Hz, 3 H, CH3), 2.16 (s,
3 H, CH3), 2.25 (s, 3 H, CH3), 2.42 (s, 3 H, CH3), 2.69 (t, J = 7.2
Hz, 2 H, CH2), 4.43 (q, J = 7.2 Hz, 2 H, CH2), 10.69 (s, 1 H, OH).
13C NMR (CDCl3, 75 MHz): d = 14.1, 14.2, 16.1, 16.9, 19.2 (CH3),
22.8, 26.3, 31.6, 61.3 (CH2), 111.4, 127.1, 134.8, 141.6, 156.9 (C),
172.2 (C=O).
MS (EI, 70 eV): m/z (%) = 208 (M+, 16), 176 (53), 161 (53), 28
(100).
HRMS (EI, 70 eV): The exact molecular mass for C12H16O3 m/z =
208.1099 2 ppm [M+].
UV-Vis (MeCN): lmax (log e) = 216 (4.35), 252 (3.78), 318 nm
(3.31).
Anal. Calcd for C12H16O3 (208.25): C, 69.21; H, 7.74. Found: C,
68.9; H, 7.77.
MS (EI, 70 eV): m/z (%) = 264 (M+, 6), 203 (24), 176 (24), 74 (31),
29 (100).
Ethyl 5-Ethyl-2-hydroxy-4,6-dimethylbenzoate (3c)
Starting with 1b (1.37 g, 5.0 mmol), 2b (1.0 g, 5.0 mmol) and TiCl4
(0.95 g, 5.0 mmol) in CH2Cl2 (8 mL), product 3c was isolated after
chromatography (silica gel, n-hexane–EtOAc, 20:1) as a yellowish
solid (0.513 g, 46%).
HRMS (EI, 70 eV): The exact molecular mass for C16H24O3 m/z =
264.1725 2 ppm [M+].
UV-Vis (MeCN): lmax (log e) = 217 (2.49), 256 (3.90), 315 nm
(3.56).
IR (KBr): 2970 (s), 2933 (s), 1658 (s), 1467 (s), 1313 (s), 1158 (s),
1074 (s), 803 cm–1 (s).
1H NMR (CDCl3, 300 MHz): d = 1.07 (t, J = 7.6 Hz, 3 H, CH3),
1.42 (t, J = 7.2 Hz, 3 H, CH3), 2.30 (s, 3 H, CH3), 2.51 (s, 3 H, CH3),
2.63 (t, J = 7.5 Hz, 2 H, CH2), 4.43 (q, J = 7.1 Hz, 2 H, CH2), 6.68
(s, 1 H, CH), 10.61 (s, 1 H, OH).
13C NMR (CDCl3, 75 MHz): d = 13.7, 14.2, 18.2, 20.7 (CH3), 22.3,
61.4 (CH2), 111.8 (C), 116.8 (CH), 133.2, 137.9, 143.4, 159.3 (C),
171.6 (C=O).
Anal. Calcd for C16H24O3 (264.36): C, 72.69; H, 9.15. Found: C,
72.41; H, 8.23.
Ethyl 3-Hexyl-2-hydroxy-4,6-dimethylbenzoate (3f)
Starting with 1e (1.432 g, 4.0 mmol), 2c (0.68 g, 4mmol) and TiCl4
(0.76 g, 4.0 mmol) in CH2Cl2 (8 mL), product 3f was isolated after
chromatography (silica gel, n-hexane–EtOAc, 20:1) as a yellowish
solid (0.472 g, 42%).
IR (KBr): 2958 (s), 2929 (s), 1653 (s), 1615 (s), 1268 (s), 1175
cm–1 (s).
1H NMR (CDCl3, 300 MHz): d = 0.89 (t, J = 7.1 Hz, 3 H, CH3),
1.24–1.29 (m, 8 H, 4 × CH2), 1.41 (t, J = 6.9 Hz, 3 H, CH3), 2.26 (s,
3 H, CH3), 2.48 (s, 3 H, CH3), 2.62 (t, J = 7.1 Hz, 2 H, CH2), 4.42
(q, J = 7.1 Hz, 2 H, CH2), 6.52 (s, 1 H, CH), 11.70 (s, 1 H, OH).
13C NMR (CDCl3, 75 MHz): d = 14.1, 14.2, 19.7, 22.7, 23.9 (CH3),
26.2, 28.9, 29.7, 31.8, 61.2 (CH2), 109.5 (C), 124.6 (CH), 127.2,
137.6, 142.7, 161.0, 172.2 (C=O).
MS (EI, 70 eV): m/z (%) = 222 (M+, 30), 176 (100), 161 (73), 105
(9), 28 (5).
HRMS (EI, 70 eV): The exact molecular mass for C13H18O3 m/z =
222.1256 2 ppm [M+].
UV-VIS (MeCN): lmax (log e) = 215 (4.34), 252 (3.78), 318 nm
(3.30).
Ethyl 2-Hydroxy-4,5,6-trimethyl-3-propylbenzoate (3d)
Starting with 1c (1.58 g, 5.0 mmol), 2a (0.93 g, 5.0 mmol) and TiCl4
(0.95 g, 5.0 mmol) in CH2Cl2 (8 mL), product 3d was isolated after
MS (EI, 70 eV): m/z (%) = 278 (M+, 42), 217 (57), 162 (100), 161
(72), 28 (38).
Synthesis 2006, No. 7, 1103–1110 © Thieme Stuttgart · New York

1108
V. T. H. Nguyen et al.
PAPER
HRMS (EI, 70 eV): The exact molecular mass for C17H26O3 m/z =
1H NMR (CDCl3, 300 MHz): d = 0.89 (t, J = 7.0 Hz, 3 H, CH3),
1.25–1.29 (m, 10 H, 5 × CH2), 1.41 (t, J = 7.1 Hz, 3 H, CH3), 2.48
(s, 3 H, CH3), 2.62 (t, J = 7.2 Hz, 2 H, CH2), 4.42 (q, J = 7.1 Hz, 2
H, CH2), 6.52 (s, 1 H, CH), 11.69 (s, 1 H, OH).
13C NMR (CDCl3, 75 MHz): d = 14.1, 14.2, 19.7 (CH3), 22.7 (CH2),
23.9 (CH3), 26.2, 28.9, 29.3, 29.9, 31.9, 61.3 (CH2), 109.6 (C),
124.6 (CH), 127.3, 137.6, 142.8, 160.9 (C), 172.3 (C=O).
278.1882 2 ppm [M+].
UV-Vis (MeCN): lmax (log e) = 217 (4.39), 254 (3.98), 317 nm
(3.54).
Anal. Calcd for C17H26O3 (278.39): C, 73.3; H, 9.41. Found: C,
72.23; H, 9.90.
Ethyl 3-Hexyl-2-hydroxy-4,5,6-trimethylbenzoate (3g)
Starting with 1e (1.43 g, 4.0 mmol), 2a (0.744 g, 4.0 mmol) and
TiCl4 (0.76 g, 4.0 mmol) in CH2Cl2 (8 mL), product 3g was isolated
after chromatography (silica gel, n-hexane–EtOAc, 20:1) as a yel-
lowish solid (0.385 g, 33%).
MS (EI, 70 eV): m/z (%) = 292 (M+, 39), 246 (34), 231 (61), 162
(100), 161 (80), 28 (26).
HRMS (EI, 70 eV): The exact molecular mass for C18H28O3 m/z =
292.2038 2 ppm [M+].
UV-Vis (MeCN): lmax (log e) = 217 (4.36), 254 (3.95), 317 nm
(3.53).
IR (KBr): 2958 (s), 2927 (s), 1654 (s), 1314 (s), 1196 (s), 1046
cm–1 (s).
1H NMR (CDCl3, 300 MHz): d = 0.91 (t, J = 6.9 Hz, 3 H, CH3),
1.28 (m, 8 H, 4 × CH2), 1.43 (t, J = 7.2 Hz, 3 H, CH3), 2.16 (s, 3 H,
CH3), 2.25 (s, 3 H, CH3), 2.42 (s, 3 H, CH3), 2.69 (t, J = 7.7 Hz, 2
H, CH2), 4.43 (q, J = 7.1 Hz, 2 H, CH2), 10.69 (s, 1 H, OH).
13C NMR (CDCl3, 75 MHz): d = 14.1, 14.2, 16.1, 16.9, 19.2 (CH3),
22.7, 26.6, 29.4, 29.7, 31.8, 61.3 (CH2), 111.4, 126.9, 127.1, 134.8,
141.5, 156.9 (C), 172.2 (C=O).
Anal. Calcd for C18H28O3 (292.41): C, 73.9; H, 9.65. Found: C,
73.53; H, 9.77.
Ethyl 2-Hydroxy-4,6-dimethyl-3-octylbenzoate (3j)
Starting with 1g (1.78 g, 5.0 mmol), 2c (0.621 g, 5.0 mmol) and
TiCl4 (0.95 g, 5.0 mmol) in CH2Cl2 (8 mL), product 3j was isolated
after chromatography (silica gel, n-hexane–EtOAc, 20:1) as a yel-
lowish solid (0.601 g, 39%).
MS (EI, 70 eV): m/z (%) = 292 (M+, 33), 231 (57), 176 (100), 147
(31), 28 (96).
IR (KBr): 2958 (s), 2856 (s), 1654 (s), 1265 (s), 1174 (s), 845 cm–1
(s).
HRMS (EI, 70 eV): The exact molecular mass for C18H28O3 m/z =
1H NMR (CDCl3, 300 MHz): d = 0.88 (t, J = 6.7 Hz, 3 H, CH3),
1.26–1.30 (m, 12 H, 6 × CH2), 1.41 (t, J = 7.1 Hz, 3 H, CH3), 2.09
(s, 3 H, CH3), 2.48 (s, 3 H, CH3), 2.59 (t, J = 7.2 Hz, 2 H, CH2), 4.39
(q, J = 7.1 Hz, 2 H, CH2), 10.69 (s, 1 H, OH).
13C NMR (CDCl3, 75 MHz): d = 14.1, 14.2, 19.7 (CH3), 22.7 (CH2),
23.9 (CH3), 26.2, 27.1, 28.9, 29.3, 29.6 (CH2), 30.0 (CH), 31.2,
31.9, 61.3 (CH2), 109.9, 124.6, 127.3, 137.6, 142.8, 161.0 (C),
172.2 (C=O).
292.2038 2 ppm [M+].
UV-Vis (MeCN): lmax (log e) = 217 (4.38), 257 (3.92), 321 nm
(3.54).
Anal. Calcd for C18H28O3 (292.41): C, 73.94; H, 9.64. Found: C,
74.05; H, 8.81.
Ethyl 3-Heptyl-2-hydroxy-4,5,6-trimethylbenzoate (3h)
Starting with 1f (1.49 g, 4.0 mmol), 2a (0.744 g, 4.0 mmol) and
TiCl4 (0.76 g, 4.0 mmol) in CH2Cl2 (8 mL), product 3h was isolated
after chromatography (silica gel, n-hexane–EtOAc, 20:1) as a yel-
lowish solid (0.511 g, 42%).
MS (EI, 70 eV): m/z (%) = 306 (M+, 31), 260 (27), 245 (60), 162
(100), 28 (28).
HRMS (EI, 70 eV): The exact molecular mass for C19H30O3 m/z =
306.2195 2 ppm [M+].
IR (KBr): 2958 (s), 2926 (s), 2856 (s), 1654 (s), 1599 (m), 1451 (m),
1404 (m), 1314 (m), 1257 (m), 1196 (m), 1119 (m), 1045 (m), 805
cm–1 (m).
1H NMR (CDCl3, 300 MHz): d = 0.89 (t, J = 6.9 Hz, 3 H, CH3),
1.33–1.38 (m, 12 H, 6 × CH2), 1.43 (t, J = 7.1 Hz, 3 H, CH3), 2.16
(s, 3 H, CH3), 2.25 (s, 3 H, CH3), 2.42 (s, 3 H, CH3), 2.69 (t, J = 7.6
Hz, 2 H, CH2), 4.42 (q, J = 7.1 Hz, 2 H, CH2), 10.69 (s, 1 H, OH).
13C NMR (CDCl3, 75 MHz): d = 14.1, 14.2, 16.1, 16.9, 19.2 (CH3),
22.7, 26.6, 29.3, 29.5, 30.0, 31.9, 61.3 (CH2), 111.3, 126.9, 127.1,
134.8, 141.5, 156.9, 172.2 (C=O).
UV-Vis (MeCN): lmax (log e) = 217 (4.21), 254 (3.75), 319 nm
(3.23).
Anal. Calcd for C19H30O3 (306.44): C, 74.47; H, 9.87. Found: C,
74.13; H, 8.73.
Ethyl 2-Hydroxy-4,6-dimethyl-3-nonylbenzoate (3k)
Starting with 1h (1.38 g, 4.0 mmol), 2c (0.680 g, 4.0 mmol) and
TiCl4 (0.76 g, 4.0 mmol) in CH2Cl2 (8 mL), product 3k was isolated
after chromatography (silica gel, n-hexane–EtOAc, 20:1) as a yel-
lowish solid (0.501 g, 39%).
MS (EI, 70 eV): m/z (%) = 306 (M+, 19), 245 (40), 176 (81), 28
(100).
IR (KBr): 2957 (s), 2927 (s), 1654 (s), 1615 (s), 1266 (s), 1173 (s),
846 cm–1 (m).
HRMS (EI, 70 eV): The exact molecular mass for C19H30O3 m/z =
1H NMR (CDCl3, 300 MHz): d = 0.89 (t, J = 6.9 Hz, 3 H, CH3),
1.27–1.32 (m, 14 H, 7 × CH2), 1.45 (t, J = 7.1 Hz, 3 H, CH3), 2.27
(s, 3 H, CH3), 2.49 (s, 3 H, CH3), 2.59 (t, J = 7.2 Hz, 2 H, CH2), 4.43
(q, J = 7.1 Hz, 2 H, CH2), 6.53 (s, 1 H, CH), 11.71 (s, 1 H, OH).
13C NMR (CDCl3, 75 MHz): d = 14.1, 14.2, 19.8 (CH3), 22.7 (CH2),
23.9 (CH3), 26.2, 26.3, 28.9, 29.4, 29.6, 30.0, 31.9, 61.3 (CH2),
109.6 (C), 124.6 (CH), 127.3, 137.6, 142.8, 161.0 (C), 172.3 (C=O).
306.2195 2 ppm [M+].
UV-Vis (MeCN): lmax (log e) = 216 (4.46), 257 (4.06), 317 nm
(3.76).
Anal. Calcd for C19H30O3 (306.44): C, 74.54; H, 9.87. Found: C,
74.13; H, 8.73.
Ethyl 3-Heptyl-2-hydroxy-4,6-dimethylbenzoate (3i)
Starting with 1f (1.489 g, 4.0 mmol), 2c (0.680 g, 4.0 mmol) and
TiCl4 (0.76 g, 4.0 mmol) in CH2Cl2 (8 mL), product 3i was isolated
after chromatography (silica gel, n-hexane–EtOAc, 20:1) as a yel-
lowish solid (0.464 g, 40%).
MS (EI, 70 eV): m/z (%) = 320 (M+, 20), 259 (40), 163 (100), 161
(94), 74 (99), 43 (92), 28 (56).
HRMS (EI, 70 eV): The exact molecular mass for C20H32O3 m/z =
320.2351 2 ppm [M+].
UV-Vis (MeCN): lmax (log e) = 217 (4.36), 254 (3.95), 317 nm
(3.53).
IR (KBr): 2957 (s), 2928 (s), 1653 (s) 1615 (s), 1265 (s), 1174
cm–1 (s).
Synthesis 2006, No. 7, 1103–1110 © Thieme Stuttgart · New York

PAPER
Synthesis of 3-Alkyl- and 3-Chloroalkyl-2-hydroxybenzoates
1109
Ethyl 3-(3-Chloropropyl)-2-hydroxy-4,5,6-trimethylbenzoate
(8a)
Starting with 7a (1.23 g, 3.5 mmol), 2a (0.61 g, 8.2 mmol) and
TiCl4 (0.66 g, 3.5 mmol) in CH2Cl2 (10 mL), product 8a was isolat-
ed after chromatography (silica gel, n-hexane–EtOAc, 30:1) as a
colorless oil (0.516 g, 52%).
13C NMR (CDCl3, 75 MHz): d = 14.2, 19.8, 23.9 (CH3), 25.9, 27.1,
28.1, 32.5, 45.1, 61.3 (CH2), 109.7 (C), 124.7 (CH), 126.7, 137.9,
142.8, 161.0, 172.3 (C=O).
MS (EI, 70 eV): m/z (%) = 300 (M+ [37Cl], 3), 298 (M+ [35Cl], 37),
252 (28), 217 (69), 162 (100), 161 (84), 91 (9), 74 (74), 29 (50).
HRMS (ESI): m/z calcd for C16H23ClO3 ([M + 1]+): 300.13845
IR (neat): 3426 (m), 2964 (s), 1650 (s), 1599 (m), 1444 (m), 1401
(s), 1373 (s), 1113 (s), 1277 (s), 1200 (s), 1036 (m), 808 cm–1 (m).
[37Cl], 298.14140 [35Cl]; found: 300.13568 [37Cl], 298.14097 [35Cl].
UV-Vis (MeCN): lmax (log e) = 216 (4.48), 254 (4.06), 316 nm
(3.65).
1H NMR (CDCl3, 300 MHz): d = 1.43 (t, J = 7.2 Hz, 3 H, CH3),
1.99 (quint, J = 6.6 Hz, 2 H, CH2), 2.25 (s, 3 H, CH3), 2.29 (s, 3 H,
CH3), 2.44 (s, 3 H, CH3), 2.87 (t, J = 6.0 Hz, 2 H, CH2), 3.61 (t,
J = 6.7 Hz, 2 H, CH2Cl), 4.44 (q, J = 7.1 Hz, 2 H, OCH2), 10.78 (s,
1 H, OH).
Anal. Calcd for C16H23ClO3 (298.81): C, 64.31; H, 7.75. Found: C,
64.62; H, 8.04.
Ethyl 3-(6-Chlorohexyl)-2-hydroxy-4,6-dimethylbenzoate (8d)
Starting with 7d (3.13 g, 8.0 mmol), 2c (1.38 g, 8.0 mmol) and TiCl4
(1.52 g, 8.0 mmol) in CH2Cl2 (16 ml), product 8d was isolated after
chromatography (silica gel, n-hexane–EtOAc, 30:1) as a yellowish
solid (1.39 g, 55%).
13C NMR (CDCl3, 75 MHz): d = 14.2, 16.1, 16.9 (CH3), 19.2, 24.1,
32.3, 45.3, 61.5 (CH2), 111.4, 124.9, 127.3, 135.5, 141.7, 157.1,
172.1 (C=O).
MS (EI, 70 eV): m/z (%) = 286 (M+ [37Cl], 5), 284 (M+ [35Cl], 19),
238 (21), 203 (100), 176 (16), 162 (28), 134 (10), 105 (8), 91 (16),
29 (9).
IR (KBr): 3420 (br), 2932 (m), 2856 (s), 1651 (s), 1616 (s), 1569
(m), 1450 (m), 1392 (m), 1351 (m), 1303 (s), 1270 (s), 1231 (s),
1175 (s), 1044 (m), 814 cm–1 (s).
1H NMR (CDCl3, 300 MHz): d = 1.22 (m, 4 H, 2 × CH2), 1.39 (t,
J = 7.1 Hz, 3 H, CH3), 1.43 – 1.51 (m, 2 H, CH2), 1.74–1.83 (quint,
J = 6.8 Hz, 2 H, CH2), 2.26 (s, 3 H, CH3), 2.48 (s, 3 H, CH3), 2.63
(t, J = 7.5 Hz, 2 H, CH2), 3.53 (t, J = 6.7 Hz, 2 H, CH2Cl), 4.42 (q,
J = 7.1 Hz, 2 H, OCH2), 6.53 (s, 1 H, CH), 11.71 (s, 1 H, OH).
HRMS (ESI): m/z calcd for C15H22ClO3 ([M + 1]+): 287.12280
[37Cl], 285.12575 [35Cl]; found: 287.12243 [37Cl], 285.12632 [35Cl].
UV-Vis (MeCN): lmax (log e) = 217 (4.39), 256 (3.94), 321 nm
(3.55).
Anal. Calcd for C15H21ClO3 (284.78): C, 63.25; H, 7.43. Found: C,
63.20; H, 7.18.
13C NMR (CDCl3, 75 MHz): d = 14.2, 19.8, 23.9 (CH3), 26.0, 26.8,
28.7, 29.2, 32.6, 45.2, 61.3 (CH2), 109.7 (C), 124.7 (CH), 126.9,
137.8, 142.8, 161.0, 172.3 (C=O).
Ethyl 3-(3-Chloro-2-methylpropyl)-2-hydroxy-4,5,6-trimethyl-
benzoate (8b)
Starting with 7b (1.09 g, 3.0 mmol), 2a (0.56 g, 3.0 mmol) and TiCl4
(0.56 g, 3.0 mmol) in CH2Cl2 (10 mL), product 8b was isolated after
chromatography (silica gel, n-hexane–EtOAc, 30:1) as a colorless
oil (0.398 g, 44%).
MS (EI, 70 eV): m/z (%) = 314 (M+ [37Cl], 10), 312 (M+ [35Cl], 34),
266 (29), 251 (24), 231 (23), 189 (11), 162 (100), 161 (75), 134
(18), 91 (17), 79 (18), 41 (20), 29 (18).
UV-Vis (MeCN): lmax (log e) = 216 (4.44), 254 (4.01), 317 nm
(3.59).
IR (neat): 2965 (m), 2931 (m), 1654 (s), 1599 (m), 1449 (m), 1403
(m), 1310 (s), 1197 (m), 1092 (m), 1042 (m), 804 cm–1 (m).
Anal. Calcd for C17H25ClO3 (312.83): C, 65.26; H, 8.05. Found: C,
64.97; H, 7.51.
1H NMR (CDCl3, 300 MHz): d = 1.06 (d, J = 6.7 Hz, 3 H, CH3),
1.42 (t, J = 7.1 Hz, 3 H, CH3), 2.11–2.14 (m, 1 H, CH), 2.16 (s, 3 H,
CH3), 2.16 (s, 3 H, CH3), 2.44 (s, 3 H, CH3), 2.69 (dq, J = 24, 7.1
Hz, 2 H, CH2), 3.49 (m, J = 5.5 Hz, 2 H, CH2Cl), 4.43 (q, J = 7.1
Hz, 2 H, OCH2), 10.77 (s, 1 H, OH).
13C NMR (CDCl3, 75 MHz): d = 14.6, 16.6, 17.8, 18.3, 19.7 (CH3),
31.4 (CH2), 36.9 (CH), 51.8, 61.9 (CH2), 111.4, 124.2, 127.3, 135.6,
142.2, 157.4, 172.1 (C=O).
Ethyl 5-(2-Chloroethyl)-3-(3-chloropropyl)-2-hydroxybenzoate
(10a)
To a CH2Cl2 solution (250 mL) of 1,1-diacetylcyclopropane (0.48
g, 3.8 mmol) and 7a (2.0 g, 5.7 mmol), was added dropwise TiCl4
(2.16 g, 11.4 mmol) at –78 °C. The mixture was allowed to warm to
20 °C during 18 h. Aq 10% HCl was added, the organic layer was
separated and the aqueous layer was extracted with CH2Cl2 repeat-
edly. The combined organic extracts were dried (Na2SO4), filtered
and the filtrate was concentrated in vacuo. The residue was purified
by column chromatography (silica gel, n-hexane–EtOAc, 25:1) to
give 10a as a colorless solid (672 mg, 53%).
MS (EI, 70 eV): m/z (%) = 300 (M+ [37Cl], 1), 298 (M+ [35Cl], 4),
217 (43), 175 (16), 162 (27), 91 (9), 32 (2), 28 (100).
UV-Vis (MeCN): lmax (log e) = 216 (4.43), 256 (3.96), 321 nm
(3.59).
Anal. Calcd for C16H23ClO3 (298.81): C, 64.31; H, 7.76. Found: C,
64.89; H, 7.97.
IR (KBr): 3400 (m), 2982 (m), 2961 (m), 1659 (s), 1594 (m), 1449
(s), 1374 (s), 1311 (s), 1277 (s), 1192 (s), 1146 (s), 1038 (s), 650
cm–1 (m).
Ethyl 3-(5-Chloropentyl)-2-hydroxy-4,6-dimethylbenzoate (8c)
Starting with 7c (1.14 g, 3.0 mmol), 2c (1.0 g, 5.0 mmol) and TiCl4
(0.57 g, 3.0 mmol) in CH2Cl2 (7 mL), product 8c was isolated after
chromatography (silica gel, n-hexane–EtOAc, 30:1) as a yellowish
solid (0.441 g, 50%).
1H NMR (300 MHz, CDCl3): d = 1.42 (t, J = 7.1 Hz, 3 H, CH3),
1.97 (m, J = 7.6 Hz, 2 H, CH2), 2.29 (s, 3 H, CH3), 2.49 (s, 3 H,
CH3), 2.85 (t, J = 5.6 Hz, 2 H, CH2), 3.14 (t, J = 6.5 Hz, 2 H, CH2),
3.50 (t, J = 7.1 Hz, 2 H, CH2Cl), 3.60 (t, J = 6.5 Hz, 2 H, CH2Cl),
4.44 (q, J = 7.1 Hz, 2 H, OCH2), 10.98 (s, 1 H, OH).
13C NMR (CDCl3, 75 MHz): d = 14.2, 16.4, 18.7 (CH3), 24.2, 31.9,
33.6, 42.2, 45.2, 61.7 (CH2), 111.8, 125.9, 126.9, 136.3, 141.9,
158.4, 171.9 (C=O).
IR (KBr): 3428 (br), 2938 (m), 1852 (s), 1616 (m), 1448 (m), 1394
(m), 1267 (s), 1177 (m), 1048 (w), 811 cm–1 (w).
1H NMR (CDCl3, 300 MHz): d = 1.41 (t, J = 7.1 Hz, 3 H, CH3),
1.51–1.54 (m, 4 H, 2 × CH2), 1.80–1.84 (m, 2 H, CH2), 2.26 (s, 3 H,
CH3), 2.48 (s, 3 H, CH3), 2.61–2.65 (m, 2 H, CH2), 3.54 (t, J = 7.2
Hz, 2 H, CH2), 4.42 (q, J = 7.1 Hz, 2 H, OCH2), 6.53 (s, 1 H, CH),
11.72 (s, 1 H, OH).
MS (EI, 70 eV): m/z (%) = 334 (M+ [37Cl 35Cl], 9), 332 (M+
[2 × 35Cl], 17), 286 (23), 251 (100), 224 (12), 189 (6), 173 (3), 159
(4), 115 (5), 91 (8), 28 (10).
Synthesis 2006, No. 7, 1103–1110 © Thieme Stuttgart · New York

1110
V. T. H. Nguyen et al.
PAPER
HRMS (ESI): m/z calcd for C16H22Cl2O3 ([M + 1]+): 333.10242
[2 × 35Cl]; found: 333.10146 [2 × 35Cl].
Dawson, R. J. Am. Chem. Soc. 1954, 76, 5070. (d) Dawson,
R.; Markiswitz, J. J. Org. Chem. 1965, 30, 1610.
(e) Adawadkar, P. D.; Elsohly, M. A. Phytochemistry 1983,
22, 1280. Bhilawanol: (f) Mason, S. J. Am. Chem. Soc.
1945, 67, 418. 5-Chlorflexirubin: (g) Sargent, M. V.;
Wangchareontrakul, S. J. Chem. Soc., Perkin Trans. 1 1989,
431. Belamcandol A: (h) Fukuyama, Y.; Okino, J.; Kodama,
M. Chem. Pharm. Bull. 1991, 39, 1877. (i) Marner, F.-J.;
Horper, W. Helv. Chim. Acta 1992, 75, 1557. (j) Oshima,
R.; Yamauchi, Y.; Watanabe, C.; Kumanotani, J. J. Org.
Chem. 1985, 50, 2613. (k) Budzikiewicz, H.; Scholl, H.;
Neuenhaus, W.; Pulverer, G.; Korth, H. Z. Naturforsch. B
1980, 35, 909. Amorfrutin B: (l) Mitscher, L. A.; Park, Y.
H.; Al-Shamma, A.; Hudson, P. B.; Haas, T. Phytochemistry
1981, 20, 781. (m) Anaya, A. L.; Mata, R.; Rivero-Cruz, F.;
Hernandez-Bautista, B. E.; Chavez-Velasco, D.; Gomez-
Pompa, A. J. Chem. Ecol. 1999, 25, 141. (n) Rivero-Cruz,
J. F.; Chavez, D.; Bautista, B. H.; Anaya, A. L.; Mata, R.
Phytochemistry 1997, 45, 1003. (o) Groweiss, A.;
Cardellina, J. H.; Pannell, L. K.; Uyakul, D.; Kashman, Y.;
Boyd, M. R. J. Nat. Prod. 1997, 60, 116. (p) David, J. M.;
Chavez, J. P.; Chai, H.-B.; Pezzuto, J. M.; Cordell, G. A. J.
Nat. Prod. 1998, 61, 287. Hierridin B: (q) Jinno, S.; Hata,
K.; Shimidzu, N.; Okita, T. J. Antibiot. 1998, 51, 508.
(r) Jinno, S.; Okita, T. Chem. Pharm. Bull. 1998, 46, 1688.
(s) Papendorf, O.; Koenig, G. M.; Wright, A. D.
Phytochemistry 1998, 49, 2383.
UV-Vis (MeCN): lmax (log e) = 219 (4.50), 256 (3.92), 318 nm
(3.55).
Ethyl 3-(2-Bromoethyl)-5-(3-chloropropyl)-6-hydroxy-2,4-di-
methylbenzoate (10b)
Starting with 7a (1.58 g, 4.5 mmol), 1,1-diacetylcyclopropane
(0.38 g, 3.0 mmol) and TiBr4 (2.21 g, 6.0 mmol) in CH2Cl2 (200
mL), product 10b was isolated after chromatography (silica gel, n-
hexane–EtOAc, 20:1) as a colorless solid (0.397 g, 35%).
IR (KBr): 3411 (m), 2991 (m), 2995 (m), 1660 (s, 1593 (m), 1446
(m), 1373 (m), 1317 (s), 1275 (m), 1190 (s), 1146 (s), 1087 (s), 1032
cm–1 (m).
1H NMR (CDCl3, 300 MHz): d = 1.42 (t, J = 7.1 Hz, 3 H, CH3),
1.97 (m, J = 6.5 Hz, 2 H, CH2), 2.34 (s, 3 H, CH3), 2.48 (s, 3 H,
CH3), 2.84 (t, J = 6.5 Hz, 2 H, CH2), 3.21 (m, 2 H, CH2), 3.34 (m, 2
H, CH2Cl), 3.60 (t, J = 6.6 Hz, 2 H, CH2Br), 4.44 (q, J = 7.1 Hz, 2
H, OCH2), 10.99 (s, 1 H, OH).
13C NMR (CDCl3, 75 MHz): d = 14.2, 16.4, 18.7 (CH3), 24.2, 29.8,
31.9, 34.0, 45.2, 61.7 (CH2), 111.8, 126.1, 128.2, 136.2, 141.7,
158.4, 171.9 (C).
MS (EI, 70 eV): m/z (%) = 380 (M+ [81Br 35Cl], 378 (M+ [81Br 35Cl],
23), 376 (M+ [79Br 35Cl], 16), 332 (27), 297 (100), 251 (15), 189
(37), 161 (16), 91 (16), 29 (25).
(3) For a review of 1,3-bis(silyl) enol ethers, see: Langer, P.
HRMS (ESI): m/z calcd for C16H23BrClO3 ([M + 1]+): 379.04896
[79Br 37Cl], 377.05191 [79Br 35Cl]; found: 379.04868 [79Br 37Cl],
377.05072 [79Br 35Cl].
Synthesis 2002, 441.
(4) (a) Chan, T.-H.; Brownbridge, P. J. Am. Chem. Soc. 1980,
102, 3534. (b) Brownbridge, P.; Chan, T.-H.; Brook, M. A.;
Kang, G. J. Can. J. Chem. 1983, 61, 688.
(5) (a) Nguyen, V. T. H.; Langer, P. Tetrahedron Lett. 2005, 46,
815. (b) Bose, G.; Nguyen, V. T. H.; Ullah, E.; Lahiri, S.;
Görls, H.; Langer, P. J. Org. Chem. 2004, 69, 9128. For
sequential [3+3] cyclization/Suzuki reactions, see:
(c) Nguyen, V. T. H.; Langer, P. Tetrahedron Lett. 2005, 46,
1013.
(6) Molander, G. A.; Cameron, K. O. J. Am. Chem. Soc. 1993,
115, 830.
(7) Nguyen, V. T. H.; Bellur, E.; Appel, B.; Langer, P.,
unpublished results.
UV-Vis (MeCN): lmax (log e) = 222 (4.49), 255 (3.98), 317 nm
(3.72).
Acknowledgment
Financial support from the Ministry of Education of Vietnam (scho-
larship for V.T.H.N.), from the DAAD (scholarship for E.B.), from
the state of Mecklenburg-Vorpommern (Landesforschungsschwer-
punkt ‘Neue Wirkstoffe und Screeningverfahren’) and from the
Deutsche Forschungsgemeinschaft is gratefully acknowledged.
(8) Langer, P.; Bellur, E. J. Org. Chem. 2003, 68, 9742.
(9) For a review of dianions, see: Thompson, C. M.; Green, D.
Tetrahedron 1991, 47, 4223.
(10) (a) Weiler, L. J. Am. Chem. Soc. 1970, 92, 6702. (b) Sum,
P.-E.; Weiler, L. Can. J. Chem. 1977, 55, 996.
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Synthesis 2006, No. 7, 1103–1110 © Thieme Stuttgart · New York