Synthesis of functionalized diaryl ethers by [3+3] cyclization of 1,3-bis(silyl enol ethers) with 2-aryloxy-3-(silyloxy)alk-2-en-1-ones

Article abstract of DOI:10.1055/s-2006-951546

Functionalized and sterically encumbered diaryl ethers were prepared by [3+3] cyclization of 1,3-bis(silyl enol ethers) with 2-aryloxy-3-(silyloxy)alk- 2-en-1-ones. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-951546

LETTER
3361
Synthesis of Functionalized Diaryl Ethers by [3+3] Cyclization of 1,3-Bis(Silyl
Enol Ethers) with 2-Aryloxy-3-(silyloxy)alk-2-en-1-ones
S
ynthesis of Fun
a
ctionalized
f
Diaryl
aE
thers r Ahmed,a,b Peter Langer*a,b
a
Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
Fax +49(381)4986412; E-mail: peter.langer@uni-rostock.de
b
Leibniz-Institut für Katalyse e. V. an der Universität Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
Received 24 August 2006
tion, the amount of the Lewis acid, the concentration, the
temperature and the work-up procedure proved to be im-
portant parameters. All products were isolated in moder-
ate to good yields.
Abstract: Functionalized and sterically encumbered diaryl ethers
were prepared by [3+3] cyclization of 1,3-bis(silyl enol ethers) with
2-aryloxy-3-(silyloxy)alk-2-en-1-ones.
Key words: arenes, cyclizations, diaryl ethers, silyl enol ethers
O
O
O
O
OH
Me
Me
R3
Diaryl ethers are of considerable pharmacological rele-
vance and occur in various natural products.1 Functional-
ized diaryl ethers containing an ester or carboxylic acid
function are present, for example, in geodinhydrate meth-
ylester and methyl chloroasterrate,2a,b 1-desgalloylsangui-
in,2c dehydrotrigallic acid,2d epiphorellic acid,2e
jolkianin,2f remurin A,2g or micareic acid.2h Diaryl ethers
have been prepared, for example, based on the Ullmann
ether synthesis and related methods3 and by various tran-
sition-metal-catalyzed C–O coupling reactions.4 Despite
their synthetic usefulness, the scope of these methods is
limited in many cases by the fact that the starting materials
are not readily available. In addition, the formation of di-
aryl ethers containing a sterically encumbered ether link-
age often proceeds in low yield or not at all. Some years
ago, Chan and coworkers reported5 an elegant approach to
salicylates by [3+3] cyclization of 1,3-bis(silyl enol
ethers)6 with 3-(siloxy)alk-2-en-1-ones. In recent years,
we have reported the application of this method to the syn-
thesis of a variety of functionalized arenes.7 Herein, we re-
port what are, to the best of our knowledge, the first [3+3]
cyclizations of 1,3-bis(silyl enol ethers) with 2-aryloxy-3-
(silyloxy)alk-2-en-1-ones. These reactions provide a con-
venient approach to sterically encumbered and functional-
ized diaryl ethers which are not readily available by other
methods. In contrast to transition-metal-catalyzed C–O
coupling reactions, our method relies on the assembly of
one of the two arene moieties.
Me
Me
O
Cl
2
R5
R3
i
R4
R5
R4
1a–f
3a–f
ii
OH
O
R1
Me3SiO
R1
OSiMe3
R2
R2
Me3SiO
Me
O
Me
Me
Me
R3
5a–e
O
O
iii
R5
R3
R5
R4
R4
For substituents R1–R5,
see Tables 1 and 2
6a–n
4a–f
Scheme 1 Synthesis of 6a–n. Reagents and conditions: i: K2CO3,
acetone, 2 h, reflux; ii: Me3SiCl, Et3N, C6H6, 20 °C, 72 h; iii: TiCl4,
CH2Cl2, –78 °C to 20 °C, 20 h.
Table 1 Synthesis of 3a–f and 4a–f
Compd 3 R3
and 4
R4
R5
Yield of 3 Yield of 4
(%)a
(%)a
The potassium carbonate mediated reaction of phenols
1a–f with 3-(chloro)pentane-2,4-dione (2) afforded, fol-
lowing a known procedure,8 the 3-(aryloxy)pentane-2,4-
diones 3a–f which were transformed into the 2-aryloxy-3-
(silyloxy)alk-2-en-1-ones 4a–f (Scheme 1, Table 1). The
TiCl4-mediated cyclization of 4a–f with 1,3-bis(silyl enol
ethers) 5a–e afforded the sterically encumbered diaryl
ethers 6a–n (Scheme 1, Table 2).9 During the optimiza-
b
a
b
c
d
e
f
H
H
H
–
79
Me
H
H
Me
H
20
35
94
Et
80
b
H
Cl
H
–
96
H
OMe
OMe
H
24
40
95
OMe
H
97
SYNLETT 2006, No. 19, pp 3361–3363
Advanced online publication: 23.11.2006
0
1
.1
2
.2
0
0
6
a Yields of isolated products.
b Commercially available.
DOI: 10.1055/s-2006-951546; Art ID: D25406ST
© Georg Thieme Verlag Stuttgart · New York

3362
Z. Ahmed, P. Langer
LETTER
Table 2 Synthesis of 6a–n
Compd 4
Compd 5
Compd 6
R1
H
R2
R3
H
R4
H
R5
H
Yield of 6 (%)a
a
a
a
b
b
c
c
d
d
d
d
e
f
a
b
c
a
b
c
d
e
f
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OMe
OEt
OEt
Me
35
30
32
58
39
60
36
54
49
43
35
30
58
35
Me
Et
H
H
H
H
H
H
a
b
a
b
d
b
c
H
Me
Me
H
H
Me
Me
H
Me
H
H
Et
g
h
i
Me
H
H
Et
H
H
Cl
H
Me
Et
H
Cl
H
j
H
Cl
H
e
k
l
H
H
Cl
H
b
a
b
Me
H
OEt
OEt
OEt
H
OMe
OMe
OMe
H
m
n
OMe
OMe
H
f
Me
H
a Yields of isolated products.
(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. (c) Muci, A. R.; Buchwald, S. R. Topics
Curr. Chem. 2002, 219, 131.
(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.
In conclusion, a variety of functionalized and sterically
encumbered diaryl ethers were prepared by [3+3] cycliza-
tions of 1,3-bis(silyl enol ethers) with 2-aryloxy-3-(silyl-
oxy)alk-2-en-1-ones.
Acknowledgment
We thank Mr. M. A. Rashid for an experimental contribution. Fi-
nancial support by the state of Mecklenburg-Vorpommern (Landes-
graduiertenstipendium for Z.A.) is gratefully acknowledged.
(6) For a review of 1,3-bis(silyl enol ethers), see: Langer, P.
Synthesis 2002, 441.
(7) (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.; Spannenberg, 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.
(8) Beer, R. J. S.; Davenport, H. F.; Robertson, A. J. Chem. Soc.
1953, 1262.
(9) General Procedure for the Synthesis of Diaryl Ethers
6a–n.
References and Notes
(1) Römpp Lexikon Naturstoffe; Steglich, W.; Fugmann, B.;
Lang-Fugmann, S., Eds.; Thieme: Stuttgart, 1997.
(2) See, for example: (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. (c) Hussein, S. A. M.; Ayoub, N. A.;
Nawwar, M. A. M. Phytochemistry 2003, 63, 905.
(d) Nawwar, M. A. M.; Hussein, S. A. M.; Buddrus, J.;
Linscheid, M. Phytochemistry 1994, 35, 1349. (e) Fiedler,
P.; Gambaro, V.; Garbarino, J. A.; Quilhot, W.
To a CH2Cl2 solution (2 mL/mmol) of 4 (1.0 mmol) and 5
(1.0 mmol) was added TiCl4 (1.0 mmol) at –78 °C. The
solution was allowed to warm to ambient temperature within
20 h. To the solution was added a sat. solution of NaHCO3
(10 mL). The organic and the aqueous layer were separated
and the latter was extracted with Et2O (3 × 30 mL). The
filtrate was concentrated in vacuo and the residue was puri-
fied by chromatography (silica gel, EtOAc–n-heptane, 1:4).
Synthesis of Methyl 4,6-Dimethyl-5-(4-chloro-
phenoxy)salicylate (6h).
Phytochemistry 1986, 25, 461. (f) Jolkianin: Lee, S.-H.;
Tanaka, T.; Nonaka, G.-i.; Nishioka, I. Chem. Pharm. Bull.
1991, 39, 630. (g) Yoshida, T.; Ahmed, A. F.; Okuda, T.
Chem. Pharm. Bull. 1993, 41, 672. (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. (b) For a recent example,
see: Sinisi, R.; Sani, M.; Candiani, G.; Parente, R.; Pecker,
F.; Bellosta, S.; Zanda, M. Tetrahedron Lett. 2005, 46, 6515;
and references cited therein.
Starting with 1,3-bis(silyl enol ether) 5d (500 mg, 1.9
mmol), 3-(siloxy)alk-2-en-1-one 4d (574 mg, 1.9 mmol) and
Synlett 2006, No. 19, 3361–3363 © Thieme Stuttgart · New York

LETTER
TiCl4 (0.21 mL, 1.9 mmol), 6h was isolated as a colorless
Synthesis of Functionalized Diaryl Ethers
3363
139.7, 143.6, 156.5, 159.7, 171.7 (C). IR (KBr): 3431 (m),
2959 (w), 1661 (s), 1486 (s), 1442 (m), 1361 (m), 1326 (s),
1318 (s), 1074 (m), 825 (m), 803 (m) cm–1. GC-MS (EI, 70
eV): m/z (%) = 306 (33) [M+], 274 (100), 246 (10), 163.1 (8).
Anal. Calcd (%) for C16H15ClO4 (306.74): C, 62.65; H, 4.93.
Found: C, 62.42; H, 4.68.
solid (315 mg, 54%); mp 83 °C. 1H NMR (300 MHz,
CDCl3): d = 2.09 (s, 3 H, CH3), 2.30 (s, 3 H, CH3), 3.95 (s, 3
H, OCH3), 6.67 (d, 2 H, J = 9.0 Hz, ArH), 6.76 (s, 1 H, ArH),
7.20 (d, 2 H, J = 9.0 Hz, ArH), 11.10 (s, 1 H, OH). 13C NMR
(75 MHz, CDCl3): d = 15.2, 17.1, 52.2 (CH3), 111.1 (C),
115.7 (2 C), 117.6 (CH), 126.3 (C), 129.6 (2 C, CH), 133.5,
Synlett 2006, No. 19, 3361–3363 © Thieme Stuttgart · New York