Regioselective synthesis of functionalized biaryls based on the first [3+3] cyclocondensations of 4-Aryl-1,3-bis(trimethylsilyloxy)buta-1,3-dienes

Article abstract of DOI:10.1055/s-0028-1083298

Sterically encumbered biaryls were regioselectively prepared by formal [3+3] cyclocondensations of novel 4-aryl-1,3- bis(trimethylsilyloxy)-1,3-dienes. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0028-1083298

PAPER
243
Regioselective Synthesis of Functionalized Biaryls Based on the First
[3+3] Cyclocondensations of 4-Aryl-1,3-bis(trimethylsilyloxy)buta-1,3-dienes
[3+3]
C
yclocondensati
u
ons of 4-Ary
h
l-1,3-bis(trim
a
ethylsilylo
m
xy)buta-1,3-dienesmad Adeel,a Muhammad A. Rashid,a Nasir Rasool,a,c Rasheed Ahmad,a Alexander Villinger,a
Helmut Reinke,a Christine Fischer,b Peter Langer*a,b
a
Institut für Chemie, Universität Rostock, Albert Einstein Str. 3a, 18059 Rostock, Germany
Leibniz-Institut für Katalyse an der Universität Rostock e.V., Albert Einstein Str. 29a, 18059 Rostock, Germany
b
Fax +49(381)4986412; E-mail: peter.langer@uni-rostock.de
G. C. University Faisalabad, Department of Chemistry, Faisalabad, Pakistan
c
Received 6 August 2008; revised 24 September 2008
OH
O
OH
Abstract: Sterically encumbered biaryls were regioselectively pre-
pared by formal [3+3] cyclocondensations of novel 4-aryl-1,3-
bis(trimethylsilyloxy)-1,3-dienes.
O
HO
HO
O
Me
OH
OH
Key words: cyclizations, salicylates, biaryls, silyl enol ethers
O
HO
HO
Functionalized biaryls containing a 3-arylsalicylate sub-
structure occur in a variety of pharmacologically relevant
natural products. The simple biaryls cynandione A–C
have been isolated from many plant sources and show
considerable in vitro activity against hepatocytes, human
bladder carcinoma T-24 cells, epidermoid carcinoma KB
cells, and human hepatoma PLC/PRF/5 cells (Figure 1).1
A number of natural products, such as knipholone, 6¢-O-
methylknipholone, or (+)-asphodelin, contain an an-
thraquinone moiety (Figure 1).2 Other compounds, e.g.
secalonic acid A or globulixanthone E, contain a bixan-
thenyl substructure.3 3-Arylsalicylates are also present in
many flavones (e.g., 2,3-dihydroamentoflavone,4a bartra-
miaflavone,4b robustaflavone,4c dichamanetin4d,e). For
some derivatives, inhibition of the human liver cathepsin
B and K has been reported.4f,g The natural product anasta-
tin A, which contains a hydroxylated dibenzofuran moi-
ety, shows hepatoprotective activity.5
OMe
O
cynandione A
knipholone
Figure 1
The 4-arylacetoacetates 2a–e were prepared by lithium di-
isopropylamide mediated reaction of methyl acetate with
the arylacetyl chlorides 1a–e (Scheme 1, Table 1). The
silylation of 2a–e afforded the 3-(silyloxy)-2-en-1-ones
3a–e. The novel 4-aryl-1,3-bis(silyloxy)-1,3-dienes 4a–e
were prepared by deprotonation (LDA) of 3a–e at –78 °C
and subsequent addition of chlorotrimethylsilane. The tri-
methylsilyl triflate catalyzed cyclization of 4-aryl-1,3-
bis(silyloxy)-1,3-dienes 4a–e with 1,1,3,3-tetramethoxy-
propane, afforded the 3-arylsalicylates 5a–e.
During the optimization of this reaction, we had to modify
the protocol recently reported by us.11 Noteworthy, the
best yields were obtained when the cyclizations were car-
ried out in a highly concentrated solution.
The most important synthetic approach to biaryls relies on
palladium(0)-catalyzed cross-coupling reactions.6,7 Al-
though these reactions are broadly applicable, the synthe-
sis of sterically encumbered products can be difficult or
not possible at all. In addition, the regioselective synthesis
of the required aryl halides or triflates can be a very diffi-
cult task. Some years ago, Chan et al. developed8 a conve-
nient approach to salicylates by formal [3+3] cyclizations9
of 1,3-bis(trimethylsilyloxy)-1,3-dienes10 with 3-(tri-
methylsilyloxy)-2-en-1-ones. Recently, we developed a
catalytic variant of this transformation.11 Herein, we re-
port, for the first time, the synthesis of 4-aryl-1,3-bis(tri-
methylsilyloxy)buta-1,3-dienes and their application to
the synthesis of functionalized biaryls that are not readily
available by other methods.
The structures of all products were established by spectro-
scopic methods. The structures of 5b and 5c were inde-
pendently confirmed by X-ray crystal structure analysis
(Figures 2 and 3).12
Table 1 Synthesis of Biaryls 5a–e
2–5
R1
R2
Yielda (%)
2
3
4
5
a
b
c
H
H
60
56
48
34
45
82
80
75
77
81
80
84
82
85
86
44
50
34
43
36
H
OMe
H
OMe
H
d
e
Cl
SYNTHESIS 2009, No. 2, pp 0243–0250
x
x
.
x
x
.2
0
0
8
Advanced online publication: 19.12.2008
DOI: 10.1055/s-0028-1083298; Art ID: T13508SS
© Georg Thieme Verlag Stuttgart · New York
H
Me
a Isolated yield

244
M. Adeel et al.
PAPER
O
O
Me3SiO
OSiMe3
OMe
O
R2
R1
O
OH
R3
OMe
Cl
R1
O
R1
i
R1
i
OMe
+
Me3SiO
Me
O
OMe
Me
Me
+
Me
R2
2a–e
R2
1a–e
R2
R3
4a–e
6a–c
7a–j
ii
Scheme 2 Synthesis of 7a–j. Reagents and conditions: (i) TiCl4,
CH2Cl2, –78 to 20 °C, 20 h.
Me3SiO
O
Me3SiO
OSiMe3
OMe
OMe
iii
R1
Me3SiO
OSiMe3
OMe
R1
R
OH
O
TiCl4
i
OMe
3a–e
4a,d
R2
4a–e
R2
O
O
Me
Me
Cl
iv
+
Me
Me
OMe OMe
OMe
R
R2
R1
9a R = H (42%)
9b R = Cl (37%)
O
OH
8
MeO
OMe
Scheme 3 Synthesis of 9a,b. Reagents and conditions: (i) TiCl4,
CH2Cl2, –78 to 20 °C, 20 h.
5a–e
Scheme 1 Synthesis of 5a–e. Reagents and conditions: (i) LDA,
THF, –78 to 20 °C, 14 h; (ii) TMSCl, Et3N, benzene , 20 °C, 72 h; (iii)
LDA, THF, –78 to 20 °C; (iv) TMSOTf (0.1 equiv), CH2Cl2, –78 to
20 °C, 20 h.
Table 2 Synthesis of Biaryls 7a–j
Substrates
Product
7a
R1
H
R2
R3
H
Yielda (%)
4a
4a
4c
4c
4b
4b
4b
4a
4d
4e
6a
6b
6a
6b
6b
6a
6c
6c
6b
6b
H
41
40
26
30
38
37
38
35
40
30
7b
7c
H
H
Cl
H
OMe
OMe
H
H
7d
7e
H
Cl
Cl
H
OMe
OMe
OMe
H
7f
H
7g
H
Me
Me
Cl
Cl
Figure 2 ORTEP plot of 5b
7h
7i
H
H
Cl
7j
H
Me
a Isolated yields
The titanium(IV) chloride mediated reaction of 1,3-bis(si-
lyloxy)-1,3-dienes 4a and 4d with 1,1-diacetylcyclopro-
pane (8) gave the 3-arylsalicylates 9a and 9b, respectively
(Scheme 3). Products 9a,b are formed by a domino [3+3]-
cyclization–homo-Michael reaction.13
Figure 3 ORTEP plot of 5c
The trimethylsilyl triflate mediated condensation of 1,3-
bis(trimethylsilyloxy)buta-1,3-diene 4e with 3-cyano-4H-
1-benzopyran-4-one (10) afforded product 11. Treatment
of the latter with triethylamine afforded methyl 3-(4-
methylphenyl)-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-
2-acetate (12) (Scheme 4). The formation of 12 proceeds
The titanium(IV) chloride mediated [3+3] cyclization of
1,3-bis(silyloxy)-1,3-dienes 4a–e with 3-(silyloxy)-2-en-
1-ones 6a–c afforded the 3-arylsalicylates 7a–j (Scheme
2, Table 2). During the optimization, it proved to be im-
portant to carry out the reactions in a highly concentrated
solution.
Synthesis 2009, No. 2, 243–250 © Thieme Stuttgart · New York

PAPER
[3+3] Cyclocondensations of 4-Aryl-1,3-bis(trimethylsilyloxy)buta-1,3-dienes
245
moderate, the products are not readily available by other
methods.
O
O
Me3SiO
OSiMe3
OMe
CN
O
O
i
OMe
All solvents were dried by standard methods and all reactions were
carried out under an inert atmosphere. For 1H and 13C NMR spectra
the deuterated solvents indicated were used. MS data were obtained
by electron ionization (EI, 70 eV), chemical ionization (CI, H2O) or
electrospray ionization (ESI). For preparative scale chromatogra-
phy, silica gel (60–200 mesh) was used. Melting points are uncor-
rected.
O
O
+
CN
Me
11
Me
ii
4e
10
Methyl 4-Arylacetoacetates 2a–e; General Procedure
Me
O
To a THF soln of LDA (2.3 equiv) [prepared by the addition of 2.5
M BuLi in hexane (0.93 mL, 2.3 mmol) to a soln of i-Pr2NH (0.32
mL, 2.3 mmol) in THF (6 mL) at 0 °C; the mixture was stirred for
30 min] was added, at 0 °C, methyl acetate (0.09 mL, 1.1 mmol) and
the mixture was stirred for 45–60 min. To the mixture was added at
–78 °C the acid chloride 1 (205 mg, 1.0 mmol) in THF (4 mL). The
temperature was allowed to rise to r.t. over 5–6 h and the soln was
stirred at 20 °C for 10 h. To the soln was added dil aq HCl and the
mixture was extracted with EtOAc (3 × 200 mL). The combined or-
ganic layers were dried (Na2SO4) and filtered. The solvent of the fil-
trate was removed in vacuo and the residue was purified by
chromatography (silica gel, EtOAc–n-heptane).
CN
O
OH
OMe
O
A
Me
O
O
N
Methyl 4-Phenylacetoacetate (2a)
O
OMe
Starting with phenylacetyl chloride (5.00 g, 32.3 mmol) and methyl
acetate (2.83 mL, 35.6 mmol), 2a was isolated as a yellowish oil;
yield: 3.72 g (60%).
12 (63% based on 10)
Scheme 4 Synthesis of 12. Reagents and conditions: (i) (1) 10,
TMSOTf, 1 h, 20 °C, (2) 4e, CH2Cl2, 0 to 20 °C, 12 h, (3) 10% HCl;
(ii) (1) Et3N, EtOH, 20 °C, 12 h, (2) 1 M HCl.
IR (neat): 3087 (w), 3030 (w), 3006 (m), 2954 (m), 1713 (s), 1602
(w), 1496 (w), 1437 (m), 1316 (m), 1301 (m), 1203 (m), 1115 (m),
1012 (m), 848 (m), 799 (m), 698 cm–1 (s).
1H NMR (250 MHz, CDCl3): d = 3.35 (s, 2 H, CH2), 3.58 (s, 2 H,
CH2), 3.70 (s, 3 H, OCH3), 7.07 (m, 1 H, ArH), 7.11 (m, 2 H, ArH),
7.20 (m, 2 H, ArH).
13C NMR (75 MHz, CDCl3): d = 47.9, 49.5 (CH2), 52.2 (OCH3),
126.9 (CH), 127.3 (2 C, CH), 128.6 (2 C, CH), 130.7 (C), 167.5,
200.7 (C=O).
Me3SiO
OSiMe3
OMe
O
O
Br
OMe
4e
OH
OH
i, ii
+
MS (EI, 70 eV): m/z (%) = 192 (M+, 35), 160 (6), 118 (47), 101 (37),
91 (100), 65 (20), 59 (21).
HRMS (EI, 70 eV): m/z [M]+ calcd for C11H12O3: 192.07810; found:
192.07829.
Me
Br
O
O
O
H
Me
14 (47%)
13
Methyl 4-(4-Methoxyphenyl)acetoacetate (2b)
Starting with (4-methoxyphenyl)acetyl chloride (5.00 g, 27.1
mmol) and methyl acetate (2.21 mL, 29.9 mmol), 2b was isolated
as a yellowish oil; yield: 3.38 g (56%).
Scheme 5 Synthesis of 14. Reagents and conditions: (i) TMSOTf
(0.3 equiv), 20 °C, 10 min; (ii) (1) 4e (1.3 equiv), CH2Cl2, 0 to 20 °C,
12 h; (2) 10% HCl.
IR (neat): 3000 (w), 2954 (m), 2837 (w), 1738 (s), 1713 (s), 1608
(m), 1510 (s), 1437 (m), 1317 (m), 1301 (m), 1244 (s), 1176 (s),
1028 (s), 829 (m), 773 cm–1 (w).
1H NMR (250 MHz, CDCl3): d = 3.37 (s, 3 H, OCH3), 3.62 (s, 2 H,
CH2), 3.67 (s, 2 H, CH2), 3.70 (s, 3 H, OCH3), 6.77 (d, J = 8.6 Hz,
2 H, ArH), 7.02 (d, J = 8.8 Hz, 2 H, ArH).
13C NMR (62 MHz, CDCl3): d = 47.7, 49.1 (CH2), 52.2, 55.1
(OCH3), 114.0 (2 C, CH), 125.1 (C), 130.8 (2 C, CH), 158.6 (C),
167.5, 200.7 (C=O).
MS (EI, 70 eV): m/z (%) = 222 (M+, 55), 180 (15), 164 (9), 148 (25),
121 (100), 101 (15), 91 (12).
HRMS (EI, 70 eV): m/z [M]+ calcd for C12H14O4: 222.08866; found:
222.08867.
via intermediate A and can be explained by a domino
retro-Michael–lactonization–aldol reaction.14
The trimethylsilyl triflate catalyzed reaction of 1,3-bis(si-
lyloxy)buta-1,3-diene 4e with 6-bromo-3-formyl-4H-1-
benzopyran-4-one (13) afforded the highly functionalized
biaryl 14 (Scheme 5). This product is formed by a domino
Michael–retro-Michael–Mukaiyama–Aldol reaction.15
In conclusion, we have reported a new and regioselective
approach to a variety of sterically encumbered biaryls
based on formal [3+3] cyclizations of novel 4-aryl-1,3-
bis(trimethylsilyloxy)-1,3-dienes. Although the yields are
Synthesis 2009, No. 2, 243–250 © Thieme Stuttgart · New York

246
M. Adeel et al.
PAPER
Methyl 4-(2-Methoxyphenyl)acetoacetate (2c)
tered, the filtrate was concentrated in vacuo, and the residue was pu-
rified by chromatography.
Starting with (4-methoxyphenyl)acetyl chloride (5.00 g, 27.2
mmol) and methyl acetate (2.4 mL, 29.9 mmol), 2c was isolated as
a colorless oil; yield: 2.90 g (48%).
Methyl 3-Phenylsalicylate (5a)
Starting with 1,1,3,3-tetramethoxypropane (0.27 mL, 1.65 mmol) in
CH2Cl2 (3.3 mL), 4a (555 mg, 1.65 mmol), and TMSOTf (0.03 mL,
0.16 mmol), 5a was isolated as a highly viscous colorless oil; yield:
164 mg (44%).
IR (neat): 3005 (w), 2953 (m), 2839 (w), 1749 (s), 1720 (s), 1602
(m), 1464 (s), 1317 (s), 1177 (s), 1027 (s), 756 (s), 519 cm–1 (w).
1H NMR (300 MHz, CDCl3): d = 3.53 (s, 3 H, OCH3), 3.77 (s, 2 H,
CH2), 3.84 (s, 2 H, CH2), 3.88 (s, 3 H, OCH3), 6.94–7.02 (m, 2 H,
ArH), 7.21 (dd, J = 1.7, 7.4 Hz, 1 H, ArH), 7.32–7.37 (dt, J = 1.7,
8.0 Hz, 1 H, ArH).
13C NMR (75 MHz, CDCl3): d = 42.7, 45.8 (CH2), 50.0, 53.2 (CH3),
118.4, 119.0 (CH), 121.7 (C), 126.8, 129.2 (CH), 155.3, 165.6,
198.8 (C).
IR (neat): 3085 (w), 3059 (w), 3031 (w), 2953 (m), 1669 (s), 1636
(w), 1427 (s), 1325 (s), 1283 (m), 1244 (s), 1197 (m), 1146 (s), 1065
(m), 968 (m), 833 (m), 753 (s), 695 cm–1 (s).
1H NMR (250 MHz, CDCl3): d = 3.88 (s, 3 H, OCH3), 6.84 (t,
J = 7.7 Hz, 1 H, ArH), 7.29 (m, 1 H, ArH), 7.35 (m, 2 H, ArH), 7.45
(m, 1 H, ArH), 7.51 (m, 1 H, ArH), 7.76 (dd, J = 6.1, 1.7 Hz, 1 H,
ArH), 11.21 (s, 1 H, OH).
13C NMR (62 MHz, CDCl3): d = 51.4 (OCH3), 111.5 (C), 118.0 (C,
CH), 125.4 (CH), 126.3 (2 C, CH), 128.3 (2 C, CH), 129.8 (C),
135.5 (CH), 136.1 (C), 157.9 (C), 169.9 (C=O).
MS (EI, 70 eV): m/z (%) = 222 (M+, 38), 148 (37), 121 (100), 101
(10), 91 (75), 78 (18), 65 (30), 51 (11).
Anal. Calcd for C12H14O4: C, 64.85; H, 6.35. Found: C, 64.87; H,
6.47.
GC-MS (EI, 70 eV): m/z (%) = 228 (M+, 67), 196 (100), 168 (95),
139 (55), 115 (13), 98 (7), 70 (7).
HRMS (EI, 70 eV): m/z [M]+ calcd for C14H12O3: 228.07810; found:
228.07832.
Methyl 4-(4-Chlorophenyl)acetoacetate (2d)
Starting with (4-chlorophenyl)acetyl chloride (5.00 g, 26.4 mmol)
and methyl acetate (2.31 mL, 29.1 mmol), 2d was isolated as a
brownish oil; yield: 2.03 g (34%).
IR (neat): 2999 (w), 2966 (m), 2932 (w), 2873 (w), 1721 (m), 1631
(m), 1491 (s), 1437 (m), 1370 (m), 1336 (m), 1205 (m), 1088 (s),
1014 (s), 805 (m), 756 (m), 593 cm–1 (m).
1H NMR (250 MHz, CDCl3): d = 3.40 (s, 2 H, CH2), 3.64 (s, 2 H,
CH2), 3.73 (s, 3 H, OCH3), 7.04 (d, J = 8.6 Hz, 2 H, ArH), 7.19 (d,
J = 8.6 Hz, 2 H, ArH).
13C NMR (75 MHz, CDCl3): d = 48.1, 49.0 (CH2), 52.4 (OCH3),
129.9 (2 C, CH), 130.9 (2 C, CH), 134.2, 132.3 (C), 167.3, 199.7
(C=O).
Methyl 3-(4-Methoxyphenyl)salicylate (5b)
Starting with 1,1,3,3-tetramethoxypropane (0.27 mL, 1.65 mmol) in
CH2Cl2 (3.3 mL), 4b (604 mg, 1.65 mmol), and TMSOTf (0.03 mL,
0.16 mmol), 5b was isolated as a colorless solid; yield: 212 mg
(50%); mp 93 °C.
IR (neat): 3188 (m), 3077 (w), 3004 (w), 2953 (m), 1668 (s), 1604
(m), 1512 (m), 1473 (w), 1434 (m), 1334 (s), 1286 (s), 1249 (s),
1149 (m), 1062 (s), 749 (s), 695 (m), 586 cm–1 (m).
1H NMR (250 MHz, CDCl3): d = 3.75 (s, 3 H, OCH3), 3.86 (s, 3 H,
OCH3), 6.80 (d, J = 7.7 Hz, 1 H, ArH), 6.86 (d, J = 8.8 Hz, 2 H,
ArH), 7.38 (d, J = 1.7 Hz, 1 H, ArH), 7.42 (d, J = 8.8 Hz, 2 H, ArH),
7.71 (dd, J = 6.1, 1.7 Hz, 1 H, ArH), 11.20 (s, 1 H, OH).
MS (EI, 70 eV): m/z (%) = 228 (M+, 37Cl, 22), 226 (M+, 35Cl, 51),
210 (5), 128 (42), 99 (4), 86 (100), 43 (51).
HRMS (EI, 70 eV): m/z [M+, 35Cl] calcd for C11H11ClO3:
13C NMR (62 MHz, CDCl3): d = 51.3, 54.2 (CH3), 111.4 (C), 112.6
(2 C, CH), 117.9 (CH), 127.7 (CH), 128.5 (C), 129.0 (C), 129.4 (2
C, CH), 135.2 (C), 142.6, 157.8 (C), 170.0 (C=O).
GC-MS (EI, 70 eV): m/z (%) = 258 (M+, 58), 226 (100), 211 (6), 198
(16), 183 (40), 155 (11), 127 (12).
HRMS (EI, 70 eV): m/z [M]+ calcd for C15H14O4: 258.08866; found:
258.08877.
226.03912; found: 226.03935.
Methyl 4-Tolylacetoacetate (2e)
Starting with 4-tolylacetyl chloride (5.00 g, 29.7 mmol) and methyl
acetate (2.83 mL, 35.6 mmol), 2e was isolated as a yellowish oil;
yield: 2.75 g (45%).
IR (neat): 3000 (w), 2954 (m), 2837 (w), 1738 (s), 1713 (s), 1608
(m), 1510 (s), 1437 (m), 1317 (m), 1301 (m), 1244 (s), 1176 (s),
1028 (s), 829 (m), 773 cm–1 (w).
1H NMR (250 MHz, CDCl3): d = 2.24 (s, 3 H, CH3), 3.62 (s, 2 H,
CH2), 3.67 (s, 2 H, CH2), 3.75 (s, 3 H, OCH3), 6.77 (d, J = 8.6 Hz,
2 H, ArH), 7.02 (d, J = 8.8 Hz, 2 H, ArH).
13C NMR (62 MHz, CDCl3): d = 21.0 (CH3), 47.7, 49.1 (CH2), 52.3
(OCH3), 114.0 (2 C, CH), 125.1 (C), 130.8 (2 C, CH), 158.6 (C),
167.5, 200.7 (C=O).
MS (EI, 70 eV): m/z (%) = 206 (M+, 47), 180 (15), 164 (9), 132 (25),
105 (100), 91 (12).
HRMS (EI, 70 eV): m/z [M]+ calcd for C12H14O3: 206.08866; found:
206.08867.
Methyl 3-(2-Methoxyphenyl)salicylate (5c)
Starting with 1,1,3,3-tetramethoxypropane (0.3 mL, 1.8 mmol) in
CH2Cl2 (3.3 mL), 4c (665 mg, 1.8 mmol), and TMSOTf (0.03 mL,
0.18 mmol), 5c was isolated as a colorless solid; yield: 158 mg
(34%); mp 123 °C.
IR (KBr): 3049 (w), 2933 (w), 2835 (w), 1666 (s), 1597 (s), 1463
(s), 1367 (m), 1249 (s), 1152 (s), 1024 (s), 795 (m), 594 cm–1 (w).
1H NMR (250 MHz, CDCl3): d = 3.65 (s, 3 H, OCH3), 3.81 (s, 3 H,
OCH3), 6.76–6.92 (m, 3 H, ArH), 7.10–7.26 (m, 2 H, ArH), 7.33
(dd, J = 1.4, 7.1 Hz, 1 H, ArH), 7.73 (dd, J = 1.7, 8.0 Hz, 1 H, ArH),
10.95 (s, 1 H, OH).
13C NMR (62 MHz, CDCl3): d = 52.3, 55.7 (CH3), 111.2 (CH),
112.2 (C), 118.5, 120.4 (CH), 126.3, 127.6 (C), 129.1, 129.2, 131.3,
137.5 (CH), 157.0, 159.3, 170.9 (C).
MS (EI, 70 eV): m/z (%) = 258 (M+, 100), 226 (44), 209 (40), 195
(36), 181 (27), 139 (16), 97 (17), 57 (26).
Biaryls 5a–e; General Procedure
To a soln of 4 (1.0 mmol) and 1,1,3,3-tetramethoxypropane in
CH2Cl2 (2 mL / mmol of 4) was added TMSOTf (0.1 mmol) at –78
°C. The soln was allowed to warm to 20 °C over 20 h. To the mix-
ture was added dil aq HCl (15 mL), the organic and the aqueous lay-
er were separated, and the latter was extracted with CH2Cl2 (3 × 15
mL). The combined organic layers were dried (Na2SO4) and fil-
Anal. Calcd for C15H14O4 (258): C, 69.76; H, 5.46. Found: C, 69.85;
H, 5.42.
Synthesis 2009, No. 2, 243–250 © Thieme Stuttgart · New York

PAPER
[3+3] Cyclocondensations of 4-Aryl-1,3-bis(trimethylsilyloxy)buta-1,3-dienes
247
Methyl-3-(4-Chlorophenyl)salicylate (5d)
13C NMR (62 MHz, CDCl3): d = 19.7, 22.7 (CH3), 51.0 (OCH3),
108.8 (C), 123.5, 126.0 (CH), 127.2 (2 C, CH), 128.9 (2 C, CH),
135.8, 138.7, 142.2, 159.3 (C), 171.4 (C=O).
GC-MS (EI, 70 eV): m/z (%) = 256 (M+, 73), 224 (100), 196 (46),
181 (64), 165 (37), 152 (25), 128 (16).
Starting with 1,1,3,3-tetramethoxypropane (0.27 mL, 1.65 mmol) in
CH2Cl2 (3.3 mL), 4d (612 mg, 1.65 mmol), and TMSOTf (0.03 mL,
0.16 mmol), 5d was isolated as a colorless solid; yield: 187 mg
(43%); mp 113 °C.
IR (neat): 3123 (m), 2962 (w), 2852 (w), 1677 (s), 1610 (m), 1594
(m), 1434 (s), 1344 (m), 1327 (m), 1245 (m), 1195 (m), 1051 (m),
1061 (m), 964 (m), 826 (s), 747 (s), 583 cm–1 (m).
HRMS (EI, 70 eV): m/z [M]+ calcd for C16H15O3: 256.10940; found:
256.10992.
1H NMR (250 MHz, CDCl3): d = 3.87 (s, 3 H, OCH3), 6.82 (t,
J = 7.7 Hz, 1 H, ArH), 7.28 (d, J = 8.6 Hz, 2 H, ArH), 7.38 (d,
J = 1.7 Hz, 1 H, ArH), 7.41 (d, J = 8.8 Hz, 2 H, ArH), 7.75 (dd,
J = 8.0, 1.7 Hz, 1 H, ArH), 11.20 (s, 1 H, OH).
Methyl 5-Chloro-4,6-dimethyl-3-phenylsalicylate (7b)
Starting with 6b (455 mg, 2.2 mmol), 4b (740 mg, 2.2 mmol), and
TiCl4 (0.24 mL, 2.2 mmol), 7b was isolated as a yellow oil; yield:
252 mg (40%).
13C NMR (62 MHz, CDCl3): d = 51.5 (OCH3), 111.6 (C), 118.0
(CH), 127.2 (2 C, CH), 128.0 (C), 128.5 (CH), 129.6 (2 C, CH),
132.3, 134.5 (C), 135.3 (CH), 157.7 (C), 169.8 (C=O).
GC-MS (EI, 70 eV): m/z (%) = 264 (M+, 37Cl, 29), 262 (M+, 35Cl,
89), 230 (100), 202 (34), 167 (13), 149 (9), 139 (98), 97 (57).
IR (neat): 3081 (w), 3058 (m), 3025 (m), 3003 (w), 2959 (m), 2954
(s), 2929 (s), 1731 (m), 1660 (s), 1604 (s), 1550 (w), 1497 (w), 1441
(s), 1388 (s), 1354 (s), 1295 (s), 1253 (w), 1212 (s), 1093 (m), 1067
(m), 1009 (m), 807 (s), 704 (s), 604 cm–1 (m).
1H NMR (250 MHz, CDCl3): d = 2.08 (s, 3 H, CH3), 2.57 (s, 3 H,
CH3), 3.89 (s, 3 H, OCH3), 7.13 (m, 1 H, ArH), 7.29 (m, 2 H, ArH),
7.34 (m, 2 H, ArH), 10.62 (s, 1 H, OH).
13C NMR (62 MHz, CDCl3): d = 18.7, 19.0 (CH3), 51.4 (OCH3),
111.4 (C), 112.9 (2 C, CH), 125.4 (CH), 127.2 (2 C, CH), 128.7 (2
C, CH), 135.6, 140.5 (C), 170.4 (C=O).
Anal. Calcd for C14H11ClO3: C, 64.01; H, 4.22. Found: C, 63.97; H,
4.28.
Methyl 3-Tolylsalicylate (5e)
Starting with 1,1,3,3-tetramethoxypropane (0.27 mL, 1.65 mmol) in
CH2Cl2 (3.3 mL), 4e (578 mg, 1.65 mmol), and TMSOTf (0.03 mL,
0.16 mmol), 5e was isolated as a colorless oil; yield: 136 mg (36%).
GC-MS (EI, 70 eV): m/z (%) = 292 (M+, 37Cl, 19), 290 (M+, 35Cl,
58), 258 (100), 230 (24), 195 (79), 165 (41), 152 (25), 111 (16).
IR (neat): 3020 (w), 2956 (m), 2922 (w), 2865 (w), 1731 (w), 1667
(s), 1609 (m), 1513 (w), 1434 (s), 1369 (m), 1326 (s), 1282 (s), 1240
(s), 1194 (m), 1144 (m), 1061 (m), 1019 (w), 963 (w), 829 (s), 812
(s), 760 (s), 727 (s), 617 (m), 586 cm–1 (m).
1H NMR (250 MHz, CDCl3): d = 2.31 (s, 3 H, CH3), 3.88 (s, 3 H,
OCH3), 6.82 (t, J = 7.7 Hz, 1 H, ArH), 7.14 (d, J = 8.5 Hz, 2 H,
ArH), 7.15 (d, J = 8.3 Hz, 1 H, ArH), 7.37 (d, J = 8.0 Hz, 2 H, ArH),
7.73 (dd, J = 8.0, 1.8 Hz, 1 H, ArH), 11.18 (s, 1 H, OH).
13C NMR (62 MHz, CDCl3): d = 20.0 (CH3), 51.4 (OCH3), 111.4
(C), 117.9 (CH), 128.1 (2 C, CH), 128.3 (C), 128.5 (CH), 128.6 (2
C, CH), 129.4, 133.6 (C), 135.4 (CH), 157.9 (C), 170.0 (C=O).
GC-MS (EI, 70 eV): m/z (%) = 242 (M+, 67), 210 (100), 195 (9), 181
(56), 168 (4), 153 (28), 139 (17).
HRMS (EI, 70 eV): m/z [M+, 35Cl] calcd for C16H15ClO3:
290.07127; found: 290.070944.
Methyl 3-(2-Methoxyphenyl)-4,6-dimethylsalicylate (7c)
Starting with 6a (500 mg, 2.9 mmol), 4c (1.07 g, 2.9 mmol), and
TiCl4 (0.31 mL, 2.9 mmol), 7c was isolated as a colorless solid;
yield: 216 mg (26%); mp 122 °C.
IR (KBr): 2997 (w), 2966 (w), 2833 (w), 1655 (s), 1449 (s), 1304
(s), 1257 (m), 1202 (s), 1048 (s), 1026 (m), 858 (w), 762 (s), 575
cm–1 (w).
1H NMR (250 MHz, CDCl3): d = 1.99 (s, 3 H, CH3), 2.51 (s, 3 H,
CH3), 3.72 (s, 3 H, OCH3), 3.90 (s, 3 H, OCH3), 6.64 (s, 1 H, ArH),
6.95–7.08 (m, 3 H, ArH), 7.29–7.36 (m, 1 H, ArH), 11.50 (s, 1 H,
OH).
13C NMR (62 MHz, CDCl3): d = 22.4, 25.8, 54.0, 57.4 (CH3), 111.6
(C), 112.1, 122.4, 126.2 (CH), 127.3, 127.7 (C), 130.7, 133.2 (CH),
141.6, 146.0, 158.8, 162.2, 174.3 (C).
HRMS (EI, 70 eV): m/z [M]+ calcd for C15H14O3: 242.09375; found:
242.09380.
Biaryls 7a–j; General Procedure
To a soln of 4 (1.0 mmol) and 6 (1.0 mmol) in CH2Cl2 (2 mL/mmol
of 4) at –78 °C was added TiCl4 (1.0 mmol). The mixture was al-
lowed to warm to r.t. over 20 h. To the mixture was added sat.
NaHCO3 soln (15 mL), the organic and the aqueous layers were sep-
arated, and the latter was extracted with Et2O (3 × 20 mL). The fil-
trate was concentrated in vacuo and the residue was purified by
chromatography (silica gel, EtOAc–n-heptane, 1:4).
MS (EI, 70 eV): m/z (%) = 286 (M+, 61), 254 (34), 239 (100), 223
(72), 181 (8), 165 (11), 127 (12), 69 (18).
Anal. Calcd for C17H18O4: C, 71.31; H, 6.34. Found: C, 70.99; H,
6.92.
Methyl 5-Chloro-3-(2-methoxyphenyl)-4,6-dimethylsalicylate
(7d)
Starting with 6b (500 mg, 2.4 mmol), 4c (888 mg, 2.4 mmol), and
TiCl4 (0.26 mL, 2.4 mmol), 7d was isolated as a colorless solid;
yield: 217 mg (30%); mp 126 °C.
Methyl 4,6-Dimethyl-3-phenylsalicylate (7a)
Starting with 6a (284 mg, 1.65 mmol), 4a (555 mg, 1.65 mmol), and
TiCl4 (0.18 mL, 1.65 mmol), 7a was isolated as a colorless solid;
yield: 172 mg (41%); mp 123 °C.
IR (KBr): 3008 (w), 2936 (w), 2840 (w), 1653 (s), 1595 (s), 1443
(s), 1362 (s), 1215 (s), 2024 (s), 959 (m), 811 (w), 755 (s), 610
cm–1 (w).
1H NMR (250 MHz, CDCl3): d = 2.37 (s, 3 H, CH3), 2.89 (s, 3 H,
CH3), 3.99 (s, 3 H, OCH3), 4.19 (s, 3 H, OCH3), 7.25–7.33 (m, 3 H,
ArH), 7.58–7.65 (m, 1 H, ArH), 10.93 (s, 1 H, OH).
13C NMR (62 MHz, CDCl3): d = 19.6, 20.4, 52.6, 55.6 (CH3), 111.4
(CH), 112.6 (C), 120.9 (CH), 125.5, 126.4, 127.5 (C), 129.5, 131.6
(CH), 136.9, 142.6, 157.2, 157.5, 171.8 (C).
IR (neat): 2955 (m), 2930 (m), 2871 (w), 2835 (w), 1725 (w), 1652
(s), 1607 (m), 1556 (w), 1512 (m), 1430 (m), 1369 (s), 1297 (s),
1257 (s), 1240 (s), 1172 (m), 1203 (s), 1172 (s), 1070 (m), 1022 (s),
987 (m), 955 (m), 810 (s), 750 cm–1 (m).
1H NMR (250 MHz, CDCl3): d = 1.98 (s, 3 H, CH3), 2.46 (s, 3 H,
CH3), 3.86 (s, 3 H, OCH3), 6.59 (s, 1 H, ArH), 7.13 (m, 1 H, ArH),
7.26 (m, 2 H, ArH), 7.33 (m, 2 H, ArH), 11.51 (s, 1 H, OH).
Synthesis 2009, No. 2, 243–250 © Thieme Stuttgart · New York

248
M. Adeel et al.
PAPER
MS (EI, 70 eV): m/z (%) = 322 (M+, 37Cl, 13), 320 (M+, 35Cl, 44),
HRMS (EI, 70 eV): m/z [M]+ calcd for C18H20O4: 300.13561; found:
287 (14), 273 (100), 257 (39), 165 (12), 144 (8), 69 (20).
300.13568.
HRMS (EI, 70 eV): m/z [M+, 35Cl] calcd for C17H17ClO4:
320.08069; found: 320.08099.
Methyl 4,5,6-Trimethyl-3-phenylsalicylate (7h)
Starting with 6c (308 mg, 1.65 mmol), 4a (555 mg, 1.65 mmol), and
TiCl4 (0.180 mL, 1.65 mmol), 7h was isolated as a colorless solid;
yield: 156 mg (35%); mp 65 °C.
Methyl 5-Chloro-3-(4-methoxyphenyl)-4,6-dimethylsalicylate
(7e)
Starting with 6b (450 mg, 2.2 mmol), 4b (806 mg, 2.2 mmol), and
TiCl4 (0.241 mL, 2.2 mmol), 7e was isolated as a colorless solid;
yield: 267 mg (38%); mp 94 °C.
IR (neat): 3022 (w), 2953 (w), 2922 (m), 2853 (w), 1727 (w), 1650
(m), 1604 (m), 1557 (w), 1427 (m), 1392 (m), 1316 (s), 1215 (s),
1068 (m), 961 (w), 807 (m), 773 (m), 722 (m), 699 cm–1 (m).
IR (KBr): 3430 (m), 3050 (w), 3002 (w), 2959 (m), 2931 (m), 2837
(m), 1653 (s), 1607 (m), 1572 (w), 1514 (s), 1444 (s), 1373 (m),
1361 (s), 1297 (s), 1253 (s), 1220 (s), 1176 (m), 1092 (m), 1036 (m),
810 (m), 686 cm–1 (m).
1H NMR (250 MHz, CDCl3): d = 2.10 (s, 3 H, CH3), 2.56 (s, 3 H,
CH3), 3.77 (s, 3 H, OCH3), 3.89 (s, 3 H, OCH3), 6.89 (d, J = 8.8 Hz,
2 H, ArH), 7.03 (d, J = 8.8 Hz, 2 H, ArH), 10.54 (s, 1 H, OH).
13C NMR (62 MHz, CDCl3): d = 19.0, 19.4 (CH3), 51.4, 54.2
(OCH3), 111.5 (C), 112.9 (2 C, CH), 126.8, 127.6, 128.3 (C), 129.9
(2 C, CH), 135.3, 140.8, 156.1, 157.8 (C), 170.5 (C=O).
1H NMR (250 MHz, CDCl3): d = 1.90 (s, 3 H, CH3), 2.08 (s, 3 H,
CH3), 2.35 (s, 3 H, CH3), 3.82 (s, 3 H, OCH3), 7.06–7.12 (m, 2 H,
ArH), 7.22–7.32 (m, 3 H, ArH), 10.02 (s, 1 H, OH).
13C NMR (62 MHz, CDCl3): d = 16.5, 19.3, 19.8 (CH3), 52.6
(OCH3), 112.6 (C), 127.5 (CH), 127.9 (C), 128.8 (2 C, CH), 130.6
(2 C, CH), 137.2, 138.2, 142.0, 156.2 (C), 172.6 (C=O).
GC-MS (EI, 70 eV): m/z (%) = 270 (M+, 46), 238 (100), 210 (45),
195 (52), 165 (21), 97 (23), 83 (34), 69 (34), 57 (49).
Anal. Calcd for C17H18O3: C, 75.53; H, 6.71. Found: C, 73.84; H,
7.03.
GC-MS (EI, 70 eV): m/z (%) = 322 (M+, 37Cl, 16), 320 (M+, 47), 288
(100), 260 (11), 245 (27), 225 (29), 181 (7), 152 (12).
HRMS (EI, 70 eV): m/z [M+, 35Cl] calcd for C17H17ClO4:
320.08099; found: 320.08088.
Methyl 5-Chloro-3-(4-chlorophenyl)-4,6-dimethylsalicylate (7i)
Starting with 6b (332 mg, 1.65 mmol), 4d (612 mg, 1.65 mmol), and
TiCl4 (0.18 mL, 1.65 mmol), 7i was isolated as a colorless solid;
yield: 215 mg (40%); mp 96 °C.
Methyl 3-(4-Methoxyphenyl)-4,6-dimethylsalicylate (7f)
Starting with 6a (284 mg, 1.65 mmol), 4b (604 mg, 1.65 mmol), and
TiCl4 (0.18 mL, 1.65 mmol), 7f was isolated as a colorless solid;
yield: 173 mg (37%); mp 66 °C.
IR (KBr): 3029 (w), 2950 (m), 2925 (w), 2849 (w), 1658 (s), 1591
(m), 1493 (m), 1434 (m), 1355 (s), 1288 (s), 1207 (s), 1082 (m),
1068 (m), 1008 (s), 980 (m), 956 (m), 824 (m), 802 (s), 727 (s), 607
cm–1 (m).
IR (neat): 3080 (w), 3061 (w), 3023 (w), 2957 (m), 1725 (w), 1650
(s), 1613 (m), 1558 (w), 1430 (m), 1392 (m), 1360 (m), 1295 (s),
1255 (s), 1197 (s), 1087 (m), 1066 (m), 955 (m), 807 (s), 767 (s),
700 (s), 570 cm–1 (m).
1H NMR (250 MHz, CDCl3): d = 2.00 (s, 3 H, CH3), 2.46 (s, 3 H,
CH3), 3.77 (s, 3 H, OCH3), 3.87 (s, 3 H, OCH3), 6.59 (s, 1 H, ArH),
6.89 (d, J = 7.5 Hz, 2 H, ArH), 7.06 (d, J = 8.8 Hz, 2 H, ArH), 11.51
(s, 1 H, OH).
1H NMR (250 MHz, CDCl3): d = 2.07 (s, 3 H, CH3), 2.56 (s, 3 H,
CH3), 3.88 (s, 3 H, OCH3), 7.03 (d, J = 8.6 Hz, 2 H, ArH), 7.31 (d,
J = 8.5 Hz, 2 H, ArH), 10.85 (s, 1 H, OH).
13C NMR (62 MHz, CDCl3): d = 18.7, 19.44 (CH3), 51.52 (OCH3),
111.2, 126.4, 127.5 (C), 127.6 (2 C, CH), 130.3 (2 C, CH), 132.4,
134.0, 136.1, 140.5, 156.2 (C), 170.5 (C=O).
GC-MS (EI, 70 eV): m/z (%) = 326 (M+, 37Cl, 35Cl, 29), 324 (M+,
2 × 35Cl, 44), 299 (100), 264 (10), 257 (28), 229 (45), 165 (45), 128
(10), 82 (22).
13C NMR (62 MHz, CDCl3): d = 19.7, 22.9 (CH3), 51.0, 54.1
(OCH3), 108.7 (C), 112.7 (2 C, CH), 123.5 (CH), 126.9 (C), 127.8
(C), 129.9 (2 C, CH), 138.5, 142.6, 157.5, 159.5 (C), 171.5 (C=O).
Anal. Calcd for C16H14Cl2O3: C, 63.65; H, 5.34. Found: C, 63.45; H,
5.67.
GC-MS (EI, 70 eV): m/z (%) = 286 (M+, 55), 254 (100), 226 (11),
211 (55), 153 (8), 127 (11).
HRMS (EI, 70 eV): m/z [M]+ calcd for C17H18O4: 286.11996; found:
286.11977.
Methyl 5-Chloro-4,6-dimethyl-3-(4-tolyl)salicylate (7j)
Starting with 6b (450 mg, 2.2 mmol), 4e (771 mg, 2.2 mmol), and
TiCl4 (0.241 mL, 2.2 mmol), 7j was isolated as a colorless oil; yield:
198 mg (30%).
Methyl 3-(4-Methoxyphenyl)-4,5,6-trimethylsalicylate (7g)
Starting with 6c (184 mg, 1.65 mmol), 4b (604 mg, 1.65 mmol), and
TiCl4 (0.18 mL, 1.65 mmol), 7g was isolated as a colorless solid;
yield: 188 mg (38%); mp 108 °C.
IR (KBr): 3045 (w), 3024 (w), 2954 (m), 2921 (m), 2852 (w), 1650
(s), 1597 (m), 1545 (w), 1512 (w), 1435 (m), 1357 (s), 1361 (s),
1289 (s), 1203 (s), 1022 (m), 1002 (m), 981 (w), 956 (m), 850 (w),
818 (s), 727 (s), 687 cm–1 (s).
IR (neat): 2996 (w), 2953 (w), 2939 (w), 2839 (w), 1650 (m), 1598
(m), 1514 (m), 1434 (m), 1393 (m), 1318 (m), 1215 (s), 1295 (s),
1175 (m), 1030 (m), 804 (s), 762 (m), 696 (m), 562 cm–1 (m).
1H NMR (250 MHz, CDCl3): d = 1.93 (s, 3 H, CH3), 2.17 (s, 3 H,
CH3), 2.41 (s, 3 H, CH3), 3.73 (s, 3 H, OCH3), 6.83 (d, J = 8.0 Hz,
2 H, ArH), 7.01 (d, J = 7.7 Hz, 2 H, ArH), 10.39 (s, 1 H, OH).
1H NMR (250 MHz, CDCl3): d = 1.96 (s, 3 H, CH3), 2.12 (s, 3 H,
CH3), 2.38 (s, 3 H, CH3), 3.76 (s, 3 H, OCH3), 3.86 (s, 3 H, OCH3),
6.88 (d, J = 8.8 Hz, 2 H, ArH), 7.03 (d, J = 8.8 Hz, 2 H, ArH), 9.97
(s, 1 H, OH).
13C NMR (62 MHz, CDCl3): d = 15.0, 17.8, 18.1 (CH3), 51.0, 54.2
(OCH3), 111.2 (C), 112.9 (2 C, CH), 126.4, 126.8, 128.7 (C), 130.2
(2 C, CH), 135.4, 140.7, 154.8, 157.6 (C), 171.1 (C=O).
13C NMR (62 MHz, CDCl3): d = 20.9, 21.1, 22.4 (CH3), 53.5
(OCH3), 113.6, 127.7, 128.5 (C), 130.3 (2 C, CH), 130.8 (2 C, CH),
134.6, 137.5, 138.2, 142.7, 158.1 (C), 172.6 (C=O).
GC-MS (EI, 70 eV): m/z (%) = 306 (M+, 37Cl, 19), 304 (M+, 35Cl,
57), 272 (100), 257 (21), 244 (21), 229 (8), 209 (61), 165 (38), 135
(16).
HRMS (EI): m/z [M+, 35Cl] calcd for C17H17ClO3: 304.08607;
found: 304.086463.
GC-MS (EI, 70 eV): m/z (%) = 300 (M+, 39), 268 (100), 240 (31),
225 (47), 197 (6), 134 (9), 69 (25).
Synthesis 2009, No. 2, 243–250 © Thieme Stuttgart · New York

PAPER
[3+3] Cyclocondensations of 4-Aryl-1,3-bis(trimethylsilyloxy)buta-1,3-dienes
249
Methyl 5-(2-Chloroethyl)-4,6-dimethyl-3-phenylsalicylate (9a)
Starting with 1,1-diacetylcyclopropane (8, 252 mg, 2 mmol), 4a
(673 mg, 2.0 mmol), TiCl4 (0.22 mL, 2.0 mmol), and CH2Cl2 (60
mL), 9a was isolated as a colorless solid; yield: 267 mg (42%); mp
110 °C.
was extracted with Et2O (3 × 100 mL). The combined organic lay-
ers were washed with H2O, dried (Na2SO4), and filtered and the fil-
trate was concentrated in vacuo. The residue was purified by
column chromatography (silica gel, EtOAc–hexane) to give 12 as a
yellow solid; yield: 333 mg (63%); mp 173–174 °C.
IR (neat): 3058 (w), 3023 (w), 2954 (m), 2871 (w), 1727 (w), 1650
(s), 1603 (m), 1592 (m), 1562 (w), 1437 (s), 1397 (m), 1331 (s),
1312 (s), 1210 (s), 1070 (m), 1042 (m), 957 (m), 806 (s), 733 (s),
697 (s), 530 cm–1 (m).
IR (KBr): 3084 (w), 3058 (w), 3009 (w), 2948 (w), 1720 (s), 1671
(s), 1613 (m), 1600 (s), 1597 (s), 1548 (m), 1467 (s), 1442 (m), 1412
(s), 1314 (m), 1271 (s), 1253 (s), 1216 (s), 1150 (s), 1069 (s), 793
(m), 755 (s), 615 cm–1 (m).
1H NMR (250 MHz, CDCl3): d = 2.04 (s, 3 H, CH3), 2.48 (s, 3 H,
CH3), 3.09 (t, J = 6.4 Hz, 2 H, CH2), 3.46 (t, J = 7.4 Hz, 2 H, CH2),
3.90 (s, 3 H, OCH3), 7.12 (m, 2 H, ArH), 7.31 (m, 1 H, ArH), 7.37
(m, 2 H, ArH), 10.54 (s, 1 H, OH).
1H NMR (250 MHz, CDCl3): d = 2.23 (s, 3 H, CH3), 3.85 (s, 3 H,
CH3), 4.60 (s, 2 H, CH2), 6.98 (d, J = 7.8 Hz, 2 H, ArH), 7.15 (d, 2
H, ArH), 7.33–7.39 (m, 1 H, ArH), 7.53 (d, J = 7.87 Hz, 1 H, ArH),
7.67–7.74 (m, 1 H, ArH), 8.20 (m, 1 H, ArH), 9.10 (s, 1 H, ArH).
13C NMR (62 MHz, CDCl3): d = 18.3, 18.7 (CH3), 33.6, 42.3 (CH2),
52.4 (OCH3), 112.7 (C), 127.2 (CH), 127.4 (C), 128.6 (2 C, CH),
128.8 (C), 130.0 (2 C, CH), 137.3, 137.5, 141.8, 157.0 (C), 171.9
(C=O).
13C NMR (62 MHz, CDCl3): d = 21.0 (CH3), 42.1 (CH2), 52.5
(OCH3), 114.3 (C), 118.6 (CH), 121.6, 123.2 (C), 125.1, 126.8
(CH), 129.0 (2 C, CH), 129.1 (2 C, CH), 135.0 (C), 135.8 (CH),
136.1 (C), 141.1 (CH), 155.6, 160.5, 165.3 (C), 168.0, 176.8 (C=O).
GC-MS (EI, 70 eV): m/z (%) = 320 (M+, 37Cl, 16), 318 (M+, 35Cl,
GC-MS (EI, 70 eV): m/z (%) = 359 (M+, 100), 327 (M+, 70), 298
46), 286 (100), 258 (8), 251 (36), 237 (75), 209 (30), 165 (40).
(17), 285 (5), 256 (5), 228 (4), 150 (7).
HRMS (EI): m/z [M+, 35Cl] calcd for C18H19ClO3: 318.10172;
HRMS (EI): m/z [M]+ calcd for C22H17NO4: 359.114605; found:
found: 318.101767.
359.11521.
Methyl 5-(2-Chloroethyl)-3-(4-chlorophenyl)-4,6-dimethylsali-
cylate (9b)
Starting with 1,1-diacetylclopropane (8, 252 mg, 2.0 mmol), 4d
(742 mg, 2.0 mmol), TiCl4 (0.219 mL, 2.0 mmol), and CH2Cl2 (60
mL), 9b was isolated as a colorless solid; yield: 260 mg (37%); mp
112 °C.
Methyl 5-(5-Bromo-2-hydroxybenzoyl)-3-(4-tolyl)salicylate
(14)
To 13 (379 mg, 1.5 mmol) was added TMSOTf (0.355 mL, 1.95
mmol) at 20 °C. After stirring for 10 min, CH2Cl2 (13.5 mL) was
added, the mixture was cooled to 0 °C, and 4e (683 mg, 1.95 mmol)
was added. The mixture was stirred at 20 °C for 12 h and was sub-
sequently poured into aq 10% HCl. The organic and the aqueous
layer were separated and the latter was extracted with CH2Cl2
(3 × 15 mL). The combined organic layers were washed with brine
(25 mL) and dried (Na2SO4). The mixture 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-hep-
tane) to give 14 as a yellow solid; yield: 310 mg (47%); mp 173–
174 °C.
IR (neat): 3022 (w), 2998 (w), 2953 (m), 2872 (w), 1727 (w), 1650
(s), 1588 (m), 1554 (m), 1492 (m), 1436 (m), 1381 (m), 1346 (s),
1329 (s), 1309 (s), 1212 (s), 1088 (m), 1071 (m), 1040 (s), 1014 (m),
960 (m), 805 (s), 759 (s), 714 (s), 541 cm–1 (s).
1H NMR (250 MHz, CDCl3): d = 2.01 (s, 3 H, CH3), 2.46 (s, 3 H,
CH3), 3.06 (t, J = 6.5 Hz, 2 H, CH2), 3.43 (t, J = 7.4 Hz, 2 H, CH2),
3.89 (s, 3 H, OCH3), 7.03 (d, J = 8.7 Hz, 2 H, ArH), 7.32 (d, J = 8.5
Hz, 2 H, ArH), 10.54 (s, 1 H, OH).
13C NMR (62 MHz, CDCl3): d = 17.3, 17.7 (CH3), 32.4, 41.1 (CH2),
51.3 (OCH3), 111.3 (C), 126.2, 126.9 (C), 128.7 (2 C, CH), 129.9
(CH), 131.4 (2 C CH), 132.2, 134.7, 137.0, 140.8, 156.2 (C), 170.9
(C=O).
GC-MS (EI, 70 eV): m/z (%) = 354 (M+, 37Cl, 35Cl, 22), 352 (M+,
2 × 35Cl, 31), 320 (100), 285 (44), 271 (68), 243 (14), 207 (16), 165
(30), 118 (20), 89 (16).
IR (neat): 3104 (w), 2961 (m), 2920 (m), 2857 (w), 1783 (w), 1678
(s), 1629 (s), 1588 (s), 1565 (m), 1467 (m), 1437 (s), 1362 (s), 1332
(m), 1286 (s), 1255 (s), 1225 (m), 1198 (s), 1086 (s), 1022 (w), 958
(s), 889 (m), 814 (s), 683 (s), 646 cm–1 (m).
1H NMR (250 MHz, CDCl3): d = 2.36 (s, 3 H, CH3), 3.94 (s, 3 H,
OCH3), 6.90 (d, J = 8.9 Hz, 1 H, ArH), 7.18–7.22 (m, 2 H, ArH),
7.40–7.44 (m, 2 H, ArH), 7.49–7.54 (m, 1 H, ArH), 7.68 (d, J = 2.3
Hz, 1 H, ArH), 7.81 (d, J = 1.9 Hz, 1 H, ArH), 8.15 (d, J = 2.3 Hz,
1 H, ArH), 11.60 (s, 1 H, OH), 11.80 (s, 1 H, OH).
HRMS (EI): m/z [M+, 2 35Cl] calcd for C18H18Cl2O3: 352.06275;
13C NMR (62 MHz, CDCl3): d = 21.2 (CH3), 52.9 (OCH3), 110.3,
112.3, 120.3 (C), 120.5 (CH), 128.1 (C), 129.11 (2 C, CH), 129.17
(2 C, CH), 131.1 (CH), 131.2, 132.8 (C), 134.9 (CH), 136.8 (CH),
137.9 (C), 138.7 (CH), 161.8, 162.4 (C), 170.4, 198.0 (C=O).
found: 352.062346.
Methyl 3-(4-Methylphenyl)-5-oxo-5H-[1]benzopyrano[2,3-
b]pyridine-2-acetate (12)
To neat 10 (256 mg, 1.5 mmol) was added TMSOTf (433 mg,
0.35 mL, 1.95 mmol) and CH2Cl2 (13.5 mL) at 20 °C. After stirring
for 1 h, CH2Cl2 and 4e (683 mg, 1.95 mmol) were added at 0 °C.
The mixture was stirred at 20 °C for 12 h and subsequently poured
into 10% HCl. The organic and the aqueous layers were separated
and the latter was extracted with CH2Cl2 (3 × 100 mL). The com-
bined organic layers were washed with H2O, dried (Na2SO4), and
filtered and the filtrate was concentrated in vacuo. The residue was
filtered through a pad of silica gel (EtOAc–hexane, 5:1) to give
crude 11. To a soln of 11 in EtOH (15 mL) was added Et3N (326 mg,
0.44 mL, 3.0 mmol) and the soln was stirred at 20 °C for 12 h. To
the soln were subsequently added to 1 M HCl and Et2O (50 mL).
The organic and the aqueous layers were separated and the latter
GC-MS (EI, 70 eV): m/z (%) = 440 (M+, 79Br, 90), 411 (24), 408
(93), 242 (19), 210 (65), 182 (30), 153 (34).
Anal. Calcd for C22H17BrO5: C, 59.88; H, 3.88. Found: C, 59.48; H,
4.11.
Acknowledgment
Financial support from the state of Pakistan (HEC scholarship for
M.A.R., N.R. and R.A.) and of the State of Mecklenburg-Vorpom-
mern is gratefully acknowledged.
Synthesis 2009, No. 2, 243–250 © Thieme Stuttgart · New York

250
M. Adeel et al.
PAPER
(5) Anastatin, A.; Yoshikawa, M.; Xu, F.; Morikawa, T.;
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Synthesis 2009, No. 2, 243–250 © Thieme Stuttgart · New York