Chelation control in the [3+3] annulation reaction of alkoxy-substituted 1,1-diacylcyclopropanes with 1,3-bis(trimethylsilyloxy)-1,3-butadienes

Article abstract of DOI:10.1016/j.tetlet.2008.05.066

Functionalized arenes were prepared by chelation-controlled '[3+3] cyclization/homo-Michael' reactions of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with benzyloxy- or methoxy-substituted 1,1-diacylcyclopropanes.

Full text of DOI:10.1016/j.tetlet.2008.05.066

Tetrahedron Letters 49 (2008) 4470–4472
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Tetrahedron Letters
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Chelation control in the [3+3] annulation reaction of alkoxy-substituted
1,1-diacylcyclopropanes with 1,3-bis(trimethylsilyloxy)-1,3-butadienes
Jennifer Hefner 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:
Received 22 March 2008
Revised 8 May 2008
Accepted 13 May 2008
Available online 16 May 2008
Functionalized arenes were prepared by chelation-controlled ‘[3+3] cyclization/homo-Michael’ reactions
of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with benzyloxy- or methoxy-substituted 1,1-diacylcyclo-
propanes.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Arenes
Cyclopropanes
Cyclizations
Regioselectivity
Silyl enol ethers
Highly substituted phenols are pharmacologically important
molecules which occur in various natural products.1 Recently, we
have reported2 the synthesis of functionalized phenols by TiCl4-
mediated [3+3] cyclization3 of 1,3-bis(trimethylsilyloxy)-1,3-buta-
dienes4 with 1,1-diacylcyclopropanes. Although symmetrical
cyclopropanes were employed in most cases, some unsymmetrical
substrates have also been studied. The cyclization of 1,3-bis(silyl-
oxy)-1,3-butadienes with 1-acetyl-1-formylcyclopropane and with
1-acetyl-1-benzoylcyclopropane proceeded by regioselective at-
tack of the terminal carbon atom of the diene onto the more reac-
tive carbonyl group (i.e., the formyl and the acetyl group,
respectively). We were intrigued by the possibility of incorporating
chelating5,6 alkoxy substituents into the diacylcyclopropane, which
could direct the regioselectivity of the cyclization. Herein, we re-
port preliminary results of this study. Noteworthy, the annulation
reactions reported provide a convenient and regioselective ap-
proach to a variety of sterically encumbered and highly functional-
ized phenols, which are not readily available by other methods.
The cyclopropanation of 1-methoxypentane-2,4-dione7 affor-
ded the novel cyclopropane 2a in 40% yield.8 The TiCl4-mediated
cyclization of 2a with 1,3-bis(trimethylsilyloxy)-1,3-butadiene
1a, readily available in two steps from methyl acetoacetate,9 affor-
ded the 5-chloroethyl-4-(methoxymethyl)salicylate 3a (Scheme
1).10
(intermediate A). The TiCl4-mediated attack of the terminal carbon
atom of 1a onto 2a gives rise to the formation of intermediate B,
which undergoes a cyclization via the central carbon atom of the
1,3-dicarbonyl unit (intermediate C). The product is subsequently
formed by Lewis acid-assisted cleavage of the spirocyclopropane
moiety and aromatization by attack of a chloride ion onto the
cyclopropane (intermediate D) and hydrolysis upon aqueous
work-up. The process can be regarded as a domino ‘[3+3] cycliza-
tion/homo-Michael’ reaction.11 The regioselectivity can be ex-
plained by the Lewis acid-directing effect of the methoxy group
of the substrate. During the optimization of the reaction, the fol-
lowing parameters proved to be important. The best yields of 3a
were obtained when 1.0 equiv of 2a, 1.5 equiv of 1a and 2.0 equiv
of TiCl4 were employed. The low concentration (c(2a) = 0.01 M)
and the presence of molecular sieves (4 Å) (for the removal of
water) also played an important role.
The novel methoxy- and benzyloxy-substituted 1,1-diacylcyclo-
propanes 2b, 2c, and 2d were prepared by cyclopropanation of
1-benzyloxypentane-2,4-dione,12 4-methoxy-1-phenylbutane-1,3-
dione, and 4-methoxy-1-phenylbutane-1,3-dione in 42%, 40%,
and 44% yield, respectively. The cyclization of 2a–d with 1,3-
bis(trimethylsilyloxy)-1,3-butadienes 1a–f, in the presence of TiCl4
or TiBr4, afforded the functionalized phenols 3a–s (Scheme 2, Table
1). All products were formed with very good regioselectivity by at-
tack of the terminal carbon atom of the diene onto the carbonyl
group located next to the alkoxy group. The structure of the prod-
ucts was confirmed by spectroscopic methods (2D NMR).
The regioselective formation of 3a can be explained by chela-
tion of TiCl4 by the methoxy and the neighboring carbonyl group
The substituted arenes prepared represent useful synthetic
building blocks. For example, salicylate 3g was transformed into
* 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.2008.05.066

J. Hefner, P. Langer / Tetrahedron Letters 49 (2008) 4470–4472
4471
Me3SiO
OH O
OSiMe3
OMe
OH O
1) TiCl4
(2 equiv.)
OH O
H2
OMe
Me
OMe
1a
OMe
Pd/C
4Å MS
Me
Cl
+
(10 mol%)
Cl
Me
O
O
OH
OBn
CH2Cl2
MeOH
Cl
MeO
_
OMe
78
20 ºC
3g
4 (68%)
Me
TiCl4
O
3a (48%)
2) HCl (10%)
OH O
NaH (2.3 equiv.),
TBAI (cat.)
DMF
2a
Me3SiOH
HCl (10%)
OMe
Me
O
Me3SiO
O
Cl4Ti
MeO
5 (62%)
O
OMe
Scheme 3. Synthesis of tetrahydrobenzopyran 5.
Me
Me
Cl
OMe
tetrahydrobenzopyran 5 by debenzylation and subsequent Wil-
liamson reaction (Scheme 3). A number of related products were
successfully prepared.
A
D
1a
TiCl4
In conclusion, we have reported the first substrate-directed
domino ‘[3+3] cyclization/homo-Michael’ reaction of 1,3-bis(tri-
methylsilyloxy)-1,3-butadienes with 1,1-diacylcyclopropanes.
These reactions provide a convenient approach to highly function-
alized phenols, which are not readily available by other methods.
The regioselectivity can be explained by the Lewis acid-directing
effect of the alkoxy groups of the substrates. We believe that the
strategy outlined herein can be applied also to other annulation
reactions of 1,3-bis(silyl enol ethers).
Me3SiCl
2 Cl3TiOH
Cl3TiOH
O
Me3SiO
Me3SiO
O
O
OMe
OTiCl3
Me
+
O
OMe
TiCl4
Cl3Ti
MeO
O
Cl3Ti
MeO
Cl _
Me
C
B
Acknowledgment
Scheme 1. Possible mechanism of the formation of 3a.
Financial support by the State of Mecklenburg-Vorpommern is
gratefully acknowledged.
Me3SiO OSiMe3
OH O
R1
References and notes
R2
R1
TiX4
R2
1a-f
(2 equiv.)
1. Römpp Lexikon Naturstoffe; Steglich, W., Fugmann, B., Lang-Fugmann, S., Eds.;
Thieme: Stuttgart, 1997.
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. For reviews of chelation control in Lewis acid-mediated reactions, see: (a)
Yamamoto, H. Lewis Acid Chemistry; Oxford University Press: Oxford, 1999; (b)
Mahrwald, R. Chem. Rev. 1999, 99, 1095; (c) Santelli, M.; Pons, J. M. Lewis Acids
and Selectivity in Organic Synthesis; CRC Press: Boca Raton, 1996; (d)
Shambayati, S.; Schreiber, S. L. In Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 1, pp 283–324.
6. Chelation control has been reported for the [4+3] annulation reaction of
benzyloxy-substituted 1,4-dicarbonyl compounds with bis(silyl enol ethers):
Molander, G. A.; Eastwood, P. R. J. Org. Chem. 1996, 61, 1910.
+
R3
O
O
4Å MS
CH2Cl2
OR4
R4O
X
R3
_
78
20 ºC
3a-s
2a-d
Scheme 2. Synthesis of 3a–s.
Table 1
Products and yields
1
2
3
R1
R2
R3
R4
X
Yielda (%)
a
b
c
d
a
a
c
e
a
a
c
f
d
a
a
e
d
a
a
a
a
a
a
b
b
b
b
c
c
c
c
c
d
d
d
d
a
b
c
d
f
H
H
Me
Me
H
OMe
OEt
OMe
Et
OMe
OMe
OMe
OMe
OMe
OMe
OMe
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
Me
Me
Me
Me
Me
Bn
Bn
Bn
Bn
Me
Me
Me
Me
Me
Bn
Bn
Bn
Bn
Cl
Cl
Cl
Cl
Br
Cl
Cl
Cl
Br
Cl
Cl
Cl
Cl
Br
Cl
Cl
Cl
Br
44
38
30
30
46
40
44
41
79
63
48
33
36
49
40
64
33
52
7. Bruce, W. F.; Coover, H. W. J. Am. Chem. Soc. 1944, 66, 2092.
8. Typical procedure for the synthesis of diacylcyclopropanes 2a–d: To a DMSO
solution (100 mL) of methoxyacetylacetone (5.00 g, 38.5 mmol) and potassium
carbonate (15.90 g, 115.5 mmol) was added 1,2-dibromoethane (9.40 g,
50.0 mmol) dropwise. The mixture was stirred at 20 °C for 24 h. The mixture
was poured into water (400 mL), and the mixture was extracted with diethyl
ether (3 Â 100 mL). The combined organic layers were washed with water and
with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Vacuum
destillation (bp = 46 °C, 0.15 mbar) afforded 2a (2.41 g, 40%) as a yellowish oil.
1H NMR (300 MHz, CDCl3): d = 1.44 (m, 2H, CH2), 1.51 (m, 2H, CH2), 2.10 (s, 3H,
CH3), 3.38 (s, 3H, OCH3), 4.31 (s, 2H, CH2). 13C NMR (75.5 MHz, CDCl3): d = 17.4
(CH2), 26.3 (CH3), 41.0 (C), 59.1 (OCH3), 77.1 (CH2OCH3), 202.9, 203.6 (CO).
9. (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.
10. Typical procedure for the synthesis of phenols 3a–s. To a CH2Cl2 solution (100 mL)
of 2a (156 mg, 1.0 mmol) and 1a (391 mg, 1.5 mmol) in the presence of
molecular sieves (4 Å, 1.00 g) was added TiCl4 (0.22 mL, 2.0 mmol) dropwise at
À78 °C under an argon atmosphere. The solution was allowed to warm to 20 °C
over 18 h with stirring and subsequently filtered. The filtrate was poured into
hydrochloric acid (10%, 100 mL) and the mixture was extracted with CH2Cl2
g
h
i
H
Me
Et
H
j
k
l
H
Me
H
Me
H
H
Et
Me
H
Ph
Ph
m
n
o
p
q
r
Et
Ph
OMe
OMe
OMe
Et
Ph
Ph
Ph
Ph
s
OMe
Ph
a
Yields of isolated products.

4472
J. Hefner, P. Langer / Tetrahedron Letters 49 (2008) 4470–4472
(3 Â 100 mL). The combined organic layers were dried (Na2SO4), filtered, and
the filtrate was concentrated in vacuo. The residue was purified by
chromatography (silica gel, heptanes/EtOAc = 10:1?7:1) to give 3a as
C
13H17ClO4 (272.72): C, 57.25; H, 6.28. Found: C, 57.24; H, 6.39. All new
products gave correct spectroscopic data and elemental analyses and/or high
resolution mass data.
a
slightly yellow solid (120 mg, 44%), mp = 77–78 °C. Rf = 0.38 (heptanes/
EtOAc = 3:1). 1H NMR (300 MHz, CDCl3): d = 2.50 (s, 3H, CH3), 3.09 (m, 2H,
CH2), 3.42 (s, 3H, OCH3), 3.54 (m, 2H, CH2Cl), 3.97 (s, 3H, OCH3), 4.43 (s, 2H,
CH2OCH3), 6.90 (s, 1H, Ar), 10.61 (s, 1H, OH). 13C NMR (75.5 MHz, CDCl3):
d = 14.5 (CH3), 32.9, 43.3 (CH2), 52.7, 59.9 (OCH3), 73.8 (CH2OCH3), 113.9 (CAr),
116.8 (CHAr), 127.3, 140.0, 143.8 (CAr), 160.7 (CArOH), 172.0 (COOCH3). IR (KBr,
cmÀ1): 3025 (m), 2966 (w), 2929 (w), 2892 (w), 1660 (s). MS (EI, 70 eV): m/z
(%) = 274 (M+, 37Cl, 16), 272 (M+, 35Cl, 46), 240 (100), 133 (96). HRMS (EI): Calcd
11. Reactions of acceptor-substituted cyclopropanes have been classified by
Danishefsky in terms of ‘strictly nucleophilic ring openings’, ‘electrophilically
assisted ring openings’, and ‘spiro-activations’: Danishefsky, S. J. Acc. Chem.
Res. 1979, 66. In the domino ‘[3+3]-cyclization-homo-Michael’ reaction
reported herein two effects are operating: (a) a ‘dynamic spiro-activation’
and (b) activation by an electrophile. For
a dynamic spiro activation,
see: Zefirov, N. S.; Kozhushkov, S. I.; Kuznetsova, T. S. Tetrahedron 1982, 38,
1693.
for
C
13H17ClO4 ([M]+, 35Cl): 272.08099, found 272.08061. Anal. Calcd for
12. Wenner, W.; Plati, J. T. J. Org. Chem. 1946, 11, 751.