Regioselective synthesis of 5-alkylsalicylates, 5-alkyl-2-hydroxy- acetophenones, and 5-alkyl-2-hydroxy-benzophenones by [3 + 3] cyclization of 1,3-bis(silyl enol ethers) with 2-alkyl-1,1,3,3-tetraethoxypropanes

Article abstract of DOI:10.1021/jo070847e

(Chemical Equation Presented) A variety of 5-alkylsalicylates, 5-alkyl-2-hydroxy-acetophenones, and 5-alkyl-2-hydroxy-benzophenones was regioselectively prepared by TiCl₄ mediated formal [3 + 3] cyclization of 1,3-bis(silyl enol ethers) with 2-alkyl-1,1,3,3- tetraethoxypropanes.

Full text of DOI:10.1021/jo070847e

reaction of alkynes with appropriate 1,3-dienes (such as furans
or fulvenones) and subsequent oxidation.6 For example, methyl
5-ethylsalicylate is available by Diels Alder cycloaddition of
2-ethylfuran with methyl propiolate.7 However, 2-alkylfurans
are not readily available, and methyl propiolate is rather
expensive. The formal [3 + 3] cyclization of 1,3-bis(silyl enol
ethers)8 with 1,3-dielectrophiles provides convenient access to
substituted arenes.9 Notably, most of these reactions rely on
the employment of 3-silyloxyalk-2-en-1-ones as 1,3-dielectro-
philic building blocks and allow the synthesis of 4,6-di- and
4,5,6-trisubstituted derivatives. Chan et al. reported the synthesis
of methyl salicylate by the cyclization of 1-methoxy-1,3-bis-
(trimethylsilyloxy)-1,3-butadiene with 1,1,3,3-tetramethoxypro-
pane.10 Herein, we wish to report a significant extension of this
reaction by what are, to the best of our knowledge, the first [3
+ 3] cyclizations of 1,3-bis(silyl enol ethers) with 2-alkyl-
1,1,3,3-tetraethoxypropanes. These reactions allow a convenient
and regioselective synthesis of salicylates, 2-hydroxy-acetophe-
nones, and 2-hydroxy-benzophenones containing an alkyl chain
located at carbon atom C-5. In contrast to the functionalization
of benzene derivatives by electrophilic substitutions or by
palladium(0)-catalyzed cross-coupling reactions, our approach
relies on the formation of the benzene moiety. From a
preparative viewpoint, substituted phenols can be regioselec-
tively prepared, and the synthesis of functionalized benzene
derivatives as starting materials is not required.
Regioselective Synthesis of 5-Alkylsalicylates,
5-Alkyl-2-hydroxy-acetophenones, and
5-Alkyl-2-hydroxy-benzophenones by [3 + 3]
Cyclization of 1,3-Bis(silyl enol ethers) with
2-Alkyl-1,1,3,3-tetraethoxypropanes
Constantin Mamat,† Stefan Bu¨ttner,† Tiana Trabhardt,†
Christine Fischer,†,‡ and Peter Langer*,†,‡
Institut fu¨r Chemie, UniVersita¨t Rostock, Albert-Einstein-Strasse
3a, 18059 Rostock, Germany, and Leibniz-Institut fu¨r Katalyse
e. V., UniVersita¨t Rostock, Albert-Einstein-Strasse 29a, 18059
Rostock, Germany
peter.langer@uni-rostock.de
ReceiVed April 23, 2007
The general procedure for the formation of the known 2-alkyl-
1,1,3,3-tetraethoxypropanes requires three steps as depicted in
Scheme 1. In the first step, commercially available aldehydes
1a-h were reacted with triethyl orthoformate in dry ethanol to
give the appropriate acetals 2a-h under acid catalysis (1 drop
of concd H2SO4).11 Following the procedure of Nerdel et al.,12
the enol ethers 3a-h were prepared by the elimination of EtOH
from acetals 2a-h. The next step involves the BF3‚OEt2
mediated reaction of these enol ethers with triethyl orthoformate
to give the respective 2-alkyl-1,1,3,3-tetraethoxypropanes 4a-
h.13 The synthesis of all precursors and intermediates was
previously reported.11-14
A variety of 5-alkylsalicylates, 5-alkyl-2-hydroxy-acetophe-
nones, and 5-alkyl-2-hydroxy-benzophenones was regiose-
lectively prepared by TiCl4 mediated formal [3 + 3]
cyclization of 1,3-bis(silyl enol ethers) with 2-alkyl-1,1,3,3-
tetraethoxypropanes.
Functionalized phenols, such as salicylates, 2-hydroxy-
acetophenones, or 2-hydroxy-benzophenones, represent impor-
tant building blocks in organic1 and medicinal2 chemistry. The
classic approach to functionalized acetophenones relies on
multistage reactions starting with phenol. However, this ap-
proach can suffer from several drawbacks, such as low regio-
selectivity. For example, 5-ethyl-2-hydroxy-acetophenone is
available by acylation and Fries rearrangement of phenol
(formation of regioisomers),3 reduction of the acetyl group,4 and
a second Fries rearrangement.5 A second strategy for the
synthesis of functionalized phenols relies on the Diels-Alder
1,3-Bis(silyl enol ethers) 5a-e were prepared, as reported
in the literature, from pentane-2,4-dione,15 benzoylacetone,15
heptane-3,5-dione,16 methyl acetoacetate,17 and ethyl acetoac-
(6) (a) For a recent application of this reaction, see: Rivera, J. M.; Martin,
T.; Rebek, J. J. Am. Chem. Soc. 2001, 123, 5213. (b) Dilthey, W.; Hurtig,
G. Chem. Ber. 1934, 67, 2004. (c) Dilthey, W.; Schommer, W.; Troesken,
O. Chem. Ber. 1933, 66, 1627. (d) Allen, C. F. H.; Van Allan, J. J. Org.
Chem. 1945, 10, 333. (e) Herz, W.; Lewis, E. J. Org. Chem. 1958, 23,
1646. (f) Borchardt, A.; Hardcastle, K.; Gantzel, P.; Siegel, J. S. Tetrahedron
Lett. 1993, 34, 273. (g) Becker, H.; King, S. B.; Taniguchi, M.; Vanhessche,
K. P. M.; Sharpless, K. B. J. Org. Chem. 1995, 60, 3940. (h) Ohta, K.;
Yamaguchi, N.; Yamamoto, I. J. Mater. Chem. 1998, 8, 2637.
(7) Moreno, A.; Gomez, M. V.; Vazquez, E.; de la Hoz, A.; Diaz-Ortiz,
A.; Prieto, P.; Mayoral, J. A.; Pires, E. Synlett 2004, 7, 1259.
(8) Review: Langer, P. Synthesis 2002, 441.
* Corresponding author. Tel.: 49-381-498-6410; fax: +49 381 4986412.
† Institut fu¨r Chemie.
‡ Leibniz-Institut fu¨r Katalyse e. V.
(1) Handbook of Hydroxyacetophenones. Preparation and Physical
Properties, 2nd ed.; Martin, R., Ed.; Springer: Berlin, 2005.
(2) Vane, J. R. Aspirin and Other Salicylates; Chapman and Hall
Medical: London, 1992.
(3) (a) Sandulesco, G.; Girad, A. Bull. Soc. Chim. Fr. 1930, 47, 1300.
(b) Krzyzanowska, E.; Olszanowski, A.; Juskowiak, M. J. Prakt. Chem.
1989, 331, 617. (c) Kobayashi, S.; Moriwaki, M.; Hachiya, I. Bull. Chem.
Soc. Jpn. 1997, 70, 267.
(4) (a) Papa, D.; Schwenk, E.; Whitman, B. J. Org. Chem. 1942, 7, 587.
(b) Takuwa, A.; Kai, R. Bull. Chem. Soc. Jpn. 1990, 63, 623. (c) Mitchell,
R. H.; Lai, Y.-H. Tetrahedron Lett. 1980, 21, 2637.
(9) Review: Feist, H.; Langer, P. Synthesis 2007, 327.
(10) (a) Chan, T.-H.; Brownbridge, P. J. Chem. Soc., Chem. Commun.
1979, 578. (b) Brownbridge, P.; Chan, T. H.; Brook, M. A.; Kang, G. J.
Can. J. Chem. 1983, 61, 688.
(11) Claisen, L. Ber. Dtsch. Chem. Ges. 1907, 40, 3903.
(12) Nerdel, F.; Buddrus, J.; Brodowski, W.; Hentschel, P.; Klamann,
D.; Weyerstahl, P. Liebigs Ann. Chem. 1967, 710, 36.
(5) (a) Kahnberg, P.; Lager, E.; Rosenberg, C.; Schougaard, J.; Camet,
L.; Sterner, O.; Nielsen, E. Ø.; Nielsen, M.; Liljefors, T. J. Med. Chem.
2002, 45, 4188. (b) Wiedenau, P.; Monse, B.; Blechert, S. Tetrahedron
1995, 51, 1167. (c) Burdeska, K. Synthesis 1982, 940.
(13) (a) Ruegg, R.; Lindlar, H.; Montavon, M.; Savey, G.; Schaeren, S.
T.; Schwieter, U.; Isler, O. HelV. Chim. Acta 1959, 42, 844. (b) Ruegg, R.;
Lindlar, H.; Montavon, M.; Savey, G.; Schaeren, S. T.; Schwieter, U.; Isler,
O. HelV. Chim. Acta 1959, 42, 859.
10.1021/jo070847e CCC: $37.00 © 2007 American Chemical Society
Published on Web 07/06/2007
J. Org. Chem. 2007, 72, 6273-6275
6273

TABLE 1. Synthesis of 6a-ad
SCHEME 1. Preparation of Bis(acetals) 4a-h
4
5
6
R1
R2
R3
Et
n-Pr
i-Pr
n-Bu
n-Pent
n-Hex
n-Hept
Me
Et
n-Pr
i-Pr
n-Bu
n-Pent
n-Hex
n-Hept
Me
% (6)a
b
c
d
e
f
g
h
a
b
c
d
e
f
g
h
a
b
c
e
f
g
h
a
b
c
e
f
a
b
b
a
b
a
b
c
c
c
c
c
a
b
c
d
e
f
g
h
i
k
l
m
n
o
p
q
r
s
t
u
v
w
x
y
z
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
OMe
OEt
OEt
OMe
OEt
OMe
OEt
Me
Me
Me
Me
Me
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Et
Et
51
50
36
35
36
34
34
55
36
58
22
36
45
54
45
48
31
55
43
43
34
54
61
40
51
38
54
32
63
c
c
c
SCHEME 2. Synthesis of 6a-ad
d
d
d
d
d
d
d
e
e
e
e
e
Et
n-Pr
n-Bu
n-Pent
n-Hex
n-Hept
Me
Et
n-Pr
n-Bu
n-Pent
n-Hex
n-Hept
etate, respectively.17 The TiCl4 mediated cyclization of bis-
(acetals) 4b-h with bis(silyl enol ethers) 5a and 5b, prepared
from methyl and ethyl acetoacetate, afforded the 5-alkylsali-
cylates 6a-g (Scheme 2and Table 1). The cyclization of bis-
(acetals) 4a-h with bis(silyl enol ether) 5c, prepared from
acetylacetone, afforded 5-alkyl-2-hydroxy-acetophenones 6h-
p. 5-Alkyl-2-hydroxy-benzophenones 6q-w were prepared from
bis(silyl enol ether) 5d, which was prepared from benzoylac-
etone. The reaction of bis(acetals) 4a-c and 4e-h with bis-
(silyl enol ether) 5e, prepared from heptane-3,5-dione, gave
5-alkyl-2-hydroxy-3-methyl-propiophenones 6x-ad.
Et
Et
Et
Et
aa
ab
ac
ad
g
h
e
e
Et
a Isolated yields.
SCHEME 3. Possible Mechanism for Formation of 6a
The formation of product 6a can be explained by the TiCl4
mediated generation of an oxonium ion from bis(acetal) 4a,
attack of the terminal carbon atom of 1,3-bis(silyl enol ether)
5a onto the oxonium ion, and extrusion of trimethylchlorosilane
to give intermediate A (Scheme 3). Activation of the second
acetal group and subsequent cyclization via the central carbon
atom of the 1,3-dicarbonyl moiety afforded intermediate B.
Aqueous workup, using hydrochloric acid (10%), resulted in
the elimation of 2 equiv of ethanol to give the final product 6a.
Products 6a-ad were isolated in the range of 22-63% yield.
The low yields can be explained by decomposition and
hydrolysis of the starting materials and by side reactions, such
as TiCl4 mediated oxidative dimerization of the 1,3-bis(silyl enol
ether). The best protocol for the cyclizations is similar to the
typical procedure previously reported for related [3 + 3]
cyclizations.9 The stoichiometry of the starting materials and
reagents played an important role. In contrast to other [3 + 3]
cyclizations, the best results were obtained when an excess of
the 1,3-bis(silyl enol ether) was employed. The use of the Lewis
acid trimethylsilyl-trifluoromethanesulfonate (Me3SiOTf) rather
than TiCl4 proved to be unsuccessful. The high concentration
of the solution (only 2 mL of solvent per 1 mmol of starting
material) proved to be a very important parameter. The yields
significantly decreased when the reactions were carried out in
more dilute solutions. To guarantee a complete elimination of
ethanol from intermediate B, hydrochloric acid (10%) was used
for the aqueous workup. A general trend for the influence of
the substitution pattern on the yield was not observed. The yields
seem to mainly depend on the quality of the starting materials,
reagents, and solvent and on the handling of each individual
experiment.
(14) (a) Yanovskaya, L. A.; Yufit, S. S.; Kucherov, V. F. Bull. Acad.
Sci. USSR, DiV. Chem. Sci. (Engl. Transl.) 1960, 1156. (b) Breitmaier, E.;
Gassenmann, S. Chem. Ber. 1971, 104, 665. (c) Sigmund, F.; Uchann, R.
Monatsh. Chem. 1929, 51, 234. (d) Barbot, F.; Miginiac, P. HelV. Chim.
Acta 1979, 62, 1451. (e) Bagard, P. Bull. Soc. Chim. 1907, 1, 346. (f)
Mikhalova, M. A.; Savelev, V. A.; Pavlyuchenko, A. I.; Grebenkin, M. F.;
Mamaev, V. P. Chem. Heterocycl. Compd. 1986, 22, 994. (g) Ciha, A. J.
J. Agric. Food Chem. 1991, 39, 2072. (h) Koradin, C.; Dohle, W.;
Rodriguez, A. L.; Schmid, B.; Knochel, P. Tetrahedron 2003, 59, 1571.
(15) (a) Barinelli, L. S.; Nicholas, K. M. J. Org. Chem. 1988, 53, 2114.
(b) Kra¨geloh, K.; Simchen, G. Synthesis 1981, 30.
(16) Kra¨geloh, K.; Simchen, G.; Schweiker, K. Liebigs Ann. Chem. 1985,
2352.
(17) (a) Molander, G. A.; Cameron, K. O. J. Am. Chem. Soc. 1993, 115,
830. (b) Chan, T.-H.; Brownbridge, P. J. Am. Chem. Soc. 1980, 102, 3534.
In conclusion, a general method for the synthesis of 5-alkyl-
salicylates, 5-alkyl-2-hydroxy-acetophenones, and 5-alkyl-2-
6274 J. Org. Chem., Vol. 72, No. 16, 2007

in vacuo. The residue was purified by column cromatography (silica
gel, n-heptane/EtOAc ) 50:1 to 20:1).
hydroxy-benzophenones by [3 + 3] cyclization of 1,3-bis(silyl
enol ethers) with 2-alkyl-1,1,3,3-tetraethoxypropanes, based on
an initial finding of Chan et al., was reported.
5-Ethyl-salicylic Acid Methylester (6a). Following the general
procedure, the starting materials 2-diethoxymethyl-1,1-diethoxybu-
tane (4b) (0.500 g, 2.01 mmol), 1-methoxy-1,3-bis(trimethylsily-
loxy)-1,3-butadiene (5a) (1.11 g, 4.04 mmol), and TiCl4 (0.22 mL,
2.01 mmol) in CH2Cl2 (4 mL) yielded 6a as a yellow syrup (186
mg, 51%). Rf ) 0.4 (n-heptane/EtOAc ) 2:1). IR (neat, cm-1): V˜
Experimental Section
Experimental details, analytical data, and spectra of compounds
6a-ad can be found in the Supporting Information. All cyclization
reactions were carried out in Schlenk tubes under an argon
atmosphere using dried solvents and freshly distilled TiCl4. The
appropriate acetals, enol ethers, and substituted 1,1,3,3-tetraeth-
oxypropanes were prepared as described in the literature.11-14 For
1H and 13C NMR spectroscopy, the deuterated solvents indicated
were used. Mass spectrometric (MS) data were obtained by electron
ionization (EI, 70 eV), chemical ionization (CI, isobutane), or
electrospray ionization (ESI). For preparative scale chromatography,
silica gel (60-200 mesh) was used. Melting points are uncorrected.
General Procedure for the Synthesis of 6a-ad. To a CH2Cl2
solution (5 mL) of 1,3-bis(silyl enol ether) 5a-e (2 equiv) and of
the respective 2-alkyl-1,1,3,3-tetraethoxypropane 4a-h (1 equiv)
was added TiCl4 (1 equiv) at -78 °C under argon atmosphere. The
temperature of this mixture was allowed to rise to 20 °C during 14
h, and subsequently, an aqueous HCl solution (10%, 10 mL) was
added. The organic layer was separated, and the residue was
extracted with CH2Cl2 (3 × 10 mL). The combined organic layers
were dried (Na2SO4) and filtered, and the filtrate was concentrated
1
) 3206 (w), 2964 (m), 1680 (s). H NMR (250 MHz, CDCl3): δ
3
3
) 1.21 (t, 3H, J ) 7.6 Hz, CH2CH3), 2.58 (q, 2H, J ) 7.6 Hz,
3
CH2CH3), 3.94 (s, 3H, OCH3), 6.91 (d, 1H, J3,4 ) 8.5 Hz, H-3),
3
4
7.30 (dd, 1H, J3,4 ) 8.5 Hz, J4,6 ) 2.2 Hz, H-4), 7.65 (d, 1H,
4J4,6 ) 2.2 Hz, H-6), 10.58 (s, 1H, OH). 13C NMR (63 MHz,
CDCl3): δ ) 15.7, 27.9, 52.2, 112.0, 117.4, 128.4, 134.9, 135.6,
159.7, 170.6. MS (EI, 70 eV): m/z (%) ) 180 (M+, 40), 148 (100),
133 (79), 105 (16), 91 (12), 77 (17), 32 (49). HRMS (EI, 70 eV):
calcd. for C10H12O3 (M+): 180.0781; found: 180.0783.
Acknowledgment. Financial support from the state of
Mecklenburg-Vorpommern is gratefully acknowledged.
Supporting Information Available: General experimental
procedures, including spectroscopic and analytical data. This mater-
ial is available free of charge via the Internet at http://pubs.acs.org.
JO070847E
J. Org. Chem, Vol. 72, No. 16, 2007 6275