Synthesis of 5-(2-aryl-2-haloethyl)salicylates by the first domino '[3+3] cyclization/ring-cleavage' reactions of 1,3-bis(silyloxy)-1,3-butadienes with 3-acetyl-5-aryl-4,5-dihydrofurans

Article abstract of DOI:10.1016/j.tetlet.2008.07.049

5-(2-Aryl-2-haloethyl)salicylates are efficiently prepared by the first domino '[3+3] cyclization/ring-cleavage' reactions of 1,3-bis(silyloxy)-1,3-butadienes with 3-acetyl-5-aryl-4,5-dihydrofurans.

Full text of DOI:10.1016/j.tetlet.2008.07.049

Tetrahedron Letters 49 (2008) 5618–5619
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Tetrahedron Letters
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Synthesis of 5-(2-aryl-2-haloethyl)salicylates by the first domino ‘[3+3]
cyclization/ring-cleavage’ reactions of 1,3-bis(silyloxy)-1,3-butadienes
with 3-acetyl-5-aryl-4,5-dihydrofurans
Matthias Lau a, Peter Langer a,b,
*
a Institut für Chemie, Universität Rostock, Albert-Einstein-Straße 3a, 18059 Rostock, Germany
b Leibniz-Institut für Katalyse e. V. an der Universität Rostock, Albert-Einstein-Straße 29a, 18059 Rostock, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
5-(2-Aryl-2-haloethyl)salicylates are efficiently prepared by the first domino ‘[3+3] cyclization/ring-
cleavage’ reactions of 1,3-bis(silyloxy)-1,3-butadienes with 3-acetyl-5-aryl-4,5-dihydrofurans.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 3 June 2008
Revised 6 July 2008
Accepted 7 July 2008
Available online 11 July 2008
Keywords:
Arenes
Cyclizations
silyl enol ethers
Highly substituted salicylates are pharmacologically important
molecules, which occur in a variety of natural products.1 Recently,
we have reported2 the synthesis of functionalized salicylates by
TiCl4-mediated domino ‘[3+3] cyclization3/homo-Michael’ reac-
tions of 1,3-bis(trimethylsilyloxy)-1,3-butadienes4 with 1,1-diacyl-
cyclopropanes. We were intrigued by the possibility of extending
this concept to new domino ‘[3+3] cyclization/ring-cleavage’ reac-
tions by application of other types of substrates. Herein, we report
preliminary results of our studies directed to what are, to the best
of our knowledge, the first domino ‘[3+3] cyclization/ring-cleavage’
reactions of 1,3-bis(silyloxy)-1,3-butadienes with 3-acetyl-5-aryl-
4,5-dihydrofurans. These reactions provide a convenient and regio-
selective approach to 5-(2-aryl-2-haloethyl)salicylates which are
not readily available by other methods.5
Me3SiO
R1
OR2
OH
O
1) TiX4 (2 eq.)
CH2Cl2
R1
OSiMe3
OR2
_
78 to 20 ºC
1a-e
18 h
Me
Me
X
Me
O
2) HCl (10%)
Me
O
+
Ar
3a-l
Ar
2a-d
Scheme 1. Synthesis of 3a–l.
The CAN-mediated reaction of styrenes with acetylacetone
afforded the 3-acetyl-5-aryl-4,5-dihydrofurans 2a–d in 80–92%
yields (Scheme 1).6 1,3-Bis(trimethylsilyloxy)-1,3-butadienes
1a–e are readily available in two steps from the corresponding
b-ketoesters.7 The reaction of 2a with 1a, in the presence of TiCl4,
afforded the 5-(2-phenyl-2-chloroethyl)salicylate 3a.8 The best
yields of 3a were obtained when 1.0 equiv of 2a, 1.7 equiv of 1a
and 2.0 equiv of TiCl4 were employed. The low concentration
(c(2a) = 0.017 M) and the use of hydrochloric acid (10%) for the
aqueous work-up also played an important role.
The formation of 3a might be explained (Scheme 2) by chelation
of TiCl4 by the carbonyl group of 2a (intermediate A). Attack of the
terminal carbon atom of 1a onto 2a with extrusion of Me3SiCl
would afford intermediate B. The attack of a second molecule of
TiCl4 onto the furan oxygen atom would give intermediate C. The
furan ring would then be cleaved by nucleophilic attack of a chlo-
ride ion, derived from TiCl4, onto the carbon attached to the phenyl
group to give intermediate D. The latter would undergo a cycliza-
tion via the central carbon atom of the 1,3-dicarbonyl unit to give
intermediate E. The product would be subsequently formed by aro-
matization and hydrolysis upon aqueous work-up. Alternatively,
the [3+3] cyclization might occur in the first and the cleavage of
the furan moiety in the second step. The overall process can be
regarded as a domino9 ‘[3+3] cyclization/ring-cleavage’ reaction.
* Corresponding author. Tel.: +49 381 4986410; fax: +49 381 4986412.
E-mail address: peter.langer@uni-rostock.de (P. Langer).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.049

M. Lau, P. Langer / Tetrahedron Letters 49 (2008) 5618–5619
5619
Table 1
Synthesis of 3a–l
Me3SiO
OMe
OSiMe3
OH
O
1) TiCl4 (2 eq.)
CH2Cl2
78 to 20 ºC
18 h
a
1
2
3
R1
R2
Ar
X
%
OMe
1a
_
a
b
c
a
a
a
a
b
c
a
b
c
d
e
f
h
g
h
i
H
H
Me
Et
H
H
H
Et
H
H
Me
Et
Ph
Ph
Ph
Ph
4-MeC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
Ph
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Br
46
44
36
51
35
58
74
56
53
66
62
45
35
+
Me
Me
Cl
Me
O
Me
Me
Me
Me
Et
Me
Me
iPr
Me
Me
Me
d
a
a
b
d
a
e
c
2) HCl (10%)
Me
O
Ph
3a (46%)
Ph
2a
c
c
d
d
d
d
a
TiCl4
HCl (10%)
O
j
k
l
Me
Et
H
O
d
a
TiCl4
Me
O
OMe
OTiCl3
Me
a
Yields of isolated products. For all 3l, a small amount of impurity could not be
Me
O
separated.
Me
Cl
Ph
A
by other methods. The preparative scope and applications of the
methodology are currently studied.
E
Ph
Me3SiCl
O
Me3SiOTiCl3
Acknowledgement
MeO
Financial support by the State of Mecklenburg-Vorpommern is
gratefully acknowledged.
MeO
O
Me3SiO
Me
OTiCl3
Me
Me3SiO
OTiCl3
Me
References and notes
O
1. Römpp Lexikon Naturstoffe; Steglich, W., Fugmann, B., Lang-Fugmann, S., Eds.;
Thieme: Stuttgart, 1997.
Cl3TiO
Me
Ph
D
Cl
2. (a) Langer, P.; Bose, G. Angew. Chem., Int. Ed. 2003, 42, 4033; (b) Bose, G.; Nguyen,
V. T. H.; Ullah, E.; Lahiri, S.; Görls, H.; Langer, P. J. Org. Chem. 2004, 69, 9128.
3. For a review of [3+3] cyclizations, see: Feist, H.; Langer, P. Synthesis 2007, 327.
4. For a review of 1,3-bis(silyl enol ethers), see: Langer, P. Synthesis 2002, 441.
5. 4-(2-Aryl-2-chloroethyl)phenols have only scarcely been reported in the
literature so far: (a) Mastrorilli, P.; Nobile, C. F.; Taccardi, N. Tetrahedron Lett.
2006, 47, 4759; (b) Valenta, V.; Holubek, J.; Svatek, E.; Dlabac, A.; Bartosova, M.;
Protiva, M. Collect. Czech. Chem. Commun. 1983, 48, 1447; (c) Kametani, T.;
Higashiyama, K.; Honda, T.; Otomasu, H. Chem. Pharm. Bull. 1984, 32, 1614; (d)
Tashchuk, K. G.; Dombrovskii, A. V. J. Org. Chem. USSR (Engl. Transl.) 1965, 1,
2034; (e). Zh. Org. Khim. 1965, 1, 1995. For a natural product, see: (f) Hashimoto,
T.; Irita, H.; Takaoka, S.; Tanaka, M.; Asakawa, Y. Tetrahedron 2000, 56, 3153.
6. Baciocchi, E.; Ruzziconi, R. J. Org. Chem. 1991, 56, 4772.
Ph
B
MeO
O
Me3SiO
TiCl4
OTiCl3
Me
Cl3Ti
Me
_
O
+
Cl
Ph
C
7. (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.
8. General procedure for the synthesis of salicylates 3a–l: To a solution of CH2Cl2 and
1 (1.0 equiv), 1,3-bis(silyl enol ethers) 2 and (1.7 equiv) TiCl4 (2.0 equiv) were
added dropwise at À78 °C under argon atmosphere. The solution was allowed to
warm to 20 °C during 18 h. To the reaction mixture was added an aqueous
solution of HCl (10%). 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-heptane/EtOAc) to give
salicylates 3. Starting with 1b (0.167 g, 0.83 mmol), 2a (0.340 g, 1.5 mmol) and
TiCl4 (0.18 mL, 1.65 mmol) in CH2Cl2 (50 mL), 3b was isolated after column
Scheme 2. Possible mechanism of the formation of 3a.
The TiCl4-mediated cyclization of 1,3-bis(silyloxy)-1,3-butadi-
enes 1a–e with 3-acetyl-5-aryl-4,5-dihydrofurans 2a–d afforded
the 5-(2-aryl-2-chloroethyl)salicylates 3a–k (Scheme 1, Table 1).
The cyclization of 1a with 2a in the presence of TiBr4 afforded
the brominated product 3l. The structure of the products was con-
firmed by spectroscopic methods (2D NMR). The yields of the prod-
ucts derived from halogenated 3-acetyl-5-aryl-4,5-dihydrofurans
2c and 2d tend to be slightly higher than those of the products
derived from 2a and 2b. This can be explained by the electron-
withdrawing effect of the halogen atoms which results in an
activation of the dihydrofuran.
In conclusion, we have reported what are, to the best of our
knowledge, the first domino ‘[3+3] cyclization/ring-cleavage’ reac-
tions of 1,3-bis(silyloxy)-1,3-butadienes with 3-acetyl-5-aryl-4,5-
dihydrofurans. These reactions provide a convenient approach to
5-(2-aryl-2-haloethyl)salicylates which are not readily available
chromatography (silica gel, n-heptane/EtOAc = 50:1) as
a colourless solid
(0.120 g, 44%); mp = 66–68 °C; Rf = 0.67 (n-heptane/EtOAc = 1:1). 1H NMR
(250 MHz, CDCl3): d 1.42 (t, 3J = 7.1 Hz, 3H, CH2CH3), 2.12, 2.42 (s, 3H, CH3),
2
3
2
3.26 (dd, JHa,Hb = 14.8 Hz, JHab,Hx = 7.3 Hz, 1H, CHab), 3.50 (dd, JHa,Hb = 14.8 Hz,
3JHab,Hx = 7.3 Hz, 1H, CHab), 4.41 (q, 3J = 7.1 Hz, 2H, CH2CH3), 4.96 (t,
3JHx,Hab = 7.3 Hz, 1H, CHCl), 6.64 (s, 1H, CHAr), 7.30 (s, 5H, Ph), 10,78 (s, 1H,
OH). 13C NMR (62.9 MHz, CDCl3): d 14.2 (OCH2CH3), 19.1, 21.4 (CH3), 40.3
(CH2CHCl), 61.6 (OCH2CH3), 63.2 (CHCl), 112.0, 127.1, 139.4, 141.2, 144.8, 160.2
(CAr,Ph), 117.2 (CAr), 126.9, 128.3, 128.4 (CPh), 171.5 (COOCH2CH3). MS (EI, 70 eV):
m/z (%) = 334 (M+, 37Cl, 0.8), 332 (M+, 35Cl, 2), 250 (7), 207 (65), 161 (100). Anal.
Calcd for C19H21ClO3 (332.82): C, 68.57; H, 6.36. Found: C, 68.67; H 6.36.
9. For reviews of domino reactions, see: (a) Tietze, L. F.; Beifuss, U. Angew. Chem.,
Int. Ed. Engl. 1993, 32, 131; Tietze, L. F.; Beifuss, U. Angew. Chem. 1993, 105, 137;
(b) Tietze, L. F. Chem. Rev. 1996, 96, 115.