Efficient synthesis of salicylates by catalytic [3 + 3] cyclizations of 1,3-bis(silyl enol ethers) with 1,1,3,3-tetramethoxypropane

Article abstract of DOI:10.1021/jo070974a

(Chemical Equation Presented) Salicylic acid derivatives were prepared by Me₃SiOTf-catalyzed [3 + 3] cyclization of 1,3-bis(silyl enol ethers) with 1,1,3,3-tetramethoxypropane.

Full text of DOI:10.1021/jo070974a

silyloxy-1,3-butadiene (Danishefsky’s diene),5,6 1-methoxy-1,3-
bis(trimethylsilyloxy)-1,3-butadiene (Chan’s diene),7 1,4-di-
Efficient Synthesis of Salicylates by Catalytic
3 + 3] Cyclizations of 1,3-Bis(silyl enol ethers)
with 1,1,3,3-Tetramethoxypropane
[
(
methoxy)-1,3-bis(trimethylsilyloxy)-1,3-butadiene (Brassard’s
8
diene), or related dienes.
The titanium tetrachloride (TiCl4) mediated formal [3 + 3]
Muhammad Sher,†,‡ T. H. Tam Dang, Zafar Ahmed,
†,‡
†,‡
9
cyclization of 1,3-bis(silyl enol ethers) with 3-siloxy-2-en-1-
†
†,‡
Muhammad A. Rashid, Christine Fischer, and
ones provides a convenient approach to a variety of function-
,
†,‡
Peter Langer*
7a,b,10
alized salicylates.
In addition, TiCl4-mediated cyclizations
of 1,3-bis(silyl enol ethers) with 1,1,3,3-tetramethoxypropane
Institut f u¨ r Chemie, UniVersit a¨ t Rostock, Albert-Einstein-Str. 3a,
7
a,b,11,12
1
8059 Rostock, Germany, and Leibniz-Institut f u¨ r Katalyse e. V.
and related bis(acetals) were reported.
All of these
an der UniVersit a¨ t Rostock, Albert-Einstein-Str. 29a,
transformations rely on the employment of stoichiometric
amounts of Lewis acid. Herein, we report what are, to the best
of our knowledge, the first catalytic [3 + 3] cyclizations of
1
8059 Rostock, Germany
1
,3-bis(silyl enol ethers) with 1,1,3,3-tetramethoxypropane.
peter.langer@uni-rostock.de
These reactions provide a convenient approach to a variety of
functionalized salicylates under mild conditions. Notably, the
products are not directly and readily available by other methods.
ReceiVed May 9, 2007
The trimethylsilyl trifluoromethanesulfonate (Me3SiOTf)
catalyzed condensation of silyl enol ethers with acetals,
13
introduced by Noyori et al., has found a number of applications
in organic synthesis. Recently, we reported the Me3SiOTf-
catalyzed condensation of 1,3-bis(silyl enol ethers) with 1-chloro-
1
4
2
,2-dimethoxyethane and 2-azido-1,1-dimethoxyethane, re-
15
spectively. The reaction of 1-methoxy-1,3-bis(trimethylsilyloxy)-
,3-butadiene (1a) with 1,1,3,3-tetramethoxypropane (2), in the
1
presence of a catalytic amount of Me3SiOTf (0.1 equiv),
afforded ethyl 2-methoxybenzoate (3a) in up to 55% yield
3
Salicylic acid derivatives were prepared by Me SiOTf-
catalyzed [3 + 3] cyclization of 1,3-bis(silyl enol ethers)
with 1,1,3,3-tetramethoxypropane.
(Scheme 1, Tables 1 and 2). During the optimization (Table 1),
the workup procedure (10% HCl), the temperature (-78 f
2
1
0 °C, 6-12 h; then 20 °C, 2-6 h), and the concentration (ca.
5 mL of CH2Cl2 per 1 mmol of 1a) proved to be important
Salicylic acid derivatives are widespread in nature and are
1
parameters. The use of tetraethoxypropane proved to be unsuc-
cessful. The use of trifluoroacetic acid (rather than Me3SiOTf)
failed to give the desired product.
of considerable relevance in medicinal chemistry. Synthetic
approaches to salicylates mainly rely on the functionalization
of phenols by electrophilic substitutions. The preparative scope
of this approach is often limited by the formation of regioiso-
meric mixtures and by the availability of the starting materials.
Salicylates are also available by base-mediated cyclization
reactions of dimethyl acetone-1,3-dicarboxylate (DMAD) with
(5) See, for example: (a) Danishefsky, S. J.; Singh, R. K.; Gammill, R.
B. J. Org. Chem. 1978, 43, 379. (b) Fink, M.; Gaier, H.; Gerlach, H. HelV.
Chim. Acta 1982, 65, 2563.
(6) Reviews: (a) Danishefsky, S. J.; Bilodeau, M. T. Angew. Chem. 1996,
2
3
1
,3-diketones, ynones, and ynals. The scope of these trans-
108, 1482; Angew. Chem., Int. Ed. Engl. 1996, 35, 1380. (b) Bednarski,
M. D.; Lyssikatos, J. P. ComprehensiVe Organic Synthesis: SelectiVity,
Strategy and Efficiency in Modern Organic Chemistry; Trost, B. M., Ed.;
Pergamon: New York, 1991; Vol. 2, 661.
formations is limited by the fact that a symmetrical, highly
activated 1,3,5-tricarbonyl compound has to be employed.
Barton et al. reported the synthesis of ethyl 5-ethylsalicylate
by cyclization of the dianion of ethyl acetoacetate with 3-(N,N-
(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. (c) Molander, G. A.; Cameron, K. O. J. Am. Chem. Soc.
4
dimethylamino)-2-ethylacrolein. Functionalized phenols are also
1
993, 115, 830.
8) See, for example: (a) Roberge, G.; Brassard, P. J. Org. Chem. 1981,
6, 4161. (b) Townsend, C. A.; Davis, S. G. J. Chem. Soc., Chem. Commun.
available by [4 + 2] cycloaddition of 1-methoxy-3-trimethyl-
(
4
*
To whom correspondence should be addressed. Fax: +381 4986412.
Institut f u¨ r Chemie, Universit a¨ t Rostock.
Leibniz-Institut f u¨ r Katalyse e. V. an der Universit a¨ t Rostock.
1983, 1420. (c) Sestelo, J. P.; del Mar Real, M.; Sarandeses, L. A. J. Org.
Chem. 2001, 66, 1395. (d) Roush, W. R.; Murphy, M. J. Org. Chem. 1992,
57, 6622. (e) Langer, P.; Kracke, B. Tetrahedron Lett. 2000, 4545.
(9) For a review of 1,3-bis(silyl enol ethers), see: Langer, P. Synthesis
2002, 441.
(10) For a review of [3 + 3] cyclizations of 1,3-bis(silyl enol ethers),
see: Feist, H.; Langer, P. Synthesis 2007, 327.
†
‡
(
1) R o¨ mpp Lexikon Naturstoffe; Steglich, W., Fugmann, B., Lang-
Fugmann, S., Eds.; Thieme: Stuttgart, 1997.
2) (a) Prelog, V.; W u¨ rsch, J.; K o¨ nigsbacher, K. HelV. Chim. Acta 1951,
4, 258. (b) Beringer, M.; Kuntz, I. J. Am. Chem. Soc. 1951, 73, 364. (c)
(
3
Bertz, S. H.; Dabbagh, G. Angew. Chem. 1982, 94, 317; Angew. Chem.,
Int. Ed. Engl. 1982, 21, 306. For intramolecular reactions of unsymmetrical
derivatives, see: (d) Yamaguchi, M.; Hasebe, K.; Minabi, T. Tetrahedron
Lett. 1986, 27, 2401. (e) Gilbreath, S. G.; Harris, C. M.; Harris, T. M. J.
Am. Chem. Soc. 1988, 110, 6172 and following publications.
(11) (a) Rashid, M. A.; Reinke, H.; Langer, P. Tetrahedron Lett. 2007,
48, 2321. (b) Nguyen, V. T. H.; Appel, B.; Langer, P. Tetrahedron 2006,
62, 7674. (c) Nguyen, V. T. H.; Bellur, E.; Langer, P. Tetrahedron Lett.
2006, 47, 113.
(12) Mamat, C.; B u¨ ttner, S.; Trabhardt, T.; Fischer, C.; Langer, P. J.
Org. Chem. 2007, in press.
(3) (a) Ried, W.; K o¨ nig, E. Liebigs Ann. Chem. 1972, 757, 153. (b)
Covarrubias-Zuniga, A. Synth. Commun. 1998, 28, 1525. (c) Covarrubias-
Zuniga, A.; Rios-Barrios, E. J. Org. Chem. 1997, 62, 5688.
(13) Murata, S.; Suzuki, M.; Noyori, R. J. Am. Chem. Soc. 1980, 102,
3248.
(14) Bellur, E.; G o¨ rls, H.; Langer, P. Eur. J. Org. Chem. 2005, 2074.
(15) Freifeld, I.; Shojaei, H.; Langer, P. J. Org. Chem. 2006, 71, 4965.
(
4) Barton, D. H. R.; Dressaire, G.; Willis, B. J.; Barrett, A. G. M.;
Pfeffer, M. J. Chem. Soc., Perkin Trans. 1 1982, 665.
10.1021/jo070974a CCC: $37.00 © 2007 American Chemical Society
6
284
J. Org. Chem. 2007, 72, 6284-6286
Published on Web 07/13/2007

SCHEME 1. Cyclization of 1,3-Bis(silyl enol ethers) 1a-d
SCHEME 2. Cyclization of 1,3-Bis(silyl enol ethers) 1e-u
with 1,1,3,3-Tetramethoxypropanea
with 1,1,3,3-Tetramethoxypropanea
a
(i) (1) Me3SiOTf (0.1 equiv), CH2Cl2, −78 f 20 °C; (2) HCl (10%).
TABLE 3. Synthesis of 4a-q
R1
1
4
R2
% (4)a
e
f
g
h
i
j
k
l
m
n
o
p
q
r
s
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
Me
Et
Et
Et
45
40
60
45
50
59
56
54
67
63
57
61
32
a
(
i) Me3SiOTf (0.1 equiv), CH2Cl2, -78 f 20 °C; (2) HCl (10%).
n-Bu
i-Bu
n-Hex
n-Hept
n-Oct
n-Dec
(CH2)6Cl
(CH2)2CHdCH2
CH2Ph
(CH2)3Ph
OMe
Me
Me
Et
Me
Et
TABLE 1. Optimization of the Synthesis of 3a
entry
1a/2
Me3SiOTf (equiv)
CH2Cl2a
workup
% (3a)b
1
2
3
4
5
1:1
1:1
1:1
1:1
0.3
0.3
0.3
0.3
0.1
2
15
15
50
15
NaHCO3
NaHCO3
10% HCl
10% HCl
10% HCl
32
35
54
45
55
Et
Me
Me
Me
Me
Me
Et
Et
Et
Et
1:1.1
a
mL (CH2Cl2)/mmol (1a). b Yields of isolated products.
b
OH
PhS
4-(MeO)C6H4S
4-MeC6H4S
27
52
42
40
TABLE 2. Synthesis of 3a-d
t
u
3
R
% (3)a
a
Yields of isolated products. b From 1r (R ) O-t-Bu).
1
a
b
c
Et
Me
(CH2)2OMe
Bn
55
32
30
40
d
(
Scheme 2, Table 3). Notably, the formation of ethyl 5-methyl-
a
Yields of isolated products
2-methoxybenzoate was not observed. The formation of 4a can
be explained, in analogy to the formation of 3a-d, by attack
of 1e onto 2 to give intermediate D and subsequent cyclization
to give E (which correspond to intermediates A and B shown
in Scheme 1). Intermediate E undergoes a rapid extrusion of
two molecules of methanol (rather than a shift of the double
bond as discussed for the formation of 3a-d). The change of
the mechanism can be explained by the fact that the presence
The Me3SiOTf-catalyzed cyclization of 2 with 1,3-bis(silyl
enol ethers) 1a-d, prepared from ethyl, methyl, methoxyethyl,
and benzyl acetoacetate, afforded the 2-methoxybenzoates 3a-
d. Their formation can be explained by the mechanism depicted
in Scheme 1: the Me3SiOTf-catalyzed attack of the terminal
carbon atom of 1 onto 2 gave intermediate A. The subsequent
Me3SiOTf-catalyzed cyclization afforded intermediate B, which
underwent a shift of the double bond to give intermediate C.
Extrusion of water and methanol from C afforded the final
product. Notably, the formation of a 2-hydroxybenzoate was
not observed, which shows that water rather than methanol was
selectively eliminated. This can be explained by the higher steric
hindrance of the methoxy compared to the hydroxy group and
the better leaving group ability of the latter. The mechanism is
supported by the isolation of a small amount of 3,5-dimethoxy-
cyclohexanone. The formation of this side product can be
explained by cleavage of the ester group of intermediate B and
subsequent decarboxylation.
1
of the substituent R seems to enhance the rate of the elimination
of methanol from intermediate E. This can be rationalized by
the assumption that the protonation and cleavage of the hydroxy
group is sterically hindered by the presence of the neighboring
methyl group, which results in selective elimination of methanol
rather than water.
The Me3SiOTf catalyzed cyclization of 2 with 1,3-bis(silyl
enol ethers) 1f-u afforded the salicylates 4b-q. The cyclization
of 2 with 1,4-di(methoxy)-1,3-bis(trimethylsilyloxy)-1,3-buta-
diene (1q) gave salicylate 4m containing a protected and a
nonprotected hydroxy group. Ethyl 3-hydroxysalicylate (4n) was
prepared from 1-ethoxy-4-(tert-butoxy)-1,3-bis(trimethylsiloxy)-
1,3-butadiene (1r). The tert-butyl group was cleaved during the
reaction. The Me3SiOTf-catalyzed cyclization of 2 with 1,3-
bis(silyl enol ethers) derived from 1,3-diketones (e.g., acety-
The Me3SiOTf-catalyzed cyclization of 1,3-bis(silyl enol
ether) 1e, prepared from ethyl 3-oxopentanoate, afforded ethyl
-methylsalicylate (i.e., ethyl 3-methyl-2-hydroxybenzoate) (4a)
3
J. Org. Chem, Vol. 72, No. 16, 2007 6285

lacetone and benzoylacetone) proved to be unsuccessful (for-
mation of complex mixtures). Most salicylates 3a-d and 4a-q
were isolated in only moderate yields. This can be explained
by the fact that not all of the 1,3-bis(silyl enol ether) was
converted into product. Some amount of the corresponding
â-ketoester, formed by hydrolysis of unreacted 1,3-bis(silyl enol
ether) during the aqueous workup, was isolated as a side product.
In conclusion, a variety of salicylates were prepared by Me3-
SiOTf-catalyzed formal [3 + 3] cyclization of 1,3-bis(silyl enol
ethers) with 1,1,3,3-tetramethoxypropane. The use of 1,3-bis-
mixture was stirred for 2-6 h at 20 °C, an aqueous solution of
HCl (10%, 50 mL) was added. The organic and aqueous layers
were separated, and the latter was extracted with CH
2
Cl
2
(3 × 50
mL). The combined organic layers were dried (MgSO ) and filtered,
4
and the filtrate was concentrated in vacuo. The residue was purified
by chromatography (silica gel, heptane/ethyl acetate).
Ethyl 2-Methoxybenzoate (3a). Starting with 1,3-bis(silyl enol
ether) 1a (2.00 g, 7.28 mmol), 1,1,3,3-tetramethoxypropane 2 (1.32
mL, 8.01 mmol, 1.1 equiv), and TMSOTf (0.11 mL, 0.73 mmol,
1
0
.1 equiv), 3a was obtained as a yellow oil (720 mg, 55%): -
HNMR (400 MHz, CDCl ) δ 1.37 (t, J ) 7.1 Hz, 3H, CH ), 3.89
3
3
(silyl enol ethers) 1a-d, containing no substituent at carbon
(s, 3 H, OCH
3
), 4.35 (q, J ) 7.1 Hz, 2H, OCH
2
), 6.95-6.99 (m,
atom C-4, resulted in the formation of 2-methoxybenzoates 3a-
d. The best yield was obtained for salicylate 3a. The yields
depend on the quality of the silyl enol ether and on the handling
of each individual experiment. 2-Hydroxy- rather than 2-meth-
oxybenzoates were generally formed when 1,3-bis(silyl enol
ethers) 1e-u, containing a substituent located at carbon atom
C-4, were employed. The best yields were obtained for alkyl-,
ω-chloroalkyl-, ω-phenylalkyl-, and thiophenoxy-substituted 1,3-
bis(silyl enol ethers) 1g,i-p,s. Most salicylates 3a-d and 4a-q
were obtained in only moderate yields. However, the method
reported provides a new and convenient approach to salicylates
under mild conditions which is complementary to known
syntheses of salicylates.
2H, Ar), 7.43-7.47 (m, 1H, Ar), 7.78 (dd, J ) 7.8, 1.8 Hz, 1H,
Ar); 13C NMR (100 MHz, CDCl
3
) δ 14.3, 56.0, 60.8, 112.0, 120.1,
-
1
1
1
20.5, 131.5, 133.3, 159.0, 166.1; IR (neat, cm ) ν˜ ) 1725 (s),
601 (m), 1491 (s), 1436 (s), 1302 (s), 1252 (s), 1080 (m); MS
+
(
(
EI, 70 eV) m/z 180 (M , 24), 135 (100), 105 (20), 92 (20), 77
38); HRMS (EI) calcd for C10 180.078678, found 180.07919.
12 3
H O
Ethyl 2-Hydroxy-3-methylbenzoate (4a). Starting with 1,3-bis-
silyl enol ether) 1e (2.00 g, 6.93 mmol), 1,1,3,3-tetramethoxypro-
(
pane 2 (1.20 mL, 7.62 mmol, 1.1 equiv), and TMSOTf (0.11 mL,
0.69 mmol, 0.1 equiv), 4a was obtained as a yellow oil (570 mg,
45%): 1H NMR (300 MHz, CDCl
) δ 1.27 (t, 3 H, J ) 5.3 Hz,
), 4.25 (q, 2 H, J ) 5.3 Hz, OCH ), 6.63
t, 1 H, J ) 5.7 Hz, ArH), 7.16 (dd, 1 H, J ) 1.5, 7.8 Hz, ArH),
.56 (dd, 1 H, J ) 1.2, 5.5 Hz, ArH); 13C NMR (100 MHz, CDCl
δ 14.1, 15.5, 61.2, 111.8, 118.3, 126.4, 127.3, 136.2, 160.0, 170.6;
3
OCH
3
), 2.13 (s, 3 H, CH
3
2
(
7
3
)
-
1
IR (neat, cm ) ν˜ 3397 (m), 2985 (s), 1670 (s), 1616 (m), 1435
Experimental Section
(m), 1290 (s), 1250 (s), 1148 (s), 1083 (s), 1027 (m), 879 (w), 755
+
(
1
s); GC-MS (EI, 70 eV): m/z (%): 180.1 (M , 61), 134,1 (100),
General Comments. All solvents were dried by standard
12 3
06.1 (95), 77.1 (31); HRMS (EI) calcd for C10H O 180.077698,
methods, and all reactions were carried out under an inert
1
13
found 180.07810.
atmosphere. For H and C NMR spectra, the deuterated solvents
indicated were used. Mass spectrometric data (MS) were obtained
Acknowledgment. Financial support by the state of Meck-
lenburg-Vorpommern (Landesgraduiertenstipendium for Z.A.)
and by Pakistan (HEC scholarship for M.A.R.) is gratefully
acknowledged.
2
by electron ionization (EI, 70 eV), chemical ionization (CI, H O),
or electrospray ionization (ESI). For preparative scale chromatog-
raphy, silica gel (60-200 mesh) was used. Melting points are
uncorrected.
Typical Procedure for the Synthesis of Salicylates 3 and 4.
To a CH Cl solution (100 mL) of 1,3-bis(trimethylsilyloxy)-1-
2 2
ethoxy-1,3-butadiene (2.00 g, 7.28 mmol) and of 1,1,3,3-tet-
ramethoxypropane (1.32 mL, 8.01 mmol, 1.1 equiv) was dropwise
added TMSOTf (0.11 mL, 0.73 mmol, 0.1 equiv) at -78 °C. The
reaction mixture was warmed to 20 °C during 6-12 h. After the
Supporting Information Available: Experimental procedures,
compound characterization, and copies of NMR spectra. This
material is available free of charge via the Internet at http:
/
/pubs.acs.org.
JO070974A
6
286 J. Org. Chem., Vol. 72, No. 16, 2007