Domino [3+3]-cyclization-homo-Michael reactions of 1,3-bissilyl enol ethers with 1,1-diacylcyclopropanes

Article abstract of DOI:10.1021/jo0485278

The Lewis acid mediated domino [3+3]-cyclization-homo-Michael reaction of 1,3-bissilyl enol ethers with 1,1-diacylcyclopropanes allows an efficient one-pot synthesis of functionalized salicylates containing a halogenated side chain. A great variety of substitution patterns could be realized by variation of the starting materials and of the Lewis acid. The mechanism of the domino process was studied.

Full text of DOI:10.1021/jo0485278

Domino “[3+3]-Cyclization-Homo-Michael” Reactions of 1,3-Bissilyl
Enol Ethers with 1,1-Diacylcyclopropanes
Gopal Bose,† Van Thi Hong Nguyen,† Ehsan Ullah,† Sunanda Lahiri,† Helmar Go¨rls,‡ and
Peter Langer*,†
Institut fu¨r Chemie und Biochemie, Ernst-Moritz-Arndt Universita¨t Greifswald, Soldmannstrasse 16,
D-17487 Greifswald, Germany, and Institut fu¨r Anorganische und Analytische Chemie, Universita¨t Jena,
August-Bebel-Strasse 2, 07740 Jena, Germany
peter.langer@uni-greifswald.de
Received August 22, 2004
The Lewis acid mediated domino “[3+3]-cyclization-homo-Michael” reaction of 1,3-bissilyl enol ethers
with 1,1-diacylcyclopropanes allows an efficient one-pot synthesis of functionalized salicylates
containing a halogenated side chain. A great variety of substitution patterns could be realized by
variation of the starting materials and of the Lewis acid. The mechanism of the domino process
was studied.
1,3-Bissilyl enol ethers can be regarded as electroneu-
tral 1,3-dicarbonyl dianion equivalents (masked di-
anions).1,2 They represent useful synthetic building blocks
in Lewis acid mediated transformations. In cyclization
reactions, 1,3-bissilyl enol ethers can react as 1,3-
dinucleophiles or, similar to the well-known Danishefsky
diene,3 as functionalized 1,4-butadienes. Chan and co-
workers have reported TiCl4-mediated [3+3] cyclizations
of 1,3-bissilyl enol ethers with 3-silyloxyalk-2-en-1-ones
and with ketals of â-keto aldehydes, â-ketoesters, and
â-ketocarboxylic chlorides to give benzene derivatives.2d,e
We have recently reported the TiCl4-mediated domino
“[3+3]-cyclization-homo-Michael” reaction of 1,3-bissilyl
enol ethers with 1,1-diacetylcyclopropane.4,5 This cycliza-
tion allows an efficient one-pot synthesis of functionalized
salicylates containing a halogenated side chain. The
strategic placement of the halide group in these products
makes them versatile synthetic intermediates. With
regard to our preliminary communication, we signifi-
cantly extended the preparative scope and developed, for
example, regioselective cyclizations of unsymmetrical 1,1-
diacylcyclopropanes. In addition, we studied the mech-
anism of the domino process.
Results and Discussion
Mechanism. The TiCl4-mediated reaction of 1,3-bis-
silyl enol ether 1a with 1,1-diacetylcyclopropane (2a)6
afforded the chlorinated salicylate 3a in 82% yield. The
best yields were obtained when 2 equiv of the Lewis acid
were used. Two mechanisms can be discussed for the
formation of 3a. Path A: Titanium enolate A is formed
by TiCl4-mediated ring-opening of 2a. The reaction of A
with 1a proceeds, in analogy to the known cyclization of
1,3-bissilyl enol ethers with 3-silyloxypent-3-en-2-one,2e
by attack of 1a onto the Michael position (intermediate
B) and subsequent cyclization. Alternatively, the cycliza-
tion could proceed by formation of the spirocyclic inter-
mediate C and subsequent TiCl4-mediated ring cleavage
(homo-Michael reaction) via intermediate D.
The mechanism of the cyclization was studied. Mech-
anism path A is supported by the following experiment:
Treatment of 2a with TiCl4 and subsequent aqueous
workup afforded 3-(2′-chloroethyl)pentane-2,4-dione (4)
in 47% yield (Scheme 2). The formation of 4 can be
explained by TiCl4-mediated formation of titanium eno-
late A and subsequent hydrolysis. Although 4 fails to
directly react with 1,3-bissilyl enol ethers, a cyclization
of 1,3-bissilyl enol ethers with intermediate A cannot be
ruled out. In fact, the related cyclization of 3-silyloxyalk-
2-en-1-ones with 1,3-bissilyl enol ethers is known (vide
supra).2d,e
* Address correspondence to this author. Fax: (+49) 3834-864373.
† Ernst-Moritz-Arndt Universita¨t Greifswald.
‡ Universita¨t Jena.
(1) For a review of 1,3-bissilyl enol ethers, see: Langer, P. Synthesis
2002, 441.
(2) (a) Chan, T.-H.; Brownbridge, P. J. Chem. Soc., Chem. Commun.
1979, 578. (b) Chan, T.-H.; Brownbridge, P. J. Am. Chem. Soc. 1980,
102, 3534. (c) Molander, G. A.; Cameron, K. O. J. Am. Chem. Soc. 1993,
115, 830. (d) Chan, T. H.; Chaly, T. Tetrahedron Lett. 1982, 23, 2935.
(e) Brownbridge, P.; Chan, T.-H.; Brook, M. A.; Kang, G. J. Can. J.
Chem. 1983, 61, 688.
(3) Reviews: (a) Jorgensen, K. A. Angew. Chem. 2000, 112, 3702;
Angew. Chem., Int. Ed. Engl. 2000, 39, 3558. (b) Danishefsky, S. J.;
Bilodeau, M. T. Angew. Chem. 1996, 108, 1482; Angew. Chem., Int.
Ed. Engl. 1996, 35, 1380. (c) Bednarski, M. D.; Lyssikatos, J. P.
Comprehensive Organic Synthesis: Selectivity, Strategy and Efficiency
in Modern Organic Chemistry; Trost, B. M., Ed.; Pergamon Press: New
York, 1991; Vol. 2, p 661.
(4) Langer, P.; Bose, G. Angew. Chem. 2003, 115, 4165; Angew.
Chem., Int. Ed. 2003, 42, 4033.
(5) For reviews of domino reactions, see: (a) Tietze, L. F.; Beifuss,
U. Angew. Chem. 1993, 105, 137; Angew. Chem., Int. Ed. Engl. 1993,
32, 131. (b) Tietze, L. F. Chem. Rev. 1996, 96, 115.
However, we believe that the cyclization of the 1,3-
bissilyl enol ether with 1,1-diacylcyclopropanes proceeds
by mechanism type B, based on the following observa-
(6) The starting materials were prepared according to a known
procedure: Zefirov, N. S.; Kuznetsova, T. S.; Kozhushkov, S. I.;
Surmina, L. S.; Rakina, Z. A. Zh. Org. Khim. 1983, 19, 541.
10.1021/jo0485278 CCC: $27.50 © 2004 American Chemical Society
Published on Web 11/20/2004
9128
J. Org. Chem. 2004, 69, 9128-9134

Efficient One-Pot Synthesis of Functionalized Salicylates
SCHEME 1. Possible Mechanisms of the
Cyclization of 1,3-Bissilyl Enol Ether 1a with
1,1-Diacetylcyclopropane
CHART 1
termediate C, Scheme 1), and subsequent hydrolysis
upon aqueous workup. Treatment of 5 with TiCl4 afforded
the salicylate 3b in 53% yield. The yield was significantly
improved when NBu4Cl was employed. The use of more
than 0.5 equiv of TiCl4 in the reaction of 1b with 2a
resulted in formation of significant amounts of 3b at the
expense of 5. In fact, salicylate 3b was isolated in 64%
yield when the cyclization was carried out in the presence
of 2.0 equiv of TiCl4. The use of BF3‚OEt2, Me3SiOTf, or
TFA resulted in formation of complex mixtures.
Acceptor-substituted cyclopropanes represent impor-
tant building blocks in homo-Michael reactions with
various nucleophiles.8 Reactions of acceptor-substituted
cyclopropanes have been classified by Danishefsky in
terms of “strictly nucleophilic ring openings”, “electro-
philically assisted ring openings”, and “spiro-activa-
tions”.9 In the domino “[3+3]-cyclization-homo-Michael”
reaction reported herein two effects are operating: (a) a
“dynamic spiro-activation”10 and (b) activation by an
electrophile.
The second step of mechanism path B, the transforma-
tion of the spirocyclopropane into the salicylate, is related
to the biosynthesis of the carcinogenic pterosins isolated
from the bracken fern Pteridium aquilinium.11 It was
shown earlier that the pterosins are formed from their
direct biogenetic precursor, the spirocyclopropane pta-
quilosin, by treatment with acid. It was proposed that
the pterosins, ptaquilosin, and illudin M (Chart 1) are
all formed from farnesyl phosphate via a common bio-
synthetic intermediate.12 The synthesis of analogues of
these compounds is of considerable pharmacological
relevance, due to their potential cytotoxic and cancero-
static activity.13
SCHEME 2. Mechanistic Studies
Preparative Scope. The TiCl4-mediated reaction of
1,1-diacetylcyclopropane (2a) with a variety of 1,3-bissilyl
enol ethers was studied. The reaction of 2a with â-ke-
toester derived 1,3-bissilyl enol ethers 1a-d afforded the
(8) (a) Houben-Weyl, Methoden der Organischen Chemie, 4th ed.;
Carbocyclic Three-Membered Ring Compounds, Vol. E17; de Meijere,
A., Ed.; Thieme: Stuttgart, Germany, 1996. (b) The Chemistry of the
Cyclopropyl Group; Rappoport, Z., Ed.; Wiley: Chichester, UK, 1987.
(9) Danishefsky, S. J. Acc. Chem. Res. 1979, 12, 6.
(10) Dynamic spiro activation: Zefirov, N. S.; Kozhushkov, S. I.;
Kuznetsova, T. S. Tetrahedron 1982, 38, 1693.
(11) (a) McMorris, T. C.; Voeller, B. Phytochemistry 1971, 10, 3253.
(b) Yoshishira, K.; Fukuoka, M.; Kuroyanagi, M.; Natori, S. Chem.
Pharm. Bull. 1971, 19, 1491. (c) Bardouille, V.; Mootoo, B. S.; Hirotsu,
K.; Clardy, J. Phytochemistry 1978, 17, 275. (d) Sengupta, P.; Sen, M.;
Niyogi, S. K.; Pakrashi, S. C.; Ali, E. Phytochemistry 1976, 15, 995. (e)
Yoshihira, K.; Fukuoka, M.; Kuroyanagi, M.; Natori, S.; Umeda, M.;
Morohoshi, T.; Enomoto, M.; Saito, M. Chem. Pharm. Bull. 1978, 26,
2346.
(12) (a) McMorris, T. C.; Anchel, M. J. Am. Chem. Soc. 1965, 87,
1594. (b) McMorris, T. C.; Kelner, M. J.; Wang, W.; Estes, L. A.;
Montoya, M. A.; Taetle, R. J. Org. Chem. 1992, 57, 6876 and references
therein.
(13) Padwa, A.; Curtis, E. A.; Sandanayaka, V. P. J. Org. Chem.
1996, 61, 73 and references therein.
tions: The reaction of 1,3-bissilyl enol ether 1b with 2a
in the presence of 0.3 rather than 2.0 equiv of TiCl4
allowed the isolation of spirocyclopropane 5 in 48% yield.7
The formation of 5 can be explained by TiCl4-mediated
cyclization, to give a spirocyclic titanium alkoxide (in-
(7) Bose, G.; Langer, P. Tetrahedron Lett. 2004, 3861.
J. Org. Chem, Vol. 69, No. 26, 2004 9129

Bose et al.
SCHEME 3. Synthesis of Salicylates
with 2a in the presence of TiBr4 resulted in the formation
of 3aa and 3ab.
The structure of all products was elucidated by spec-
troscopic methods. The structure of 3w was indepen-
dently confirmed by crystal structure analysis (see
Supporting Information). As expected from the structure
in solution, an intramolecular hydrogen bond O-H‚‚‚O
is observed. The two aryl moieties are orthogonally
twisted.
In conclusion, we have reported the TiCl4- or TiBr4-
mediated domino “[3+3]-cyclization-homo-Michael” reac-
tion of 1,3-bissilyl enol ethers with 1,1-diacylcyclopro-
panes. These reactions allow a convenient one-pot
synthesis of a great variety of functionalized salicylates
containing a chlorinated or brominated side chain.
TABLE 1. Products and Yields
3
R1
R2
R3
R4
X
yield (%)a
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
H
H
H
H
H
Me
Et
OMe
OiPr
OEt
O(CH2)2OMe
Me
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
82
64
72
56
82
32
38
67
44
41
51
45
47
55
45
47
42
37
42
73
57
34
73
42
33
82
43
45
OMe
OEt
Experimental Section
nPr
nBu
nHex
nHept
nOct
nNon
nDec
OBn
H
OEt
General. All solvents were dried by standard methods and
all reactions were carried out under an inert atmosphere. For
the 1H and 13C NMR spectra (1H NMR, 300, 600 MHz; 13C
NMR, 75, 150 MHz) the deuterated solvents indicated were
used. Mass spectrometric data (MS) were obtained with the
electron ionization (70 eV), the chemical ionization (CI, H2O),
or the electrospray ionization technique (ESI). For preparative
scale chromatography silica gel (60-200 mesh) was used.
Melting points are uncorrected
Typical Procedure for the Preparation of Salicylates
3. To a stirred CH2Cl2 solution (100 mL) of 1,1-diacetylcyclo-
propane (2a) (0.136 g, 1.1 mmol) and 1,3-bis(trimethylsilyloxy)-
1,3-butadiene (1a) (0.421 g, 1.6 mmol) was added TiCl4 (0.22
mL, 2.0 mmol in 2 mL of CH2Cl2) at -78 °C under argon
atmosphere in the presence of molecular sieves (4 Å) (1.0 g).
The temperature of the reaction mixture was allowed to rise
to 20 °C over 6 h. The solution was stirred for an additional 6
h at 20 °C. The reaction mixture was filtered and the filtrate
was poured into an aqueous solution of HCl (10%, 100 mL).
The organic layer was separated and the aqueous layer was
extracted with CH2Cl2 (3 × 100 mL). The combined organic
layers were dried (Na2SO4) and filtered and the filtrate was
concentrated in vacuo. The residue was purified by column
chromatography (silica gel; hexane/ethyl acetate ) 4:1) to give
3a (0.251 g, 82%) as colorless crystals.
Methyl 4-(2-Chloroethyl)-1-hydroxy-3,5-dimethyl-2-
benzoate (3a). Starting with 2a (0.136 g, 1.08 mmol), 1-meth-
oxy-1,3-bis(trimethylsilyloxy)buta-1,3-diene (0.420 g, 1.61 mmol),
and TiCl4 (0.22 mL, 2.00 mmol), 3a was isolated (0.215 g, 82%)
as a colorless solid; mp 73-74 °C; Rf 0.53 (hexane/ethyl acetate
) 4:1); IR (KBr) ν˜ ) 2956 (m), 1722 (w), 1657 (s), 1601 (m),
1574 (m), 1437 (s), 1239 (s), 1072 (m), 804 (m) cm-1; 1H NMR
(300 MHz, CDCl3) δ 10.68 (s, 1 H, OH), 6.70 (s, 1 H, ArH),
3.94 (s, 3 H, OCH3), 3.51-3.46 (m, 2 H, CH2), 3.12-3.06 (m, 2
H, CH2), 2.48 (s, 3 H, CH3), 2.33 (s, 3 H, CH3); 13C NMR (75
MHz, CDCl3) δ 171.8, 160.3, 144.2, 139.0, 127.1, 117.2, 111.9,
52.1, 42.2, 32.9, 21.0, 18.5; MS (EI, 70 eV) m/z (%) 244.6 ([M]+,
14), 242.5 ([M]+, 42), 212.5 (37), 210.4 (85), 193.5 (21), 161.4
(100), 104.8 (14), 77.5 (13). Elemental analysis calcd for
C12H15O3Cl: C 59.39, H 6.22. Found: C 59.56, H 6.50.
Isopropyl 4-(2-Chloroethyl)-1-hydroxy-3,5-dimethyl-2-
benzoate (3b). Starting with 2a (0.126 g, 1.00 mmol), 1-iso-
propyloxy-1,3-bis(trimethylsilyloxy)buta-1,3-diene (0.375 g,
1.30 mmol), and TiCl4 (0.22 mL, 2.00 mmol), 3b was isolated
(0.173 g, 64%) as a colorless solid; mp 51-52 °C; Rf 0.66
(hexane/ethyl acetate ) 4:1); IR (KBr) ν˜ 2982 (m), 1731 (w),
1656 (s), 1601 (w), 1574 (m), 1467 (m), 1372 (s), 1238 (s), 1105
(m), 804 (w), 703 (w) cm-1; 1H NMR (300 MHz, CDCl3) δ 10.77
(s, 1 H, OH), 6.70 (s, 1 H, ArH), 5.32 (sep, 1 H, J ) 6.2 Hz,
OCH), 3.53-3.46 (m, 2 H, CH2), 3.12-3.06 (m, 2 H, CH2), 2.50
(s, 3 H, CH3), 2.33 (s, 3 H, CH3), 1.46 (d, 6 H, J ) 6.2 Hz,
CH3); 13C NMR (75 MHz, CDCl3) δ 170.8, 160.2, 143.9, 138.9,
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OMe
OEt
Et
Et
H
Et
Et
Et
Et
H
OiPr
O(CH2)2OMe
OMe
OEt
s
t
H
Me
Me
Me
Me
H
Ph
Ph
Ph
Ph
Me
Me
Me
Me
Me
H
u
v
w
x
y
z
H
H
OiPr
OiBu
OEt
H
H
H
Et
OEt
Me
Me
Me
H
OMe
OEt
aa
ab
nBu
nHex
OEt
a Isolated yields.
functionalized salicyclates 3a-d in good yields (Scheme
3, Table 1). Starting with 2a and 2,4-bis(trimethylsilyl-
oxy)-1,3-pentadiene (1e), the acetophenone 3e was ob-
tained. The reaction of 2a with bissilyl enol ethers 1f-n
afforded the alkyl-substituted salicylates 3f-n. The
benzyloxy-substituted salicylate 3o was prepared from
1o. The 1,1-diacylcyclopropane was varied next. Cycliza-
tion of 1a-d with 1,1-dipropionylcyclopropane (2b) af-
forded the ethyl-substituted salicylates 3p-s. The reac-
tion of â-ketoester derived 1,3-bissilyl enol ethers with
(unsymmetrical) 1-acetyl-1-benzoylcyclopropane (2c) gave
the methyl- and phenyl-substituted salicyclates 3t-w.
The products were formed with very good regioselectivity
and the cyclizations proceeded by attack of the terminal
carbon of the bissilyl enol ether onto the (more reactive)
acetyl group rather than onto the benzoyl group. The
cyclization of 1b and 1g with (unsymmetrical) 1-acetyl-
1-formylcyclopropane (2d) afforded the salicylates 3x and
3y, respectively. The products were again formed with
very good regioselctivity and the cyclizations proceeded
by initial attack of the terminal carbon of the 1,3-bissilyl
enol ethers onto the aldehyde and subsequent cyclization.
The TiBr4-mediated cyclization of 1a with 2a resulted
in formation of salicylate 3z containing a bromo-
substituted side chain. Similarly, reaction of 1i and 1j
9130 J. Org. Chem., Vol. 69, No. 26, 2004

Efficient One-Pot Synthesis of Functionalized Salicylates
127.0, 117.2, 112.3, 69.7, 42.2, 33.0, 21.9, 21.0, 18.6; MS (EI,
70 eV): m/z (%) 272.1 ([M]+, 5), 270.1 ([M]+, 15), 212.0 (26),
210.1 (74), 161.1 (100), 91.1 (8), 77.5 (7), 28.0 (35). Elemental
analysis calcd for C14H19O3Cl: C 62.10, H 7.07. Found:
62.07, H 7.49.
(0.119 g, 38%) as a colorless solid; mp 38-39 °C; Rf 0.61
(hexane/ethyl acetate ) 4:1); IR (KBr) ν˜ 2971 (m), 1652 (s),
1597 (w), 1565 (w), 1452 (m), 1275 (s), 1198 (s), 809 (w) cm-1
;
C
1H NMR (300 MHz, CDCl3) δ 10.91 (s, 1 H, OH), 4.42 (q, 2 H,
J ) 7.2 Hz, OCH2), 3.52-3.47 (m, 2 H, CH2), 3.16-3.11 (m, 2
H, CH2), 2.70 (q, 2 H, J ) 7.5 Hz, CH2), 2.48 (s, 3 H, CH3),
2.32 (s, 3 H, CH3), 1.41 (t, 3 H, J ) 7.2 Hz, CH3), 1.09 (t, 3 H,
J ) 7.5 Hz, CH3); 13C NMR (75 MHz, CDCl3) δ 171.9, 158.0,
141.4, 135.6, 129.0, 126.7, 111.7, 61.6, 42.3, 33.6, 19.8, 18.6,
16.1, 14.2, 13.3; MS (EI, 70 eV) m/z (%) 286.2 ([M]+, 9), 284.2
([M]+, 28), 240.2 (36), 238.2 (100), 212.1 (9), 210.1 (28), 203.1
(91), 189.2 (34), 91.1 (8), 29.1 (12). Elemental analysis calcd
for C15H21O3Cl: C 63.26, H 7.43. Found: C 63.12, H 7.43.
Ethyl 4-(2-Chloroethyl)-1-hydroxy-3,5-dimethyl-6-pro-
pyl-2-benzoate (3h). Starting with 2a (0.190 g, 1.51 mmol),
1-ethoxy-1,3-bis(trimethylsilyloxy)hepta-1,3-diene (0.711 g,
2.25 mmol), and TiCl4 (0.33 mL, 3.00 mmol), 3h was isolated
(0.273 mg, 67%) as a colorless solid; mp 38-39 °C; Rf 0.66
(hexane/ethyl acetate ) 7:3); IR (KBr) ν˜ 2960 (m), 1653 (s),
1593 (w), 1449 (m), 1190 (s), 1041 (w), 769 (w) cm-1; 1H NMR
(300 MHz, CDCl3) δ 10.90 (s, 1 H, OH), 4.44 (q, 2 H, J ) 7.2
Hz, OCH2), 3.50-3.46 (m, 2 H, CH2), 3.15-3.08 (m, 2 H, CH2),
2.48 (s, 3 H, CH3), 2.31 (s, 3 H, CH3), 1.38-1.46 (m, 4 H, CH2),
1.41 (t, 3 H, J ) 7.2 Hz, CH3), 0.89 (t, 3 H, J ) 6.9 Hz, CH3);
13C NMR (75 MHz, CDCl3) δ 171.9, 158.3, 141.7, 135.6, 127.7,
126.7, 111.7, 61.6, 42.2, 33.6, 28.7, 22.3, 18.6, 16.4, 14.4, 14.2;
MS (EI, 70 eV) m/z (%) 300.0 ([M]+, 11), 298.0 ([M]+, 35), 254.0
(34), 252.0 (100), 239.0 (8), 237.0 (29), 217.0 (58), 91.0 (9), 28.0
(36). The exact molecular mass for C16H23O3Cl (m/z 298.1336
( 2 mD) was confirmed by HRMS (EI, 70 eV).
Ethyl 4-(2-Chloroethyl)-1-hydroxy-3,5-dimethyl-2-ben-
zoate (3c). Starting with 2a (0.127 g, 1.00 mmol), 1-ethoxy-
1,3-bis(trimethylsilyloxy)buta-1,3-diene (0.355 g, 1.30 mmol),
and TiCl4 (0.22 mL, 2.00 mmol), 3c was isolated (0.186 g, 72%)
as a colorless solid; mp 53-54 °C; Rf 0.57 (hexane/ethyl acetate
) 4:1); IR (KBr) ν˜ 2978 (m), 1666 (s), 1606 (w), 1561 (m), 1467
(m), 1311 (s), 1072 (m), 699 (w) cm-1 1H NMR (300 MHz,
;
CDCl3) δ 10.74 (s, 1 H, OH), 6.70 (s, 1 H, ArH), 4.43 (q, 2 H,
J ) 7.2 Hz, OCH2), 3.52-3.47 (m, 2 H, CH2), 3.13-3.07 (m, 2
H, CH2), 2.51 (s, 3 H, CH3), 2.34 (s, 3 H, CH3), 1.42 (t, 3 H, J
) 7.2 Hz, CH3); 13C NMR (75 MHz, CDCl3) δ 171.3, 160.2,
144.0, 139.0, 127.0, 117.2, 112.0, 61.6, 42.2, 32.9, 21.0, 18.5,
14.1; MS (EI, 70 eV) m/z (%) 258.4 ([M]+, 12), 256.4 ([M]+, 38),
212.2 (34), 210.2 (88), 161.2 (100), 91.1 (5), 77.5 (4). Elemental
analysis calcd for C13H17O3Cl: C 60.82, H 6.67. Found:
60.81, H 7.09.
C
2-Methoxyethyl 4-(2-Chloroethyl)-1-hydroxy-3,5-di-
methyl-2-benzoate (3d). Starting with 2a (0.127 g, 1.00
mmol), 1-(2-methoxy)ethoxy-1,3-bis(trimethylsilyloxy)buta-1,3-
diene (0.395 g, 1.30 mmol), and TiCl4 (0.22 mL, 2.00 mmol),
3d was isolated (0.162 g, 56%) as a colorless solid; mp. 41-42
°C; Rf 0.51 (hexane/ethyl acetate ) 4:1); IR (KBr) ν˜ 2960 (m),
1727 (m), 1659 (s), 1610 (m), 1573 (m), 1467 (m), 1237 (s), 1072
(m), 802 (w), 703 (w) cm-1; 1H NMR (300 MHz, CDCl3) δ 10.29
(s, 1 H, OH), 6.70 (s, 1 H, ArH), 4.50 (t, 2 H, J ) 4.7 Hz, OCH2),
3.72 (t, 2 H, J ) 4.7 Hz, OCH2), 3.52-3.46 (m, 2 H, CH2), 3.42
(s, 3 H, OCH3), 3.12-3.08 (m, 2 H, CH2), 2.51 (s, 3 H, CH3),
2.33 (s, 3 H, CH3); 13C NMR (75 MHz, CDCl3) δ 170.7, 159.7,
144.1, 139.2, 127.0, 117.3, 112.4, 70.0, 64.1, 58.9, 42.2, 33.0,
21.0, 18.4; MS (EI, 70 eV) m/z (%) 288.1 ([M]+, 6), 286.2 ([M]+,
20), 212.0 (27), 210.0 (81), 161.0 (100), 91.1 (7), 77.5 (5), 28.1
(19). Elemental analysis calcd for C14H19O4Cl: C 58.64, H 6.68.
Found: C 58.54, H 6.97.
Ethyl 6-Butyl-4-(2-chloroethyl)-1-hydroxy-3,5-dimeth-
yl-2-benzoate (3i). Starting with 2a (0.190 g, 1.51 mmol),
1-ethoxy-1,3-bis(trimethylsilyloxy)octa-1,3-diene (0.743 g, 2.25
mmol), and TiCl4 (0.33 mL, 3.00 mmol), 3i was isolated (0.206
g, 44%) as a colorless oil; Rf 0.69 (hexane/ethyl acetate ) 7:3);
IR (neat) ν˜ )2929 (m), 1654 (s), 1597 (w), 1567 (w), 1450 (m),
1
1195 (s), 1039 (w), 806 (w) cm-1; H NMR (300 MHz, CDCl3)
δ 10.89 (s, 1 H, OH), 4.47 (q, 2 H, J ) 7.2 Hz, OCH2), 3.52-
3.46 (m, 2 H, CH2), 3.16-3.10 (m, 2 H, CH2), 2.69-2.65 (m, 2
H, CH2), 2.47 (s, 3 H, CH3), 2.31 (s, 3 H, CH3), 1.38-1.46 (m,
4 H, CH2), 1.41 (t, 3 H, J ) 7.2 Hz, CH3), 0.89 (t, 3 H, J ) 6.9
Hz, CH3); 13C NMR (75 MHz, CDCl3) δ 172.2, 158.4, 141.8,
135.8, 128.1, 126.9, 111.9, 61.8, 42.5, 33.9, 31.5, 26.6, 23.2, 18.8,
16.5, 14.3, 14.2; MS (EI, 70 eV) m/z (%) 314.0 ([M]+, 17), 312.0
([M]+, 55), 268.0 (28), 266.0 (81), 253.0 (26), 251.0 (81), 223.9
(100), 188.9 (41), 91.0 (21), 28.0 (67). The exact molecular mass
for C17H25O3Cl (m/z 312.1492 ( 2 mD) was confirmed by
HRMS (EI, 70 eV).
2-Acetyl-[4-(2-chloroethyl)]-1-hydroxy-3,5-dimethyl-
benzene (3e). Starting with 2a (0.138 g, 1.09 mmol), 1-meth-
yl-1,3-bis(trimethylsilyloxy)buta-1,3-diene (0.400 g, 1.64 mmol),
and TiCl4 (0.22 mL, 2.00 mmol), 3e (0.215 g, 82%) was obtained
as a colorless oil; Rf 0.56 (hexane/ethyl acetate ) 4:1); IR (neat)
ν˜ 3332 (br), 2956 (w), 1673 (s), 1600 (m), 1574 (m), 1446 (s),
1
1301 (s), 1239 (m), 723 (w) cm-1; H NMR (300 MHz, CDCl3)
δ 10.72 (s, 1 H, OH), 6.67 (s, 1 H, ArH), 3.54-3.46 (m, 2 H,
CH2), 3.09-3.06 (m, 2 H, CH2), 2.59 (s, 3 H, CH3), 2.47 (s, 3
H, CH3), 2.32 (s, 3 H, CH3); 13C NMR (75 MHz, CDCl3) δ 206.2,
158.2, 143.9, 136.7, 127.2, 122.9, 117.4, 42.1, 32.8, 32.6, 20.7,
19.2; MS (EI, 70 eV) m/z (%) 228.3 ([M]+, 20), 226.3 ([M]+, 60),
213.2 (28), 211.2 (79), 177.3 (100), 159.3 (56), 91.1 (23), 77.5
(11). The exact molecular mass for C12H15O2Cl (m/z 226.0761
( 2 mD) was confirmed by HRMS (EI, 70 eV).
Ethyl 4-(2-Chloroethyl)-6-hexyl-1-hydroxy-3,5-dimeth-
yl-2-benzoate (3j). Starting with 2a (0.190 g, 1.51 mmol),
1-ethoxy-1,3-bis(trimethylsilyloxy)deca-1,3-diene (0.806 g, 2.25
mmol), and TiCl4 (0.33 mL, 3.00 mmol), 3j was isolated (0.208
g, 41%) as a colorless oil; Rf 0.67 (hexane/ethyl acetate ) 7:3);
IR (neat) ν˜ 2927 (s), 1725 (w), 1654 (s), 1597 (w), 1566 (w),
1452 (m), 1195 (s), 1041 (w), 808 (w) cm-1; 1H NMR (300 MHz,
CDCl3) δ 10.89 (s, 1 H, OH), 4.47 (q, 2 H, J ) 7.2 Hz, OCH2),
3.56-3.46 (m, 2 H, CH2), 3.16-3.10 (m, 2 H, CH2), 2.69-2.64
(m, 2 H, CH2), 2.47 (s, 3 H, CH3), 2.31 (s, 3 H, CH3), 1.41 (t, 3
H, J ) 7.2 Hz, CH3), 1.30-1.23 (br, 8 H, CH2), 0.89 (t, 3 H, J
) 6.9 Hz, CH3); 13C NMR (75 MHz, CDCl3) δ 172.2, 158.4,
141.8, 135.8, 128.2, 126.9, 111.9, 61. 8, 42.5, 33.8, 31.9, 29.9,
29.3, 26.9, 22.9, 18.8, 16.6, 14.4, 14.3; MS (EI, 70 eV) m/z (%)
342.0 ([M]+, 17), 340.0 ([M]+, 51), 296.0 (22), 294.0 (58), 281.0
(11), 279.0 (43), 225.0 (35), 223.0 (100), 189.0 (34), 91.0 (15),
28.0 (32). The exact molecular mass for C19H29O3Cl (m/z
340.1805 ( 2 mD) was confirmed by HRMS (EI, 70 eV).
Methyl 4-(2-Chloroethyl)-1-hydroxy-3,5,6-trimethyl-2-
benzoate (3f). Starting with 2a (0.128 g, 1.02 mmol), 1-meth-
oxy-1,3-bis(trimethylsilyloxy)penta-1,3-diene (2f) (0.363 g, 1.32
mmol), and TiCl4 (0.22 mL, 2.00 mmol), 3f was isolated (0.083
g, 32%) as a colorless solid; mp 95-96 °C; Rf 0.63 (hexane/
ethyl acetate ) 4:1); IR (KBr) ν˜ 2955 (m), 1649 (s), 1599 (m),
1564 (m), 1442 (s), 1211 (s), 1099 (m), 811 (m) cm-1; 1H NMR
(300 MHz, CDCl3) δ 10.94 (s, 1 H, OH), 3.95 (s, 3 H, OCH3),
3.51-3.45 (m, 2 H, CH2), 3.17-3.12 (m, 2 H, CH2), 2.46 (s, 3
H, CH3), 2.29 (s, 3 H, CH3), 2.18 (s, 3 H, CH3); 13C NMR (75
MHz, CDCl3) δ 172.4, 158.2, 142.4, 135.4, 126.5, 122.9 111.3,
52.1, 42.3, 33.5, 18.6, 16.9, 12.2; MS (EI, 70 eV) m/z (%) 258.4
([M]+, 13), 256.4 ([M]+, 37), 226.3 (39), 224.3 (90), 189.3 (569,
175.3 (100), 146.8 (16), 91.2 (9). Elemental analysis calcd for
C13H17O3Cl: C 60.82, H 6.68. Found: C 61.01, H 7.13.
Ethyl 4-(2-Chloroethyl)-6-heptyl-1-hydroxy-3,5-dimeth-
yl-2-benzoate (3k). Starting with 2a (0.190 g, 1.51 mmol),
1-ethoxy-1,3-bis(trimethylsilyloxy)undeca-1,3-diene (0.865 g,
2.25 mmol), and TiCl4 (0.33 mL, 3.00 mmol), 3k was isolated
(0.269 g, 51%) as a colorless oil; Rf 0.67 (hexane/ethyl acetate
) 7:3); IR (KBr) ν˜ 2927 (s), 1727 (w), 1655 (s), 1597 (w), 1567
Ethyl 4-(2-Chloroethyl)-6-ethyl-1-hydroxy-3,5-dimeth-
yl-2-benzoate (3g): Starting with 2a (0.139 g, 1.10 mmol),
1-ethoxy-1,3-bis(trimethylsilyloxy)hexa-1,3-diene (2g) (0.500 g,
1.65 mmol), and TiCl4 (0.24 mL, 2.20 mmol), 3g was isolated
J. Org. Chem, Vol. 69, No. 26, 2004 9131

Bose et al.
1
(w), 1452 (m), 1195 (s), 1039 (w), 853 (w) cm-1; H NMR (300
°C; Rf 0.58 (hexane/ethyl acetate ) 7:3); IR (KBr) ν˜ 3429 (br),
MHz, CDCl3) δ 10.90 (s, 1 H, OH), 4.42 (q, 2 H, J ) 7.2 Hz,
OCH2), 3.46-3.52 (m, 2 H, CH2), 3.16-3.10 (m, 2 H, CH2),
2.69-2.64 (m, 2 H, CH2), 2.47 (s, 3 H, CH3), 2.31 (s, 3 H, CH3),
1.41 (t, 3 H, J ) 7.2 Hz, CH3), 1.37-1.25 (br, 10 H, CH2), 0.91-
0.89 (m, 3 H, CH3); 13C NMR (75 MHz, CDCl3) δ 172.2, 158.4,
141.8, 135.8, 128.2, 126.9, 111.9, 61. 8, 42.5, 33.9, 32.1, 30.2,
29.4, 29.4, 26.9, 22.9, 18.8, 16.6, 14.4, 14.3; MS (EI, 70 eV)
m/z (%) 356.1 ([M]+, 2), 354.1 ([M]+, 7), 310.0 (2), 308.0 (6),
226.0 (4), 223.9 (15), 122.0 (24), 73.0 (36), 28.0 (100). The exact
molecular mass for C20H31O3Cl (m/z 354.1962 ( 2 mD) was
confirmed by HRMS (EI, 70 eV).
2929 (w), 1654 (s), 1594 (w), 1449 (m), 1276 (s), 1067 (m), 807
(w) cm-1 1H NMR (300 MHz, CDCl3) δ 10.53 (s, 1 H, OH),
;
7.48-7.43 (m, 5 H, ArH), 4.97 (s, 2 H, OCH2Ph), 4.45 (q, 2 H,
J ) 7.2 Hz, OCH2), 3.49-3.43 (m, 2 H, CH2), 3.11-3.06 (m, 2
H, CH2), 2.46 (s, 3 H, CH3), 2.21 (s, 3 H, CH3), 1.43 (t, 3 H, J
) 7.2 Hz, CH3); 13C NMR (75 MHz, CDCl3) δ 171.5, 153.5,
143.6, 137.7, 136.8, 133.4, 128.6, 128.3, 127.2, 113.7, 74.5, 61.9,
42. 33.5, 18.4, 14.4, 13.5; MS (EI, 70 eV) m/z (%) 363.4 ([M]+,
5), 361.4 ([M]+, 16), 291.1 (16), 276.5 (24), 197.5 (10), 90.7 (100),
28.0 (79). Elemental analysis calcd for C20H32O4Cl: C 66.20,
H 6.38. Found: C 65.84, H 6.97. The exact molecular mass
for C20H32O4Cl (m/z 362.1285 ( 2 mD) was confirmed by
HRMS (EI, 70 eV).
Ethyl 4-(2-Chloroethyl)-1-hydroxy-3,5-dimethyl-6-oc-
tyl-2-benzoate (3l). Starting with 2a (0.190 g, 1.51 mmol),
1-ethoxy-1,3-bis(trimethylsilyloxy)dodeca-1,3-diene (0.869 g,
2.25 mmol), and TiCl4 (0.33 mL, 3.00 mmol), 3l was isolated
(0.249 g, 45%) as a colorless oil; Rf 0.68 (hexane/ethyl acetate
) 7:3); IR (neat) ν˜ 2926 (s), 1697 (w), 1655 (s), 1597 (w), 1460
Methyl 4-(2-Chloroethyl)-3,5-diethyl-1-hydroxy-2-ben-
zoate (3p). Starting with 2b (0.152 g, 0.99 mmol), 1-methoxy-
1,3-bis(trimethylsilyloxy)buta-1,3-diene (0.340 g, 1.30 mmol),
and TiCl4 (0.22 mL, 2.00 mmol), 3p was isolated (0.126 g, 47%)
as a colorless oil; Rf 0.69 (hexane/ethyl acetate ) 7:3); IR (KBr)
ν˜ 2966 (m), 1732 (w), 1663 (s), 1604 (m), 1570 (m), 1438 (s),
(m), 1195 (s), 1040 (w) cm-1 1H NMR (300 MHz, CDCl3) δ
;
10.89 (s, 1 H, OH), 4.42 (q, 2 H, J ) 7.2 Hz, OCH2), 3.52-3.46
(m, 2 H, CH2), 3.16-3.10 (m, 2 H, CH2), 2.69-2.64 (m, 2 H,
CH2), 2.47 (s, 3 H, CH3), 2.31 (s, 3 H, CH3), 1.41 (t, 3 H, J )
7.2 Hz, CH3), 1.37-1.23 (br, 12 H, CH2), 0.90-0.80 (m, 3 H,
CH3); 13C NMR (75 MHz, CDCl3) δ 172.2, 158.4, 141.8, 135.8,
128.2, 126.9, 111.9, 61.8, 42.5, 33.9, 32.1, 30.3, 29.7, 29.5, 29.4,
26.9, 22.9, 18.9, 16.6, 14.4, 14.3; MS (EI, 70 eV) m/z (%) 368.1
(M+, 3), 296.1 (6), 281.0 (10), 240.0 (12), 196.9 (36), 122.1 (75),
73.1 (100), 28.0 (43). Elemental analysis calcd for C21H33O3Cl:
C 68.36, H 9.01. Found: C 68.37, H 8.40. The exact molecular
mass for C21H33O3Cl (m/z 368.2118 ( 2 mD) was confirmed
by HRMS (EI, 70 eV).
1
1335 (s), 1080 (m), 850 (w) cm-1; H NMR (300 MHz, CDCl3)
δ 10.65 (s, 1 H, OH), 6.75 (s, 1 H, ArH), 3.96 (s, 3 H, OCH3),
3.52-3.46 (m, 2 H, CH2), 3.12-3.06 (m, 2 H, CH2), 2.94 (q, 2
H, J ) 7.5 Hz, CH2), 2.65 (q, 2 H, J ) 7.5 Hz, CH2), 1.25 (t, 3
H, J ) 7.5 Hz, CH3), 1.19 (t, 3 H, J ) 7.5 Hz, CH3); 13C NMR
(75 MHz, CDCl3) δ 171.5, 160.6, 150.5, 145.2, 125.7, 115.7,
111.1, 52.1, 43.1, 31.9, 26.5, 24.3, 15.9, 14.7; MS (EI, 70 eV)
m/z (%) 272.2 ([M]+, 6), 270.2 ([M]+, 19), 240.2 (23), 238.1 (70),
221.2 (11), 189.2 (100), 91.1 (12); the exact molecular mass
for C14H19O3Cl (m/z 270.1023 ( 2 mD) was confirmed by
HRMS (EI, 70 eV).
Ethyl 4-(2-Chloroethyl)-1-hydroxy-3,5-dimethyl-6-nonyl-
2-benzoate (3m). Starting with 2a (0.190 g, 1.51 mmol),
1-ethoxy-1,3-bis(trimethylsilyloxy)trideca-1,3-diene (0.901 g,
2.25 mmol), and TiCl4 (0.33 mL, 3.00 mmol), 3m was isolated
(0.270 g, 47%) as a colorless oil; Rf 0.71 (hexane/ethyl acetate
) 7:3); IR (neat) ν˜ 2926 (s), 1698 (w), 1655 (s), 1597 (w), 1567
Ethyl 4-(2-Chloroethyl)-3,5-diethyl-1-hydroxy-2-ben-
zoate (3q). Starting with 2b (0.155 g, 1.00 mmol), 1-ethoxy-
1,3-bis(trimethylsilyloxy)buta-1,3-diene (0.355 g, 1.30 mmol),
and TiCl4 (0.22 mL, 2.00 mmol), 3q was isolated (0.119 g, 42%)
as a colorless solid; mp 62-63 °C; Rf 0.74 (hexane/ethyl acetate
) 7:3); IR (KBr) ν˜ 3432 (w), 2970 (m), 1725 (w), 1657 (s), 1602
(m), 1570 (m), 1235 (s), 1078 (m), 711 (w) cm-1; 1H NMR (300
MHz, CDCl3) δ 10.77 (s, 1 H, OH), 6.74 (s, 1 H, ArH), 4.43 (q,
2 H, J ) 7.1 Hz, OCH2), 3.52-3.46 (m, 2 H, CH2), 3.11-3.05
(m, 2 H, CH2), 2.97 (q, 2 H, J ) 7.4 Hz, CH2), 2.64 (q, 2 H, J
) 7.5 Hz, CH2), 1.43 (t, 3 H, J ) 7.2 Hz, CH3), 1.24 (t, 3 H, J
) 7.4 Hz, CH3), 1.19 (t, 3 H, J ) 7.4 Hz, CH3); 13C NMR (75
MHz, CDCl3) δ 171.2, 160.8, 150.2, 145.3, 125.8, 115.8, 111.3,
61.7, 43.2, 32.0, 26.5, 24.3, 16.1, 14.8, 14.0; MS (EI, 70 eV)
m/z (%) 286.2 ([M]+, 6), 284.2 ([M]+, 20), 240.2 (26), 238.2 (81),
189.2 (100), 91.1 (6). Elemental analysis calcd for C15H21O3Cl:
C 63.26, H 7.43. Found: C 63.32, H 7.69.
1
(w), 1461 (m), 1195 (s), 1040 (w), 847 (w) cm-1; H NMR (300
MHz, CDCl3) δ 10.93 (s, 1 H, OH), 4.47 (q, 2 H, J ) 7.2 Hz,
OCH2), 3.56-3.51 (m, 2 H, CH2), 3.21-3.15 (m, 2 H, CH2),
2.69-2.63 (m, 2 H, CH2), 2.47 (s, 3 H, CH3), 2.30 (s, 3 H, CH3),
1.42 (t, 3 H, J ) 7.2 Hz, CH3), 1.37-1.23 (br, 14 H, CH2), 0.70
(t, 3 H, J ) 6.6 Hz, CH3); 13C NMR (75 MHz, CDCl3) δ 172.2,
158.5, 141.8, 135.8, 128.2, 126.9, 111.9, 61.8, 42.5, 33.9, 32.1,
30.3, 29.8, 29.6, 29.4, 26.9, 22.9, 18.9, 16.6, 14.4, 14.3; MS (EI,
70 eV) m/z (%) 384.3 ([M]+, 7), 382.3 ([M]+, 24), 338.1 (4), 336.1
(14), 265.1 (21), 240.0 (34), 197.1 (37), 122.1 (75), 73.7 (100),
43.1 (42). The exact molecular mass for C22H35O3Cl (m/z
382.2275 ( 2 mD) was confirmed by HRMS (EI, 70 eV).
Isopropyl 4-(2-Chloroethyl)-3,5-diethyl-1-hydroxy-2-
benzoate (3r). Starting with 2b (0.156 g, 1.01 mmol), 1-iso-
propyloxy-1,3-bis(trimethylsilyloxy)buta-1,3-diene (0.475 g,
1.65 mmol), and TiCl4 (0.22 mL, 2.00 mmol), 3r was isolated
(0.112 g, 37%) as a colorless oil; Rf 0.78 (hexane/ethyl acetate
) 7:3); IR (neat) ν˜ 2978 (m), 1725 (w), 1656 (s), 1601 (m), 1570
Ethyl 4-(2-Chloroethyl)-6-decyl-1-hydroxy-3,5-dimeth-
yl-2-benzoate (3n). Starting with 2a (0.380 g, 3.02 mmol),
1-ethoxy-1,3-bis(trimethylsilyloxy)tetradeca-1,3-diene (1.864 g,
4.5 mmol), and TiCl4 (0.66 mL, 6.00 mmol), 3n was isolated
(0.512 g, 55%) as a colorless oil; Rf 0.68 (hexane/ethyl acetate
) 7:3); IR (KBr) ν˜ 2926 (s), 1697 (w), 1655 (s), 1620 (w), 1460
1
(m), 1457 (s), 1369 (s), 1104 (m), 838 (w) cm-1; H NMR (300
(m), 1195 (s), 1040 (w) cm-1
;
1H NMR (300 MHz, CDCl3) δ
MHz, CDCl3) δ 10.81 (s, 1 H, OH), 6.73 (s, 1 H, ArH), 5.34
(sep, 1 H, J ) 6.3 Hz, OCH), 3.51-3.46 (m, 2 H, CH2), 3.11-
3.05 (m, 2 H, CH2), 2.94 (q, 2 H, J ) 7.5 Hz, CH2), 2.65 (q, 2
H, J ) 7.5 Hz, CH2), 1.41 (d, 6 H, J ) 6.3 Hz, CH3), 1.23 (t, 3
H, J ) 7.2 Hz, CH3), 1.21 (t, 3 H, J ) 7.5 Hz, CH3); 13C NMR
(75 MHz, CDCl3) δ 171.2, 161.3, 150.5, 145.7, 126.2, 116.2,
112.1, 70.3, 43.8, 32.5, 27.0, 24.8, 22.3, 16.8, 15.3; MS (EI, 70
eV) m/z (%) 300.0 ([M]+, 6), 298.1 ([M]+, 20), 240.0 (33), 238.1
(100), 189.0 (97), 91.0 (8), 28.0 (28). The exact molecular mass
for C16H23O3Cl (m/z 298.1336 ( 2 mD) was confirmed by
HRMS (EI, 70 eV).
10.89 (s, 1 H, OH), 4.42 (q, 2 H, J ) 7.2 Hz, OCH2), 3.51-3.46
(m, 2 H, CH2), 3.16-3.10 (m, 2 H, CH2), 2.69-2.64 (m, 2 H,
CH2), 2.47 (s, 3 H, CH3), 2.31 (s, 3 H, CH3), 1.41 (t, 3 H, J )
7.2 Hz, CH3), 1.36-1.22 (br, 16 H, CH2), 0.87 (t, 3 H, J ) 6.6
Hz, CH3); 13C NMR (75 MHz, CDCl3) δ 172.1, 158.5, 141.8,
135.8, 128.2, 126.9, 111.8, 61.8, 42.5, 32.9, 32.1, 30.3, 30.2, 29.8,
29.8, 29.6, 29.4, 27.0, 22.9, 18.8, 16.6, 14.4, 14.2; MS (EI, 70
eV) m/z (%) 398.0 ([M]+, 15), 396.0 ([M]+, 47), 352.0 (11), 350.0
(30), 265.1 (53), 223.9 (70), 167.1 (86), 70.1 (100), 41.1 (95),
28.0 (73). The exact molecular mass for C23H37O3Cl (m/z
396.2431 ( 2 mD) was confirmed by HRMS (EI, 70 eV).
2-Methoxyethyl 4-(2-Chloroethyl)-3,5-diethyl-1-hydroxy-
2-benzoate (3s). Starting with 2b (0.152 g, 0.99 mmol), 1-(2-
methoxyethoxy)-1,3-bis(trimethylsilyloxy)buta-1,3-diene (0.450
g, 1.48 mmol), and TiCl4 (0.22 mL, 2.00 mmol), 3s was isolated
(0.130 g, 42%) as a colorless oil; Rf 0.58 (hexane/ethyl acetate
) 7:3); IR (neat) ν˜ 2966 (m), 1736 (w), 1665 (s), 1602 (m), 1588
Ethyl 1-Benzyloxy-5-(2-chloroethyl)-2-hydroxy-4,6-di-
methyl-3-benzoate (3o). Starting with 2a (0.380 g, 3.00
mmol), 1-ethoxy-4-benzyloxy-1,3-bis(trimethylsilyloxy)buta-
1,3-diene (1.71 g, 4.5 mmol), and TiCl4 (0.65 mL, 6.00 mmol),
3o was isolated (0.492 g, 45%) as a colorless solid; mp 52-53
9132 J. Org. Chem., Vol. 69, No. 26, 2004

Efficient One-Pot Synthesis of Functionalized Salicylates
1
(m), 1444 (s), 1335 (s), 1074 (m), 834 (w) cm-1; H NMR (300
6.6 Hz, CH3); 13C NMR (75 MHz, CDCl3) δ 171.4, 160.6, 144.7,
144.2, 141.4, 128.5, 128.3, 128.0, 127.1, 119.1, 71.8, 42.8, 33.4,
20.9, 19.3, 19.0; MS (EI, 70 eV) m/z (%) 348.0 ([M]+, 10), 346.1
([M]+, 34), 274.0 (34), 272.0 (100), 222.9 (93), 210.0 (78), 104.6
(34), 28.0 (78). Elemental analysis calcd for C19H21O3Cl: C
69.25, H 6.68. Found: C 69.72, H 6.45.
MHz, CDCl3) δ 10.26 (s, 1 H, OH), 6.73 (s, 1 H, ArH), 4.50 (t,
2 H, J ) 4.8 Hz, OCH2), 3.72 (t, 2 H, J ) 4.8 Hz, OCH2), 3.51-
3.46 (m, 2 H, CH2), 3.41 (s, 3 H, OCH3), 3.11-3.05 (m, 2 H,
CH2), 2.94 (q, 2 H, J ) 7.5 Hz, CH2), 2.65 (q, 2 H, J ) 7.5 Hz,
CH2), 1.23 (t, 3 H, J ) 7.5 Hz, CH3), 1.21 (t, 3 H, J ) 7.5 Hz,
CH3); MS (EI, 70 eV) m/z (%) 316.0 ([M]+, 7), 314.0 ([M]+, 24),
240.0 (32), 238.1 (100), 189.0 (99), 91.0 (8), 28.0 (18); the exact
molecular mass for C16H23O4Cl (m/z 298.1336 ( 2 mD) was
confirmed by HRMS (EI, 70 eV).
Methyl 4-(2-Chloroethyl)-1-hydroxy-5-methyl-3-phen-
yl-2-carboxylate (3t). Starting with 2c (0.376 g, 2.00 mmol),
1-methoxy-1,3-bis(trimethylsilyloxy)buta-1,3-diene (0.780 g,
3.00 mmol), and TiCl4 (0.44 mL, 4.00 mmol), 3t was isolated
(0.437 g, 73%) as a colorless solid; mp 95-96 °C; IR (KBr) ν˜
1663 (s), 1600 (m), 1572 (m), 1441 (s), 1347 (s), 1204 (s), 854
(m), 778 (w) cm-1; 1H NMR (300 MHz, CDCl3) δ 10.83 (s, 1 H,
OH), 7.32-7.04 (m, 3 H, ArH), 7.09-7.06 (m, 2 H, ArH), 3.34
(s, 3 H, OCH3), 3.30-3.24 (m, 2 H, CH2), 2.79-2.56 (m, 2 H,
CH2), 2.04 (s, 3 H,CH3); 13C NMR (75 MHz, CDCl3) δ 171.4,
160.3, 144.8, 144.4, 141.3, 128.5, 127.8, 127.1, 119.1, 111.3 (C),
51.9, 42.8, 33.4, 20.9; MS (EI, 70 eV) m/z (%) 306.4 ([M]+, 17),
304.3 ([M]+, 50), 274.3 (36), 272.3 (88), 223.3 (100), 195.3 (17),
165.2 (36), 151.5 (28). Elemental analysis calcd for C17H17O3-
Cl: C 66.99, H 5.62. Found: C 64.72, H 5.95. The exact
molecular mass for C17H17O3Cl (m/z 304.0866 ( 2 mD) was
confirmed by HRMS (EI, 70 eV).
Ethyl 4-(2-Chloroethyl)-1-hydroxy-5-methyl-3-phenyl-
2-carboxylate (3u). Starting with 2c (0.376 g, 2.00 mmol),
1-ethoxy-1,3-bis(trimethylsilyloxy)buta-1,3-diene (0.822 g, 3.00
mmol), and TiCl4 (0.44 mL, 4.00 mmol), 3u was isolated (0.367
g, 57%) as a colorless solid; mp 104-105 °C; Rf 0.59 (hexane/
ethyl acetate ) 4:1); IR (KBr) ν˜ 2984 (m),1657 (s), 1597 (m),
1575 (m), 1462 (m), 1240 (s), 1015 (w), 776 (w) cm-1; 1H NMR
(300 MHz, CDCl3) δ 10.04 (s, 1 H, OH), 7.38-7.33 (m, 3 H,
ArH), 7.11-7.07 (m, 2 H, ArH), 6.88 (s, 1 H, ArH), 3.86 (q, 2
H, J ) 7.2 Hz, OCH2), 3.29-3.24 (m, 2 H, CH2), 2.78-2.72
(m, 2 H, CH2), 2.39 (s, 3 H, CH3), 0.66 (t, 3 H, J ) 7.2 Hz,
CH3); 13C NMR (75 MHz, CDCl3) δ 171.1, 160.6, 144.7, 144.4,
141.5, 128.6, 127.1, 119.2, 111.3, 61.0, 42.8, 33.4, 20.9, 13.1;
MS (EI, 70 eV) m/z (%) 319.4 ([M]+, 13), 317.4 ([M]+, 39), 273.5
(16), 271.5 (77), 222.6 (100), 164.7 (19), 150.8 (15), 128.2 (24).
Elemental analysis calcd for C18H19O3Cl: C 67.81, H 6.00.
Found: C 67.89, H 5.94.
Ethyl 4-(2-Chloroethyl)-1-hydroxy-3-methyl-2-benzoate
(3x). Starting with 2d (0.100 g, 0.89 mmol), 1-ethoxy-1,3-bis-
(trimethylsilyloxy)buta-1,3-diene (0.366 g, 1.33 mmol), and
TiCl4 (0.20 mL, 1.80 mmol), 3x was obtained (0.090 g, 42%)
as a colorless solid; mp 43-44 °C; IR (KBr) ν˜ 2963 (m), 1727
1
(w), 1661 (s), 1598 (m), 1471 (m), 1221 (s), 839 (m) cm-1; H
NMR (300 MHz, CDCl3) δ 11.26 (s, 1H, OH), 7.22 (d, 1 H, J )
8.7 Hz, ArH), 6.81 (d, 1 H, J ) 9 Hz, ArH), 4.46 (q, 2 H, J )
7.2 Hz, OCH2), 3.60 (t, 2 H J ) 6.9 Hz, CH2 Cl), 3.06 (t, 2 H,
J ) 7.8 Hz, CH2), 2.49 (s, 3 H, CH3), 1.43 (t, 3 H, J ) 6.3 Hz,
CH3); 13C NMR (75 MHz, CDCl3) δ 171.4, 160.9, 138.6, 136.1,
128.2, 115.4, 114.0, 61.2, 43.8, 37.1, 18.4, 14.2; MS (EI, 70 eV)
m/z (%) 244.1 ([M]+, 6), 242.0 ([M]+, 20), 198 (26), 196.0 (76),
146.5 (100), 91.0 (11), 43.1 (3.5), 28.0 (35.8). Elemental analysis
calcd for C12H15O3Cl: C 59.50, H 6.96. Found: C 58.90, H 7.39.
Ethyl 4-(2-Chloroethyl)-6-ethyl-1-hydroxy-3-methyl-2-
benzoate (3y). Starting with 2d (0.150 g, 1.33 mmol),
1-ethoxy-1,3-bis(trimethylsilyloxy)hexa-1,3-diene (0.607 mg,
2.00 mmol), and TiCl4 (0.290 mL, 2.66 mmol), 3y was obtained
(0.903 g, 33%) as a colorless oil; IR (neat) ν˜ 2968 (m), 1728
(w), 1656 (s), 1614 (w), 1448 (m), 1283 (m), 1187 (s), 807 (m)
cm-1; 1H NMR (300 MHz, CDCl3) δ 10.98 (s, 1 H, OH), 7.10 (s,
1 H, ArH), 4.43 (q, 2 H, J ) 7.2 Hz, OCH2), 3.59 (t, 2 H, J )
7.2 Hz, CH2Cl), 3.04 (t, 2 H, J ) 7.5 Hz, CH2), 2.64 (q, 2 H, J
) 7.5 Hz, CH2), 2.45 (s, 3 H, CH3), 1.42 (t, 3 H, J ) 7.2 Hz,
CH3), 1.20 (t, 3 H, J ) 7.5 Hz, CH3); 13C NMR (75 MHz, CDCl3)
δ 171.9, 158.9, 135.6, 135.5, 130.0, 127.4, 113.4, 61.7, 43.9, 37.2,
22.9, 18.2, 14.2, 13.8; MS (EI, 70 eV) m/z (%) 272.0 ([M]+, 9),
270.0 ([M]+, 26), 225.9 (33), 223.9 (100), 195.9 (82), 175.0 (40),
91(18), 77(8), 28.0 (35). Elemental analysis calcd for C14H19O3-
Cl: C 62.22, H 7.00. Found: C 62.33, H 6.96.
Methyl 4-(2-Bromoethyl)-1-hydroxy-3,5-dimethyl-2-
benzoate (3z). Starting with 2a (0.136 g, 1.08 mmol) and
1-methoxy-1,3-bis(trimethylsilyloxy)buta-1,3-diene (2b) (0.420
g, 1.61 mmol), 3z was obtained (0.215 g, 82%) as a colorless
solid; mp 73-74 °C; IR (KBr) ν˜ 2950 (m), 1721 (w), 1656 (s),
1599 (m), 1574 (m), 1436 (s), 1355 (s), 1237 (s), 1071 (m), 805
(w) cm-1 1H NMR (300 MHz, CDCl3) δ 10.69 (s, 1 H, OH),
;
6.69 (s, 1 H, ArH), 3.95 (s, 3 H, OCH3), 3.35-3.29 (m, 2 H,
CH2), 3.19-3.15 (m, 2 H, CH2), 2.47 (s, 3 H, CH3), 2.32 (s, 3
H, CH3); 13C NMR (75 MHz, CDCl3) δ 171.8, 160.3, 144.0,
138.8, 128.2, 117.3, 111.8, 52.2, 33.3, 29.7, 20.9, 18.5; MS (EI,
70 eV) m/z (%) 288.0 ([M]+, 24), 286.0 ([M]+, 26), 256.0 (63),
254.0 (62), 207.0 (62), 193.0 (23), 175.0 (31), 161.0 (100), 77.0
Isopropyl 4-(2-Chloroethyl)-1-hydroxy-5-methyl-3-phen-
yl-2-carboxylate (3v). Starting with 2c (0.376 g, 2.00 mmol),
1-isopropyloxy-1,3-bis(trimethylsilyloxy)buta-1,3-diene (0.864
g, 3.00 mmol), and TiCl4 (0.44 mL, 4.00 mmol), 3v was isolated
(0.229 g, 34%) as a colorless solid; Rf 0.62 (hexane/ethyl acetate
) 4:1); IR (KBr) ν˜ 2981 (m), 1656 (s), 1599 (m), 1575 (m), 1458
1
(m), 1370 (s), 1240 (s), 1102 (m), 702 (w) cm-1; H NMR (300
(12). Elemental analysis calcd for C12H15O3Br (287.15):
50.13, H 5.26. Found: C 50.29, H 5.43.
C
MHz, CDCl3) δ 10.72 (s, 1 H, OH), 7.40-7.33 (m, 3 H, ArH),
7.10-7.06 (m, 2 H, ArH), 6.88 (s, 1 H, ArH), 4.87 (d, 1 H, J )
6.3 Hz, OCH), 3.29-3.23 (m, 2 H, CH2), 2.76-2.71 (m, 2 H,
CH2), 2.39 (s, 3 H, CH3), 0.84 (d, 6 H, J ) 6.3 Hz, CH3); 13C
NMR (75 MHz, CDCl3) δ 170.6, 160.6, 144.5, 144.3, 141.6,
128.8, 127.9, 127.0, 119.0, 111.6, 68.8, 42.8, 33.4, 21.0, 20.9;
MS (EI, 70 eV) m/z (%) 333.9 ([M]+, 11), 331.9 ([M]+, 34), 274.0
(33), 272.0 (100), 222.9 (99), 165.1 (17), 151.2 (13), 28.0 (25).
Elemental analysis calcd for C19H21O3Cl: C 68.56, H 6.36.
Found: C 68.90, H 5.80.
Isobutyl 4-(2-Chloroethyl)-1-hydroxy-5-methyl-3-phen-
yl-2-carboxylate (3w). Starting with 2c (0.376 g, 2.00 mmol),
1-isobutyloxy-1,3-bis(trimethylsilyloxy)buta-1,3-diene (0.980 g,
3.00 mmol), and TiCl4 (0.44 mL, 4.00 mmol), 3w was isolated
(0.509 g, 73%) as a colorless solid; mp 74-75 °C; Rf 0.63
(hexane/ethyl acetate ) 4:1); IR (KBr) ν˜ 2980 (m), 1651 (s),
1598 (m), 1465 (m), 1244 (s), 755 (m) cm-1; 1H NMR (300 MHz,
CDCl3) δ 11.04 (s, 1 H, OH), 7.38-7.32 (m, 3 H, ArH), 7.19-
7.08 (m, 2 H, ArH), 6.89 (s, 1 H, ArH), 3.62 (d, 2 H, J ) 6.9
Hz, OCH2), 3.28-3.22 (m, 2 H, CH2), 2.75-2.69 (m, 2 H, CH2),
2.39 (s, 3 H, CH3), 1.24-1.17 (m, 1 H, CH), 0.60 (d, 6 H, J )
Ethyl 4-(2-Bromoethyl)-6-butyl-1-hydroxy-3,5-dimeth-
yl-2-benzoate (3aa). Starting with 2a (0.252 g, 2.00 mmol),
1-ethoxy-1,3-bis(trimethylsilyloxy)octa-1,3-diene (0.990 g, 3.00
mmol), and TiBr4 (1.500 g, 4.00 mmol), 3aa was isolated (0.308
g, 43%) as a colorless oil; IR (neat) ν˜ 2959 (s), 1715 (m), 1653
(s), 1598 (s), 1567 (m), 1451 (m), 1193 (s), 1031 (m), 850 (m);
1H NMR (300 MHz, CDCl3) δ 10.91 (s, 1 H, OH), 4.42 (q, 2 H,
J ) 7.2 Hz, OCH2), 3.34-3.30 (m, 2 H, CH2), 3.23-3.20 (m, 2
H, CH2), 2.70-2.63 (m, 2 H, CH2), 2.47 (s, 3 H, CH3), 2.30 (s,
3 H, CH3), 1.46-1.25 (m, 7 H, 1 × CH3, 2 × CH2), 0.96-0.87
(m, 3 H, CH3); 13C NMR (75 MHz, CDCl3) δ 171.9, 258.3, 141.5,
135.5, 128.0, 111.7, 61.6, 34.1, 31.3, 29.9, 26.4, 23.1, 18.6, 16.4,
14.2, 14.0; MS (EI, 70 eV) m/z (%) 358.5 (M+ + 2, 21), 354.5
(M+, 21), 312.3 (33), 310.3 (33), 270.3 (42), 268.3 (44), 231.3
(47), 189.2 (44), 91.1 (47), 73.7 (55), 41.2 (44), 29.1 (100); UV-
vis λmax (log ꢀ) 222 (4.3), 255 (3.82), 320 (3.44); C17H25O3Br.
Ethyl 4-(2-Bromoethyl)-6-hexyl-1-hydroxy-3,5-dimeth-
yl-2-benzoate (3ab). Starting with 2a (0.380 g, 3.00 mmol),
1-ethoxy-1,3-bis(trimethylsilyloxy)deca-1,3-diene (1.730 g, 4.5
mmol), and TiBr4 (2.210 g, 6.00 mmol), 3ab was isolated (0.520
J. Org. Chem, Vol. 69, No. 26, 2004 9133

Bose et al.
g, 45%) as a colorless oil; IR (neat) ν˜ 2927 (s), 1715 (s), 1654
OH), 3.49 (t, 2 H, J ) 8.1 Hz, CH2Cl), 2.73 (t, 2 H, J ) 7.8 Hz,
CH2), 2.18 (s, 6 H, CH3); 13C NMR (75 MHz, CDCl3) δ 198.8,
106.8, 43.3, 31.1, 23.1; minor isomer (keto form) 1H NMR (300
MHz, CDCl3) δ 4.01 (t, 1 H, J ) 7.2 Hz, CH), 3.53 (t, 2 H, J )
7.5 Hz, CH2Cl), 2.28 (q, 2 H, J ) 7.2 Hz, CH2), 2.24 (s, 6 H,
CH3); 13C NMR (75 MHz, CDCl3) δ 203.1, 64.8, 42.6, 31.3, 29.6;
MS (EI, 70 eV) m/z (%) 164.0 (M+, 7), 162.0 (M+, 21), 148.3
(5), 146.5 (15), 227.2 (16), 112.1 (99), 70.0 (20), 43.1 (100). The
exact molecular mass for C7H11O2Cl (m/z 162.0448 ( 2 mD)
was confirmed by HRMS (EI, 70 eV).
1
(s), 1597 (m), 1460 (m), 1193 (s), 1031 (m), 848 (m); H NMR
(300 MHz, CDCl3) δ 10.91 (s, 1 H, OH), 4.46 (q, 2 H, J ) 7.2
Hz, OCH2), 3.36-3.30 (m, 2 H, CH2), 3.23-3.19 (m, 2 H, CH2),
2.69-2.64 (m, 2 H, CH2), 2.47 (s, 3 H, CH3), 2.30 (s, 3 H, CH3),
1.39 (t, 3 H, J ) 7.2 Hz, CH3), 1.34-1.21 (m, 8 H, CH2), 0.91-
0.88 (m, 3 H, CH3); 13C NMR (75 MHz, CDCl3) δ 171.9, 258.2,
141.4, 135.5, 128.0, 127.9, 111.7, 61.6, 34.1, 31.7, 29.9, 29.7,
29.1, 26.7, 22.6, 18.6, 16.3, 14.2, 14.1; MS (EI, 70 eV) m/z (%)
386.0 (M+ + 2, 3), 384.0 (M+, 3), 340.0 (4), 337.9 (4), 269.9
(10), 268 (10), 189.0 (10), 161.0 (10), 73.7 (10), 43.1 (14), 28.0
(100); UV-vis λmax (log ꢀ) 222 (4.3), 255 (3.73), 320 (3.29);
C19H29O3Br.
Synthesis of Isopropyl 8-Hydroxy-4,8-dimethyl-6-oxo-
spiro[5.2]oct-4-ene-5-carboxylate (5). A CH2Cl2 solution (1
mL) of TiCl4 (0.03 mL, 0.3 mmol) was added dropwise at -78
°C under argon atmosphere to a stirred CH2Cl2 solution (100
mL) of 2a (0.131 g, 1.0 mmol) and 1b (0.450 g, 1.6 mmol) in
the presence of molecular sieves (4 Å, 1.0 g). The reaction
mixture was allowed to warm to 20 °C over 6 h, stirred for an
additional 6 h at 20 °C, and subsequently filtered. The filtrate
was poured into an aqueous solution of HCl (1.0 M, 100 mL).
The organic layer was collected and the aqueous layer was
extracted with CH2Cl2 (3 × 100 mL). The combined organic
layers were dried (Na2SO4), filtered, and concentrated in vacuo.
The residue was purified by column chromatography (silica
gel, hexane/EtOAc ) 4:1f1:1) to give 5 (0.125 g, 48%) as a
colorless oil; Rf 0.18 (hexane/EtOAc ) 1:1); IR (neat) ν 3399
(br), 2983 (w), 1729 (s), 1659 (s), 1617 (m), 1380 (m), 1243 (s),
Crystal Structure Determination of 3w. The intensity
data for the compound were collected on a Nonius KappaCCD
diffractometer, using graphite-monochromated Mo KR radia-
tion. Data were corrected for Lorentz and polarization effects,
but not for absorption effects.14,15 The structures were solved
by direct methods (SHELXS)16 and refined by full-matrix least-
squares techniques against Fo (SHELXL-97).17 For the hy-
2
droxy group O1 the hydrogen atom was located by difference
Fourier synthesis and refined isotropically. All other hydrogen
atoms were included at calculated positions with fixed thermal
parameters. All non-hydrogen atoms were refined anisotropi-
cally.17 XP (SIEMENS Analytical X-ray Instruments, Inc.) was
used for structure representations.
Crystal Data for 3w: C20H23ClO3, Mr ) 346.83 g mol-1
,
1024 (m), 745 (w) cm-1 1H NMR (300 MHz, CDCl3) δ 5.17
;
colorless prism, size 0.03 × 0.03 × 0.02 mm3, monoclinic, space
group P21/n, a ) 8.8561(2) Å, b ) 12.9712(3) Å, c ) 15.8805-
(4) Å, â ) 104.172(1)°, V ) 1768.74(7) Å3, T ) -90 °C, Z ) 4,
(sept, 1 H, J ) 6.3 Hz, CH), 2.71 (d, 1 H, J ) 15.6 Hz, CH2),
2.59 (d, 1 H, J ) 15.6 Hz, CH2), 2.40 (br, 1 H, OH), 1.68 (s, 3
H, CH3), 1.49-1.37 (m, 1 H, CH2), 1.30 (d, 6 H, J ) 6.3 Hz,
CH3), 1.26 (s, 3 H, CH3), 1.15-1.04 (m, 2 H, CH2), 0.88-0.81
(m, 1 H, CH2); 13C NMR (75 MHz, CDCl3) δ 194.0, 166.8, 160.5,
133.2, 70.5, 69.0, 51.5, 32.1, 25.4, 21.7, 16.7, 10.8, 9.5; MS (EI,
70 eV) m/z (%) 252.2 (M+, 40), 237.1 (13), 193.1 (65), 177.1
(41), 164.1 (47), 148.1 (100), 91.1 (17), 43.1 (78); the exact
molecular mass for C14H20O4 (m/z 252.1362 ( 2 mD) was
confirmed by HRMS (EI, 70 eV).
F
calc. ) 1.302 g cm-3, µ(Mo KR) ) 2.31 cm-1, F(000) ) 736, 6834
reflections in h (-11/11), k (-16/15), l (-20/20), measured in
the range 2.42° e Θ e 27.48°, completeness Θmax ) 99.6%,
4050 independent reflections, Rint ) 0.019, 3299 reflections
with Fo > 4σ(Fo), 221 parameters, 0 restraints, R1obs ) 0.037,
wR2obs ) 0.090, R1all ) 0.050, wR2all ) 0.097, GOOF ) 1.025,
largest difference peak and hole 0.236/-0.268 e Å-3
.
Synthesis of 3-(2-Chloroethyl)pentane-2,4-dione (4). To
a CH2Cl2 solution (100 mL) of 2a (0.151 g, 1.2 mmol) was added
dropwise TiCl4 (0.13 mL, 1.2 mmol) at -78 °C under argon
atmosphere. The reaction mixture was allowed to warm to 20
°C over 12 h and was stirred for an additional 6 h at 20 °C.
The mixture was poured into an aqueous solution of HCl (1.0
M, 100 mL). The organic layer was collected and the aqueous
layer was extracted with CH2Cl2 (3 × 100 mL). The combined
organic layers were dried (Na2SO4), filtered, and concentrated
in vacuo. The residue was purified by column chromatography
(silica gel, hexane/EtOAc ) 1:4 f 1:1) to give 4 (0.086 g, 47%)
as a colorless oil; IR (KBr) ν 3429 (br), 1725 (w), 1702 (m),
1605 (s), 1421 (s), 1284 (m), 985 (m), 688 (w) cm-1; major
isomer (enol from) 1H NMR (300 MHz, CDCl3) δ 16.88 (s, 1 H,
Procedure for the Preparation of 3b from 5. A CH2Cl2
solution (1 mL) of TiCl4 (0.06 mL, 0.5 mmol) was added
dropwise at 0 °C to a CH2Cl2 solution (20 mL) of 5 (0.126 g,
0.5 mmol) and the solution was stirred for 1 h (TLC monitor-
ing). The reaction mixture was extracted with an aqueous
solution of HCl (1.0 M, 20 mL) and the aqueous layer was
washed with CH2Cl2 (2 × 20 mL). The combined organic layers
were dried (Na2SO4), filtered, and concentrated in vacuo. The
crude product was purified by column chromatography (silica,
hexane/EtOAc ) 9:1f 4:1) to give 3b (0.072 g, 53%) as a
colorless solid.
Acknowledgment. This work was supported by the
Deutsche Forschungsgemeinschaft. We are grateful to
the government of Vietnam for a graduate scholarship
for V.T.H.N.
(14) COLLECT; Data Collection Software: Nonius B.V., The Neth-
erlands, 1998.
(15) Otwinowski, Z.; Minor, W. Processing of X-ray Diffraction Data
Collected in Oscillation Mode. In Methods in Enzymology; Vol. 276,
Macromolecular Crystallography, Part A; Carter, C. W., Sweet, R. M.,
Eds.; Academic Press: New York, 1997; pp 307-326.
(16) Sheldrick, G. M. Acta Crystallogr. Sect. A 1990, 46, 467-473.
(17) Sheldrick, G. M. SHELXL-97, Release 97-2; University of
Go¨ttingen: Go¨ttingen, Germany, 1997.
Supporting Information Available: Details of the crys-
tal structure analysis of 3w. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO0485278
9134 J. Org. Chem., Vol. 69, No. 26, 2004