BCl3-promoted synthesis of benzofurans

Article abstract of DOI:10.1016/j.tetlet.2008.09.034

Lewis acidic nature of boron trichloride (BCl₃) to coordinate to the carbonyl functionality was exploited for the synthesis of benzofurans via dehydrative cyclization. This mild and efficient procedure allowed for facile access to a number of h

Full text of DOI:10.1016/j.tetlet.2008.09.034

Tetrahedron Letters 49 (2008) 6579–6584
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Tetrahedron Letters
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BCl3-promoted synthesis of benzofurans
*
Ikyon Kim , Sei-Hee Lee, Sunkyung Lee
Center for Medicinal Chemistry, Korea Research Institute of Chemical Technology Daejeon 305-600, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Lewis acidic nature of boron trichloride (BCl3) to coordinate to the carbonyl functionality was exploited
for the synthesis of benzofurans via dehydrative cyclization. This mild and efficient procedure allowed for
facile access to a number of highly substituted benzofurans in a regioselective manner. The structural
requirement for the successful cyclodehydration was examined in the cases, where competitive demeth-
ylation could occur.
Received 19 August 2008
Accepted 8 September 2008
Available online 11 September 2008
Keywords:
Benzofuran
Ó 2008 Elsevier Ltd. All rights reserved.
Naphthofuran
Cyclodehydration
Regioselectivity
Lewis acid
Boron trichloride
Benzofurans are ubiquitous structural motifs in both natural
products and synthetic pharmaceuticals.1 As depicted in Figure 1,
for instance, malibatol A exhibiting cytotoxicity to the host cells
(CEM SS) in the antiviral assay was isolated from the organic
extract of the leaves of Hopea malibato by Boyd and coworkers in
1998,2 whereas shoreaphenol or hopeafuran was isolated from
the bark of Shorea robusta or the stem wood of Hopea utilis.3
Recently, iantheran A, a dimeric polybrominated benzofuran, was
evaluated as a Na, K-ATPase inhibitor.4
Due to the remarkably diverse array of biological activities asso-
ciated with this previledged structure,5 a number of synthetic
strategies have been developed.6 Among these, cyclodehydration
of aryloxyketones has been amply implemented for the synthesis
of benzofurans, partly due to the easy preparation of cyclization
precursor, aryloxyketones (Scheme 1).
A variety of Lewis acids or Brønsted acids have been utilized
to effect the cyclodehydration approach. However, elevated
temperatures are also required for the successful cyclodehydration
of aryloxyketones to occur in many cases. Besides, unwanted rear-
rangement sometimes takes place under the certain harsh reaction
conditions to afford a mixture of products.7 Furthermore, a mixture
of regioisomers results from the conditions where the aryloxy-
ketones are submitted as a consequence of non-regioselective ring
closure. In view of these drawbacks, search for the milder cyclo-
dehydrating conditions is, therefore, still in demand. Recently, we
discovered that boron trichloride (BCl3) induces smooth cyclo-
dehydration of aryloxyketones to afford benzofurans. Although it
HO
HO
OH
OH
OH
OH
HO
O
H
H
OH
OH
O
O
HO
HO
malibatol A
shoreaphenol
or hopeafuran
OH
Br
O
Br
OSO3Na
NaSO3O
O
Br
Br
HO
iantheran A
Figure 1. Some representative benzofuran-containing natural products.
is well known for its ability to cleave ether linkages via coordina-
tion to the neighboring carbonyl functionality as a dealkylating
agent, use of BCl3 as a cyclodehydrating agent has not been dis-
closed yet in the literature.8 Here, we wish to describe our findings.
* Corresponding author. Tel.: +82 42 860 7177; fax: +82 42 860 7160.
E-mail address: ikyon@krict.re.kr (I. Kim).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.034

6580
I. Kim et al. / Tetrahedron Letters 49 (2008) 6579–6584
cyclodehydration
R2
O
X
R2
R3
O
O
R2
R3
+
R3
OH
R1
O
R1
R1
O-alkylation
Scheme 1.
In the course of our medicinal program, we needed to convert 1
to 3. For this purpose, BCl3 was chosen since it had been widely
used for selective demethylation of methoxy benzene compounds
bearing a carbonyl functional group at the ortho position. Thus,
BCl3 (1.0 M solution in CH2Cl2, 1.2 equiv) was added to a solution
of 1 in CH2Cl2 at ꢀ78 °C. After the addition was complete, the reac-
OMe
I
I
BCl3
-78 ºC to rt
MeO
O
OMe
MeO
MeO
MeO
MeO
MeO
89%
O
O
2
1
I
HO
OMe
MeO
MeO
O
O
3 (expected)
Scheme 2.
I
Cl
Cl
MeO
O
OMe
B
Cl
MeO
MeO
O
1
OMe
I
Cl
Cl
Me
O
I
MeO
OMe
OMe
B
O
MeO
MeO
MeO
MeO
O
2
O
path a
OMe
path b
Me
I
I
Me
O
I
HO
O
Cl
O
Base
MeO
OMe
B
O
H
MeO
MeO
MeO
MeO
O
O
H
MeO
O
3
Base
Scheme 3.

I. Kim et al. / Tetrahedron Letters 49 (2008) 6579–6584
6581
Table 1
5
A
2
BCl3 (1.2 equiv)
R2
6 O
R2
4
3
R1
CH2Cl2
R3
1
R3 -78 ºC to rt
O
O
R1
4
5
Entry
1
4
5
Yield (%)
42
4a
5a
O
O
O
O
O
O
2
3
4b
4c
5b
5c
63
90
OMe
OMe
O
O
MeO
O
MeO
MeO
O
O
4
4d
5d
89
MeO
O
O
O
5
6
4e
4f
5e
5f
30a
OMe
OMe
O
O
O
OMe
66
OMe
MeO
MeO
O
MeO
MeO
O
O
7
8
4g
4h
5g
5h
59
85
83
O
OMe
OMe
O
O
O
OMe
OMe
O
9
4i
4j
5i
5j
O
O
O
10
99
Me
MeO
O
Me
O
MeO
(continued on next page)

6582
I. Kim et al. / Tetrahedron Letters 49 (2008) 6579–6584
Table 1 (continued)
Entry
4
5
Yield (%)
OMe
OMe
OMe
O
O
OMe
11
4k
5k
95
MeO
O
MeO
OMe
OMe
MeO
MeO
O
O
4l
5l
91
MeO
MeO
12
13
O
O
OMe
OMe
O
O
4m
OMe
5m
93
86
OMe
OMe
MeO
MeO
MeO
MeO
O
O
14
15
4n
OMe
5n
MeO
MeO
O
OMe
4o
5o
96
O
O
OMe
MeO
O
MeO
OMe
OMe
CO2Me
O
MeO2C
16
4p
4q
5p
5q
84b
MeO
MeO
O
O
O
MeO
OMe
O
OMe
17
88
O
MeO
a
The demethylated product 5e0 was also isolated in about 30% yield.
2.5 equiv of BCl3 was used.
b
tion mixture was stirred at rt for 30 min. Surprisingly, however,
benzofuran 2 was isolated as a major product instead of the
expected phenol 3 (see Scheme 2).
presence of potassium carbonate. When these aryloxyketones
were exposed to BCl3, the corresponding benzofurans were
obtained as outlined in Table 1.9,10 When there was no substitution
of electron-donating group at the phenolic part (ring A) of aryl-
oxyketones, modest yields of benzofurans were obtained (entries
1 and 5).11 Aryloxyketones bearing a methoxy group at the ortho,
meta, or para position of ring A were then treated with BCl3,
respectively. While 4c and 4d were converted to the corresponding
benzofurans 5c and 5d in excellent yields, 5b was produced from
4b in 63% yield (entries 2–4). When R2 was a 2-methoxyphenyl
and ring A had a 3-methoxyl, competitive demethylation was
reduced and the desired cyclization occurred to afford 3-aryl-
benzofuran in a reasonable yield (entry 6). Additional methoxy
group at 4 or 5 position of ring A increased the product yields dra-
matically (entries 13 and 14). In addition, aryloxyketones 4k and 4l
Certainly, the formation of this benzofuran 2 can be rationalized
as depicted in Scheme 3. The initial coordination of BCl3 to the
carbonyl oxygen can induce subsequent steps in two ways. One
option is demethylation as can be seen in path a. Alternatively,
the nucleophilic attack of the neighboring aromatic moiety to the
carbonyl group followed by dehydration would lead to benzofuran
2 (path b). Obviously, the rate of cyclization seemed to be faster
than that of demethylation in this case. Intrigued by this result,
we decided to further explore the generality of this reaction with
other aryloxyketones.
The requisite aryloxyketones were easily prepared from the
reaction of phenols or naphthols with aa-bromoketones in the

I. Kim et al. / Tetrahedron Letters 49 (2008) 6579–6584
6583
Kizirgil, A.; Kazaz, C. Eur. J. Med. Chem. 2008, 43, 300; (c) Filzen, G. F.; Bratton,
L.; Cheng, X.-M.; Erasga, N.; Geyer, A.; Lee, C.; Lu, G.; Pulaski, J.; Sorenson, R. J.;
Unangst, P. C.; Trivedi, B. K.; Xu, X. Bioorg. Med. Chem. Lett. 2007, 17, 3630; (d)
Salih, K. S. M.; Ayoub, M. T.; Saadeh, H. A.; Al-Masoudi, N. A.; Mubarak, M. S.
Heterocycles 2007, 717, 1577; (e) Dixit, M.; Tripathi, B. K.; Tamrakar, A. K.;
Srivastava, A. K.; Kumar, B.; Goel, A. Bioorg. Med. Chem. 2007, 15, 727.
6. For recent examples, see: (a) Huang, X.-C.; Liu, Y.-L.; Liang, Y.; Pi, S.-F.; Wang,
F.; Li, J.-H. Org. Lett. 2008, 10, 1525; (b) Fürstner, A.; Davies, P. W. J. Am. Chem.
Soc. 2005, 127, 15024; (c) Yue, D.; Yao, T.; Larock, R. C. J. Org. Chem. 2005, 70,
10292; (d) Kraus, G. A.; Schroeder, J. D. Synlett 2005, 2504; (e) Lu, K.; Luo, T.;
Xiang, Z.; You, Z.; Fathi, R.; Chen, J.; Yang, Z. J. Comb. Chem. 2005, 7, 958; (f)
Kraus, G. A.; Kim, I. Org. Lett. 2003, 5, 1191; g Nicolaou, K. C.; Snyder, S. A.; Bigot,
A.; Pfefferkorn, J. Angew. Chem., Int. Ed. 2000, 39, 1093.
7. Chen, Z.; Wang, X.; Lu, W.; Yu, J. Synlett 1991, 121.
8. Although BBr3 was used to make benzofurans via demethylation and
cyclodehydration, only four examples are shown and the yields are low.
Dupont, R.; Cotelle, P. Synthesis 1999, 1651.
9. General procedure: To a stirred solution of 4 (0.4 mmol) in CH2Cl2 (3 mL) was
added BCl3 (1.2 equiv, 1.0 M solution in CH2Cl2) at ꢀ78 °C. After being stirred at
rt for 1 h, the reaction mixture was quenched with cold H2O. The mixture was
extracted with CH2Cl2 two times. The combined organic layers were dried over
MgSO4, and concentrated under reduced pressure. The resulting residue was
purified by silica gel column chromatography to give the benzofuran or
naphthofuran 5.
10. Spectral data: 5a: 1H NMR (300 MHz, CDCl3) d 7.84 (dd, J = 7.6, 1.7 Hz, 1H), 7.78
(s, 1H), 7.64 (d, J = 7.3 Hz, 2H), 7.54 (dd, J = 7.6, 1.2 Hz, 1H), 7.47 (t, J = 7.5 Hz,
2H), 7.40–7.26 (m, 3H); 13C NMR (75 MHz, CDCl3) d 155.8, 141.3, 132.1, 129.0,
127.5, 127.4, 126.5, 124.6, 123.0, 122.3, 120.4, 111.8; HRMS (EI) calcd for
[C14H10O]+: m/z 194.0732, found: 194.0736. Compound 5b: 1H NMR (300 MHz,
CDCl3) d 7.79 (s, 1H), 7.64 (d, J = 8.1 Hz, 2H), 7.50–7.32 (m, 4H), 7.23 (t,
J = 7.9 Hz, 1H), 6.86 (d, J = 7.6 Hz, 1H), 4.04 (s, 3H); 13C NMR (75 MHz, CDCl3) d
145.7, 145.2, 141.4, 132.0, 128.9, 128.2, 127.5, 127.4, 123.7, 122.7, 122.7, 106.6,
56.1; HRMS (EI) calcd for [C15H12O2]+: m/z 224.0837, found: 224.0835.
Compound 5c: 1H NMR (300 MHz, CDCl3) d 7.68 (s, 1H), 7.67 (d, J = 8.6 Hz,
1H), 7.61 (dd, J = 8.3, 1.4 Hz, 2H), 7.44 (t, J = 7.2 Hz, 2H), 7.37–7.29 (m, 1H), 7.05
(d, J = 2.2 Hz, 1H), 6.93 (dd, J = 8.7, 2.3 Hz, 1H), 3.82 (s, 3H); 13C NMR (75 MHz,
CDCl3) d 158.2, 156.9, 140.4, 132.3, 129.0, 127.4, 127.3, 122.1, 120.6, 119.8,
112.1, 96.2, 55.7; HRMS (EI) calcd for [C15H12O2]+: m/z 224.0837, found:
224.0833. Compound 5d: 1H NMR (300 MHz, CDCl3) d 7.75 (s, 1H), 7.64–7.58
(m, 2H), 7.52–7.41 (m, 3H), 7.40–7.33 (m, 1H), 7.26 (d, J = 2.6 Hz, 1H), 6.96 (dd,
J = 8.9, 2.6 Hz, 1H), 3.85 (s, 3H); 13C NMR (75 MHz, CDCl3) d 156.3, 150.8, 142.2,
132.2, 129.0, 127.5, 127.4, 127.0, 122.4, 113.3, 112.2, 102.9, 56.0; HRMS (EI)
calcd for [C15H12O2]+: m/z 224.0837, found: 224.0839. Compound 5e: 1H NMR
(300 MHz, CDCl3) d 7.94 (s, 1H), 7.73 (dd, J = 7.4, 1.8 Hz, 1H), 7.63 (dd, J = 7.5,
1.7 Hz, 1H), 7.54 (dd, J = 8.0, 1.1 Hz, 1H), 7.38–7.21 (m, 3H), 7.10–7.00 (m, 2H),
3.87 (s, 3H); 13C NMR (75 MHz, CDCl3) d 156.8, 155.2, 143.8, 130.0, 128.5,
127.2, 124.1, 122.6, 121.2, 120.9, 120.8, 117.5, 111.6, 111.2, 55.5; HRMS (EI)
calcd for [C15H12O2]+: m/z 224.0837, found: 224.0835. Compound 5f: 1H NMR
(300 MHz, CDCl3) d 7.86 (s, 1H), 7.65-7.56 (m, 2H), 7.33 (td, J = 7.9, 1.7 Hz, 1H),
7.10–6.97 (m, 3H), 6.90 (dd, J = 8.7, 2.3 Hz, 1H), 3.86 (s, 6H); 13C NMR (75 MHz,
CDCl3) d 157.9, 156.8, 156.1, 142.8, 129.8, 128.4, 121.4, 121.1, 120.8, 120.5,
117.4, 111.7, 111.2, 96.0, 55.7, 55.5; HRMS (EI) calcd for [C16H14O3]+: m/z
254.0943, found: 254.0946. Compound 5g: 1H NMR (300 MHz, CDCl3) d 7.39 (d,
J = 8.5 Hz, 1H), 7.33 (d, J = 1.2 Hz, 1H), 7.01 (d, J = 2.2 Hz, 1H), 6.90 (dd, J = 8.5,
2.2 Hz, 1H), 3.86 (s, 3H), 2.23 (s, 3H); 13C NMR (75 MHz, CDCl3) d 158.0, 156.2,
140.5, 122.5, 119.5, 115.5, 111.2, 96.0, 55.7, 7.9; HRMS (EI) calcd for
[C10H10O2]+: m/z 162.0681, found: 162.0683. Compound 5h: 1H NMR
(300 MHz, CDCl3) d 8.32 (d, J = 8.1 Hz, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.82 (d,
J = 8.5 Hz, 1H), 7.81 (s, 1H), 7.67 (d, J = 8.7 Hz, 1H), 7.63–7.53 (m, 3H), 7.48 (t,
J = 7.8 Hz, 1H), 7.00 (d, J = 8.4 Hz, 2H), 3.82 (s, 3H); 13C NMR (75 MHz, CDCl3) d
159.2, 151.3, 139.9, 131.5, 128.8, 128.3, 126.4, 125.3, 124.6, 123.5, 123.1, 122.1,
121.6, 120.1, 118.8, 114.5, 55.4; HRMS (EI) calcd for [C19H14O2]+: m/z 274.0994,
found: 274.0993. Compound 5i: 1H NMR (300 MHz, CDCl3) d 8.01 (d, J = 8.2 Hz,
1H), 7.90 (d, J = 7.8 Hz, 1H), 7.72 (d, J = 9.0 Hz, 1H), 7.66 (d, J = 9.0 Hz, 1H), 7.62
(s, 1H), 7.48 (d, J = 8.5 Hz, 2H), 7.43–7.31 (m, 2H), 7.01 (d, J = 7.8 Hz, 2H), 3.86
(s, 3H); 13C NMR (75 MHz, CDCl3) d 159.4, 153.1, 141.6, 131.0, 130.8, 128.9,
128.4, 125.9, 125.8, 125.2, 124.3, 124.0, 123.3, 121.0, 114.1, 112.7, 55.4; HRMS
(EI) calcd for [C19H14O2]+: m/z 274.0994, found: 274.0991. Compound 5j: 1H
Figure 2. Crystal structure of 5p.
bearing a 4-methoxyphenyl at R2 site underwent smooth dehydra-
tive cyclization to furnish excellent yields of 5k and 5l, respectively
(entries 11 and 12).
Methylketone 4g was transformed to the cyclized product 5g in
59% yield (entry 7). Naphthofurans were accessed in good yields
(entries 8 and 9). Interestingly, only one regioisomer 5i was iso-
lated in case of 4i.12,13 Substrates having substituents at both R2
and R3 positions also worked well under these conditions to give
the highly substituted benzofurans (entries 10 and 17). Biphenyl
containing benzofuran 5o was also prepared in 96% yield (entry
15). Intriguingly, one regioisomer 5p was isolated from the reac-
tion of 4p with BCl3 (entry 16).14 The structure of 5p was unambig-
uously determined on the basis of an X-ray crystallographic
analysis (Fig. 2).15
In summary, we discovered that boron trichloride (BCl3) is a
very mild and convenient reagent for the synthesis of benzofurans
and naphthofurans via dehydrative cyclization. By varying the
electron density and substitution pattern of the phenolic part of
aryloxyketones, we were able to find the structural requirement
for the successful cyclization even when competitive demethyl-
ation via coordination of BCl3 to the carbonyl functionality can
be possible. Currently, efforts are being made to apply this protocol
to the synthesis of benzofuran-containing natural products as well
as other heterocycles and will be reported in due course.
References and notes
1. (a) McCallion, G. D. Curr. Org. Chem. 1999, 3, 67; (b) Kadieva, M. G.; Oganesyan,
É. T. Chem. Heterocycl. Compd. 1997, 33, 1245; (c) Comprehensive Heterocyclic
Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon Press,
1996; Vol. 2, p 259; (d)Comprehensive Heterocyclic Chemistry; Katritzky, A. R.,
Rees, C. W., Eds.; Pergamon Press, 1984; Vol. 4, p 531.
2. Dai, J.-R.; Hallock, Y. F.; Cardellina, J. H., II; Boyd, M. R. J. Nat. Prod. 1998, 61, 351.
3. For the isolation of shoreaphenol, see: Saraswathy, A.; Purushothaman, K. K.;
Patra, A.; Dey, A. K.; Kundu, A. B. Phytochemistry 1992, 31, 2561; For the
isolation of hopeafuran, see: Tanaka, T.; Ito, T.; Ido, Y.; Nakaya, K.; Iinuma, M.;
Chelladurai, V. Chem. Pharm. Bull. 2001, 49, 785.
4. For the isolation of iantheran A, see: (a) Okamoto, Y.; Ojika, M.; Suzuki, S.;
Murakami, M.; Sakagami, Y. Bioorg. Med. Chem. 2001, 9, 179; (b) Okamoto, Y.;
Ojika, M.; Sakagami, Y. Tetrahedron Lett. 1999, 40, 507. For the isolation and
biological studyof other iantherans, see: (c) Greve, H.; Meis, S.; Kassack, M. U.;
Kehraus, S.; Krick, A.; Wright, A. D.; König, G. M. J. Med. Chem. 2007, 50, 5600.
5. For selected examples, see: (a) Rizzo, S.; Riviere, C.; Piazzi, L.; Bisi, A.; Gobbi, S.;
Bartolini, M.; Andrisano, V.; Morroni, F.; Tarozzi, A.; Monti, J.-F.; Rampa, A. J.
Med. Chem. 2008, 51, 2883; (b) Kirilmis, C.; Ahmedzade, M.; Servi, S.; Koca, M.;
NMR (300 MHz, CDCl3)
d 7.52–7.40 (m, 5H), 7.37–7.29 (m, 1H), 7.00 (d,
J = 2.2 Hz, 1H), 6.84 (dd, J = 8.6, 2.3 Hz, 1H), 3.84 (s, 3H), 2.49 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 157.6, 154.9, 150.2, 133.0, 128.8, 128.7, 127.0, 122.2, 119.5,
116.6, 111.2, 95.9, 55.8, 12.8; HRMS (EI) calcd for [C16H14O2]+: m/z 238.0994,
found: 238.0991. Compound 5k: 1H NMR (300 MHz, CDCl3) d 7.52 (dt, J = 8.8,
2.1 Hz, 2H), 7.42 (s, 1H), 6.77 (dt, J = 8.8, 2.1 Hz, 2H), 6.95 (d, J = 2.0 Hz, 1H),
6.34 (d, J = 2.0 Hz, 1H), 3.83 (s, 6H), 3.78 (s, 3H); 13C NMR (75 MHz, CDCl3) d
159.1, 158.9, 157.8, 154.7, 139.3, 130.4, 124.8, 122.3, 113.4, 110.0, 94.5, 88.3,
55.7, 55.4, 55.3; HRMS (EI) calcd for [C17H16O4]+: m/z 284.1049, found:
284.1053. Compound 5l: 1H NMR (300 MHz, CDCl3) d 7.63 (s, 1H), 7.53 (dd,
J = 8.2, 0.7 Hz, 2H), 7.18 (s, 1H), 7.09 (s, 1H), 7.02 (dd, J = 8.3, 0.7 Hz, 2H), 3.95 (s,
3H), 3.93 (s, 3H), 3.87 (s, 3H); 13C NMR (75 MHz, CDCl3) d 159.0, 150.4, 148.2,
146.7, 139.7, 128.5, 124.7, 122.0, 118.5, 114.5, 101.6, 95.6, 56.5, 56.2, 55.3;
HRMS (EI) calcd for [C17H16O4]+: m/z 284.1049, found: 284.1055. Compound
5m: 1H NMR (300 MHz, CDCl3) d 7.57 (s, 1H), 7.48 (dd, J = 7.4, 1.7 Hz, 1H), 7.35
(td, J = 7.6, 1.8 Hz, 1H), 7.04 (dd, J = 7.5, 0.9 Hz, 1H), 6.99 (d, J = 8.0 Hz, 1H), 6.71
(d, J = 2.0 Hz, 1H), 6.35 (d, J = 1.9 Hz, 1H), 3.88 (s, 3H), 3.82 (s, 3H), 3.75 (s, 3H);
13C NMR (75 MHz, CDCl3) d 159.2, 157.8, 157.5, 155.0, 141.2, 132.1, 128.8,

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I. Kim et al. / Tetrahedron Letters 49 (2008) 6579–6584
121.7, 120.2, 117.8, 111.3, 110.8, 94.8, 88.5, 56.0, 55.7, 55.6; HRMS (EI) calcd
11. Exposure of 4e to 3 equiv of BCl3 led to the only demethylated product 5e0.
for [C17H16O4]+: m/z 284.1049, found: 284.1055. Compound 5n: 1H NMR
(300 MHz, CDCl3) d 7.81 (s, 1H), 7.57 (dd, J = 7.5, 1.7 Hz, 1H), 7.34 (td, J = 7.5,
1.8 Hz, 1H), 7.13 (s, 1H), 7.09 (dd, J = 7.5, 1.1 Hz, 1H), 7.08 (s, 1H), 7.04 (d,
J = 7.9 Hz, 1H), 3.93 (s, 3H), 3.90 (s, 3H), 3.86 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 156.8, 149.9, 148.0, 146.4, 142.7, 129.9, 128.5, 121.2, 120.8, 119.1, 117.9,
111.3, 102.8, 95.4, 56.5, 56.3, 55.4; HRMS (EI) calcd for [C17H16O4]+: m/z
284.1049, found: 284.1047. Compound 5o: 1H NMR (300 MHz, CDCl3) d 7.80–
7.60 (m, 5H), 7.55 (d, J = 2.4 Hz, 1H), 7.46 (td, J = 7.8, 1.6 Hz, 2H), 7.35 (td,
J = 7.4, 1.9 Hz, 1H), 7.26 (d, J = 2.5 Hz, 1H), 6.71 (t, J = 2.1 Hz, 1H), 6.38 (t, J = 2.1
Hz, 1H), 3.88 (s, 3H), 3.84 (s, 3H); 13C NMR (75 MHz, CDCl3) d 159.2, 158.0,
154.7, 141.0, 140.0, 139.9, 131.4, 129.6, 128.8, 127.2, 127.1, 126.7, 126.8, 122.5,
109.8, 94.6, 88.4, 55.8, 55.4; HRMS (EI) calcd for [C22H18O3]+: m/z 330.1256,
found: 330.1255. Compound 5p: 1H NMR (300 MHz, CDCl3) d 7.55 (s, 1H), 7.35
(d, J = 2.3 Hz, 1H), 7.25 (d, J = 8.3 Hz, 2H), 7.21 (d, J = 1.3 Hz, 1H), 6.95 (d,
J = 8.7 Hz, 2H), 3.89 (s, 3H), 3.85 (s, 3H), 3.29 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 167.6, 158.9, 157.3, 157.0, 142.9, 129.6, 125.7, 125.4, 122.4, 119.0, 113.6,
113.0, 100.2, 56.0, 55.3, 51.6; HRMS (EI) calcd for [C18H16O5]+: m/z 312.0998,
found: 312.0996. Compound 5q: 1H NMR (300 MHz, CDCl3) d 6.57 (s, 1H), 6.26
(s, 1H), 3.83 (s, 3H), 3.81 (s, 3H), 2.80–2.70 (m, 2H), 2.70–2.60 (m, 2H), 1.95–
1.83 (m, 2H), 1.83–1.70 (m, 2H); 13C NMR (75 MHz, CDCl3) d 158.0, 155.9,
154.1, 151.0, 112.2, 112.1, 93.6, 88.4, 55.7, 55.4, 23.3, 23.0, 22.9, 22.2; HRMS
(EI) calcd for [C14H16O3]+: m/z 232.1099, found: 232.1097.
O
OH
O
5e'
12. Mashiraqui, S. H.; Patil, M. B.; Sangvikar, Y.; Ashraf, M.; Mistry, H. D.; Daub, E. T.
H.; Meetsma, A. J. Heterocycl. Chem. 2005, 42, 947. 45% isolated yield of 5i upon
treatment of 4i with CH3SO3H was reported in this Letter.
13. For other synthesis and biological evaluation of 5i as a novel anticancer agent,
see: Srivastava, V.; Negi, A. S.; Kumar, J. K.; Faridi, U.; Sisodia, B. S.; Darokar, M.
P.; Luqman, S.; Khanuja, S. P. S. Bioorg. Med. Chem. Lett. 2006, 16, 911.
14. No reaction took place with 1 equiv of BCl3, which is believed to be consumed
as a consequence of the coordination to the ester moiety in 4p.
15. CCDC 694499 contains the supplementary crystallographic data for compound
5p. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.