Synthesis of functionalized arylalkyl and diaryl ethers by [3+3] cyclization of 3-alkoxy- and 3-aryloxy-1-siloxy-1,3-butadienes with 3-(silyloxy)alk-2-en-1-ones

Article abstract of DOI:10.1016/j.tetlet.2006.09.126

Functionalized diaryl ethers were prepared by [3+3] cyclization of 3-aryloxy-1-siloxy-1,3-butadienes with 3-(silyloxy)alk-2-en-1-ones.

Full text of DOI:10.1016/j.tetlet.2006.09.126

Tetrahedron Letters 47 (2006) 8519–8521
Synthesis of functionalized arylalkyl and diaryl ethers
by [3+3] cyclization of 3-alkoxy- and
3-aryloxy-1-siloxy-1,3-butadienes with 3-(silyloxy)alk-2-en-1-ones
Gerson Mroßa and Peter Langera,b,
*
aInstitut fu¨r Chemie, Universita¨t Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
bLeibniz-Institut fu¨r Katalyse e. V. an der Universita¨t Rostock Albert-Einstein-Str. 29a, 18059 Rostock, Germany
Received 31 July 2006; revised 20 September 2006; accepted 25 September 2006
Available online 17 October 2006
Abstract—Functionalized diaryl ethers were prepared by [3+3] cyclization of 3-aryloxy-1-siloxy-1,3-butadienes with 3-(silyloxy)alk-
2-en-1-ones.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Diaryl ethers occur in a great variety of pharmacologi-
cally important natural products, such as the prominent
antibiotic vancomycin.1 Diaryl ethers containing an
ester or carboxylic acid function next to the ether linkage
constitute an important subgroup of naturally occurring
diaryl ethers.2 Classic syntheses of diaryl ethers rely on
the Ullmann ether synthesis and related methods.3 More
recently, diaryl ethers have been prepared by various
transition metal catalysed C–O coupling reactions.4 De-
spite their great synthetic usefulness, the scope of these
methods can be limited by the availability of the arene
starting materials and by problems related to the synthe-
sis of diaryl ethers containing a sterically encumbered
ether linkage. Some years ago, Chan and co-workers re-
ported5 the synthesis of salicylates based on [3+3] cycli-
zations of 1,3-bis(silyl enol ethers) with 3-(siloxy)alk-2-
en-1-ones.6 We have recently reported the application
of this methodology to the synthesis of a variety of func-
tionalized arenes.7 Chan and Prasad reported the syn-
thesis of 2-(phenylthio)benzoates by [3+3] cyclization
of 3-(silyloxy)alk-2-en-1-ones with 1-silyloxy-1-meth-
oxy-3-phenylthio-1,3-butadiene.8 Herein, we report
[3+3] cyclizations of 3-alkoxy- and 3-aryloxy-1-siloxy-
1,3-butadienes. These reactions provide a convenient
approach to arylalkyl and diaryl ethers containing an
ester function next to the ether linkage. In contrast to
transition metal catalysed C–O coupling reactions, our
method relies on the assembly of one of the two arene
moieties.
3-Alkoxy-1-siloxy-1,3-butadienes 1a–c9 were prepared
by phosphorus(V)chloride mediated chlorination of the
respective b-ketoester, substitution of the chloride by
an alkoxy group and subsequent silylation. The TiCl4
mediated cyclization of 3-methoxy-1-methoxy-1-siloxy-
1,3-butadiene (1a, Brassard’s diene) with 1,1,3,3-tetra-
methoxypropane (2) afforded methyl 2-methoxybenzo-
ate (3), albeit, in only low yield (Scheme 1).
The TiCl4 mediated cyclization of 1a with 3-(siloxy)alk-
2-en-1-one 4a, readily available from 3-methylacetylace-
tone, afforded methyl 2-methoxy-4,5,6-trimethylbenzo-
ate (5a). The formation of 5a can be explained, in
analogy to the corresponding reaction of 1,3-bis(silyl
enol ethers), by conjugate addition of the terminal car-
bon atom of 1a onto 4a, cyclization and aromatization
MeO OSiMe3
MeO
O
OMe
1a
i
OMe
OMe OMe
OMe
+
MeO
3 (25%)
2
Keywords: Arenes; Cyclizations; Diaryl ethers; Silyl enol ethers.
*
Scheme 1. Synthesis of 3. Reagents and conditions: (i) TiCl4, CH2Cl2,
ꢀ78!20 ꢁC.
Corresponding author. Tel.: +49 381 4986410; fax: +49 381
4986412; e-mail: peter.langer@uni-rostock.de
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.09.126

8520
G. Mroß, P. Langer / Tetrahedron Letters 47 (2006) 8519–8521
OR2 OSiMe3
MeO OSiMe3
R1
MeO
O
OR2 O
OR3
OMe
1a
R1
R6
i
OMe
Me
1a-c
Me3SiO
i
OR3
Me3SiO
O
O
Me
+
R4
+
Me
Me
Me
R6
R4
R5
Me
R5
4a-d
5a (40%)
4a
5a-f
+ TiCl4
Me3SiCl
_
Scheme 3. Synthesis of 5a–f. Reagents and conditions: (i) TiCl4,
CH2Cl2, ꢀ78!20 ꢁC.
TiCl3OH
_
MeO
O
MeO
O
Table 1. Products and yields
OMe
Me
OTiCl3
OMe
Me
R1
R2
R3
R4
R5
R6
% (5)a
Me3SiO
Me
1
4
5
Me
_
a
b
b
c
a
b
a
a
c
a
b
c
d
e
f
H
H
H
Et
H
H
Me
Et
Et
Et
Me
Me
Me
Et
Et
Et
Me
Me
Me
Me
Me
Me
Ph
Me
H
Me
Me
H
Me
Me
Me
Me
Me
Me
40
48
34
36b
43
28
Me3SiOH
Me
Me OTiCl3
Scheme 2. Synthesis of 5a. Reagents and conditions: (i) TiCl4, CH2Cl2,
ꢀ78!20 ꢁC.
a
a
d
–(CH2)4–
a Yields of isolated products.
(Scheme 2). During the optimization, the amount of the
Lewis acid, the concentration, the temperature and the
work-up procedure proved to be important parameters.
As a side-product, methyl 2-hydroxy-4,5,6-trimethyl-
benzoate was formed by partial hydrolytic cleavage of
the methoxy group. The byproduct could be removed
by washing the reaction mixture with an aqueous solu-
tion of sodium hydroxide.
b A small amount of ethyl 3-ethyl-4,5,6-trimethylsalicylate could not be
separated.
reported. 1-Aryloxy-3-siloxy-1,3-butadienes 7a–d were
prepared by reaction of the corresponding 3-chlorocrot-
onates and phenols to give the 3-(aryloxy)crotonates
6a–d and subsequent deprotonation (LDA) and silylation
of the latter. The cyclization of 7a–d with 3-(siloxy)alk-2-
en-1-ones 4a–c,e,f afforded diaryl ethers 8a–h (Scheme
4). The best yields were obtained in the reactions of
the alkyl-substituted 3-(siloxy)alk-2-en-1-ones 4a and
4b (Table 2).
The preparative scope was next studied. The cyclization
of 1-alkoxy-3-siloxy-1,3-butadienes 1a–c with 3-(sil-
oxy)alk-2-en-1-ones 4a–d afforded the 2-alkoxybenzo-
ates 5a–f (Scheme 3).10 The formation of 5e and 5f
proceeded with very good regioselectivity, which can
be explained as previously reported for the reactions
of 1,3-bis(silyl enol ethers) (Table 1).5,7
In conclusion, functionalized arylalkyl and diaryl ethers
were prepared by [3+3] cyclizations of 3-alkoxy- and 3-
aryloxy-1-siloxy-1,3-butadienes with 3-(silyloxy)alk-2-
en-1-ones.
The preparation of 1-aryloxy-3-alkoxy-3-siloxy-1,3-buta-
dienes has, to the best of our knowledge, not yet been
R1
R1
i
OH
O
O
Cl
O
+
OR2
OR2
6a-d
ii
R1
Me3SiO
R5
O
R1
R3
O
O
R4
O
OSiMe3
OR2
OR2
4a-c,e,f
R5
R3
iii
R4
7a-d
8a-h
Scheme 4. Synthesis of 8a–h. Reagents and conditions: (i) K2CO3, acetone, reflux, 8 h; (ii) (1) LDA, THF, ꢀ78 ꢁC, 30 min, (2) Me3SiCl, ꢀ78!20 ꢁC;
(iii) TiCl4, CH2Cl2, ꢀ78!20 ꢁC.

G. Mroß, P. Langer / Tetrahedron Letters 47 (2006) 8519–8521
8521
Table 2. Products and yields
7. For [3+3] cyclizations of 1,3-bis(silyl enol ethers) from our
laboratory, see: (a) Dede, R.; Langer, P. Tetrahedron Lett.
2004, 45, 9177; (b) Nguyen, V.; Langer, P. Tetrahedron
Lett. 2005, 46, 1013; (c) Ahmed, Z.; Fischer, C.; Span-
nenberg, A.; Langer, P. Tetrahedron 2006, 62, 4800; (d)
Nguyen, V. T. H.; Bellur, E.; Appel, B.; Langer, P.
Synthesis 2006, 1103; (e) Nguyen, V. T. H.; Bellur, E.;
Langer, P. Tetrahedron Lett. 2006, 47, 113; (f) Mamat, C.;
Pundt, T.; Schmidt, A.; Langer, P. Tetrahedron Lett. 2006,
47, 2183; (g) Ahmed, Z.; Langer, P. Tetrahedron Lett.
2006, 47, 417.
4
7
8
R1
R2
R3
R4
R5
% (8)a
b
a
c
a
c
a
e
f
a
a
a
b
b
c
a
b
c
d
e
f
H
H
H
Me
Me
Cl
OMe
OMe
Et
Et
Et
Me
Me
Me
Me
Me
Me
Me
Ph
Me
Ph
Me
Me
Et
H
Me
H
Me
H
Me
OArc
H
Me
Me
Me
Me
Me
Me
Me
Et
45
44
37b
56
22
47
18
15
d
d
g
h
a Yields of isolated products.
b A small amount of ethyl 4-methyl-6-phenylsalicylate could not be
8. Chan, T. H.; Prasad, C. V. C. J. Org. Chem. 1986, 51,
3012.
9. (a) Savard, J.; Brassard, P. Tetrahedron Lett. 1979, 4911;
(b) Brady, W. T.; Agho, M. O. J. Heterocycl. Chem. 1983,
20, 501; (c) Midland, M. M.; Graham, R. S. J. Am. Chem.
Soc. 1984, 106, 4294; (d) Bell, S. H.; Cameron, D. W.;
Feutrill, G. I.; Skelton, B. W.; White, A. H. Tetrahedron
Lett. 1985, 26, 6519; (e) Simoneau, B.; Brassard, P.
Tetrahedron 1988, 22, 1015; (f) Midland, M. M.; Koops,
R. W. J. Org. Chem. 1990, 55, 5058; (g) Caron, B.;
Brassard, P. Tetrahedron 1991, 25, 4287; (h) Coleman, R.
S.; Grant, E. B. J. Org. Chem. 1991, 56, 1357; (i) Ito, T.;
Aoyama, T.; Shioiri, T. Tetrahedron Lett. 1993, 34, 6583;
(j) Kawecki, R. Synthesis 2001, 828; (k) Krohn, K.; Vitz, J.
Eur. J. Org. Chem. 2004, 209.
separated.
c Ar = 4-EtC6H4.
Acknowledgement
We thank Dr. G. Bose for an experimental contribution.
Financial support by the state of Mecklenburg-Vor-
pommern (Landesforschungsschwerpunkt) is gratefully
acknowledged.
References and notes
10. Typical procedure for the synthesis of arylalkyl and diaryl
ethers: To a dichloromethane solution (9 mL) of 2
(2.0 mmol) and of 7 (2.0 mmol) was added a dichloro-
methane solution (1 mL) of TiCl4 (0.23 mL, 2.0 mmol) at
ꢀ78 ꢁC. The solution was allowed to warm to ambient
temperature within 14 h. To the solution was added 25 mL
of dichlormethane and 30 mL of hydrochloric acid (10%).
The organic and the aqueous layer were separated and the
latter was extracted with dichloromethane (3 · 15 mL).
The combined organic layers were washed four times with
an aqueous solution of sodium hydroxide (2 M), dried
(Na2SO4), and filtered. The filtrate was concentrated in
vacuo and the residue was purified by chromatography
(silica gel, EtOAc/n-heptane = 1:20, column length =
30 cm, diameter = 4 cm).
1. Ro¨mpp Lexikon Naturstoffe; Steglich, W., Fugmann, B.,
Lang-Fugmann, S., Eds.; Thieme: Stuttgart, 1997.
2. Geodinhydrate methylester and methyl chloroasterrate:
(a) Lee, H. J.; Lee, J. H.; Hwang, B. Y.; Kim, H. S.; Lee, J.
J. J. Antibiot. 2002, 55, 552; (b) Hargreaves, J.; Park, J.-o.;
Ghisalberti, E. L.; Sivasithamparam, K.; Skelton, B. W.;
White, A. H. J. Nat. Prod. 2002, 65, 7; 1-des-
galloylsanguiin: (c) Hussein, S. A. M.; Ayoub, N. A.;
Nawwar, M. A. M. Phytochemistry 2003, 63, 905; dehydro-
trigallic acid: (d) Nawwar, M. A. M.; Hussein, S. A. M.;
Buddrus, J.; Linscheid, M. Phytochemistry 1994, 35, 1349;
epiphorellic acid: (e) Fiedler, P.; Gambaro, V.; Garbarino,
J. A.; Quilhot, W. Phytochemistry 1986, 25, 461; Jolkianin:
(f) Lee, S.-H.; Tanaka, T.; Nonaka, G.-i.; Nishioka, I.
Chem. Pharm. Bull. 1991, 39, 630; remurin A: (g) Yoshida,
T.; Ahmed, A. F.; Okuda, T. Chem. Pharm. Bull. 1993, 41,
672; micareic acid: (h) Elix, J. A.; Jones, A. J.; Lajide, L.;
Coppins, B. J.; James, P. W. Aust. J. Chem. 1984, 37,
2349.
3. For a review, see: (a) Moroz, A. A.; Shvartsberg, M. S.
Russ. Chem. Rev. 1974, 43, 679; for a recent example, see:
(b) Sinisi, R.; Sani, M.; Candiani, G.; Parente, R.; Pecker,
F.; Bellosta, S.; Zanda, M. Tetrahedron Lett. 2005, 46,
6515, and references cited therein.
4. (a) Harkal, S.; Kumar, K.; Michalik, D.; Zapf, A.;
Jackstell, R.; Rataboul, F.; Riermeier, T.; Monsees, A.;
Beller, M. Tetrahedron Lett. 2005, 46, 3237, and references
cited therein; (b) Harkal, S.; Rataboul, F.; Zapf, A.;
Fuhrmann, C.; Riermeier, T. H.; Monsees, A.; Beller, M.
Adv. Synth. Catal. 2004, 346, 1742; for a review, see: (c)
Muci, A. R.; Buchwald, S. L. Topics Curr. Chem. 2002,
219, 131.
Synthesis of ethyl 4,6-trimethyl-2-phenoxysalicylate (8a):
Starting with 4-(trimethylsiloxy)pent-3-en-2-on (4a) (0.372 g,
2.0 mmol), 1-ethoxy-3-phenoxy-1-(trimethylsiloxy)buta-
1,3-diene (7a) (1.0 mmol), TiCl4 (0.23 mL, 2.0 mmol,
dissolved in 1 mL of CH2Cl2), and CH2Cl2 (9 mL), 8a was
isolated as a slightly yellow oil (0.121 g, 45%). Dienes 7
could not be isolated in pure form. They were used as a
defined mixture (by 1H NMR) of 7 and 6 containing
1.0 mmol of 7. Dienes 1a–c were obtained and used in
pure form. 1H NMR (250 MHz, CDCl3): d = 1.19 (t, 3J =
7.2 Hz, 3H, OCH2CH3), 2.24 (s, 3H, CH3), 2.34 (s, 3H,
CH3), 4.25 (q, 3J = 7.2 Hz, 2H, OCH2CH3), 6.57 (q,
4J = 0.6 Hz, 1H, Ar), 6.79 (m, 4J = 0.6 Hz, 1H, Ar), 6.95–
7.09 (m, 3H, Ph), 7.25–7.32 (m, 2H, Ph). 13C NMR
(75.5 MHz, CDCl3): d = 14.1 (CH3), 19.4, 21.3 (CH3),
61.0 (CH2), 118.4, 118.8, 122.9 (CHAr), 126.3 (CAr), 129.5,
129.7 (CHAr), 137.2, 140.9, 153.9, 157.7 (CAr), 167.6 (CO).
IR (neat, cmꢀ1): ~v ¼ 2981 (w), 2926 (w), 1728 (s), 1616
(m), 1591 (m), 1489 (s), 1455 (m), 1303 (s), 1270 (s), 1216
(s), 1160 (m), 1087 (s), 1021 (m). MS (EI, 70 eV): m/z
(%) = 270 (M+, 88), 225 (100), 223 (73), 170 (99). Anal.
Calcd for C17H18O3 (270.33): C, 75.53; H, 6.77. Found: C,
75.58; H, 6.58.
5. (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.
6. For a review of 1,3-bis(silyl enol ethers), see: Langer, P.
Synthesis 2002, 441.