Synthesis of diaryl ethers based on one-pot [3+3] cyclizations of 1,3-bis(silyl enol ethers)

Article abstract of DOI:10.1016/j.tet.2007.03.143

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.

Full text of DOI:10.1016/j.tet.2007.03.143

Tetrahedron 63 (2007) 4929–4936
Synthesis of diaryl ethers based on one-pot [3D3]
cyclizations of 1,3-bis(silyl enol ethers)
Muhammad Sher,a,b Zafar Ahmed,a,b Muhammad A. Rashid,a Christine Fischer,a,b
Anke Spannenberga,b 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 19 February 2007; revised 21 March 2007; accepted 22 March 2007
Available online 27 March 2007
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.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
moieties (in contrast to transition metal catalyzed C–O
coupling reactions). Notably, functionalized and sterically
encumbered diaryl ethers, which are not readily available
by other methods, can be prepared.
Diaryl ethers containing an ester or carboxylic acid function
constitute an important subgroup of the pharmacologically
important substance class of diaryl ethers.1 They occur in
a number of natural products such as geodinhydrate methyl-
ester and methyl chloroasterrate,2a,b 1-desgalloylsanguiin,3
dehydrotrigallic acid,4 epiphorellic acid,5 jolkianin,6 re-
murin A,7 or micareic acid.8 Diaryl ethers are available by
classic Ullmann reactions and related methods.9 In recent
years, the Buchwald–Hartwig reaction and related transfor-
mations proved to be versatile methods for the synthesis of
diaryl ethers.10 Recently, Beller et al. reported the transition
metal catalyzed coupling of phenols with aryl chlorides.11
Despite their great synthetic utility, the scope of all these
methods is limited by the availability of the starting mate-
rials. In fact, the synthesis of more complex aryl halides or
triflates by regioselective functionalization of arenes is often
a difficult task. In addition, the transition metal catalyzed
formation of diaryl ethers containing a sterically encum-
bered ether linkage often proceeds in low yield or not at all.
2. Results and discussion
3-(Phenoxy)pentane-2,4-diones 3a–i were prepared, follow-
ing a known procedure,15 by potassium carbonate mediated
reaction of phenols 1a–i with 3-(chloro)pentane-2,4-dione
(2). The synthesis of derivatives 3a and 3d was previously
reported.15 The silylation16 of 3a–i afforded the novel 2-
aryloxy-3-(silyloxy)alk-2-en-1-ones 4a–i (Scheme 1 and
Table 1). Only moderate to low yields were obtained for
3a–i. The silylation proceeded in very good yields.
O
O
O
O
OH
Me
R3
Me
R1
Me
Me
O
Cl
2
R3
R1
i
R2
The formal [3+3] cyclization of 1,3-bis(silyl enol ethers)12
with 3-(siloxy)alk-2-en-1-ones provides a versatile method
for the synthesis of functionalized arenes.13 Recently, we
reported the application of this method to the synthesis of
functionalized diaryl ethers.14 Herein, we report full details
of these studies. With regard to our preliminary communica-
tion,14 the preparative scope has been significantly extended.
Our method relies on assembly of one of the two arene
R2
3a-i
1a-i
Me3SiO
Me
O
ii
Me
R1
O
For substituents
R3
R
1 - R3: see Table 1
R2
4a-i
Keywords: Arenes; Cyclizations; Diaryl ethers; Silyl enol ethers.
* Corresponding author. Fax: +49 381 4986412; e-mail: peter.langer@
uni-rostock.de
Scheme 1. Synthesis of 4a–i. Reagents and conditions: (i) K2CO3, acetone,
2 h, reflux; (ii) Me3SiCl, NEt3, C6H6, 20 ꢀC, 72 h.
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.03.143

4930
M. Sher et al. / Tetrahedron 63 (2007) 4929–4936
Table 1. Synthesis of 3a–i and 4a–i
stoichiometric amounts of the starting materials and TiCl4
were used. The latter was added to a dichloromethane solu-
tion of the starting materials at ꢁ78 ꢀC with subsequent
warming of the mixture to 20 ꢀC. 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. The quality of the starting mate-
rials, reagents and solvent also played an important role.
3 and 4
R1
R2
R3
3a (%)
4a (%)
b
a
b
c
d
e
f
g
h
i
H
Me
H
H
H
OMe
H
H
H
H
H
Me
H
H
H
H
H
H
H
—
91
94
80
96
95
97
84
82
87
20
35
—
Et
Cl
OMe
OMe
Br
b
24
40
25
25
26
CN
CH2CO2Me
H
Notably, the presence of functional groups (chloride, bro-
mide, cyano, ester or methoxy groups) proved to be—in
principle—compatible with the reaction conditions. A vari-
ety of functionalized diaryl ethers (6h–w) were successfully
prepared without any decrease in yield compared to reac-
tions of non-functionalized substrates. In most of the cycli-
zation reactions, b-ketoester derived 1,3-bis(silyl enol
ethers) were employed. However, the use of 1,3-bis(silyl
enol ether) 5e, prepared from acetylacetone, also proved to
be successful. In contrast, employment of 1,3-bis(trimethyl-
silyloxy)-1-phenyl-1,3-butadiene (derived from benzoylace-
tone) resulted in the formation of complex mixtures. This
can be explained by its lower reactivity compared to b-
ketoester derived 1,3-bis(silyl enol ethers). The cyclization
of 2-aryloxy-3-(silyloxy)alk-2-en-1-ones with 1,3-bis(silyl
enol ethers) 5b, 5c and 5g, containing an additional alkyl
group attached to carbon atom C-4, afforded heavily
substituted diaryl ethers. However, most derivatives (6b,
6c, 6e, 6g, 6j, 6l, 6n and 6w) were obtained in relatively
low yield. On the other hand, no decrease in the yield was
observed in case of 6i and 6u. In conclusion, relatively low
yields were obtained for diaryl ethers 6a–c, 6e, 6g, 6l, 6n
and 6w. The reason for this remains unclear at present, since
considerably better yields were obtained for closely related
derivatives. Therefore, the quality of the starting materials
employed for each individual experiment seems to play an
important role.
a
Yields of isolated products.
Commercially available.
b
Me3SiO OSiMe3
R4
OH
O
O
R5
R4
5a-g
R5
Me3SiO
Me
O
Me
Me
i
Me
R1
O
+
R3
R1
R2
R3
R2
6a-w
4a-i
For substituents R1 - R5:
see Table 2
Scheme 2. Synthesis of 6a–w. Reagents and conditions: (i) TiCl4, CH2Cl2,
ꢁ78 ꢀC/20 ꢀC, 20 h.
The TiCl4 mediated cyclization of 2-aryloxy-3-(silyloxy)-
alk-2-en-1-ones 4a–i with 1,3-bis(silyl enol ethers) 5a–g
afforded the diaryl ethers 6a–w in moderate to good yields
(Scheme 2 and Table 2). The reactions were carried out fol-
lowing a typical procedure previously reported for related
[3+3] cyclizations.13 The best results were obtained when
Table 2. Synthesis of 6a–w
4
5
6
R1
R2
R3
R4
R5
6a (%)
a
a
a
b
b
c
c
d
d
d
d
e
f
a
b
c
a
b
a
b
d
b
c
e
b
a
b
a
f
a
f
a
f
g
e
b
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
s
H
H
H
Me
Me
H
H
H
H
H
H
H
OMe
OMe
H
H
H
H
H
H
H
H
Et
Et
Cl
Cl
Cl
H
H
H
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OMe
OEt
OEt
Me
OEt
OEt
OEt
OEt
OCH2Ph
OEt
35
30
32
58
39
60
36
54
49
43
35
30
58
35
58
59
50
54
50
65
54
55
30
Me
Et
H
Me
H
Me
H
Me
Et
H
H
H
Me
H
H
H
H
H
H
n-Hex
H
Me
Cl
OMe
OMe
OMe
Br
Br
CN
CN
CH2CO2Me
CH2CO2Me
CH2CO2Me
CH2CO2Me
OMe
f
g
g
h
h
i
i
i
i
e
H
H
H
H
H
H
OCH2Ph
OEt
OCH2Ph
OEt
Me
t
u
v
w
OEt
a
Yields of isolated products.

M. Sher et al. / Tetrahedron 63 (2007) 4929–4936
4931
1505 (s), 1298 (m), 1213 (m), 831 (m) cmꢁ1; GC–MS (EI,
70 eV): m/z (%): 220 (M+, 100), 178 (25), 122 (88), 107
(29), 91 (28), 77 (31), 43 (64); elemental analysis: calcd
(%) for C13H16O3 (220.26): C 70.89, H 7.32; found: C
71.05, H 7.07.
3.1.1.2. 3-(4-Ethylphenoxy)pentane-2,4-dione (3c).
Starting with 2 (10.00 g, 74.3 mmol), 4-ethylphenol
(12.90 g, 105.5 mmol) and K2CO3 (25.60 g, 185.7 mmol),
3c was isolated as a colourless oil (5.30 g, 35%); H NMR
1
(300 MHz, CDCl3): d¼1.21 (t, 3H, J¼7.5 Hz, CH3), 2.03
(s, 6H, CH3), 2.60 (q, 2H, J¼7.8 Hz, CH2), 6.82 (d, 2H,
J¼8.7 Hz, ArH), 7.12 (d, 2H, J¼8.8 Hz, ArH), 14.42 (s,
1H, OH); 13C NMR (75 MHz, CDCl3): d¼15.7, 20.8 (2C,
CH3), 27.9 (CH2), 114.1 (2C), 129.1 (2C, CH), 131.0,
137.9, 156.0, 186.5 (2C, C); IR (KBr): ~n ¼ 3436 ðwÞ, 2965
(m), 1739 (m), 1610 (m), 1505 (s), 1298 (m), 1213 (m),
831 (m) cmꢁ1; GC–MS (EI, 70 eV): m/z (%): 220.1 (M+,
90), 178.1 (29), 122.1 (61), 107.1 (64), 43.1 (100); HRMS
(EI): calcd for C13H16O3 [M]+: 220.1091; found: 220.1094.
Figure 1. ORTEP plot of 6d.
The structures of diaryl ethers 6 were proved by spectro-
scopic methods. The structure of derivative 6d was indepen-
dently confirmed by X-ray crystal structure analysis
(Fig. 1).17
3.1.1.3. 3-(4-Methoxyphenoxy)pentane-2,4-dione (3e).
Starting with 2 (4.00 g, 29.7 mmol), 4-methoxyphenol
(5.20 g, 42.2 mmol) and K2CO3 (10.20 g, 74.3 mmol), 3e
1
In conclusion, a variety of functionalized and sterically
encumbered diaryl ethers were prepared by formal [3+3]
cyclizations of 1,3-bis(silyl enol ethers) with 2-aryloxy-3-
(silyloxy)alk-2-en-1-ones. A general rule for the influence of
a specific substitution pattern of the starting materials on
the yield of the reactions could not be observed. In contrast,
the quality of the starting materials employed for each indi-
vidual experiment seems to play an important role.
was isolated as a colourless oil (1.50 g, 24%); H NMR
(300 MHz, CDCl3): d¼2.02 (s, 6H, CH3), 3.77 (s, 3H,
OCH3), 6.83 (s, 4H, ArH), 14.39 (s, 1H, OH); 13C NMR
(75 MHz, CDCl3): d¼20.8 (2C), 55.6 (CH3), 114.91 (2C),
114.95 (2C, CH), 131.2, 151.9, 154.7, 186.5 (2C, C); IR
(KBr): ~n ¼ 3085 ðwÞ, 3003 (m), 2956 (m), 2839 (w), 1607
(s), 1507 (s), 1309 (s), 1262 (s), 1228 (s), 1194 (s), 1166
(s), 1128 (s), 1026 (s), 951 (s), 740 (m) cmꢁ1; MS (EI,
70 eV): m/z (%): 222.0 (M+, 100), 151.0 (16), 124.0 (40),
108.0 (22); HRMS (EI): calcd for C12H14O4 [M]+:
222.0878; found: 222.0886.
3. Experimental section
3.1. General
3.1.1.4. 3-(3,4-Dimethoxyphenoxy)pentane-2,4-dione
(3f). Starting with 2 (6.00 g, 44.5 mmol), 3,4-dimethoxyphe-
nol (9.70 g, 63.3 mmol) and K2CO3 (15.40 g, 111.4 mmol),
All solvents were dried by standard methods and all reac-
tions were carried out under an inert atmosphere. For the
1H and 13C NMR spectra the deuterated solvents indicated
were used. 13C NMR spectral assignments are supported by
DEPT analyses. Mass spectral data (MS) were obtained by
electron ionization (EI, 70 eV), chemical ionization (CI,
H2O) or electrospray ionization (ESI). For preparative scale
chromatography silica gel (60–200 mesh) was used. Melting
points are uncorrected.
1
3f was isolated as a pink solid (4.50 g, 40%); H NMR
(300 MHz, CDCl3): d¼2.03 (s, 6H, CH3), 3.83 (s, 3H,
OCH3), 3.86 (s, 3H, OCH3), 6.31 (dd, 1H, J¼8.7, 2.8 Hz,
ArH), 6.55 (d, 1H, J¼2.8 Hz, ArH), 6.75 (d, 1H,
J¼8.7 Hz, ArH), 14.42 (s, 1H, OH); 13C NMR (75 MHz,
CDCl3): d¼20.8 (2C), 55.9, 56.3 (CH3), 99.9, 103.6, 111.8
(CH), 131.5, 144.3, 150.2, 152.4, 186.5 (2C, C); IR (KBr):
~n ¼ 3085 ðwÞ, 3003 (m), 2956 (m), 2839 (w), 1607 (s),
1507 (s), 1309 (s), 1262 (s), 1228 (s), 1194 (s), 1166 (s),
1128 (s), 1026 (s), 951 (s), 740 (m) cmꢁ1; MS (CI): 253.1
(100); elemental analysis: calcd (%) for C13H16O5
(252.26): C 61.90, H 6.39; found: C 61.73, H 6.30.
3.1.1. Synthesis of 3-(aryloxy)pentane-2,4-diones 3a–i.
The reactions were carried out according to a known pro-
cedure.15 The synthesis of 3a and 3d was previously
reported.15
3.1.1.5. 3-(4-Bromophenoxy)pentane-2,4-dione (3g).
Starting with 2 (10.00 g, 74.3 mmol), 4-bromophenol
(14.40 g, 105.5 mmol) and K2CO3 (25.60 g, 185.7 mmol),
3g was isolated as a pink oil (5.10 g, 25%); 1H NMR
(300 MHz, CDCl3): d¼2.01 (s, 6H, CH3), 6.81 (d, 2H,
J¼8.7 Hz, ArH), 7.40 (d, 2H, J¼8.7 Hz, ArH), 14.39 (s,
1H, OH); 13C NMR (75 MHz, CDCl3): d¼20.7 (2C, CH3),
114.4 (C), 116.0 (2C, CH), 130.7 (C), 132.8 (2C, CH),
157.1, 186.3 (2C, C); IR (KBr): ~n ¼ 2925 ðwÞ, 1593 (m),
1481 (s), 1303 (m), 1213 (m), 1165 (m), 1070 (m), 825
(m) cmꢁ1; GC–MS (EI, 70 eV): m/z (%): 272.0 (M+, 42),
3.1.1.1.
3-(3,5-Dimethylphenoxy)pentane-2,4-dione
(3b). Starting with 2 (10.00 g, 74.3 mmol), 3,5-dimethyl-
phenol (12.00 g, 104.0 mmol) and K2CO3 (25.00 g,
185.7 mmol), 3b was isolated as a yellow solid (3.00 g,
1
19%), mp 83–85 ꢀC; H NMR (300 MHz, CDCl3): d¼2.02
(s, 6H, CH3), 2.28 (s, 3H, CH3), 2.29 (s, 3H, CH3), 6.51 (s,
2H, ArH), 6.66 (s, 1H, ArH), 14.41 (s, 1H, OH); 13C NMR
(75 MHz, CDCl3): d¼20.8 (2C), 21.3 (2C, CH3), 111.9
(2C), 123.9 (CH), 130.9, 139.8 (2C), 158.0, 186.4 (2C, C);
IR (KBr): ~n ¼ 3436 ðwÞ, 2965 (m), 1739 (m), 1610 (m),

4932
M. Sher et al. / Tetrahedron 63 (2007) 4929–4936
270.0 (43), 230.0 (17), 228.0 (18), 174.0 (39), 172.0 (40),
101.1 (32); HRMS (EI): calcd for C11H11BrO3 [M]+:
269.9890; found: 269.9886.
133.7, 139.8, 143.8, 157.9, 159.6, 171.3 (C); IR (KBr):
~n ¼ 3432 ðwÞ, 2980 (w), 1657 (s), 1474 (s), 1373 (s),
GC–MS (EI, 70 eV): m/z (%): 286.1 (M+, 24), 240.0
(100), 211.0 (10), 135.0 (10); elemental analysis: calcd
(%) for C17H18O4 (286.32): C 71.31, H 6.34; found: C
71.03, H 6.62.
1318 (s), 1226 (s), 1207 (m), 1058 (m), 751 (m) cmꢁ1
;
3.1.1.6. 3-(4-Cyanophenoxy)pentane-2,4-dione (3h).
Starting with 2 (10.00 g, 74.3 mmol), 4-cyanophenol
(12.50 g, 105.5 mmol) and K2CO3 (26.50 g, 185.8 mmol),
3h was isolated as a colourless oil (4.20 g, 25%), mp 67–
1
68 ꢀC; H NMR (300 MHz, CDCl3): d¼2.02 (s, 6H, CH3),
3.1.3.2. Ethyl 3-phenoxy-6-hydroxy-2,4,5-trimethyl-
benzoate (6b). Starting with 1,3-bis(silyl enol ether)
5b (400 mg, 1.3 mmol), 3-(siloxy)alk-2-en-1-one 4a
(367 mg, 1.3 mmol) and TiCl4 (0.15 mL, 1.3 mmol), 6b
was isolated as a colourless solid (130 mg, 30%); 1H
NMR (400 MHz, CDCl3): d¼1.40 (t, 3H, J¼7.1 Hz, CH3),
2.08 (s, 3H, CH3), 2.20 (s, 3H, CH3), 2.32 (s, 3H, CH3),
4.42 (q, 2H, J¼7.1 Hz, OCH2), 6.72–7.27 (m, 5H, ArH),
11.51 (s, 1H, OH); 13C NMR (100 MHz, CDCl3): d¼10.9,
12.8, 13.1, 14.3 (CH3), 60.6 (CH2), 109.4 (C), 113.5 (2C),
120.3 (CH), 123.0 (C), 128.6 (2C, CH), 129.2, 137.1,
142.4, 156.8, 157.2, 170.9 (C); IR (KBr): ~n ¼ 3438 ðwÞ,
2937 (w), 1649 (s), 1396 (s), 1293 (s), 1222 (s), 1031
(m), 810 (m), 753 (m) cmꢁ1; MS (EI, 70 eV): m/z (%):
300.0 (M+, 88), 254.0 (100), 226.0 (72), 211.0 (17);
HRMS (EI): calcd for C18H20O4 [M]+: 300.13563; found:
300.13561.
7.02 (d, 2H, J¼9.0 Hz, ArH), 7.65 (d, 2H, J¼9.0 Hz,
ArH), 14.42 (s, 1H, OH); 13C NMR (100 MHz, CDCl3):
d¼20.7 (CH3), 106.0 (C), 115.2 (CHAr), 118.5, 130.4 (C),
134.5 (CHAr), 161.2, 186.0 (C); IR (KBr): ~n ¼ 3390 ðwÞ,
2953 (w), 1738 (s), 1611 (s), 1296 (m), 1223 (s), 1165
(m), 827 (m), 732 (s) cmꢁ1; GC–MS (EI, 70 eV): m/z (%):
217 (M+, 69), 175 (25), 101 (30), 43 (100); elemental anal-
ysis: calcd (%) for C12H11O3N (217.23): C 66.34, H 5.11, N
6.45; found: C 65.97, H 4.88, N 6.33.
3.1.1.7. Methyl 2-(4-(2,4-dioxopentane-3-yloxy)-
phenyl) acetate (3i). Starting with 2 (10.00 g, 74.3 mmol),
methyl 4-hydroxy acetate (17.20 g, 104.0 mmol) and
K2CO3 (25.60 g, 185.7 mmol), 3i was isolated as a colourless
oil (4.30 g, 26%); 1H NMR (300 MHz, CDCl3): d¼2.02 (s,
3H, CH3), 2.04 (s, 3H, CH3), 3.69 (s, 3H, OCH3), 5.29 (s,
2H, CH2), 6.87 (d, 2H, J¼8.7 Hz, ArH), 7.22 (d, 2H,
J¼8.7 Hz, ArH), 14.42 (s, 1H, OH); 13C NMR (100 MHz,
CDCl3): d¼20.7 (CH3), 40.0 (CH2), 51.9 (OCH3), 114.3
(CHAr), 127.6 (C), 130.6 (CHAr), 130.8, 157.0, 172.0,
186.3 (C); IR (KBr): ~n ¼ 3436 ðwÞ, 2965 (m), 1739 (m),
3.1.3.3. Ethyl 5-ethyl-3-phenoxy-6-hydroxy-2,4-di-
methylbenzoate (6c). Starting with 1,3-bis(silyl enol ether)
5c (400 mg, 1.3 mmol), 3-(siloxy)alk-2-en-1-one 4a
(349 mg, 1.3 mmol) and TiCl4 (0.14 mL, 1.3 mmol), 6c
was isolated as a colourless solid (130 mg, 32%); 1H NMR
(300 MHz, CDCl3): d¼1.10 (t, 3H, J¼7.5 Hz, CH3), 1.38
(t, 3H, J¼7.1 Hz, CH3), 2.09 (s, 3H, CH3), 2.29 (s, 3H,
CH3), 2.70 (q, 2H, J¼7.5 Hz, CH2), 4.40 (q, 2H,
J¼7.1 Hz, OCH2), 6.69–7.23 (m, 5H, ArH), 11.44 (s, 1H,
OH); 13C NMR (75 MHz, CDCl3): d¼13.0, 13.3, 14.1,
15.3 (CH3), 19.7, 61.5 (CH2), 110.6 (C), 114.5 (2C),
121.2, 129.6 (2C, CH), 130.1, 130.4, 137.4, 143.5, 157.6,
158.2, 171.9 (C); IR (KBr): ~n ¼ 2969 ðmÞ, 1651 (s), 1599
(m), 1492 (s), 1394 (s), 1320 (s), 1221 (s), 1052 (m), 748
(m) cmꢁ1; GC–MS (EI, 70 eV): m/z (%): 314.1 (M+, 46),
268.1 (100), 240.1 (10), 225.1 (2); elemental analysis: calcd
(%) for C19H22O4 (314.37): C 72.59, H 7.05; found: C 72.65,
H 6.95.
1610 (m), 1505 (s), 1298 (m), 1213 (m), 831 (m) cmꢁ1
;
GC–MS (EI, 70 eV): m/z (%): 264 (M+, 100), 222.1 (36),
205.1 (47), 166.1 (34), 107.1 (87), 43.1 (61); elemental anal-
ysis: calcd (%) for C14H16O5 (442.56): C 63.63, H 6.10;
found: C 63.26, H 5.88.
3.1.2. Synthesis of 2-aryloxy-3-(silyloxy)alk-2-en-1-ones
4a–i. The reactions were carried out according to a known
procedure.16 Due to their low stability, silyl enol ethers
4a–i were used directly after their preparation and not char-
acterized by spectroscopy.
3.1.3. General procedure for the synthesis of diaryl ethers
6a–w. To a dichloromethane 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 satu-
rated solution of NaHCO3 (10 mL). The organic and the
aqueous layers were separated and the latter was extracted
with diethyl ether (3ꢂ30 mL). The filtrate was concentrated
in vacuo and the residue was purified by chromatography
(silica gel, EtOAc/n-heptane¼1:4).
3.1.3.4. Ethyl 3-(3,5-dimethylphenoxy)-6-hydroxy-2,4-
dimethylbenzoate (6d). Starting with 1,3-bis(silyl enol
ether) 5a (500 mg, 1.8 mmol), 3-(siloxy)alk-2-en-1-one 4b
(533 mg, 1.8 mmol) and TiCl4 (0.19 mL, 1.8 mmol), 6d
was isolated as a colourless solid (330 mg, 58%), mp 125–
126 ꢀC; 1H NMR (300 MHz, CDCl3): d¼1.41 (t, 3H,
J¼7.1 Hz, CH3), 2.11 (s, 3H, CH3), 2.24 (s, 6H, CH3),
2.34 (s, 3H, CH3), 4.43 (q, 2H, J¼7.1 Hz, OCH2), 6.35 (s,
2H, ArH), 6.62 (s, 1H, ArH), 6.76 (s, 1H, ArH), 11.19 (s,
1H, OH); 13C NMR (75 MHz, CDCl3): d¼14.1, 15.4, 17.3,
21.3 (2C, CH3), 61.6 (CH2), 111.1 (C), 112.1 (2C), 117.3,
123.3 (CH), 133.7, 139.4 (2C), 139.9, 143.9, 158.0, 159.5,
171.4 (C); IR (KBr): ~n ¼ 3030 ðwÞ, 2957 (m), 1660 (s),
1505 (s), 1470 (s), 1397 (s), 1373 (s), 1313 (s), 1241 (s),
1220 (s), 1077 (m), 826 (m), 799 (m) cmꢁ1; GC–MS (EI,
70 eV): m/z (%): 314.2 (M+, 34), 268.1 (100); elemental
analysis: calcd (%) for C19H22O4 (314.37): C 72.59, H
7.05; found: C 72.18, H 6.88.
3.1.3.1. Ethyl 3-phenoxy-6-hydroxy-2,4-dimethylbenz-
oate (6a). Starting with 1,3-bis(silyl enol ether) 5a
(350 mg, 1.2 mmol), 3-(siloxy)alk-2-en-1-one 4a (342 mg,
1.2 mmol) and TiCl4 (0.14 mL, 1.2 mmol), 6a was isolated
1
as a colourless solid (125 mg, 35%); H NMR (400 MHz,
CDCl3): d¼1.27 (t, 3H, J¼7.1 Hz, CH3), 1.96 (s, 3H,
CH3), 2.21 (s, 3H, CH3), 4.28 (q, 2H, J¼7.1 Hz, OCH2),
6.59–7.13 (m, 6H, ArH), 11.04 (s, 1H, OH); 13C NMR
(100 MHz, CDCl3): d¼14.1, 15.3, 17.2 (CH3), 61.6 (CH2),
111.1 (C), 114.4 (2C), 117.4, 121.4, 129.6 (2C, CH),

M. Sher et al. / Tetrahedron 63 (2007) 4929–4936
4933
3.1.3.5. Ethyl 3-(3,5-dimethylphenoxy)-6-hydroxy-
2,4,5-trimethylbenzoate (6e). Starting with 1,3-bis(silyl
enol ether) 5b (500 mg, 1.7 mmol), 3-(siloxy)alk-2-en-
1-one 4b (506 mg, 1.7 mmol) and TiCl4 (0.18 mL,
1.7 mmol), 6e was isolated as a colourless solid (220 mg,
39%), mp 111–112 ꢀC; 1H NMR (300 MHz, CDCl3):
d¼1.42 (t, 3H, J¼7.1 Hz, CH3), 2.09 (s, 3H, CH3), 2.22 (s,
3H, CH3), 2.25 (s, 6H, CH3), 2.33 (s, 3H, CH3), 4.44 (q,
2H, J¼7.1 Hz, OCH2), 6.35 (s, 2H, ArH), 6.62 (s, 1H,
ArH), 11.54 (s, 1H, OH); 13C NMR (75 MHz, CDCl3):
d¼11.9, 13.9, 14.1, 15.3, 21.3 (2C, CH3), 61.5 (CH2), 110.3
(C), 112.2 (2C), 123.1 (CH), 123.8, 130.3, 138.2, 139.4 (2C),
143.5, 157.7, 158.3, 172.0 (C); IR (KBr): ~n ¼ 3430 ðwÞ,
2921 (m), 1647 (s), 1612 (s), 1594 (s), 1400 (s), 1378 (s),
1318 (s), 1289 (s), 1218 (s), 1142 (s), 1032 (m), 834
(m) cmꢁ1; GC–MS (EI, 70 eV): m/z (%): 328.2 (M+, 38),
282.2 (100), 239.2 (14); elemental analysis: calcd (%) for
C20H24O4 (328.40): C 73.14, H 7.36; found: C 73.16, H 7.57.
was isolated as a colourless solid (315 mg, 54%), mp
1
83 ꢀC; H NMR (300 MHz, CDCl3): d¼2.09 (s, 3H, CH3),
2.30 (s, 3H, CH3), 3.95 (s, 3H, OCH3), 6.67 (d, 2H,
J¼9.0 Hz, ArH), 6.76 (s, 1H, ArH), 7.20 (d, 2H,
J¼9.0 Hz, ArH), 11.10 (s, 1H, OH); 13C NMR (75 MHz,
CDCl3): d¼15.2, 17.1, 52.2 (CH3), 111.1 (C), 115.7 (2C),
117.6 (CH), 126.3 (C), 129.6 (2C, CH), 133.5, 139.7,
143.6, 156.5, 159.7, 171.7 (C); IR (KBr): ~n ¼ 3431 ðmÞ,
2959 (w), 1661 (s), 1486 (s), 1442 (m), 1361 (m), 1326
(s), 1318 (s), 1074 (m), 825 (m), 803 (m) cmꢁ1; GC–MS
(EI, 70 eV): m/z (%): 306 (M+, 33), 274 (100), 246 (10),
163.1 (8); elemental analysis: calcd (%) for C16H15ClO4
(306.74): C 62.65, H 4.93; found: C 62.42, H 4.68.
3.1.3.9. Ethyl 3-(4-chlorophenoxy)-6-hydroxy-2,4,5-
trimethylbenzoate (6i). Starting with 1,3-bis(silyl enol
ether) 5b (662 mg, 2.1 mmol), 3-(siloxy)alk-2-en-1-one 4d
(654 mg, 2.1 mmol) and TiCl4 (0.24 mL, 2.1 mmol), 6i
was isolated as a colourless solid (325 mg, 43%); 1H NMR
(300 MHz, CDCl3): d¼1.40 (t, 3H, J¼7.1 Hz, CH3), 2.06
(s, 3H, CH3), 2.20 (s, 3H, CH3), 2.29 (s, 3H, CH3), 4.42
(q, 2H, J¼7.1 Hz, OCH2), 6.66 (d, 2H, J¼9.0 Hz, ArH),
7.19 (d, 2H, J¼9.0 Hz, ArH), 11.52 (s, 1H, OH); 13C
NMR (75 MHz, CDCl3): d¼11.8, 13.7, 14.1, 15.2 (CH3),
61.6 (CH2), 110.4 (C), 115.8 (2C, CH), 124.2, 126.1 (C),
129.5 (2C, CH), 130.0, 137.7, 143.2, 156.9, 157.9, 171.8
(C); IR (KBr): ~n ¼ 2978 ðwÞ, 1650 (s), 1484 (s), 1398 (m),
1316 (s), 1221 (s), 1033 (m), 805 (m) cmꢁ1; GC–MS (EI,
70 eV): m/z (%): 334.1 (M+, 34), 288.1 (100), 260.1 (20);
elemental analysis: calcd (%) for C18H19ClO4 (334.79):
C 64.57, H 5.72; found: C 64.26, H 5.86.
3.1.3.6. Ethyl 3-(4-ethylphenoxy)-6-hydroxy-2,4-di-
methylbenzoate (6f). Starting with 1,3-bis(silyl enol ether)
5a (500 mg, 1.8 mmol), 3-(siloxy)alk-2-en-1-one 4c
(533 mg, 1.8 mmol) and TiCl4 (0.19 mL, 1.8 mmol), 6f
was isolated as a colourless solid (339 mg, 60%), mp 52–
53 ꢀC; 1H NMR (300 MHz, CDCl3): d¼1.20 (t, 3H,
J¼7.5 Hz, CH3), 1.40 (t, 3H, J¼7.1 Hz, CH3), 2.10 (s, 3H,
CH3), 2.34 (s, 3H, CH3), 2.58 (q, 2H, J¼7.5 Hz, CH2),
4.42 (q, 2H, J¼7.1 Hz, OCH2), 6.65 (d, 2H, J¼8.7 Hz,
ArH), 6.75 (s, 1H, ArH), 7.06 (d, 2H, J¼8.7 Hz, ArH),
11.17 (s, 1H, OH); 13C NMR (75 MHz, CDCl3): d¼14.2,
15.4, 15.7, 13.3 (CH3), 27.9, 61.7 (CH2), 111.2 (C), 114.3
(2C), 117.4, 129.9 (2C, CH), 133.8, 137.2, 140.0, 144.1,
156.0, 159.6, 171.5 (C); IR (KBr): ~n ¼ 3030 ðwÞ, 2957
(m), 1660 (s), 1505 (s), 1470 (s), 1397 (s), 1373 (s), 1313
3.1.3.10. Ethyl 4-ethyl-3-(4-chlorophenoxy)-6-hy-
droxy-2,4-dimethylbenzoate(6j). Starting with 1,3-bis(silyl
enol ether) 5c (662 mg, 2.1 mmol), 3-(siloxy)alk-2-en-1-
one 4d (654 mg, 2.1 mmol) and TiCl4 (0.24 mL,
2.1 mmol), 6j was isolated as a colourless solid (325 mg,
43%); 1H NMR (300 MHz, CDCl3): d¼1.12 (t, 3H,
J¼7.5 Hz, CH3), 1.40 (t, 3H, J¼7.1 Hz, CH3), 2.09 (s, 3H,
CH3), 2.29 (s, 3H, CH3), 2.72 (q, 2H, J¼7.5 Hz, CH2),
4.42 (q, 2H, J¼7.1 Hz, OCH2), 6.67 (d, 2H, J¼9.0 Hz,
ArH), 7.20 (d, 2H, J¼9.0 Hz, ArH), 11.48 (s, 1H, OH);
13C NMR (75 MHz, CDCl3): d¼13.0, 13.2, 14.1, 15.3
(CH3), 19.7, 61.6 (CH2), 110.6 (C), 115.8 (2C, CH),
126.1 (C), 129.5 (2C, CH), 130.2, 130.3, 137.1, 143.3,
156.8, 157.8, 171.8 (C); IR (KBr): ~n ¼ 2978 ðwÞ, 1650 (s),
1484 (s), 1398 (m), 1316 (s), 1221 (s), 1033 (m), 805
(m) cmꢁ1; GC–MS (EI, 70 eV): m/z (%): 347.9 (M+, 51),
301.9 (100), 273.9 (38); elemental analysis: calcd (%) for
C19H21ClO4 (347.9): C 65.42, H 6.07; found: C 65.80, H
6.22.
(s), 1241 (s), 1220 (s), 1077 (m), 826 (m), 799 (m) cmꢁ1
;
GC–MS (EI, 70 eV): m/z (%): 314.2 (M+, 29), 268.2
(100); elemental analysis: calcd (%) for C19H22O4
(314.37): C 72.59, H 7.05; found: C 72.42, H 7.11.
3.1.3.7. Ethyl 3-(4-ethylphenoxy)-6-hydroxy-2,4,5-tri-
methylbenzoate (6g). Starting with 1,3-bis(silyl enol ether)
5b (500 mg, 1.7 mmol), 3-(siloxy)alk-2-en-1-one 4c
(507 mg, 1.7 mmol) and TiCl4 (0.18 mL, 1.7 mmol), 6g
was isolated as a colourless solid (200 mg, 36%), mp 49–
50 ꢀC; 1H NMR (300 MHz, CDCl3): d¼1.20 (t, 3H,
J¼7.5 Hz, CH3), 1.39 (t, 3H, J¼7.1 Hz, CH3), 2.08 (s,
3H, CH3), 2.19 (s, 3H, CH3), 2.31 (s, 3H, CH3), 2.58 (q,
2H, J¼7.5 Hz, CH2), 4.41 (q, 2H, J¼7.1 Hz, OCH2), 6.63
(d, 2H, J¼8.7 Hz, ArH), 7.06 (d, 2H, J¼8.7 Hz, ArH),
11.51 (s, 1H, OH); 13C NMR (75 MHz, CDCl3): d¼11.9,
13.9, 14.1, 15.3, 15.6 (CH3), 27.9, 61.6 (CH2), 110.3 (C),
114.3 (2C, CH), 123.9 (C), 128.8 (2C, CH), 130.3, 136.9,
138.2, 143.6, 156.3, 157.7, 172.0 (C); IR (KBr):
~n ¼ 2969 ðmÞ, 1651 (s), 1599 (m), 1492 (s), 1394 (s), 1320
(s), 1221 (s), 1052 (m), 748 (m) cmꢁ1; GC–MS (EI,
70 eV): m/z (%): 328.2 (M+, 31), 282.2 (100), 254.2 (13),
225.1 (8); HRMS (EI): calcd for C20H24O4 [M]+:
328.14543; found: 328.14541.
3.1.3.11. 1-(3-(4-Chlorophenoxy)-6-hydroxy-2,4-di-
methylphenyl)ethanone (6k). Starting with 1,3-bis(silyl
enol ether) 5e (500 mg, 2.0 mmol), 3-(siloxy)alk-2-en-1-
one 4d (609 mg, 2.0 mmol) and TiCl4 (2.04 mL,
2.0 mmol), 6k was isolated as a yellow solid (205 mg,
1
35%); H NMR (400 MHz, CDCl3): d¼2.09 (s, 3H, CH3),
2.33 (s, 3H, CH3), 2.63 (s, 3H, CH3), 6.69 (d, 2H,
J¼9.0 Hz, ArH), 6.76 (s, 1H, ArH), 7.22 (d, 2H,
J¼9.0 Hz, ArH), 11.94 (s, 1H, OH); 13C NMR (100 MHz,
CDCl3): d¼16.0, 17.2, 33.0 (CH3), 115.7 (2C), 118.4
(CH), 120.9, 126.5 (C), 129.7 (2C, CH), 131.7, 140.2,
3.1.3.8. Methyl 3-(4-chlorophenoxy)-6-hydroxy-2,4-
dimethylbenzoate (6h). 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 TiCl4 (0.21 mL, 1.9 mmol), 6h

4934
M. Sher et al. / Tetrahedron 63 (2007) 4929–4936
143.6, 156.4, 159.3, 205.3 (C); IR (KBr): ~n ¼ 3341 ðwÞ,
2925 (w), 1629 (m), 1485 (s), 1296 (m), 1227 (s), 1091
(m), 827 (m) cmꢁ1; MS (EI, 70 eV): m/z (%): 290.0 (M+,
95), 275.0 (100), 165.0 (43); HRMS (EI): calcd for
C16H15ClO3 [M]+: 290.07042; found: 290.07056.
MS (EI, 70 eV): m/z (%): 360.2 (M+, 49), 314.2 (100),
215.1 (2), 138.1 (6); elemental analysis: calcd (%) for
C20H24O6 (360.40): C 66.65, H 6.71; found: C 66.47, H 7.14.
3.1.3.15. Ethyl 3-(4-bromophenoxy)-6-hydroxy-2,4-di-
methylbenzoate (6o). Starting with 1,3-bis(silyl enol ether)
5a (400 mg, 1.4 mmol), 3-(siloxy)alk-2-en-1-one 4g
(497 mg, 1.4 mmol) and TiCl4 (0.16 mL, 1.4 mmol), 6o
was isolated as a yellow solid (305 mg, 58%), mp 50–
52 ꢀC; 1H NMR (300 MHz, CDCl3): d¼1.41 (t, 3H,
J¼7.1 Hz, CH3), 2.09 (s, 3H, CH3), 2.31 (s, 3H, CH3),
4.42 (q, 2H, J¼7.1 Hz, OCH2), 6.63 (d, 2H, J¼9.0 Hz,
ArH), 6.76 (s, 1H, ArH), 7.34 (d, 2H, J¼9.0 Hz, ArH),
11.19 (s, 1H, OH); 13C NMR (100 MHz, CDCl3): d¼14.1,
15.3, 17.1 (CH3), 61.7 (OCH2), 111.2, 113.6 (C), 116.0
(CHAr), 117.6 (C), 132.5 (CHAr), 139.5, 143.5, 157.1,
159.7, 171.2 (C); IR (KBr): ~n ¼ 3430 ðwÞ, 2995 (m), 1660
(s), 1483 (s), 1373 (s), 1346 (m), 1316 (s), 1217 (s), 1067
(m), 1058 (m), 1003 (m), 836 (s), 799 (s), 599 (m), 501
(m) cmꢁ1; GC–MS (EI, 70 eV): m/z (%): 366 (M+, 81Br
30), 364 (79Br, 30), 320 (100), 318 (99), 163 (8); elemental
analysis: calcd (%) for C17H17O4Br (365.218): C 55.91, H
4.69; found: C 56.19, H 4.33.
3.1.3.12. Ethyl 3-(4-methoxyphenoxy)-6-hydroxy-2,4-
dimethylbenzoate (6l). Starting with 1,3-bis(silyl enol
ether) 5a (589 mg, 2.1 mmol), 3-(siloxy)alk-2-en-1-one 4e
(627 mg, 2.1 mmol) and TiCl4 (0.23 mL, 2.1 mmol), 6l
was isolated as a colourless solid (344 mg, 52%), mp 88–
89 ꢀC; 1H NMR (400 MHz, CDCl3): d¼1.41 (t, 3H,
J¼7.1 Hz, CH3), 2.11 (s, 3H, CH3), 2.35 (s, 3H, CH3),
3.76 (s, 3H, OCH3), 4.43 (q, 2H, J¼7.1 Hz, OCH2), 6.67
(d, 2H, J¼9.1 Hz, ArH), 6.76 (s, 1H, ArH), 6.80 (d, 2H,
J¼9.1 Hz, ArH), 11.67 (s, 1H, OH); 13C NMR (100 MHz,
CDCl3): d¼14.1, 15.3, 17.2, 55.6 (CH3), 61.6 (CH2), 111.1
(C), 114.7 (2C), 115.0 (2C), 117.4 (CH), 133.8, 139.9,
144.2, 152.0, 154.1, 159.5, 171.3 (C); IR (KBr):
~n ¼ 3423 ðwÞ, 2993 (m), 1659 (s), 1505 (s), 1405 (s), 1374
(m), 1316 (s), 1217 (s), 1075 (m), 824 (m) cmꢁ1; GC–MS
(EI, 70 eV): m/z (%): 316.2 (M+, 58), 270.2 (100), 199.1
(5), 135.1 (14); elemental analysis: calcd (%) for
C18H20O5 (316.34): C 68.34, H 6.37; found: C 68.13, H 6.67.
3.1.3.16. Benzyl 3-(4-bromophenoxy)-6-hydroxy-2,4-
dimethylbenzoate (6p). Starting with 1,3-bis(silyl enol
ether) 5f (300 mg, 0.89 mmol), 3-(siloxy)alk-2-en-1-one
4g (306 mg, 0.89 mmol) and TiCl4 (0.09 mL, 0.89 mmol),
6p was isolated as a yellow solid (220 mg, 59%); 1H NMR
(300 MHz, CDCl3): d¼1.91 (s, 3H, CH3), 2.43 (s, 3H,
CH3), 5.26 (s, 2H, CH2), 6.52 (d, 2H, J¼7.1 Hz, ArH),
6.64 (s, 1H, ArH), 6.71 (d, 2H, J¼7.1 Hz, ArH), 7.22–7.35
(m, 5H, ArH), 11.21 (s, 1H, OH); 13C NMR (100 MHz,
CDCl3): d¼15.5, 17.2 (CH3), 67.5 (OCH2), 111.6, 113.6
(C), 116.0, 116.2, 117.6 (CHAr), 128.5, 128.6, 132.5, 132.7
(CHAr), 134.9, 139.8, 143.5, 157.0, 159.9, 171.0, 186.2
(C); IR (KBr): ~n ¼ 3033 ðwÞ, 2959 (w), 1662 (s), 1428 (s),
1385 (m), 1309 (s), 1229 (s), 1162 (m), 1069 (s), 1005
(m), 828 (s), 697 (s) cmꢁ1; GC–MS (EI, 70 eV): m/z (%):
428 (M+, 81Br 93), 426 (79Br, 90), 320 (88), 318 (87), 91
(100); HRMS (EI): calcd for C22H19BrO4 [M]+:
426.045476; found: 426.046612.
3.1.3.13. Ethyl 3-(3,4-dimethoxyphenoxy)-6-hydroxy-
2,4-dimethylbenzoate (6m). Starting with 1,3-bis(silyl
enol ether) 5a (500 mg, 1.8 mmol), 3-(siloxy)alk-2-en-1-
one 4f (590 mg, 1.8 mmol) and TiCl4 (0.19 mL,
1.8 mmol), 6m was isolated as a colourless solid (362 mg,
58%); 1H NMR (300 MHz, CDCl3): d¼1.41 (t, 3H,
J¼7.1 Hz, CH3), 2.11 (s, 3H, CH3), 2.35 (s, 3H, CH3),
3.81 (s, 3H, OCH3), 3.84 (s, 3H, OCH3), 4.43 (q, 2H,
J¼7.1 Hz, OCH2), 6.05 (dd, 1H, J¼2.8, 8.7 Hz, ArH),
6.52 (d, 1H, J¼2.8 Hz, ArH), 6.68 (d, 1H, J¼8.7 Hz,
ArH), 6.76 (s, 1H, ArH), 11.17 (s, 1H, OH); 13C NMR
(75 MHz, CDCl3): d¼14.1, 15.3, 17.2, 55.8, 56.3 (CH3),
61.6 (CH2), 100.0, 104.0 (CH), 111.1 (C), 111.7, 117.4
(CH), 133.8, 139.9, 143.7, 144.0, 150.0, 152.4, 159.5,
171.3 (C); IR (KBr): ~n ¼ 3426 ðwÞ, 2939 (m), 1659 (s),
1512 (s), 1466 (s), 1450 (s), 1393 (m), 1260 (m), 1211 (s),
1124 (m), 1023 (m), 802 (m) cmꢁ1; GC–MS (EI, 70 eV):
m/z (%): 346.2 (M+, 65), 300.2 (100), 285.1 (19), 150.1
(7); elemental analysis: calcd (%) for C19H22O6 (346.37):
C 65.88, H 6.40; found: C 66.10, H 6.04.
3.1.3.17. Ethyl 3-(4-cyanophenoxy)-6-hydroxy-2,4-di-
methylbenzoate (6q). Starting with 1,3-bis(silyl enol ether)
5a (500 mg, 1.82 mmol), 3-(siloxy)alk-2-en-1-one 4h
(530 mg, 1.82 mmol) and TiCl4 (0.20 mL, 1.82 mmol), 6q
was isolated as a colourless solid (284 mg, 50%); 1H NMR
(300 MHz, CDCl3): d¼1.41 (t, 3H, J¼7.1 Hz, CH3), 2.08
(s, 3H, CH3), 2.30 (s, 3H, CH3), 4.44 (q, 2H, J¼7.1 Hz,
OCH2), 6.80 (d, 2H, J¼8.5 Hz, ArH), 6.84 (s, 1H, ArH),
7.57 (d, 2H, J¼8.5 Hz, ArH), 11.22 (s, 1H, OH); 13C NMR
(100 MHz, CDCl3): d¼14.1, 15.2 (CH3), 61.8 (OCH2),
105.1, 111.3 (C), 115.4, 117.8 (CHAr), 118.8, 133.3 (C),
134.3 (CHAr), 139.0, 142.8, 143.7, 160.1, 161.3, 171.1 (C);
IR (KBr): ~n ¼ 3390 ðwÞ, 2953 (w), 1738 (s), 1611 (s),
1296 (m), 1223 (s), 1165 (m), 827 (m), 732 (s) cmꢁ1; GC–
MS (EI, 70 eV): m/z (%): 311 (M+, 26), 265 (100), 135
(4); elemental analysis: calcd (%) for C18H17O4N
(311.34): C 69.44, H 4.49; found: C 69.32, H 4.35.
3.1.3.14. Ethyl 3-(3,4-dimethoxyphenoxy)-6-hydroxy-
2,4,5-trimethylbenzoate (6n). Starting with 1,3-bis(silyl
enol ether) 5b (500 mg, 1.7 mmol), 3-(siloxy)alk-2-en-1-
one 4f (562 mg, 1.7 mmol) and TiCl4 (0.18 mL,
1.7 mmol), 6n was isolated as a colourless solid (215 mg,
35%), mp 110–111 ꢀC; 1H NMR (400 MHz, CDCl3):
d¼1.40 (t, 3H, J¼7.1 Hz, CH3), 2.09 (s, 3H, CH3), 2.20 (s,
3H, CH3), 2.32 (s, 3H, CH3), 3.81 (s, 3H, OCH3), 3.84 (s,
3H, OCH3), 4.42 (q, 2H, J¼7.1 Hz, OCH2), 6.02 (dd, 1H,
J¼2.8 Hz, 8.7 Hz, ArH), 6.52 (d, 1H, J¼2.8 Hz, ArH),
6.67 (d, 1H, J¼8.7 Hz, ArH), 11.51 (s, 1H, OH); 13C
NMR (100 MHz, CDCl3): d¼11.8, 13.8, 14.1, 15.3, 55.8,
56.3 (CH3), 61.6 (CH2), 100.1, 104.1 (CH), 110.3 (C),
111.7 (CH), 123.9, 130.3, 138.2, 143.64, 143.69, 150.0,
152.7, 157.7, 171.9 (C); IR (KBr): ~n ¼ 3442 ðwÞ, 2992
(m), 1643 (s), 1510 (s), 1447 (m), 1393 (m), 1312 (s),
1260 (s), 1212 (s), 1192 (s), 1131 (m), 836 (m) cmꢁ1; GC–
3.1.3.18. Benzyl 3-(4-cyanophenoxy)-6-hydroxy-2,4-
dimethylbenzoate (6r). Starting with 1,3-bis(silyl enol

M. Sher et al. / Tetrahedron 63 (2007) 4929–4936
4935
ether) 5f (400 mg, 1.19 mmol), 3-(siloxy)alk-2-en-1-one 4h
(340 mg, 1.19 mmol) and TiCl4 (0.13 mL, 1.19 mmol), 6r
was isolated as a yellow oil (292 mg, 54%); 1H NMR
(300 MHz, CDCl3): d¼2.02 (s, 3H, CH3), 2.22 (s, 3H,
CH3), 5.35 (s, 2H, OCH2), 6.76 (d, 2H, J¼9.0 Hz, ArH),
7.20 (s, 1H, ArH), 7.30–7.37 (m, 5H, Ph), 7.50 (d, 2H,
J¼9.0 Hz, ArH), 11.11 (s, 1H, OH); 13C NMR (100 MHz,
CDCl3): d¼15.4, 15.7 (CH3), 67.5 (CH2), 105.0, 111.1
(C), 115.3, 118.8 (CHAr), 118.7 (C), 125.1, 128.1 (CHAr),
128.6 (C), 133.2 (CHAr), 134.7, 139.3, 142.7, 160.1, 161.1,
170.8 (C); MS (EI, 70 eV): m/z (%): 373 (M+, 34), 265
(13), 91 (100); elemental analysis: calcd (%) for
C23H19NO4 (373.40): C 73.98, H 5.13, N 3.75; found: C
73.51, H 4.98, N 3.72.
2.67 (t, 2H, J¼8.2 Hz, CH2), 3.56 (s, 2H, OCH2), 3.69 (s,
2H, CH2), 4.11 (q, 2H, J¼7.1 Hz, OCH2), 6.67 (d, 2H,
J¼8.7 Hz, ArH), 7.15 (d, 2H, J¼8.7 Hz, ArH), 11.42 (s,
1H, OH); 13C NMR (100 MHz, CDCl3): d¼13.3, 14.0,
15.3 (CH3), 22.6, 26.5, 29.0, 29.6, 31.7, 40.2 (CH2), 52.0
(OCH3), 61.5 (CH2), 110.5 (C), 114.6 (CHAr), 126.7,
128.9, 130.3 (C), 130.4 (CHAr), 137.6, 143.4, 157.3, 157.8,
171.9, 172.3 (C); IR (KBr): ~n ¼ 2954 ðsÞ, 2928 (s), 1742
(s), 1655 (s), 1609 (m), 1373 (m), 1315 (s), 1222 (s), 1159
(m), 1052 (s), 1014 (m), 806 (s) cmꢁ1; GC–MS (EI,
70 eV): m/z (%): 442 (M+, 100), 396 (63), 367 (46), 353
(34), 326 (90), 233 (33); elemental analysis: calcd (%) for
C28H34O6 (442.56): C 70.56, H 7.74; found: C 70.21, H 7.30.
3.1.3.22. Methyl 2-(4-(3-acetyl-4-hydroxy-2,4-dime-
thyl)phenoxy)phenylacetate (6v). Starting with 1,3-bis(silyl
enol ether) 5e (400 mg, 1.63 mmol), 3-(siloxy)alk-2-en-1-
one 4i (540 mg, 1.63 mmol) and TiCl4 (0.17 mL,
1.6 mmol), 6v was isolated as a yellow oil (280 mg, 55%);
1H NMR (300 MHz, CDCl3): d¼2.09 (s, 3H, CH3), 2.33
(s, 3H, CH3), 2.62 (s, 3H, CH3), 3.57 (s, 2H, CH2), 3.69 (s,
3H, OCH3), 6.71 (d, 2H, J¼8.6 Hz, ArH), 6.75 (s, 1H,
ArH), 7.17 (d, 2H, J¼8.6 Hz, ArH), 11.91 (s, 1H, OH);
13C NMR (100 MHz, CDCl3): d¼16.0, 17.2, 33.0 (CH3),
40.0 (CH2), 51.9 (OCH3), 114.4, 118.4 (CHAr), 120.8,
127.0 (C), 130.5 (CHAr), 131.7, 140.3, 143.7, 156.8, 157.0,
172.0, 186.3, 205.3 (C); IR (KBr): ~n ¼ 3390 ðwÞ, 2953
(w), 1738 (s), 1611 (s), 1296 (m), 1223 (s), 1165 (m), 827
(m), 732 (s) cmꢁ1; GC–MS (EI, 70 eV): m/z (%): 311 (M+,
26), 265 (100), 135 (4); elemental analysis: calcd (%) for
C19H22O4 (314.38): C 72.59, H 7.05; found: C 72.23, H 7.06.
3.1.3.19. Ethyl 3-(4-methylacetatephenoxy)-6-hy-
droxy-2,4-dimethylbenzoate (6s). Starting with 1,3-bis(silyl
enol ether) 5a (400 mg, 1.45 mmol), 3-(siloxy)alk-2-en-
1-one 4i (480 mg, 1.45 mmol) and TiCl4 (0.16 mL,
1.45 mmol), 6s was isolated as a colourless solid (259 mg,
1
50%), mp 72–73 ꢀC; H NMR (300 MHz, CDCl3): d¼1.40
(t, 3H, J¼7.1 Hz, CH3), 2.09 (s, 3H, CH3), 2.33 (s, 3H,
CH3), 3.55 (s, 2H, CH2), 3.68 (s, 3H, OCH3), 4.42 (q, 2H,
J¼7.1 Hz, OCH2), 6.69 (d, 2H, J¼8.7 Hz, ArH), 6.75 (s,
1H, ArH), 7.15 (d, 2H, J¼8.7 Hz, ArH), 11.17 (s, 1H, OH);
13C NMR (100 MHz, CDCl3): d¼14.0, 15.3, 17.2 (CH3),
40.1 (CH2), 51.9 (OCH3), 61.6 (OCH2), 111.1 (C), 114.5,
117.4 (CHAr), 126.8 (C), 130.4 (CHAr), 136.6, 139.7,
143.7, 157.6, 159.5, 171.3, 172.1 (C); IR (KBr):
~n ¼ 3438 ðwÞ, 2987 (s), 1740 (s), 1605 (s), 1505 (s), 1318
(s), 1216 (s), 1143 (s), 1012 (m), 874 (m), 802 (s), 642
(m) cmꢁ1; GC–MS (EI, 70 eV): m/z (%): 358 (M+, 28),
312 (100), 253 (13); elemental analysis: calcd (%) for
C20H22O6 (358.39): C 67.03, H 6.19; found: C 67.38, H 6.37.
3.1.3.23. Ethyl 3-(4-methoxyphenoxy)-6-hydroxy-
2,4,5-trimethylbenzoate (6w). Starting with 1,3-bis(silyl
enol ether) 5b (341 mg, 1.2 mmol), 3-(siloxy)alk-2-
en-1-one 4e (353 mg, 1.2 mmol) and TiCl4 (0.13 mL,
1.2 mmol), 6w was isolated as a colourless solid (120 mg,
30%); 1H NMR (400 MHz, CDCl3): d¼1.40 (t, 3H,
J¼7.1 Hz, CH3), 2.08 (s, 3H, CH3), 2.19 (s, 3H, CH3), 2.32
(s, 3H, CH3), 3.75 (s, 3H, OCH3), 4.42 (q, 2H, J¼7.1 Hz,
OCH2), 6.65 (d, 2H, J¼9.1 Hz, ArH), 6.78 (d, 2H,
J¼9.1 Hz, ArH), 11.51 (s, 1H, OH); 13C NMR (100 MHz,
CDCl3): d¼10.8, 12.8, 13.1, 14.3, 54.6 (CH3), 60.5 (CH2),
109.3 (C), 113.7 (2C), 114.1 (2C, CH), 122.9, 129.3,
137.2, 142.8, 151.3, 153.0, 156.7, 170.9 (C); IR (KBr):
~n ¼ 2969 ðmÞ, 1651 (s), 1599 (m), 1492 (s), 1394 (s), 1320
(s), 1221 (s), 1052 (m), 748 (m) cmꢁ1; GC–MS (EI,
70 eV): m/z (%): 330.2 (M+, 44), 284.2 (100); HRMS (EI):
calcd for C19H22O5 [M]+: 330.14618; found: 330.14616.
3.1.3.20. Benzyl 6-hydroxy 3-(4-(2-methoxy-2-oxo-
ethyl)phenoxy)-2,4-dimethylbenzoate (6t). Starting with
1,3-bis(silyl enol ether) 5f (500 mg, 1.49 mmol), 3-(siloxy)-
alk-2-en-1-one 4i (500 mg, 1.49 mmol) and TiCl4 (0.16 mL,
1.49 mmol), 6t was isolated as a yellow solid (292 mg,
1
54%), mp 66–67 ꢀC; H NMR (300 MHz, CDCl3): d¼2.09
(s, 3H, CH3), 2.30 (s, 3H, CH3), 3.54 (s, 2H, CH2), 3.68 (s,
3H, OCH3), 5.39 (s, 2H, OCH2), 6.67 (d, 2H, J¼8.7 Hz,
ArH), 6.76 (s, 1H, ArH), 7.25 (d, 2H, J¼8.7 Hz, ArH),
7.35–7.43 (m, 5H, Ph), 11.11 (s, 1H, OH); 13C NMR
(100 MHz, CDCl3): d¼15.6, 17.2 (CH3), 40.1 (CH2), 67.5
(CH2), 110.9 (C), 114.4, 114.5, 117.5 (CHAr), 126.9 (C),
128.3, 128.5, 128.6, 130.5, 130.7 (CHAr), 133.7, 134.9,
140.1, 143.7, 157.0, 159.7, 171.1, 172.2; IR (KBr):
~n ¼ 3441 ðwÞ, 2955 (m), 1736 (s), 1655 (s), 1612 (m),
1509 (s), 1435 (m), 1387 (s), 1313 (s), 1231 (s), 1161 (s),
1055 (m), 908 (m), 803 (s), 751 (s), 695 (s), 585 (m); elemen-
tal analysis: calcd (%) for C25H24O6 (420.45): C 71.41, H
5.75; found: C 71.51, H 5.38.
Acknowledgements
Financial support by the state of Pakistan (HEC scholarship
for M.A.R.) and by the state of Mecklenburg-Vorpommern
(Landesgraduiertenstipendium for Z.A.) is gratefully
acknowledged.
3.1.3.21. Ethyl 3-(4-(2-methoxy-2-oxoethyl)phenoxy)-
5-hydroxy-4-n-hexyl-2,4-dimethylbenzoate (6u). Starting
with 1,3-bis(silyl enol ether) 5g (500 mg, 1.39 mmol), 3-
(siloxy)alk-2-en-1-one 4i (460 mg, 1.39 mmol) and TiCl4
(0.15 mL, 1.39 mmol), 6u was isolated as a yellow oil
References and notes
1
(292 mg, 54%); H NMR (300 MHz, CDCl3): d¼0.88 (t,
3H, J¼6.9 Hz, CH3), 1.28–1.32 (m, 8H, CH2), 1.39 (t, 3H,
J¼7.1 Hz, CH3), 2.09 (s, 3H, CH3), 2.29 (s, 3H, CH3),
1. Ro€mpp Lexikon Naturstoffe; Steglich, W., Fugmann, B., Lang-
Fugmann, S., Eds.; Thieme: Stuttgart, 1997.

4936
M. Sher et al. / Tetrahedron 63 (2007) 4929–4936
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.; Sivasithamparam, K.; Skelton, B. W.;
White, A. H. J. Nat. Prod. 2002, 65, 7.
3. Hussein, S. A. M.; Ayoub, N. A.; Nawwar, M. A. M.
Phytochemistry 2003, 63, 905.
10. Review: Muci, A. R.; Buchwald, S. R. Top. Curr. Chem. 2002,
219, 131.
11. (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.
4. Nawwar, M. A. M.; Hussein, S. A. M.; Buddrus, J.; Linscheid,
M. Phytochemistry 1994, 35, 1349.
5. Fiedler, P.; Gambaro, V.; Garbarino, J. A.; Quilhot, W.
Phytochemistry 1986, 25, 461.
6. Lee, S.-H.; Tanaka, T.; Nonaka, G.-i.; Nishioka, I. Chem.
Pharm. Bull. 1991, 39, 630.
7. Yoshida, T.; Ahmed, A. F.; Okuda, T. Chem. Pharm. Bull. 1993,
41, 672.
8. Elix, J. A.; Jones, A. J.; Lajide, L.; Coppins, B. J.; James, P. W.
Aust. J. Chem. 1984, 37, 2349.
9. 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.
12. Review: Langer, P. Synthesis 2002, 441.
13. Review: Feist, H.; Langer, P. Synthesis 2007, 327.
14. Ahmed, Z.; Langer, P. Synlett 2006, 3361.
15. Beer, R. J. S.; Davenport, H. F.; Robertson, A. J. Chem. Soc.
1953, 1262.
16. Molander, G. A.; Cameron, K. O. J. Am. Chem. Soc. 1993,
115, 830.
17. CCDC-636362 contains all crystallographic details of this pub-
lication and is available free of charge at www.ccdc.cam.ac.uk/
conts/retrieving.html or can be ordered from the following
address: Cambridge Crystallographic Data Centre, 12 Union
Road, GB-Cambridge CB21EZ; fax: +44 1223 336 033; or
deposit@ccdc.cam.ac.uk.