Synthesis of dibenzo[b,d]pyran-6-ones based on [3 + 3] cyclizations of 1,3-bis(silyl enol ethers) with 3-silyloxy-2-en-1-ones

Article abstract of DOI:10.1021/jo070608r

(Chemical Equation Presented) Functionalized dibenzo[b,d]pyran-6-ones were prepared by formal [3 + 3] cyclization of 1,3-bis(silyl enol ethers) with 3-silyloxy-2-en-1-ones or 1,1-diacetylcyclopropane to give functionalized salicylates, Suzuki cross-coupling reactions of the corresponding triflates, and subsequent BBr₃-mediated lactonization. A second approach to dibenzo[b,d]pyran-6-ones relies on the [3 + 3] cyclization of 1,3-bis(silyl enol ethers) with 1-(2-methoxyphenyl)-1-(trimethylsilyloxy)alk-1-en-3-ones and subsequent BBr₃-mediated lactonization.

Full text of DOI:10.1021/jo070608r

1,3-bis(silyl enol ethers) with 3-silyloxy-2-en-1-ones (Scheme
1).8 Recently, we reported9 the synthesis of dibenzo[b,d]pyran-
6-ones based on [3 + 3] cyclizations10 of 1,3-bis(silyl enol
ethers)11 with 3-silyloxyalk-2-en-1-ones to give salicylates,
Suzuki coupling of their triflates with o-methoxyboronic acids,
and subsequent BBr3-mediated lactonization. Herein, we report
full details of this work. In addition to our preliminary
communication,9 we also report a related approach to dibenzo-
[b,d]pyran-6-ones based on what are, to the best of our
knowledge, the first [3 + 3] cyclizations of 1,3-bis(silyl enol
ethers) with 1-(2-methoxyphenyl)-1-(trimethylsilyloxy)alk-1-en-
3-ones. The chemistry reported complements known methods
for the synthesis of dibenzo[b,d]pyran-6-ones.
Synthesis of Dibenzo[b,d]pyran-6-ones Based on
[3 + 3] Cyclizations of 1,3-Bis(silyl enol ethers)
with 3-Silyloxy-2-en-1-ones
Ibrar Hussain,† Van Thi Hong Nguyen,†
Mirza Arfan Yawer,† Tuan Thanh Dang,† Christine Fischer,‡
Helmut Reinke,† and Peter Langer*,†,‡
Institut fu¨r Chemie, UniVersita¨t Rostock, Albert-Einstein-Str. 3a,
18059 Rostock, Germany, and Leibniz-Institut fu¨r Katalyse e.V.
an der UniVersita¨t Rostock, Albert-Einstein-Str. 29a, 18059
Rostock, Germany
peter.langer@uni-rostock.de
1,3-Bis(silyl enol ethers) 1a-c were prepared, as previously
reported, from methyl acetoacetate, ethyl acetoacetate, and
methyl 4-methoxyacetoacetate, respectively.8 4-(Silyloxy)pent-
3-en-2-ones 2a-g were prepared from acetylacetone, 3-methy-
lacetylacetone, 3-ethylacetylacetone, benzoylacetone, 2-formyl-
cyclohexanone, 2-acetylcyclohexanone, and 2-acetyltetralone,
respectively. The TiCl4-mediated [3 + 3] cyclization of 1a-c
with 2a-g afforded the salicylates 3a-h which were trans-
formed into their triflates 4a-h (Scheme 2 and Table 1). The
Suzuki reaction12 of 4a-h with (2-methoxyphenyl)boronic acids
5a-c afforded biaryls 6a-k which were transformed into
dibenzo[b,d]pyran-6-ones 7a-k (Scheme 3 and Table 2) by
BBr3-mediated lactonization.13 The [3 + 3] cyclizations pro-
ceeded in moderate to good yields. The following steps (triflate
formation, Suzuki reaction, and lactonization) proceeded, in most
cases, in good to excellent yield.
Recently, we reported the domino [3 + 3] cyclization/homo-
Michael reaction of 1,3-bis(silyl enol ethers) with 1,1-diacyl-
cyclopropanes.14 These reactions proceed by cyclization and
subsequent TiX4 (X ) Cl, Br)-mediated cleavage of the
cyclopropane moiety to give salicylates with a chlorinated or
brominated side chain. The TiCl4-mediated cyclization of 1,3-
bis(silyl enol ether) 1b with 1,1-diacetylcyclopropane (8)
afforded, as previously reported, chloroethyl-substituted sali-
cylate 3i which was transformed into triflate 4i. The Suzuki
reaction of 4i with boronic acid 5a afforded 6l which was
transformed into chloroethyl-substituted dibenzo[b,d]pyran-6-
one 7l. The TiBr4-mediated cyclization of 1b with 8 afforded
ReceiVed March 23, 2007
Functionalized dibenzo[b,d]pyran-6-ones were prepared by
formal [3 + 3] cyclization of 1,3-bis(silyl enol ethers) with
3-silyloxy-2-en-1-ones or 1,1-diacetylcyclopropane to give
functionalized salicylates, Suzuki cross-coupling reactions
of the corresponding triflates, and subsequent BBr3-mediated
lactonization. A second approach to dibenzo[b,d]pyran-6-
ones relies on the [3 + 3] cyclization of 1,3-bis(silyl enol
ethers) with 1-(2-methoxyphenyl)-1-(trimethylsilyloxy)alk-
1-en-3-ones and subsequent BBr3-mediated lactonization.
Functionalized dibenzo[b,d]pyran-6-ones and related lactones
are of pharmacological relevance and occur in a number of
natural products, such as alternariol,1 autumnariol, autum-
nariniol2 and altenuisol,3 ellagic or coruleoellagic acid,4 de-
fucogilvocarcin V, gilvocarcins, chrysomycins, and ravidomy-
cins. Known syntheses of dibenzo[b,d]pyran-6-ones rely on the
cyclization of o-bromobenzoic acid with phenols,5 intramolecu-
lar Pd(II)-catalyzed coupling reactions,6 and directed ortho-
metalations (DOM) with subsequent Suzuki cross-coupling
reactions.7 Some years ago, Chan et al. reported an elegant
approach to salicylates based on formal [3 + 3] cyclizations of
(8) (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.
(9) Nguyen, V. T. H.; Langer, P. Tetrahedron Lett. 2005, 46, 1013.
(10) For a review of [3 + 3] cyclizations of 1,3-bis(silyl enol ethers),
see: Feist, H.; Langer, P. Synthesis 2007, 327.
(11) For a review of 1,3-bis(silyl enol ethers) in general, see: Langer,
P. Synthesis 2002, 441.
(12) For Suzuki reactions of salicylate-derived triflates with arylboronic
acids, see: Schmidt, J. M.; Tremblay, G. B.; Page, M.; Mercure, J.; Feher,
M.; Dunn-Dufault, R.; Peter, M. G.; Redden, P. R. J. Med. Chem. 2003,
46, 1289.
* To whom correspondence should be addressed. Fax: +381 4986412.
† Institut fu¨r Chemie.
‡ Leibniz-Institut fu¨r Katalyse.
(1) Raistrick, H.; Stilkings, C. E.; Thomas, R. Biochemistry 1953, 55,
421.
(2) Tamm, C. Arzneim.-Forsch. 1972, 22, 1776.
(3) Pero, R. W.; Harvan, D.; Blois, M. C. Tetrahedron Lett. 1973, 14,
945.
(4) (a) Sayer, J. M.; Haruhiko, Y.; Wood, A. W.; Conney, A. H.; Jerina,
D. M. J. Am. Chem. Soc. 1982, 104, 5562. (b) Gunawardana, Y. A. G. P.;
Kumar, N. S.; Sultanbawa, M. U. S. Phytochemistry 1979, 18, 1017.
(5) Hurtley, W. R. H. J. Chem. Soc. 1929, 1870.
(6) Bringmann, G.; Reuscher, H. Tetrahedron Lett. 1989, 30, 5249.
(7) Alo, B. I.; Kandil, A.; Patil, P. A.; Sharp, M. J.; Siddiqui, M. A.;
Snieckus, V. J. Org. Chem. 1991, 56, 3763.
(13) For BBr3-mediated lactonizations, see: (a) Kanakam, C. C.; Mani,
N. S.; Rao, G. S. R. S. J. Chem. Soc., Perkin Trans. 1 1990, 8, 2233. (b)
Coghlan, M. J.; Kym, P. R.; Elmore, S. W.; Wang, A. X.; Luly, J. R.;
Wilcox, D.; Stashko, M.; Lin, C.-W.; Miner, J.; Tyree, C.; Nakane, M. J.
Med. Chem. 2001, 44, 2879. For the use of HBr, see for example: (c)
Manthey, M. K.; Pyne, S. G.; Truscott, R. J. W. J. Org. Chem. 1990, 55,
4581.
(14) (a) Langer, P.; Bose, G. Angew. Chem. 2003, 115, 4165; Angew.
Chem., Int. Ed. 2003, 42, 4033. (b) Bose, G.; Nguyen, V. T. H.; Ullah, E.;
Lahiri, S.; Go¨rls, H.; Langer, P. J. Org. Chem. 2004, 69, 9128.
10.1021/jo070608r CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/30/2007
J. Org. Chem. 2007, 72, 6255-6258
6255

SCHEME 1. Possible Mechanism of the Formal [3 + 3]
Cyclization of 1,3-Bis(silyl enol ethers) with
3-Silyloxy-2-en-1-onesa
SCHEME 3. Synthesis of 7a-ma
a Conditions: (i) Pd(PPh3)4 (3 mol %), K3PO4 (1.5 equiv), dioxane,
reflux, 4 h; (ii) (1) BBr3 (4 equiv), CH2Cl2, 0 f 20 °C, 18 h, (2) KOtBu,
H2O, 15 min, 20 °C.
a Conditions: (i) TiCl4, CH2Cl2, -78 f 20 °C.
SCHEME 2. Synthesis of 4a-ja
TABLE 2. Products and Yields
6, 7
R
R1 R2
R3
R4 R5
R6
R7 % 6a % 7a
a
b
c
d
e
e
f
g
h
i
i
j
j
k
k
l
Me
Me
Me
Et
H
Me
Me Me
Me Et
H
Me
Me
Me
Ph
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
75
73
95
95
83
92
71
81
73
H
H
H
Me
H
H
H
Me OMe Me
Me OH Me
76
91
67
62
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
(CH2)4
79
61
55
65
Me (CH2)4
Me (CH2)2C6H4
Me Et
Me Et
Me Et
Me Et
Me
Me
Me (CH2)2Cl
Me (CH2)2Br
H
Me
Me
Me
Me
Me OMe
Me OH
OMe
OH
H
H
H
H
H
H
79
96
OMe 47
OH
H
H
H
H
H
H
59
87
98
76
a Conditions: (i) TiCl4, CH2Cl2, -78 f 20 °C; (ii) Tf2O, pyridine, -78
f -10 °C.
Me
Me
H
H
78
90
m
TABLE 1. Products and Yields
a Yields of isolated products.
3, 4
R
R1
R2
R3
R4
% 3a
% 4a
a
b
c
d
e
f
g
h
i
Me
Me
Me
Et
Me
Me
Me
Me
Me
Me
H
H
H
H
OMe
H
H
H
H
Me
Me
Me
Me
Me
H
Me
Me
Me
Me
H
Me
Me
Me
Ph
38
51
45
31
50
30
32
48
61b
51c
73
74
85
90
65
92
75
61
92
90
biaryls 12a-l with very good regioselectivity. The regioselec-
tivity can be explained by TiCl4-mediated isomerization of 11a,b
(shift of the trimethylsilyl group from one oxygen atom to the
other), attack of the terminal carbon atom of the 1,3-bis(silyl
enol ether) onto the carbon atom attached to the silyloxy group,
and subsequent cyclization via the central carbon atom. Treat-
ment of biaryls 12a-l with BBr3 and subsequent addition of
an aqueous solution of KOtBu afforded the dibenzo[b,d]pyran-
6-ones 13a-l (Scheme 4 and Table 3). The [3 + 3] cyclizations
proceeded in moderate yields. 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 individual
experiment seems to play an important role. The lactonization
again proceeded in good yields.
Me
Et
H
H
(CH2)4
Me
(CH2)4
(CH2)2C6H4
(CH2)2Cl
(CH2)2Br
Me
Me
j
H
a Yields of isolated products. b From 1,1-diacetylcyclopropane (8) and
TiCl4. c From 1,1-diacetylcyclopropane (8) and TiBr4.
bromoethyl-substituted salicylate 3j. The Suzuki reaction of
triflate 4j with 5a gave 6m which was transformed into dibenzo-
[b,d]pyran-6-one 7m. All reactions proceeded in good to
excellent yield. The lactonization proceeded in good yield
despite the presence of the remote halide function.
(2-Methoxybenzoyl)acetone (10a) and (2-methoxybenzoyl)-
butan-2-one (10b) were prepared by LDA-mediated reaction
of acetone and butan-2-one with 2-methoxybenzoyl chloride (9),
respectively. The [3 + 3] cyclization of 1-(2-methoxyphenyl)-
1-(trimethylsilyloxy)alk-1-en-3-ones 11a,b, prepared from 10a,b,
with 1,3-bis(silyl enol ethers) 1a and 1c-h,15 afforded the
The structure of all products was established by spectroscopic
methods. The structure of 13c was independently confirmed by
X-ray crystal structure analysis (see Supporting Information).16
In conclusion, two methods for the synthesis for the synthesis
of dibenzo[b,d]pyran-6-ones based on [3 + 3] cyclizations of
(15) Nguyen, V. T. H.; Bellur, E.; Appel, B.; Langer, P. Synthesis 2006,
1103.
6256 J. Org. Chem., Vol. 72, No. 16, 2007

SCHEME 4. Synthesis of 13a-la
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 electrospray ionization (ESI). For preparative scale chromatog-
raphy, silica gel (60-200 mesh) was used. Melting points are
uncorrected.
General Procedure for the Synthesis of Salicylates 3 and 12:
To a CH2Cl2 solution of silyl enol ether 2 (1.0 equiv) and 1,3-bis-
(silyl enol ether) 1 (1.0 equiv) was dropwise added TiCl4 (1.0 equiv)
at -78 °C under argon atmosphere. The solution was stirred at
-78 °C for 30 min and then allowed to warm to 20 °C during 18
h. To the solution was added a saturated aqueous solution of
NaHCO3. The organic layer was separated, and the aqueous layer
was repeatedly extracted with CH2Cl2. The combined organic
extracts were dried (Na2SO4) and filtered. The filtrate was
concentrated in vacuo, and the residue was purified by chroma-
tography (silica gel, n-hexane/EtOAc) to give salicylates 3. The
synthesis of 3a has been previously reported.8a
Methyl 4,5,6-Trimethyl-2-hydroxybenzoate (3b). Starting with
1-methoxy-1,3-bis(trimethylsilyloxy)buta-1,3-diene 1a (1.04 g, 4.0
mmol), 2b (0.744 g, 4.0 mmol), and TiCl4 (0.760 g, 4.0 mmol) in
CH2Cl2 (8 mL), 3b was isolated after chromatography (silica gel,
n-hexane/EtOAc ) 20:1) as a colorless solid (0.395 g, 51%): mp
a Conditions: (i) LDA (1.5 equiv), THF; (ii) NEt3 (1.6 equiv), Me3SiCl
(1.8 equiv), C6H6, 20 °C, 3 d; (iii) TiCl4, CH2Cl2, -78 f 20 °C; (iV) (1)
BBr3 (4 equiv), CH2Cl2, 0 f 20 °C, 18 h, (2) KOtBu, H2O, 15 min, 20 °C.
1
) 66 °C; H NMR (CDCl3, 300 MHz) δ ) 2.13 (s, 3H, CH3),
2.27 (s, 3H, CH3), 2.44 (s, 3H, CH3), 3.94 (s, 3H, CH3), 6.69 (s,
1H, CH), 10.84 (s, 1H, OH); 13C NMR (CDCl3, 75 MHz) δC
)
TABLE 3. Products and Yields
15.2, 18.8, 21.5, 51.5 (CH3), 111.3 (C), 116.2 (CH), 127.2, 138.1,
143.8, 159.0, 171.9 (C); IR (KBr, cm-1) ν˜ ) 3240 (w), 3002 (w),
2956 (s), 1657 (s), 1209 (s), 1236 (s), 1156 (s), 1065 (s), 805 (w);
UV-vis (CH3CN, nm) λmax (log ꢀ) ) 214 (4.38), 252 (3.88), 314
(3.58); MS (EI, 70 eV) m/z (%) ) 193 (M+, 35), 162 (100), 134
(34), 28 (16). The exact molecular mass m/z ) 194.0913 ( 2 ppm
[M+] for C11H14O3 was confirmed by HRMS (EI, 70 eV). Anal.
Calcd for C11H14O3 (194.227): C, 68.02; H, 7.27. Found: C, 68.13;
H, 8.21.
1
12, 13
R1
R2
% 12a
% 13a
a
c
d
e
f
g
h
a
c
d
e
h
a
b
c
d
e
f
g
h
i
Me
Me
Me
Me
Me
Me
Me
nPr
nPr
nPr
nPr
nPr
H
Me
Et
nHex
nHept
nOct
nUndec
H
Me
Et
47
27
34
26
25
52
47
22
21
30
32
43
92
69
62
65
54
60
71
77
73
71
62
86
Ethyl 3-Hydroxy-2′-methoxy-5-methyl[1,1′-biphenyl]-2-car-
boxylate (12a). Starting with bis(silyl enol ether) 1a (0.659 g, 2.4
mmol), TiCl4 (0.455 g, 2.4 mmol), CH2Cl2 (8 mL), and mono(silyl
enol ether) 11a (0.582 g, 2.2 mmol), 12a was isolated (0.293 g,
47%) by column chromatography (silica gel, n-hexane/EtOAc )
30:1 f 20:1) as a colorless solid: mp ) 91-93 °C; 1H NMR (250
MHz, CDCl3) δ ) 0.78 (t, J ) 7.2 Hz, 3H, CH3), 2.34 (s, 3H,
CH3), 3.70 (s, 3H, OCH3), 3.97 (q, J ) 7.3 Hz, 2H, OCH2CH3),
6.87-6.58 (m, 1H, Ar), 6.80-6.81 (m, 1H, Ar), 6.85 (dd, J ) 8.1,
1.2 Hz, 1H, Ar), 6.99 (ddd, J ) 7.3, 7.6, 1.2 Hz, 1H, Ar), 7.15
(dd, J ) 7.3, 1.5 Hz, 1H, Ar), 7.32 (ddd, J ) 8.6, 7.3, 1.8 Hz, 1H,
Ar), 10.93 (s, 1H, OH); 13C NMR (75 MHz, CDCl3) δ ) 13.5,
22.2 (CH3), 55.6 (OCH2CH3), 60.8 (OCH3), 109.9, 117.2, 120.5
(CH), 122.8 (C) 124.2, 128.4, 129.5 (CH), 140.8, 145.0, 151.6,
156.4, 161.4, 171.2 (C); IR (KBr, cm-1) ν˜ ) 3432 (m), 2924 (s),
1655 (s), 1616 (m), 1462 (s), 1278 (m), 1217 (m), 1197 (m), 1107
(m), 1026 (m), 871 (w), 759 (m); MS (EI, 70 eV) m/z (%) ) 286
(M+, 40), 255 (2), 240 (100), 211 (15), 197 (22), 169 (11), 152
(7), 141 (7), 115 (9), 77 (2); HRMS (EI) calcd for C17H18O4,
286.11996; found, 286.120041.
j
k
l
nHex
nUndec
a Yields of isolated products.
1,3-bis(silyl enol ethers) were reported. Known syntheses of
dibenzo[b,d]pyran-6-ones rely on the transition-metal-catalyzed
coupling of two appropriate benzene derivatives and are, thus,
limited by the availability of the latter. The synthesis of
functionalized and heavily substituted benzene derivatives can
be a difficult task. In contrast to known methods, the methodol-
ogy reported herein involves the assembly of one of the two
benzene moieties during the synthesis. Therefore, products can
be prepared which are not readily available by other methods.
Notably, the two strategies outlined herein, both relying on [3
+ 3] cyclizations as the key step, complement each other since
different substitution patterns are accessible. The overall yields
of the dibenzo[b,d]pyran-6-ones are mainly limited by the [3
+ 3] cyclization step which mostly proceeds only in moderate
yield. However, the substitution pattern available by the [3 +
3] cyclization is not readily available by other methods.
General Procedure for the Synthesis of Triflates 4. To a CH2-
Cl2 solution of 4 (1.0 equiv) was added pyridine (2.0 equiv) at
-78 °C. After 10 min, triflic anhydride (Tf2O, 1.2 equiv) was added
at -78 °C. The solution was allowed to warm to 0 °C and was
stirred for 4 h. The product was isolated by column chromatography
(silica gel, CH2Cl2) as a colorless viscous oil.
Experimental Section
General Comments. All solvents were dried by standard
methods, and all reactions were carried out under an inert
Ethyl 2,4-Dimethyl-6-(trifluoromethylsulfonyloxy)benzoate
(4a). Starting with 3a (0.415 g, 2.14 mmol) in 20 mL of CH2Cl2,
pyridine (0.339 g, 4.28 mmol), and Tf2O (0.727 g, 2.57 mmol), 4a
was isolated as a colorless oil (0.505 g, 73%): 1H NMR (300 MHz,
CDCl3) δ ) 1.39 (t, J ) 7.1 Hz, 3H, OCH2CH3), 2.37 (s, 3H, CH3),
2.41 (s, 3H, CH3), 4.39 (q, J ) 7.1 Hz, 2H, OCH2CH3), 6.95 (s,
1H, Ar), 7.06 (s, 1H, Ar); 13C NMR (75 MHz, CDCl3) δ ) 13.9,
(16) CCDC-640386 contains all crystallographic details of this publication
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.
J. Org. Chem, Vol. 72, No. 16, 2007 6257

20.2, 21.3 (CH3), 26.0 (CH2), 116.5 (C), 119.6 (CH), 124.3 (C),
131.3 (CH), 139.4, 142.2, 146.8, 165.1 (C); IR (KBr, cm-1) ν˜ )
2986 (m), 1733 (s), 1624 (s), 1569 (m), 1426 (s), 1274 (s), 1211
(s), 1142 (s), 1089 (s), 1021 (s), 957 (s), 856 (s), 821 (s), 764 (m),
607 (s); MS (EI, 70 eV) m/z (%) ) 327 ([M + 1]+, 5), 326 (M+,
76), 281 (96), 193 (4), 165 (100), 147 (45), 119 (27), 91 (86), 28
(37). Anal. Calcd for C12H13O5SF3: C, 44.18; H, 4.01. Found: C,
44.25; H, 3.97.
General Procedure for the Synthesis of Biaryls 6 by Suzuki
Cross-Coupling Reactions. A dioxane solution of the boronic acid,
potassium phosphate, Pd(PPh3)4, and triflate 4 was stirred at 110
°C for 4 h. After cooling to 20 °C, a saturated aqueous solution of
NH4Cl was added. The organic and the aqueous layer were
separated, and the latter was extracted with CH2Cl2. The combined
organic layers were dried (Na2SO4) and filtered, and the filtrate
was concentrated in vacuo. The residue was purified by chroma-
tography (silica gel, n-hexane/EtOAc ) 20:1).
g, 3.89 mmol), and KOtBu (20 mL, 0.1 M aqueous solution), 13a
was isolated as a colorless solid (0.219 g, 92%): mp ) 150-151
1
°C; H NMR (250 MHz, CDCl3) δ ) 2.42 (s, 3H, CH3), 6.77-
6.78 (m, 1H, Ar), 7.15 (s, 1H, Ar), 7.21 (dd, J ) 7.0, 1.5 Hz, 1H,
Ar), 7.25-7.27 (m, 1H, Ar), 7.37 (ddd, J ) 8.3, 7.0, 1.5 Hz, 1H,
Ar), 7.90 (dd, J ) 7.9, 1.2 Hz, 1H, Ar), 11.20 (s, 1H, OH); 13C
NMR (75 MHz, CDCl3) δ ) 23.0 (CH3), 104.3 (C), 113.5, 117.4,
118.1 (CH), 118.7 (C) 123.7, 125.4, 130.9 (CH), 135.3, 149.4,
151.1, 162.8, 165.8 (C); IR (KBr, cm-1) ν˜ ) 3438 (m), 3068 (m),
2923 (w), 1680 (s), 1627 (s), 1568 (s), 1512 (w), 1456 (m), 1421
(m), 1276 (s), 1235 (s), 1208 (s), 1148 (m), 1078(s), 842 (m), 750
(s), 511 (m); GC-MS (EI, 70 eV) m/z (%) ) 226 (M+, 100), 197
(20), 169 (8), 141 (8), 115 (11), 77 (3); HRMS (EI) calcd for
C14H10O3, 226.06245; found, 226.061951.
Procedure for the Synthesis of 4-Hydroxy-4-(2-methoxyphe-
nyl)-3-buten-2-one (10a). To a stirred solution of LDA (75 mmol)
in THF (62 mL) was added acetone (2.904 g, 50.0 mmol) at -78
°C. After the solution was stirred for 1 h, 2-methoxy anisoyl chloride
(10.235 g, 60.0 mmol) was added. The temperature of the solution
was allowed to rise to 20 °C during 12 h. A saturated solution of
NH4Cl was added, the layers were separated, and the aqueous layer
was extracted with ethylacetate (3 × 150 mL). The combined
organic layers were dried (Na2So4) and filtered, and the solvent
was removed in vacuo. The residue was purified by chromatography
(silica gel, n-hexane/EtOAc 30:1 f 20:1) to give 10a as a yellowish
oil (3.550 g, 37%): 1H NMR (250 MHz, CDCl3) δ ) 1.99 (s, 3H,
CH3), 3.69 (s, 3H, OCH3), 6.28 (s, 1H, CH), 6.76 (dd, J ) 8.5, 0.9
Hz, 1H, Ar), 6.84 (ddd, J ) 7.3, 7.3, 0.9 Hz, 1H, Ar), 7.22 (ddd,
J ) 8.5, 8.2, 1.8 Hz, 1H, Ar), 7.70 (dd, J ) 7.6, 1.8 Hz, 1H, Ar),
15.3 (br s, 1H, OH); 13C NMR (62 MHz, CDCl3) δ ) 26.1 (CH3),
55.4 (OCH3), 101.9, 111.6, 120.9, 130.8, 133.1 (CH), 134.8, 158.4,
181.3, 194.6 (C); IR (Nujol, cm-1) ν˜ ) 3076 (w), 3005 (w) 2962
(w), 1721 (m), 1603 (s), 1490 (s), 1250 (s), 1164 (m), 1022 (m),
989 (m), 755 (m), 533 (w); MS (EI, 70 eV) m/z (%) ) 192 ([M]+,
12), 174 (10), 161 (54), 136 (10), 135 (100), 120 (5), 105 (4), 92
(11), 77 (25), 63.1 (5), 51 (5), 43 (11); HRMS (EI) calcd for
C11H12O3, 192.07810; found, 192.07797. Anal. Calcd for
C11H12O3: C, 68.73; H, 6.29. Found: C, 69.16; H, 6.52.
Ethyl 2,4-Dimethyl-6-(2-methoxyphenyl)benzoate (6a). Start-
ing with 2-methoxyphenylboronic acid (5a, 1.3 equiv, 0.306 g, 2.01
mmol), potassium phosphate (1.6 equiv, 0.509 g, 2.40 mmol), Pd-
(PPh3)4 (3 mol %, 0.052 g, 0.045 mmol), dioxane (5 mL), and 4a
(1.0 equiv, 0.489 g, 1.5 mmol), 6a was isolated as a colorless
viscous oil (0.320 g, 75%): 1H NMR (300 MHz, CDCl3) δ ) 0.89
(t, J ) 7.1 Hz, 3H, OCH2CH3), 2.34 (s, 3H, CH3), 2.41 (s, 3H,
CH3), 3.74 (s, 3H, CH3O), 3.98 (q, J ) 7.2 Hz, 2H, OCH2CH3),
6.89-6.91 (d, J ) 8.3 Hz, 1H, Ar), 6.94-6.96 (dd, J ) 1.0, 6.5
Hz, 1H, Ar), 6.98 (s, 1H, Ar), 7.02 (s, 1H, Ar), 7.16-7.19 (dd, J
) 1.7, 5.7 Hz, 1H, Ar), 7.29-7.32 (td, J ) 1.8, 6.8 Hz, 1H, Ar);
13C NMR (75 MHz, CDCl3) δ ) 13.6, 20.2, 21.2, 55.4 (CH3), 60.3
(CH2), 110.4 (C), 120.4, 128.6 (CH), 129.0 (2CH), 130.3 (C), 130.5
(CH), 130.6, 135.9, 137.5, 139.3, 156.3, 169.1 (C); IR (KBr, cm-1
)
ν˜ ) 2978 (s), 2931 (s), 1724 (s), 1605 (s), 1580 (m), 1497 (s),
1459 (s), 1434 (s), 1384 (m), 1265 (s), 1180 (s), 1107 (s), 1081
(s), 1027 (s), 861 (s), 754 (s); UV-vis (CH3CN, nm) λmax (log ꢀ)
) 210.3 (4.56), 281.7 (3.59); MS (EI, 70 eV) m/z (%) ) 285 ([M
+ 1]+, 7), 284 (M+, 100), 253 (64), 239 (58), 225 (61), 195 (32),
181 (28), 165 (27), 151 (15), 115 (5), 29 (12); HRMS (ESI) calcd
for C18H20O3 [M + 1]+, 285.14907; found, 285.14842. Anal. Calcd
for C18H20O3: C, 76.02; H, 7.09. Found: C, 75.82; H, 6.61.
Procedure for the Synthesis of 4-(2-Methoxyphenyl)-4-[(tri-
methylsilyl)oxy]-3-buten-2-one (11a). To a stirred benzene solution
(37 mL) of 10a (2.854 g, 14.9 mmol) was added triethylamine
(2.406 g, 23.8 mmol). After the solution was stirred for 2 h,
trimethylchlorosilane (2.905 g, 26.7 mmol) was added. After the
solution was stirred for 72 h, the solvent was removed in vacuo
and hexane (75 mL) was added to the residue to give a suspension.
The latter was filtered under argon atmosphere. The filtrate was
concentrated in vacuo to give 11a as yellowish oil (2.893 g, 73%):
1H NMR (250 MHz, CDCl3) δ ) 0.21 (s, 9H, 3CH3), 2.31 (s, 3H,
CH3), 3.78 (s, 3H, OCH3), 6.16 (s, 1H, CH), 6.84-6.86 (m, 1H,
Ar), 6.90 (dd, J ) 8.7, 1.1 Hz, 1H, Ar), 7.28-7.30 (m, 1H, Ar),
7.51 (dd, J ) 8.7, 2.1 Hz, 1H, Ar); 13C NMR (75 MHz, CDCl3) δ
) 0.16 (3CH3), 21.9 (CH3), 55.1 (OCH3), 101.3, 111.0, 119.8,
130.5, 131.5 (CH), 132.7, 157.2, 169.7, 191.3 (C).
General Procedure for the Synthesis of Benzo[c]chromen-6-
ones 7 and 13 by Lactonization with BBr3. To a CH2Cl2 solution
of 6 was added BBr3 at 0 °C. The solution was allowed to warm
to 20 °C during 18 h. To the solution was added an aqueous solution
of KOtBu (0.1 M), and the solution was stirred for 15 min. The
organic and the aqueous layers were separated, and the latter was
extracted with CH2Cl2. The combined organic layers were dried
(Na2SO4) and filtered, and the filtrate was concentrated in vacuo.
The product was purified by chromatography (silica gel, n-hexane/
EtOAc ) 20:1) as a colorless solid.
7,9-Dimethyl-6H-benzo[c]chromen-6-one (7a). Starting with
6a (0.240 g, 0.85 mmol) in CH2Cl2 (2.5 mL), BBr3 (0.423 g, 1.69
mmol), and KOtBu (10 mL, 0.1 M aqueous solution), 7a was
1
isolated as a colorless solid (0.175 g, 92%): mp ) 155.5 °C; H
NMR (300 MHz, CDCl3) δ ) 2.51 (s, 3H, CH3), 2.84 (s, 3H, CH3),
7.22 (s, 1H, Ar), 7.29 (d, 1H, Ar), 7.35 (m, 1H, Ar), 7.44 (m, 1H,
Ar), 7.81 (s, 1H, Ar), 8.05 (d, 1H, Ar); 13C NMR (75 MHz, CDCl3)
δ ) 21.9, 23.7 (CH3), 117.3 (CH), 118.3 (C), 120.1, 122.9, 124.1,
130.1, 133.4 (CH), 136.1, 144.3, 144.8, 151.5, 153.2, 160.5 (C);
IR (KBr, cm-1) ν˜ ) 3429 (m), 2921 (m), 1721 (s), 1610 (s), 1452
(s), 1422 (m), 1265 (s), 1224 (s), 1169 (s), 1052 (s), 859 (m), 752
(s); UV-vis (CH3CN, nm) λmax (log ꢀ) ) 237.9 (4.58), 263.1 (4.05),
272.9 (4.04), 288.2 (3.71), 298.6 (3.87), 317.1 (3.87); MS (EI, 70
eV) m/z (%) ) 225 ([M + 1]+, 16), 224 (M+, 100), 195 (12), 181
(15), 165 (13), 151 (10), 128 (2), 91 (13); HRMS (ESI) calcd for
C15H12O2 ([M + 1]+), 225.09155; found, 225.09142. Anal. Calcd
for C15H12O2: C, 80.34; H, 5.39. Found: C, 80.02; H, 5.65.
Acknowledgment. Financial support from the state of
Pakistan (HEC scholarship for I.H. and M.A.Y.), from the state
of Vietnam (MOET scholarship for V.T.H.N. and D.T.T.), and
from the state of Mecklenburg-Vorpommern (Landesfors-
chungsschwerpunkt ‘Neue Wirkstoffe and Screeningverfahren’)
is gratefully acknowledged.
Supporting Information Available: Experimental procedures,
compound characterization, copies of NMR spectra, and details of
the X-ray crystal structure analysis. This material is available free
of charge via the Internet at http://pubs.acs.org.
7-Hydroxy-9-methyl-6H-benzo[c]chromen-6-one (13a). Start-
ing with 12a (0.278 g, 0.971 mmol) in CH2Cl2 (15 mL), BBr3 (0.973
JO070608R
6258 J. Org. Chem., Vol. 72, No. 16, 2007