Regioselective synthesis of sterically encumbered diaryl ethers based on one-pot cyclizations of 4-aryloxy-1,3-bis(trimethylsilyloxy)-1,3-dienes

Article abstract of DOI:10.1016/j.tet.2007.11.005

Sterically encumbered diaryl ethers are prepared based on formal [3+3] cyclizations of novel 4-aryloxy-1,3-bis(trimethylsilyloxy)-1,3-dienes.

Full text of DOI:10.1016/j.tet.2007.11.005

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 529e535
www.elsevier.com/locate/tet
Regioselective synthesis of sterically encumbered diaryl ethers based on
one-pot cyclizations of 4-aryloxy-1,3-bis(trimethylsilyloxy)-1,3-dienes
Muhammad A. Rashid a, Nasir Rasool a, Muhammad Adeel a, Helmut Reinke a,
Anke Spannenberg b, Christine Fischer b, Peter Langer a,b,
*
a Institut fu¨r Chemie, Universita¨t Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
b Leibniz-Institut fu¨r Katalyse e. V. an der Universita¨t Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
Received 1 October 2007; received in revised form 26 October 2007; accepted 1 November 2007
Available online 5 November 2007
Abstract
Sterically encumbered diaryl ethers are prepared based on formal [3þ3] cyclizations of novel 4-aryloxy-1,3-bis(trimethylsilyloxy)-1,3-dienes.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
based on reactions of 2-aryloxy- and 2-thioaryloxy-3-trimethyl-
silyloxy-2-en-1-ones, respectively.10 Herein, we report, for the
first time, the synthesis of 4-aryloxy-1,3-bis(trimethylsilyl-
oxy)-1,3-dienes and their application to the synthesis of diaryl
ethers. Noteworthy, the reactions reported herein allow a conve-
nient and regioselective synthesis of sterically encumbered and
functionalized diaryl ethers, which are not readily available by
other methods.
Functionalized diaryl ethers are of pharmacological rele-
vance and occur in a variety of natural products.1 This includes,
for example, geodinhydrate methylester, methyl chloroasterra-
te,2a,b 1-desgalloylsanguiin,2c dehydrotrigallic acid,2d epiphor-
ellic acid,2e jolkianin,2f remurin A2g and micareic acid
(Scheme 1).2h The most important approach to diaryl ethers
relies on the Ullmann3 and BuchwaldeHartwig4 reaction and
on related transformations.5 Although these methods are very
important, the scope is limited by the availability of the starting
materials. In fact, the synthesis of more complex aryl halides or
triflates by regioselective functionalizations of arenes is often
a difficult task. In addition, the transition metal catalyzed forma-
tion of diaryl ethers containing a sterically encumbered ether
linkage is often difficult or not possible at all. Some years ago,
Chan et al. developed6 a convenient approach to salicylates
based on the cyclization of 1,3-bis(trimethylsilyloxy)-1,3-
dienes7 with 3-trimethylsilyloxy-2-en-1-ones. We reported the
application of this method to the synthesis of a variety of
substituted benzene derivatives.8 Recently, we reported the
synthesis of 5-aryloxysalicylates9 and 5-thioaryloxysalicylates
CO2H
HO
O
nHept
HO2C
nHept
OMe
Scheme 1. Micareic acid.
2. Results and discussion
Ethyl 4-phenoxyacetoacetate (2a) was prepared by base-
mediated reaction of ethyl 4-chloroacetoacetate and phenol
(Scheme 2, Table 1). The methyl 4-phenoxyacetoacetates
2b,c were prepared by Claisen condensation of methyl acetate
with the corresponding a-aryloxyacetic chlorides. The silyla-
tion of 2aec gave the 3-silyloxy-2-en-1-ones 3aec. The novel
4-aryloxy-1,3-bis(silyloxy)-1,3-dienes 4aec were prepared by
* Corresponding author. Tel.: þ49 381 4986410; fax: þ49 381 4986412.
E-mail address: peter.langer@uni-rostock.de (P. Langer).
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.11.005

530
M.A. Rashid et al. / Tetrahedron 64 (2008) 529e535
deprotonation (LDA) of 3aec at ꢀ78 ꢁC and subsequent addi-
tion of trimethylchlorosilane. The Me3SiOTf-catalyzed cycli-
zation of 4-aryloxy-1,3-bis(silyloxy)-1,3-dienes 4aec with
1,1,3,3-tetramethoxypropane, following our recently reported
protocol,11 afforded the 3-aryloxysalicylates 5aec. During
the optimization of cyclization, the concentration and stoichio-
metry proved to play an important role.
Table 2
Synthesis of diaryl ethers 7aeg
4
6
7
R1
R2
R3
% (7)a
a
a
a
a
a
b
c
a
b
c
a
b
c
d
e
f
H
OEt
OEt
OEt
OEt
OEt
OMe
OMe
H
37
43
38
30
30
40
40
H
Me
Cl
ArOb
PhS
Cl
H
d
e
H
H
c
Me
Cl
b
g
Me
O
O
Cl
a
OR2
XH
Isolated yields.
Ar¼3,4-(MeO)2C6H3.
b
i
R1
O
O
+
O
structure of 7g was independently confirmed by X-ray crystal
structure analysis (Fig. 1).12
The TiCl4- and TiBr4-mediated reaction of 1,3-bis(silyl-
oxy)-1,3-diene 4a with 1,1-diacetylcyclopropane (8) afforded
the 3-phenoxysalicylates 9a,b containing a remote halide
OR2
O
ii
R1
2a-c
OR2
O
O
Cl
iii
+
R1
1a,b
Me3SiO
O
O
Me3SiO OSiMe3
iv
OR2
O
OR2
R1
O
R1
4a-c
3a-c
v
OMe OMe
OMe
OH
MeO
O
OR2
R1
5a-c
Scheme 2. Synthesis of 5aec: (i) NEt3/KOH, CH2Cl2/DMSO, 30 min, 0 ꢁC/
5 h, 20 ꢁC; (ii) LDA, THF, ꢀ78/20 ꢁC, 14 h; (iii) Me3SiCl, NEt3, C6H6,
20 ꢁC, 72 h; (iv) LDA, THF, ꢀ78/20 ꢁC; (v) Me3SiOTf, CH2Cl2, ꢀ78/
20 ꢁC, 20 h.
Figure 1. Ortep plot of 7g.
function (Scheme 4, Table 3). The formation of the products
can be explained by means of a domino ‘[3þ3]-cyclizatione
homo-Michael’ reaction.13 The structures of 9a and 9b were
independently confirmed by X-ray crystal structure analyses
(Figs. 2 and 3).
Table 1
Synthesis of diaryl ethers 5aec
2e5
R1
R2
% (2)a
% (3)a
% (4)a
% (5)a
a
b
c
a
H
OEt
60
30
40
91
74
75
82
82
84
45
46
48
Cl
Me
OMe
OMe
Me3SiO OSiMe3
OH
O
O
Isolated yields.
OEt
O
OEt
4a
TiX4
O
O
i
Me
Me
X
The TiCl4-mediated [3þ3] cyclization of 1,3-bis(silyloxy)-
1,3-dienes 4aec with 3-silyloxy-2-en-1-ones 6aee afforded
the 3-aryloxysalicylates 7aeg (Scheme 3, Table 2). During
the optimization, it proved to be important to carry out the re-
actions in a highly concentrated solution. In addition, the
stoichiometry and temperature are important parameters. The
+
Me
Me
9a,b
8
Scheme 4. Synthesis of 9a,b: (i) TiX4 (X¼Cl, Br), CH2Cl2, ꢀ78/20 ꢁC, 20 h.
The Me3SiOTf-catalyzed reaction of 1,3-bis(silyloxy)-
1,3-diene 4a with 3-formylchromone 10 afforded the highly
functionalized diaryl ether 11 (Scheme 5). The products are
Me3SiO OSiMe3
O
OH
O
OR2
O
Table 3
Synthesis of 9a,b
OR2
4a-c
R1
i
Me3SiO
Me
O
R1
Me
Me
9
X
% (9)a
+
R3
Me
R3
6a-e
a
Cl
Br
40
33
7a-g
b
a
Scheme 3. Synthesis of 7aeg: (i) TiCl4, CH2Cl2, ꢀ78/20 ꢁC, 20 h.
Isolated yields.

M.A. Rashid et al. / Tetrahedron 64 (2008) 529e535
Me3SiO OSiMe3
531
O
O
O
O
O
OEt
OEt
i
4a
O
O
O
+
12
13
ii
O
OH
O
O
14 (70% from 12)
Scheme 6. Synthesis of 14: (i) (1) Me3SiOTf (0.3 equiv), 20 ꢁC, 1 h; (2) 4a
(1.3 equiv), CH2Cl2, 0/20 ꢁC, 12 h; (3) HCl (10%); (ii) NEt3 (2.0 equiv),
EtOH, 20 ꢁC, 12 h.
Figure 2. Ortep plot of 9a.
Figure 4. Ortep plot of 14.
3. Experimental section
Figure 3. Ortep plot of 9b.
3.1. General comments
formed by a domino ‘Michaeleretro-MichaeleMukaiyama-
Aldol’ reaction.14
All solvents were dried by standard methods and all reac-
tions were carried out under an inert atmosphere. For 1H
and 13C NMR spectra the deuterated solvents indicated were
used. Mass spectrometric data (MS) were obtained by electron
ionization (EI, 70 eV), chemical ionization (CI, H2O) or elec-
trospray ionization (ESI). For preparative scale chromatogra-
phy, silica gel (60e200 mesh) was used. Melting points are
uncorrected.
Me3SiO OSiMe3
O
O
O
OEt
Me
OEt
OH
4a
i , ii
O
O
OH
Me
+
O
H
O
10
11 (35%)
3.2. General procedure for the synthesis of
aryloxyacetoacetates 2aec
Scheme 5. Synthesis of 11: (i) Me3SiOTf (0.3 equiv), 20 ꢁC, 10 min; (ii) (1) 4a
(1.3 equiv), CH2Cl2, 0/20 ꢁC, 12 h; (2) HCl (10%).
Method A: To a mixture of potassium hydroxide (2.0 mmol)
in 2 mL of DMSO was dropwise added a solution of phenol
(1.0 mmol) in 0.2 mL of DMSO. The mixture was stirred at
room temperature for 30 min and then ethyl 4-chloroacetoace-
tate (1.0 mmol) was added. The mixture was stirred at room
temperature overnight and then acidified by addition of hydro-
chloric acid (4 M). The mixture was extracted with EtOAc and
the organic layer was washed with water and then with brine,
and dried over Na2SO4. The solution was filtered and the sol-
vent of the filtrate was removed under reduced pressure. The
crude product was purified by chromatography (silica gel,
EtOAc/n-heptane).
The Me3SiOTf-catalyzed reaction of 4a with chromone
(12) afforded product 13, which was transformed (without
purification) into the diaryl ether 14 (Scheme 6). The transfor-
mation of 13 into 14 proceeds by a domino ‘Michaeleretro-
Michaelelactonization’ reaction.15 The structure of 14 was
independently confirmed by X-ray crystal structure analysis
(Fig. 4).
In conclusion, a variety of sterically encumbered diaryl
ethers were prepared based on formal [3þ3] cyclizations
of novel 4-aryloxy-1,3-bis(trimethylsilyloxy)-1,3-dienes. The
products are not readily available by other methods.

532
M.A. Rashid et al. / Tetrahedron 64 (2008) 529e535
Method B: ATHF solution of 2.3 equiv of LDAwas prepared
114.4 (2C, CH), 130.1 (2C, CH), 131.5, 155.1, 167.3, 200.8
(C); IR (neat): ~n¼3030 (w), 2954 (w), 2926 (w), 1731 (s),
1613 (m), 1511 (s), 1437 (m), 1236 (s), 1178 (s), 1066(s),
1039 (m), 817 (s), 510 (w); m/z (%): 222 (Mþ, 92), 206 (7),
190 (71), 148 (34), 128 (55), 121 (100), 101 (41), 86 (82),
77 (49), 59 (28); HRMS (EI): calcd for C12H14O4 [Mþ]:
222.08869, found 222.08866.
by addition of n-BuLi (0.93 mL, 2.3 mmol, 2.5 M solution in
hexanes) to a THF solution (6 mL) of diisopropylamine
(0.32 mL, 2.3 mmol) at 0 ꢁC. After stirring of the solution for
30 min, methyl acetate (0.09 mL, 1.1 mmol) was added at
0 ꢁC. After stirring for 45e60 min, to the solution was added
a THF solution (4 mL) of the acid chloride (205 mg,
1.0 mmol) at ꢀ78 ꢁC. The temperature was allowed to rise to
20 ꢁC during 5e6 h and the solution was stirred at 20 ꢁC for
8 h. To the solution was added a diluted aqueous solution of
HCl and the mixture was extracted with EtOAc (3ꢂ200 mL).
The organic layers were dried and filtered, the solvent of the
filtrate was removed in vacuo, and the residue was purified by
chromatography (silica gel, EtOAc/n-heptane).
3.3. General procedure for the synthesis of
diaryl ethers 5aec
To a dichloromethane solution (2 mL/mmol of 4) of 4
(1.0 mmol) and of 1,1,3,3-tetramethoxypropane was added
TMSOTf (0.1 mmol) at ꢀ78 ꢁC. The solution was allowed
to warm to 20 ꢁC within 20 h. To the solution was added a sat-
urated aqueous solution of HCl (15 mL). The organic and the
aqueous layer were separated and the latter was extracted with
dichloromethane (3ꢂ15 mL). The combined organic layers
were dried (Na2SO4), filtered, and the filtrate was concentrated
in vacuo and the residue was purified by chromatography.
3.2.1. Ethyl 4-phenoxyacetoacetate (2a)
Starting with 4-chloroacetoacetate (14.4 mL, 106.3 mmol),
phenol (10.00 g, 106.3 mmol), KOH (11.80 g, 212.7 mmol)
and DMSO (212 mL), 2a was isolated as a colourless oil
1
(14.30 g, 60%); H NMR (300 MHz, CDCl3): d¼1.29 (t, 3H,
J¼7.0 Hz, CH3), 3.67 (s, 2H, CH2), 4.21 (q, 2H, J¼7.0 Hz,
OCH2), 4.68 (s, 2H, CH2), 6.85e6.96 (m, 2H, ArH), 7.02e
7.07 (m, 1H, ArH), 7.25e7.34 (m, 2H, ArH); 13C NMR
(62 MHz, CDCl3): d¼14.1 (CH3), 46.5, 62.0, 72.8 (CH2),
114.6 (2C, CH), 122.4 (CH), 129.9 (2C, CH) 157.4, 166.9,
200.7 (C); IR (neat): ~n¼3043 (w), 2983 (m), 2937 (w), 1724
(s), 1599 (s), 1496 (s), 1322 (s), 1244 (s), 1175 (s), 1032 (s),
813 (m), 755 (s), 692 (s), 508 (w); MS (EI, 70 eV): m/z (%):
222 (Mþ, 84), 176 (67), 134 (66), 129 (72), 107 (100), 94
(45), 77 (97), 51 (39); HRMS (EI): calcd for C12H14O4
[Mþ]: 222.08881, found 222.08866.
3.3.1. Ethyl 3-phenoxysalicylate (5a)
Starting with tetramethoxypropane (0.3 mL, 1.8 mmol),
1,3-bis(silyl enol ether) 4a (660 mg, 1.8 mmol) and TMSOTf
(0.03 mL, 0.18 mmol), 5a was isolated as a highly viscous
1
colourless oil (210 mg, 45%); H NMR (250 MHz, CDCl3):
d¼1.35 (t, 3H, J¼7.1 Hz, CH3), 4.35 (q, 2H, J¼7.1 Hz,
OCH2), 6. 77 (t, 1H, J¼7.9 Hz, ArH), 6.91 (dd, 2H, J¼1.1,
8.6 Hz, ArH), 6.99 (m, 1H, ArH), 7.11 (m, 1H, ArH), 7.20
(m, 2H, ArH), 7.62 (dd, 1H, J¼1.5, 8.0 Hz, ArH), 10.95 (s,
1H, OH); 13C NMR (62 MHz, CDCl3): d¼14.1 (CH3), 61.7
(CH2), 114.2 (C), 117.0 (2C, CH), 118.7, 122.7, 125.7,
126.7 (CH), 129.6 (2C, CH), 144.2, 154.0, 157.6, 170.0 (C);
IR (neat): ~n¼3072 (w), 2983 (w), 1674 (s), 1585 (s), 1460
(s), 1323 (s), 1253 (s), 1150 (s), 1025 (s), 854 (m), 752 (s),
690 (m), 580 (w), 498 (w); MS (EI, 70 eV): m/z (%): 258
(Mþ, 65), 212 (100), 184 (46), 128 (13), 105 (31), 77 (15),
51 (12); elemental analysis: calcd (%) for C15H14O4: C
69.76, H 5.46; found: C 69.68, H 5.63.
3.2.2. Methyl 4-(4-chlorophenoxy)acetoacetate (2b)
Starting with 2-(4-chlorophenoxy)acetyl chloride (5.00 g,
24.0 mmol) and methyl acetate (2.14 mL, 26.8 mmol), 2b
was isolated as a colourless solid (2.00 g, 30%), mp 57 ꢁC;
1H NMR (250 MHz, CDCl3): d¼3.55 (s, 2H, CH2), 3.65 (s,
3H, OCH3), 4.55 (s, 2H, CH2), 6.74 (d, 2H, J¼9.1 Hz,
ArH), 7.16 (d, 2H, J¼9.1 Hz, ArH); 13C NMR (62 MHz,
CDCl3): d¼45.7 (CH2), 52.4 (CH3), 72.6 (CH2), 115.8 (2C,
CH), 126.6 (C), 129.4 (2C, CH) 156.0, 167.1, 199.6 (C); IR
(KBr): ~n¼3008 (w), 2958 (w), 2931 (w), 1737 (s), 1595 (m),
1493 (s), 1326 (s), 1233 (s), 1158 (s), 1024(s), 986 (m), 823
(s), 636 (m), 512 (m), 495 (w); MS (EI, 70 eV): m/z (%):
244 (Mþ, 37Cl, 11), 242 (Mþ, 35Cl, 39), 210 (28), 168 (13),
141 (76), 128 (17), 115 (92), 101 (39), 85.9 (80), 83.9
(100), 59 (23); HRMS (EI): calcd for C11H11ClO4 [Mþ,
35Cl]: 242.03335, found 242.03404.
3.3.2. Methyl 3-(4-chlorophenoxy)salicylate (5b)
Starting with tetramethoxypropane (0.25 mL, 1.5 mmol),
1,3-bis(silyl enol ether) 4b (582 mg, 1.5 mmol) and TMSOTf
(0.027 mL, 0.15 mmol), 5b was isolated as a highly viscous
1
colourless oil (192 mg, 46%); H NMR (250 MHz, CDCl3):
d¼3.88 (s, 3H, OCH3), 6.81 (m, 3H, ArH), 7.15 (m, 3H,
ArH), 7.61 (dd, 1H, J¼1.5, 8.0 Hz, ArH), 10.23 (s, 1H,
OH); 13C NMR (62 MHz, CDCl3): d¼52.5 (CH3), 114.1 (C),
118.0 (2C, CH), 118.9, 125.8, 127.0 (CH), 127.6 (C) 129.5
(2C, CH), 143.8, 153.9, 156.3, 170.3 (C); IR (neat): ~n¼3099
(w), 2954 (m), 2854 (w), 1680 (s), 1583 (s), 1485 (s), 1329
(s), 1254 (s), 1007 (s), 824 (s), 662 (m), 499 (m), 441 (w);
MS (EI, 70 eV): m/z (%): 280 (Mþ, 37Cl, 24), 278 (Mþ,
35Cl, 71), 246 (100), 218 (26), 211 (50), 155 (9), 139 (34),
107 (20), 75 (9); HRMS (EI): calcd for C14H11ClO4 [Mþ,
35Cl]: 278.03435, found 278.03404.
3.2.3. Methyl 4-(4-methylphenoxy)acetoacetate (2c)
Starting with 2-(4-methylphenoxy)acetyl chloride (10.00 g,
54.3 mmol), and methyl acetate (4.8 mL, 59.7 mmol), 2c was
isolated as a colourless oil (4.80 g, 40%); 1H NMR (250 MHz,
CDCl3): d¼2.21 (s, 3H, CH3), 3.56 (s, 2H, CH2), 3.64 (s, 3H,
OCH3), 4.52 (s, 2H, CH2), 6.70 (d, 2H, J¼8.6 Hz, ArH), 7.01
(distorted d, 2H, J¼8.6 Hz, ArH); 13C NMR (62 MHz,
CDCl3): d¼20.3 (CH3), 46.1 (CH2), 52.4 (CH3), 72.6 (CH2),

M.A. Rashid et al. / Tetrahedron 64 (2008) 529e535
533
3.3.3. Methyl 3-(4-methylphenoxy)salicylate (5c)
(m, 2H, ArH), 10.08 (s, 1H, OH); 13C NMR (62 MHz, CDCl3):
d¼13.8, 14.1, 15.8, 18.8 (CH3), 61.7 (CH2), 113.4 (C), 114.6
(2C, CH), 121.6 (CH), 127.7 (C), 129.5 (2C, CH), 134.3, 136.7,
138.4, 151.6, 158.0, 171.0 (C); IR (KBr): ~n¼2992 (w),
2923 (w), 1663 (s), 1591 (s), 1414 (s), 1312 (s), 1251 (s),
1189 (s), 1018 (s), 801 (m), 753 (s), 693 (m), 507 (w), 418
(w); MS (EI, 70 eV): m/z (%): 300 (Mþ, 46), 254 (100), 239
(27), 211 (15), 149 (15), 105 (57), 77 (22); elemental analysis:
calcd (%) for C18H20O4 (300.1): C 71.98, H 6.71; found: C
71.66, H 6.77.
Starting with tetramethoxypropane (0.25 mL, 1.5 mmol),
1,3-bis(silyl enol ether) 4c (554 mg, 1.5 mmol) and TMSOTf
(0.027 mL, 0.15 mmol), 5c was isolated as a highly viscous
1
oil (186 mg, 48%); H NMR (250 MHz, CDCl3): d¼2.24 (s,
3H, CH3), 3.89 (s, 3H, OCH3), 6.72e6.82 (m, 3H, ArH),
7.02e7.09 (m, 3H, ArH), 7.56 (dd, 1H, J¼1.5, 8.0 Hz, ArH),
10.87 (s, 1H, OH); 13C NMR (62 MHz, CDCl3): d¼20.5,
52.5 (CH3), 112.8 (C), 116.2 (2C, CH), 117.7, 126.7, 127.5 (CH),
129.2 (2C, CH), 131.3, 143.9, 152.7, 154.1, 169.5 (C); IR (neat):
~n¼2955 (w), 2924 (m), 2855 (w), 1680 (s), 1505 (s), 1440 (s),
1329 (s), 1252 (s), 1150 (s), 1006 (m), 815 (m), 718 (w), 501
(w); MS (EI, 70 eV): m/z (%): 258 (Mþ, 75), 226 (100), 198
(37), 119(34), 107(14), 91(11), 65(8), 51(5); HRMS (EI):calcd
for C15H15O4 [Mþ]: 258.08868, found 258.08866.
3.4.3. Ethyl 4,6-dimethyl-5-chloro-3-phenoxysalicylate (7c)
Starting with 3-(siloxy)alk-2-en-1-one 6c (400 mg,
1.93 mmol), 1,3-bis(silyl enol ether) 4a (707 mg, 1.93 mmol)
and TiCl4 (0.21 mL, 1.93 mmol), 7c was isolated as a colour-
less solid (234 mg, 38%), mp 47 ꢁC; 1H NMR (250 MHz,
CDCl3): d¼1.34 (t, 3H, J¼7.1 Hz, CH3), 2.20 (s, 3H, CH3),
2.56 (s, 3H, CH3), 4.38 (q, 2H, J¼7.1 Hz, CH2), 6.75 (d,
2H, J¼7.9 Hz, ArH), 6.91 (t, 1H, J¼7.3 Hz, ArH), 7.18 (m,
2H, ArH), 10.68 (s, 1H, OH); 13C NMR (62 MHz, CDCl3):
d¼13.3, 14.0, 18.6 (CH3), 61.1 (CH2), 112.4 (C), 113.0 (2C,
CH), 120.9 (CH), 125.7 (C), 128.5 (2C, CH), 133.3, 136.0,
138.3, 152.2, 156.5, 169.5 (C); IR (Nujol): ~n¼3069 (w), 1664
(s), 1591 (m), 1490 (s), 1401 (s), 1376 (s), 1347 (m), 1246
(s), 1184 (s), 1074 (m), 854 (w), 749 (s), 686 (m), 433 (w);
MS (EI, 70 eV): m/z (%): 322 (Mþ, 37Cl, 15), 320 (Mþ, 35Cl,
43), 274 (100), 245 (15), 211 (13), 169 (8), 139 (34), 105
(43), 77 (21); elemental analysis: calcd (%) for C17H17ClO4
(320.08): C 63.65, H 5.34; found: C 63.23, H 5.70.
3.4. General procedure for the synthesis of
diaryl ethers 7aeg
To a dichloromethane solution (2 mL/mmol of 4) of 4
(1.0 mmol) and of 6 (1.0 mmol) was added TiCl4 (1.0 mmol)
at ꢀ78 ꢁC. The solution was allowed to warm to 20 ꢁC within
20 h. To the solution was added a saturated aqueous solution
of NaHCO3 (15 mL). The organic and the aqueous layer
were separated and the latter was extracted with diethyl ether
(3ꢂ20 mL). The combined organic layers were dried
(Na2SO4), filtered, and the filtrate was concentrated in vacuo
and the residue was purified by chromatography (silica gel,
EtOAc/n-heptane¼1:4).
3.4.1. Ethyl 4,6-dimethyl-3-(phenoxy)salicylate (7a)
3.4.4. Ethyl 4,6-dimethyl-3-phenoxy 5-(3,4-dimethoxy-
phenoxy)salicylate (7d)
Starting with 3-(silyloxy)alk-2-en-1-one 6a (600 mg,
3.48 mmol), 1,3-bis(silyl enol ether) 4a (1.27 g, 3.48 mmol)
and TiCl4 (0.38 mL, 3.48 mmol), 7a was isolated as a colour-
less solid (354 mg, 37%), mp 69 ꢁC; 1H NMR (300 MHz,
CDCl3): d¼1.35 (t, 3H, J¼7.2 Hz, CH3), 2.08 (s, 3H, CH3),
2.46 (s, 3H, CH3), 4.35 (q, 2H, J¼7.0 Hz, OCH2), 6.54 (s, 1H,
ArH), 6.78 (d, 2H, J¼8.7 Hz, ArH), 6.90 (t, 1H, J¼7.4 Hz,
ArH), 7.18 (t, 2H, J¼8.1 Hz, ArH), 11.43 (s, 1H, OH); 13C
NMR (62 MHz, CDCl3): d¼14.1, 16.3, 23.7 (CH3), 61.6 (CH2),
111.4 (C), 114.6 (2C, CH), 121.6, 124.3 (CH), 129.4 (2C, CH),
137.1, 138.1, 138.9, 155.9, 157.8, 171.2 (C); IR (KBr): ~n¼2988
(m), 2930 (w), 1651 (s), 1590 (m), 1494 (s), 1377 (s), 1300 (s),
1213(s), 1164 (s), 1029 (m), 842 (w), 793 (s), 692 (s), 577 (w),
421 (w); MS (EI, 70 eV): m/z (%): 286 (Mþ, 42), 240 (100), 211
(13), 197 (9), 135 (10), 105 (43), 77 (16); elemental analysis:
calcd (%) for C17H18O4 (286.1): C 71.31, H 6.43; found: C
71.18, H 6.66.
Starting with 3-(siloxy)alk-2-en-1-one 6d (600 mg,
1.83 mmol), 1,3-bis(silyl enol ether) 4a (671 mg, 1.83 mmol)
and TiCl4 (0.2 mL, 1.83 mmol), 7d was isolated as a highly
viscous oil (207 mg, 30%); 1H NMR (250 MHz, CDCl3):
d¼1.35 (t, 3H, J¼7.1 Hz, CH3), 1.95 (s, 3H, CH3), 2.31 (s,
3H, CH3), 3.75 (s, 3H, OCH3), 3.77 (s, 3H, OCH3), 4.36 (q,
2H, J¼7.2 Hz, OCH2), 6.02 (dd, 1H, J¼2.8, 8.6 Hz, ArH),
6.44 (d, 1H, J¼2.8 Hz, ArH), 6.64 (d, 1H, J¼8.8 Hz, ArH),
6.77e6.81 (m, 2H, ArH), 6.88e6.95 (m, 1H, ArH), 7.16e
7.23 (m, 2H, ArH), 11.09 (s, 1H, OH); 13C NMR (62 MHz,
CDCl3): d¼10.9, 14.1, 15.1, 55.9, 56.3 (CH3), 62.0 (CH2),
100.0, 104.1, 111.9 (CH), 112.0 (C), 114.5 (2C, CH), 121.8
(CH), 129.5 (2C, CH), 130.4, 133.8, 139.4, 143.7, 143.9,
150.1, 152.4, 153.1, 157.7, 171.1 (C); IR (neat): ~n¼2999 (w),
2936 (w), 1601 (s), 1508 (s), 1452 (s), 1301 (s), 1261 (s), 1192
(s), 1027 (s), 833 (m), 753 (w), 653 (w), 475 (w); MS (EI,
70 eV): MS (EI, 70 eV): m/z (%): 438.1 (Mþ, 100), 392.1
(87), 377.1 (49), 287.1 (3), 255 (3), 138 (13), 105 (59), 77
(16); HRMS (EI): calcd for C25H26O7 [Mþ]: 438.16708, found
438.16730.
3.4.2. Ethyl 4,5,6-trimethyl-3-phenoxysalicylate (7b)
Starting with 3-(siloxy)alk-2-en-1-one 6b (600 mg,
3.2 mmol), 1,3-bis(silyl enol ether) 4a (1.18 g, 3.2 mmol)
and TiCl4 (0.35 mL, 3.2 mmol), 7b was isolated as a colourless
solid (414 mg, 43%), mp 75 ꢁC; 1H NMR (250 MHz, CDCl3):
d¼1.28 (t, 3H, J¼7.1 Hz, CH3), 2.02 (s, 3H, CH3), 2.05 (s, 3H,
CH3), 2.33 (s, 3H, CH3), 4.30 (q, 2H, J¼7.0 Hz, OCH2), 6.71
(dd, 2H, J¼1.1, 8.6 Hz, ArH), 6.84 (m, 1H, ArH), 7.09e7.15
3.4.5. Ethyl 4,6-dimethyl-3-phenoxy-5-thiophenoxy-
salicylate (7e)
Starting with 3-(siloxy)alk-2-en-1-one 6e (500 mg,
1.8 mmol), 1,3-bis(silyl enol ether) 4a (647 mg, 1.8 mmol)

534
M.A. Rashid et al. / Tetrahedron 64 (2008) 529e535
and TiCl4 (0.19 mL, 1.8 mmol), 7e was isolated as a colourless
solid (210 mg, 30%), mp 103 ꢁC; 1H NMR (300 MHz,
CDCl3): d¼1.34 (t, 3H, J¼7.0 Hz, CH3), 2.26 (s, 3H, CH3),
2.69 (s, 3H, CH3), 4.37 (q, 2H, J¼7.2 Hz, OCH2), 6.77 (dis-
torted d, 2H, J¼7.8 Hz, ArH), 6.86 (dd, 2H, J¼1.3, 8.1 Hz,
ArH), 6.92e7.02 (m, 2H, ArH), 7.11e7.22 (m, 4H, ArH),
10.99 (s, 1H, OH); 13C NMR (62 MHz, CDCl3): d¼14.1,
16.0, 21.1 (CH3), 62.2 (CH2), 114.0 (C), 114.6 (2C, CH),
121.9 (CH), 123.2 (C), 124.6, 124.8 (CH), 125.3 (2C, CH),
129.0 (2C, CH), 129.1 (2C, CH), 137.9, 139.5, 143.2, 144.2,
155.6, 157.5, 170.9 (C); IR (KBr): ~n¼3069 (w), 2978 (w),
2928 (m), 2851 (m), 1662 (s), 1599 (s), 1476 (s), 1374 (s),
1244 (s), 1159 (s), 1077 (m), 752 (m), 686 (m), 488 (w);
MS (EI, 70 eV): m/z (%): 394 (Mþ, 93), 349 (37), 348
(100), 247 (22), 333 (16), 290 (5), 270 (7), 211 (10), 177
(28), 161 (19), 105 (28), 57 (31); HRMS (EI): calcd for
C23H22O4S [Mþ]: 394.12333, found 394.12343.
3.4.8. Ethyl 4,6-dimethyl-5-(2-chloroethyl)-3-phenoxy-
salicylate (9a)
Starting 1,1-diacetylclopropane (15) (300 mg, 2.4 mmol),
1,3-bis(silyl enol ether) 4a (1.200 g, 3.3 mmol), TiCl4
(0.52 mL, 4.8 mmol) and CH2Cl2 (110 mL), 9a was isolated
1
as colourless crystals (328 mg, 40%), mp 75 ꢁC; H NMR
(250 MHz, CDCl3): d¼1.34 (t, 3H, J¼7.25 Hz, CH3), 2.14
(s, 3H, CH3), 2.45 (s, 3H, CH3), 3.07 (t, 2H, J¼6.45 Hz,
CH2), 3.45 (t, 2H, J¼7.5 Hz, CH2), 4.37 (q, 2H, J¼6.5 Hz,
CH2), 6.76 (m, 2H, ArH), 6.94 (m, 1H, ArH), 7.76 (m, 2H,
ArH), 10.41 (s, 1H, OH); 13C NMR (62 MHz, CDCl3): d¼12.4,
13.1, 17.3 (CH3), 32.2, 41.1, 60.9 (CH2), 112.9 (C), 113.6 (2C
CH), 120.7 (CH), 126.4 (C), 128.5 (2C CH), 133.9 136.0,
138.0, 151.9, 156.7, 169.8 (C); IR (Nujol): ~n¼3381 (w), 2981
(s), 1728 (m), 1669 (m), 1590 (m), 1491 (m), 1301 (m), 1218
(m), 1167 (m), 1036 (m), 788 (w) 750 (m) cmꢀ1; GCeMS (EI,
70 eV): m/z (%): 450 (Mþ, 37Cl, 13), 448 (Mþ, 35Cl, 41), 403
(73), 267 (83), 253 (43), 105 (100), 77 (22); HRMS (EI): calcd
for C19H21O4Cl [Mþ, 35Cl]: 448.11229, found 448.11180.
3.4.6. Methyl 4,6-dimethyl-5-chloro-3-
(4-methylphenoxy)salicylate (7f)
3.4.9. Ethyl 4,6-dimethyl-5-(2-bromoethyl)-3-phenoxy-
salicylate (9b)
Starting with 3-(siloxy)alk-2-en-1-one 6c (400 mg,
1.9 mmol), 1,3-bis(silyl enol ether) 4b (711 mg, 1.9 mmol)
and TiCl4 (0.21 mL, 1.93 mmol), 7f was isolated as a highly
viscous oil (248 mg, 40%); 1H NMR (300 MHz, CDCl3):
d¼2.20 (s, 6H, CH3), 2.53 (s, 3H, CH3), 3.88 (s, 3H, CH3),
6.65 (d, 2H, J¼8.5 Hz, ArH), 6.97 (d, 2H, J¼8.8 Hz, ArH),
10.55 (s, 1H, OH); 13C NMR (75 MHz, CDCl3): d¼14.0,
18.6, 19.5, 51.5 (CH3), 112.3 (C), 113.3 (2C, CH), 125.7 (C),
129.0 (2C, CH), 130.3, 133.0, 136.1, 138.5, 152.1, 154.4,
169.9 (C); IR (neat): ~n¼297 (m), 2927 (m), 2871 (w), 1661
(s), 1506 (s), 1444 (s), 1248 (s), 1164 (s), 1040 (m), 846 (m),
707 (w), 612 (w), 503 (w); MS (EI, 70 eV): m/z (%): 322 (Mþ,
37Cl, 15), 320 (Mþ, 35Cl, 46), 288 (100), 273 (9), 259 (15),
169 (10), 119 (87), 91 (22), 77 (18); HRMS (EI): calcd for
C17H17ClO4 [Mþ, 35Cl]: 320.08106, found 320.08099.
Starting with 1,1-diacetylcyclopropane 15 (300 mg,
2.4 mmol), 1,3-bis(silyl enol ether) 4a (1.20 g, 3.3 mmol),
TiBr4 (873 mg, 2.4 mmol) and CH2Cl2 (110 mL), 9b was iso-
1
lated as colourless crystals (315 mg, 33%), mp 103 ꢁC; H
NMR (250 MHz, CDCl3): d¼1.24 (t, 3H, J¼7.1 Hz, CH3),
2.03 (s, 3H, CH3), 2.34 (s, 3H, CH3), 3.05 (m, 2H, CH2),
3.22 (m, 2H, CH2), 4.27 (q, 2H, J¼7.1 Hz, CH2), 6.65 (m, 2H,
ArH), 6.83 (m, 1H, ArH), 7.08 (m, 2H, ArH), 10.23 (s, 1H,
OH); 13C NMR (62 MHz, CDCl3): d¼11.4, 12.2, 16.3 (CH3),
27.6, 31.6, 59.9 (CH2), 111.9 (C), 112.6 (2C CH), 119.5 (CH),
126.5 (C), 127.6 (2C CH), 132.8, 134.9, 137.0, 151.0, 155.7,
168.8 (C); IR (Nujol): ~n¼3375 (w), 2978 (s), 1734 (m), 1675
(m), 1590 (m), 1490 (m), 1319 (m), 1219 (m), 1176 (m),
1029 (m), 751 (w) 690 (m) cmꢀ1; GCeMS (EI, 70 eV): m/z
(%): 393 (Mþ, 81Br, 40), 391 (Mþ, 79Br, 40), 347 (62), 313 (26),
267 (100), 253 (33), 105 (89), 77 (34); HRMS (EI): calcd for
C19H21O4Br ([(Mþ1)þ, 79Br]: 392.06177, found 392.06199.
3.4.7. Methyl 4,5,6-trimethyl-3-(4-chlorophenoxy)-
salicylate (7g)
3.4.10. Synthesis of ethyl-5-(2-hydroxy-3-methylbenzoyl)-
3-phenoxysalicylate (11)
Starting with 3-(silyloxy)alk-2-en-1-one 6b (400 mg,
2.1 mmol), 1,3-bis(silyl enol ether) 4c (814 mg, 2.1 mmol)
and TiCl4 (0.23 mL, 2.1 mmol), 7g was isolated as a colourless
solid (272 mg, 40%), mp 98 ꢁC; 1H NMR (300 MHz, CDCl3):
d¼2.01 (s, 3H, CH3), 2.05 (s, 3H, CH3), 2.32 (s, 3H, CH3),
3.82 (s, 3H, CH3), 6.65 (d, 2H, J¼8.9 Hz, ArH), 7.05 (d,
2H, J¼8.8 Hz, ArH), 10.23 (s, 1H, OH); 13C NMR
(62 MHz, CDCl3): d¼13.8, 15.9, 18.8, 52.3 (CH3), 113.1
(C), 116.0 (2C, CH), 126.4, 127.8 (C), 129.4 (2C, CH), 134.7,
136.7, 138.3, 151.6, 156.6, 171.6 (C); IR (KBr): ~n¼3005(w),
2952 (w), 2926 (w), 1667 (s), 1595 (m), 1485 (s), 1318 (s),
1248 (s), 1298 (s), 1064 (s), 994 (m), 823 (s), 626 (w), 457 (w);
MS (EI, 70 eV): m/z (%): 322 (Mþ, 37Cl, 21), 320 (Mþ, 35Cl, 62),
288 (70), 273 (13), 253 (71), 225 (11), 139 (100), 91 (13), 77
(18); elemental analysis: calcd (%) for C17H17ClO4 (320.08):
C 63.65, H 5.34; found: C 63.59, H 5.39.
Me3SiOTf (0.3 equiv) was added to the 3-formylchromone
(1.0 equiv) at 20 ꢁC. After stirring for 10 min, CH2Cl2 (8 mL)
was added, the solution was cooled to 0 ꢁC and the 1,3-bis-
(silyl enol ether) (1.3 equiv) was added. The mixture was
stirred at 20 ꢁC for 12 h and was subsequently poured into
an aqueous solution of HCl (10%). The organic and the aque-
ous layer were separated and the latter was extracted with
CH2Cl2 (3ꢂ15 mL). The combined organic layers were
washed with brine (25 mL) and dried over Na2SO4. The mix-
ture was filtered and the solvent of the filtrate was removed un-
der reduced pressure. The crude product was purified by
chromatography (silica gel, EtOAc/n-heptane). Starting with
3-formylchromone 10 (411 mg, 2.2 mmol), 1,3-bis(silyl enol
ether) 4a (800 mg, 2.2 mmol) and Me3SiOTf (0.65 mL,
1.2 mmol), 11 was isolated as a highly viscous oil (300 mg,

M.A. Rashid et al. / Tetrahedron 64 (2008) 529e535
535
35%); 1H NMR (250 MHz, CDCl3): d¼1.35 (t, 3H, J¼7.1 Hz,
CH3), 2.17 (s, 3H, CH3), 4.39 (q, J¼7.1 Hz, 2H, CH2), 6.88
(m, 1H, ArH), 6.94e7.06 (m, 3H, ArH), 7.21e7.30 (m, 4H,
ArH), 7.44 (d, J¼2.1 Hz, 1H, ArH), 8.02 (d, J¼2.2 Hz, 1H,
ArH), 11.45 (s, 1H, OH), 11.49 (s, 1H, OH); 13C NMR
(62 MHz, CDCl3): d¼14.1, 20.4 (CH3), 62.3 (CH2), 113.8
(C), 116.9 (C), 117.7 (2C, CH), 118.3 (CH), 118.5 (C), 123.6,
126.1, 127.0 (CH), 127.8, 128.6 (C), 129.8 (2C, CH), 132.5,
137.3 (CH), 144.8, 156.8, 156.9, 160.9, 169.6, 198.3 (C); IR
(neat): ~n¼2982 (w), 2926 (w), 2869 (w), 1678 (s), 1587 (s),
1401 (s), 1376 (s), 1212 (s), 1109 (m), 1028 (s), 827 (m), 788
(s), 691(m), 475 (w) cmꢀ1; GCeMS (EI, 70 eV): m/z (%): 392
(Mþ, 100), 347 (43), 258 (31), 212 (44), 184 (13), 135 (54),
105 (24), 77 (27); HRMS (EI) calcd for C23H20O6 [Mþ]:
392.12554, found 392.12544.
100), 287 (15), 199 (22), 171 (7), 115 (9), 77 (7), 51 (4);
HRMS (EI) calcd for C19H12O4 [Mþ]: 304.07316, found
304.07301.
Acknowledgements
Financial support from the state of Pakistan (HEC scholar-
ship for M.A.R. and N.R) is gratefully acknowledged.
References and notes
1. Ro¨mpp Lexikon Naturstoffe; Steglich, W., Fugmann, B., Lang-Fugmann,
S., Eds.; Thieme: Stuttgart, 1997.
2. (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.;
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3.4.11. Synthesis of 8-phenoxy-7-hydroxy-6H-
benzo[c]chromen-6-one (14)
Me3SiOTf (1.3 equiv) was added to the chromone
(1.0 equiv) at 20 ꢁC. After stirring for 1 h, CH2Cl2 (8 mL)
was added, the solution was cooled to 0 ꢁC and the 1,3-bis-
(silyl enol ether) (1.3 equiv) was added. The mixture was
stirred at 20 ꢁC for 12 h and was subsequently poured into
an aqueous solution of HCl (10%). The organic and the aque-
ous layer were separated and the latter was extracted with
CH2Cl2 (3ꢂ15 mL) and dried over Na2SO4. The mixture
was filtered and the solvent of the filtrate was removed under
reduced pressure to give crude product 13. To an EtOH solu-
tion (10 mL) of the latter was added NEt3 (2.0 equiv) and the
mixture was stirred for 12 h at 20 ꢁC. To the solution was
added hydrochloric acid (1 M) and then EtOAc. The organic
and the aqueous layer were separated and the latter was ex-
tracted with EtOAc and dried over Na2SO4. The mixture
was filtered and the solvent of the filtrate was removed under
reduced pressure. The crude product was purified by chroma-
tography (silica gel, EtOAc/n-heptane). Starting with chro-
mone 12 (500 mg, 3.42 mmol), 1,3-bis(silyl enol ether) 4a
(1.62 g, 4.4 mmol), Me3SiOTf (0.8 mL, 4.4 mmol) and NEt3
(0.95 mL, 6.8 mmol), 14 was isolated as a colourless solid
(728 mg, 70%), mp 151 ꢁC; 1H NMR (250 MHz, CDCl3):
d¼6.93 (dd, 2H, J¼1.1, 8.6 Hz, ArH), 7.03 (m, 1H, ArH),
7.20e7.28 (m, 4H, ArH), 7.32e7.36 (m, 2H, ArH), 7.43 (dis-
torted d, J¼8.6 Hz, 1H, ArH), 7.86 (dd, J¼1.8, 8.6 Hz, 1H,
ArH), 11.42 (s, 1H, OH); 13C NMR (62 MHz, CDCl3):
d¼107.5 (C), 112.2 (CH), 117.4 (2C, CH), 117.6 (CH), 118.1
(C), 122.9, 123.3, 125.3, 128.5 (CH), 129.7 (2C, CH), 130.2
(CH), 130.5, 143.6, 150.1, 153.9, 157.1, 165.3 (C); IR (KBr):
~n¼3138 (w), 3070 (w), 2923 (w), 1684(s), 1586 (s), 1481 (s),
1318 (m), 1220 (s), 1128 (s), 1081 (m), 869 (m), 756 (s), 717
(m), 456 (w) cmꢀ1; GCeMS (EI, 70 eV): m/z (%): 304 (Mþ,
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.; Can-
diani, G.; Parente, R.; Pecker, F.; Bellosta, S.; Zanda, M. Tetrahedron
Lett. 2005, 46, 6515 and references cited therein.
4. Review: Muci, A. R.; Buchwald, S. R. Top. Curr. Chem. 2002, 219, 131.
5. (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.
6. (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.
7. Review of 1,3-bis(trimethylsilyloxy)-1,3-dienes in general: Langer, P.
Synthesis 2002, 441.
8. Review: Feist, H.; Langer, P. Synthesis 2007, 327.
9. Sher, M.; Ahmed, Z.; Rashid, M. A.; Fischer, C.; Spannenberg, A.;
Langer, P. Tetrahedron 2007, 63, 4929.
10. Rashid, M. A.; Reinke, H.; Langer, P. Tetrahedron Lett. 2007, 48, 2321.
11. Sher, M.; Ahmed, Z.; Rashid, M. A.; Fischer, C.; Langer, P. J. Org. Chem.
2007, 72, 6284.
12. CCDC-662730 (7g), CCDC-660640 (9a), CCDC-660641 (9b) and
CCDC-660642 (14) contain all crystallographic details of this publication
which are available free of charge at www.ccdc.cam.ac.uk/conts/retrieving
.html or can be ordered from the following address: Cambridge Crystallo-
graphic Data Centre, 12 Union Road, GB-Cambridge CB21EZ; fax:
(þ44)1223-336-033; or deposit@ccdc.cam.ac.uk.
13. Bose, G.; Nguyen, V. T. H.; Ullah, E.; Lahiri, S.; Gorls, H.; Langer, P.
¨
J. Org. Chem. 2004, 69, 9128.
14. Appel, B.; Rotzoll, S.; Reinke, H.; Langer, P. Eur. J. Org. Chem. 2006,
3638.
15. Appel, B.; Saleh, N. N. R.; Langer, P. Chem.dEur. J. 2006, 12, 1221.