A convenient synthesis of 2-substituted benzofurans from salicylaldehydes

Article abstract of DOI:10.1039/c4ra14948c

Base-mediated cyclocondensation of 2-hydroxybenzaldehydes with 3-bromo-1-(arylsulfonyl)propenes and 4-bromocrotonates afforded (E)-2-(2-sulfonylvinyl)benzofurans and (E)-2-benzofuranyl-3-acrylates respectively.

Full text of DOI:10.1039/c4ra14948c

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ARTICLE
A Convenient Synthesis of 2-Substituted Benzofurans
from Salicylaldehydes
Cite this: DOI: 10.1039/x0xx00000x
Swetha Reddy,a Srinivas Thadkapally,a Mounika Mamidyala,a Jagadeesh Babu
Nanubolub and Rajeev S. Menon*a
Received 00th January 2012,
Accepted 00th January 2012
Baseꢀmediated
(arylsulfonyl)propenes and 4ꢀbromocrotonates afforded (
and ( )ꢀ2ꢀbenzofuranylꢀ3ꢀacrylates respectively. Previous reports of benzoxepine formation in
the latter case were found to be incorrect.
cyclocondensation
of
2ꢀhydroxybenzaldehydes
with
3ꢀbromoꢀ1ꢀ
E
)ꢀ2ꢀ(2ꢀsulfonylvinyl)benzofurans
DOI: 10.1039/x0xx00000x
E
www.rsc.org/
Introduction
As part of a program in screening heterocycles for developing
new anticancer therapeutics, we were interested in investigating
the cytotoxicity profile of 4ꢀsulfonylꢀ1ꢀbenzoxepine derivatives
1
(Figure 1). The benzoxepine framework is found in a number
of important natural products1 and 1ꢀbenzoxepine derivatives
are known to exhibit biological activities such as estrogen
regulator modulation.2
Figure 1: 4-sulfonyl-1-benzoxepine framework
Scheme 1: Planned synthesis of 1 (eq.1) and reported syntheses of its carboxy-
analogue 2 (eq.2)
A straightforward assembly of the 1ꢀbenzoxepine framework
was envisaged as depicted in Scheme 1 (eq. 1) in order to
generate a library of derivatives for biological screening. This
synthetic plan was adapted from the reports by Ciganek3 and
Zeitler4 that described the formation of the corresponding
carboxylate esters (eq. 2, Scheme 1). For example, 4ꢀ
Results and Discussion
The attempted synthesis of
alkylation of salicylaldehyde 4a with the previously described
bromide 5a 5
This seemingly straightforward Oꢀalkylation,
1 began with baseꢀmediated Oꢀ
.
methoxycarbonylꢀ1ꢀbenzoxepine
2 has been synthesized by
however, afforded a mixture of products that were difficult to
separate from each other by chromatography (The mixture of
products arises presumably due to the baseꢀcatalyzed
isomerization of the vinyl sulfone moiety into the
corresponding allyl sulfone6 subsequent to the alkylation)
Pleasingly, it was found that this mixture can be converted into
a single product by exposing it again to base for a longer period
of time. Further experiments revealed that the isolation of the
Oꢀalkylated intermediate was not necessary, as prolonged
treatment of salicylaldehyde 4a and the bromosulfone 5a with 2
equivalents of cesium carbonate in acetonitrile for 12h resulted
in the formation of a single product. Spectroscopic analysis,
baseꢀmediated cyclization of the salicylaldehydeꢀderived ester
3
.
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VJieowuArrtnicalelONnlainme e
DOI: 10.1039/C4RA14948C
however, indicated that the product is the benzofuran derivative
6aa (Scheme 2).
The annulation reaction appears to be general affording 2ꢀ(2ꢀ
sulfonylvinyl)benzofurans
6 in moderate to good yields. It is
noteworthy that 2ꢀfunctionalized benzofurans can be accessed
in a oneꢀpot operation from readily available starting materials,
albeit in moderate yields. Out of the four substituted
salicylaldehydes employed, 5ꢀnitrosalicylaldehyde 4d failed to
react under the optimized conditions, presumably due to the
sluggish
Oꢀalkylation of the rather stable oꢀformylꢀpꢀ
nitrophenolate intermediate.
Thus it was evident that the approach3ꢀ4 that led to 4ꢀ
methoxycarbonylꢀ1ꢀbenzoxepins (Scheme 1) was not suitable
for the construction of the corresponding sulfonyl derivatives.
Scheme 2: Formation of 2-substituted benzofuran from salicylaldehyde
In the 1H NMR spectrum of 6aa, the olefinic proton adjacent to
This was surprising when the known propensity of
sulfones to undergo baseꢀmediated isomerisation to
E
Z
ꢀvinyl
ꢀallyl
the sulfonyl group resonated at
coupling constant of 15.0 Hz, confirming the presence of a
δ 7.57 as a doublet with
sulfones6 was taken into consideration. The unanticipated
outcome of this reaction prompted us to investigate the
trans double bond. The remaining olefinic hydrogen resonated
along with four of the aromatic protons (
resonance corresponding to the benzofuranꢀ3ꢀH was discernible
at 7.04 (1H). All other signals were in agreement with the
assigned structure.
δ 7.65ꢀ7.55). A singlet
previously
salicylaldehyde and methylꢀ4ꢀbromocrotonate. Thus, the ester
derived from salicylaldehyde when subjected to the
described
benzoxepine
formation
from
δ
3,
cyclocondensation conditions as reported by Ciganek3 and
Natural and manmade molecules containing the benzofuran Zeitler,4 afforded the benzofuran derivative 7aa (Scheme 4).
nucleus exhibit a wide range of biological activities.7 This
includes, inter alia, antifungal,8a analgesic,8b antipsychotic8c and
antimitotic8d activities. Therefore, the aboveꢀdescribed
annulation reaction that affords a benzofuran
6 endowed with a
functionalizable handle at the 2ꢀposition appeared worth
pursuing. Thus, a number of substituted salicylaldehydes 4a-d
was treated with
γꢀbromovinyl sulfones 5a-b under the
optimized reaction conditions. The results are summarized in
table 1.
Scheme 4: Benzofuran formation via base-mediated annulation of
3
The product 7aa was characterized by spectroscopic analysis.9
1
In the H NMR, the olefinic protons were discernible as two
mutually coupled doublets (J = 15.7 Hz) at
3ꢀbenzofuranyl hydrogen resonated at
may be pointed out here that the spectroscopic data reported by
Ciganek3 for the compound
matches with that obtained for
δ
7.56 and 6.58. The
δ
6.94 as a singlet. It
2
7aa in our laboratory. Most significantly, the presence of a
mutually coupled pair of trans olefinic protons is inconsistent
with the reported3 benzoxepine structure
2
. Thus, in view of the
new evidence, it may be concluded that the baseꢀmediated
cyclocondensation of leads to the benzofuran derivative 7aa
instead of the benzoxepine 2 10
Entr
y
Aldehyde
4
Bromide
5
Product
6
Yielda
3
.
Optimization experiments revealed that the substituted
benzofuran derivatives could be prepared in a oneꢀpot operation
by treating substituted salicylaldehydes 4a-d and 4ꢀ
1
62%
52%
55%
51%
53%
50%
0b
4a
4a
4b
4b
4c
4c
4d
4d
5a
5b
5a
5b
5a
5b
5a
5b
6aa
6ab
6ba
6bb
6ca
6cb
6da
6db
2
bromocrotonates 8a-b with
2
equivalents of 1,8ꢀ
3
diazabicycloundecꢀ7ꢀene (DBU) in acetonitrile at room
temperature (Table 2).
As depicted in table 2, the oneꢀpot alkylationꢀannulation
reaction can be extended to substituted salicylaldehydes. The
4
5
benzofuran derivatives
7 are formed in moderate to good yields.
6
It is important to note that the yields reported here correspond
to the overall yield of two reactions, ie, Oꢀalkylation and
cyclization.
7
8
0b
aisolated yield after chromatography; b4d along with mixture of
unidentified products were obtained.
Table 1: One-pot synthesis of 2-(2-sulfonylvinyl)benzofurans
2 | J. Name., 2012, 00, 1-3
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ARTICLE
DOI: 10.1039/C4RA14948C
R1
Br
NC
O
R1
CHO
OH
DBU
MeO2C
7aa
NaH
O S
CO2R2
CH3CN, rt
12 h
O
R2O2C
8a-b
2
4a-d
1
4a
, R = H
7aa-db
DMSO:THF
25 °C, 6h
NH
O
1
4b
, R = Cl,
4c, R1 = OMe
4d, R1 = NO2
9
8a
8b
, R = Me
2
Me
Scheme 5: Synthesis of a 3,4-disubstituted pyrrole from 7aa
52% (86% brsm)
, R = Et
Entry
Aldehyde
4
Bromide
8
Product
7
Yielda
Conclusions
1
2
3
4
5
6
7
8
61%
71%
57%
56%
53%
55%
42%
45%
4a
4a
4b
4b
4c
4c
4d
4d
8a
7aa
7ab
7ba
7bb
7ca
7cb
7da
7db
In conclusion, a convenient oneꢀpot method for the synthesis of
2ꢀalkenyl
(arylsulfonyl)propenes
substituted
benzofurans
or 4ꢀbromocrotonates
from
3ꢀbromoꢀ1ꢀ
and
8b
8a
8b
8a
8b
8a
8b
salicylaldehydes was developed. It is noteworthy that both the
salicylaldehydes and 4ꢀbromocrotonates are commercially
available and the benzofurans generated are amenable to further
functionalization. The “pluripotent” phenylsulfonyl functional
group13 has been termed as “arguably the most versatile
functional group” and it is reasonable to assume that the
benzofurans
6 possessing this functional group could also be
employed in further transformations.
Experimental
General Information
1
All H NMR and 13C NMR spectra were recorded in CDCl3
solvent on Varian Bruker 300 MHz, a Varian Unity 400 MHz
and Avance 500 MHz spectrometer at ambient temperature. IR
spectra were recorded on Nicolet 380 FTꢀIR spectrophotometer.
Mass spectra were obtained on a Finnegan Mat1020B, a
micromass VG 70ꢀ70H or an Agilent technologies LC/MSD
treapSL spectrometer operating at 70eV using the direct inlet
system and high resolution mass spectra (HRMS) were
recorded on a QSTAR XL Hybrid MS/MS mass spectrometer.
Melting points were recorded on an electrothermal apparatus
and are uncorrected. All the reagents and solvents were used
without further purification unless specified otherwise.
Technical grade ethyl acetate and petroleum ether used for
column chromatography were distilled prior to use. Column
chromatography was carried out using silica gel (60ꢀ120 mesh
and 100ꢀ200 mesh) packed in glass columns. All reactions were
performed in ovenꢀdried glassware with magnetic stirring.
Salicylaldehydes (4a-d), methylꢀ4ꢀbromocrotonates (8a, 85%
aisolated yield after chromatography
Table 2: One-pot synthesis of (E)-2-benzofuranyl-3-acrylates
Additionally, unambiguous evidence for the assigned structure
(7) was obtained from single crystal Xꢀray analysis of a
representative compound 7cb (Figure 2).11
technical grade) and ethylꢀ4ꢀbromocrotonates
(8b, 75%
technical grade) used in the study were obtained from Aldrich
and were used as received. 4ꢀ(2ꢀFormylphenoxy)ꢀbutꢀ2ꢀenoate
Figure 2: ORTEP diagram of 7cb
3
was prepared by potassium carbonateꢀmediated alkylation of
salicylaldehyde 4a with (E)ꢀ3ꢀbromoꢀ1ꢀ
8a 3
.
(arylsulfonyl)propenes 5a-b were prepared as described by
Gallagher and Grayson.14
The
α,βꢀunsaturated ester functionality offers a number of
possibilities of further synthetic manipulations. For example,
treatment of the benzofuran 7aa with van Leusen’s reagent12
(tosylmethyl isocyanide) in presence of base afforded the 3,4ꢀ
General procedure for the synthesis of 2-(
sulfonylvinyl)benzofurans 6aa-cb
β-
disubstituted pyrrole derivative
on recovered stating material).
9 in 86% isolated yield (based
Cesium carbonate (326 mg, 1 mmol) was added to a solution of
salicylaldehyde 4a-d (0.5 mmol) and 3ꢀbromoꢀ1ꢀ
(arylsulfonyl)propene 5a-b (0.5 mmol) in anhydrous
acetonitrile (5mL). The resulting solution was stirred at ambient
temperature for 12h. The reaction mixture was then partitioned
between dichloromethane and ice cold water, and aqueous
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ARTICLE
DOI: 10.1039/C4RA14948C
phase was extracted with ethyl acetate. The combined organic 1621, 1593, 1475, 1463, 1317, 1304, 1221, 1193, 1140, 1085,
phases were dried with anhydrous sodium sulfate and 964, 860, 832, 811, 785 cmꢀ1 1H NMR (500 MHz, CDCl3) δ:
;
concentrated under reduced pressure. Column chromatography 7.83 (d,
J
= 8.2 Hz, 2H), 7.50 (d,
J
= 15.0 Hz, 1H), 7.35 (d,
J =
on silica gel using petroleum etherꢀethyl acetate as eluent 8.2 Hz, 2H), 7.31 (d,
J
= 9.0 Hz, 1H), 7.01 (d, J = 2.4 Hz, 1H),
afforded
analytically
pure
samples
of
2ꢀ(2ꢀ 6.98ꢀ6.94 (m, 3H), 3.83 (s, 3H(, 2.44 (s, 3H); 13C NMR (75
MHz, CDCl3) δ: 156.4, 150.9, 144.5, 137.7, 130.0, 128.7,
128.6, 127.9, 127.7, 116.5, 113.0, 112.0, 103.6, 55.9, 21.6;
sulfonylvinyl)benzofurans 6aa-6cb
.
(
E
)ꢀ2ꢀ[2ꢀ(phenylsulfonyl)vinyl]benzofuran
(6aa). Compound HRMS calcd for C18H16O4SNa (M+Na) 351.0667; found
6aa (88 mg, 62%) was obtained as a yellow crystalline solid; 351.0664.
°
Mp. 123ꢀ125 C (CH2Cl2ꢀhexane); IR νmax (KBr): 3448, 2924,
General procedure for the synthesis of 2-(
alkoxycarbonylvinyl)benzofurans 7aa-db
β-
2853, 1736, 1620, 1468, 1316, 1287, 1213, 1154, 1085, 1026,
1
954, 86, 827cmꢀ1; H NMR (500 MHz, CDCl3) δ: 7.97 (d,
J
J
=
=
J
8.7 Hz, 2H), 7.65ꢀ7.55 (m, 5H), 7.44ꢀ7.42 (m, 1H), 7.37 (dt,
DBU (152 mg, 1 mmol) was added to a solution of
salicylaldehyde 4a-d (0.5 mmol) and the 4ꢀbromocrotonate
7.2 Hz, 1.2 Hz, 1H), 7.27ꢀ7.24 (m, 1H), 7.04 (s, 1H), 7.01 (d,
= 15.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ: 155.7, 150.0,
140.4, 133.5, 129.4, 129.1, 127.9, 127.7, 127.6, 127.1, 123.6,
122.1, 113.2, 111.4; HRMS calcd for C16H13O3SNa(M+Na)
307.0405; found 307.0392.
ester
8 (0.5 mmol; 0.07 mL for 8a and 0.09 mL for 8b) in
anhydrous acetonitrile (5mL). The resulting solution was stirred
at ambient temperature for 12h. The reaction mixture was then
partitioned between dichloromethane and ice cold water, and
aqueous phase was extracted with ethyl acetate. The combined
organic phases were dried with anhydrous sodium sulfate and
concentrated under reduced pressure. Column chromatography
on silica gel using petroleum etherꢀethyl acetate as eluent
afforded analytically pure samples of 2ꢀsubstituted benzofurans
(E)ꢀ2ꢀ(2ꢀtosylvinyl)benzofuran (6ab). Compound 6ab (78 mg,
°
52%) was obtained as a pale yellow solid; Mp. 138ꢀ140 C
(CH2Cl2ꢀhexane); IR max (KBr): 2924, 2853, 1743, 1593, 1448,
1317, 1292, 1141, 1085, 954, 884, 852, 810, 795, 754 cmꢀ1; H
NMR (500 MHz, CDCl3) δ: 7.84 (d, = 8.4 Hz, 2H), 7.59 (d,
= 7.8 Hz, 1H), 7.54 (d, = 15.0 Hz, 1H), 7.42 (dd, = 8.4 Hz,
0.8 Hz, 1H), 7.38ꢀ7.34 (m, 3H), 7.27ꢀ7.23 (m, 1H), 7.02 (s,
1H), 7.00 (d,
= 15.0 Hz, 1H), 2.44 (s, 3H); 13C NMR (75
ν
1
J
J
J
J
7aa-7db
)ꢀmethyl 3ꢀ(benzofuranꢀ2ꢀyl)acrylate (7aa). Compound 7aa
(62 mg, 61%) was obtained as an offꢀwhite solid; Mp. 83ꢀ85
°C15 (CH2Cl2ꢀhexane); IR
max (KBr): 3408, 2923, 2852, 1712,
.
(
E
J
MHz, CDCl3) δ 150.2, 144.5, 137.6, 133.3, 130.0, 128.6, 128.2,
128.0, 127.8, 127.0, 123.6, 122.0, 112.9, 111.4, 21.6; HRMS
calcd for C17H14O3SNa (M+Na) 321.0561; found 321.0565.
ν
1634, 1451, 1329, 1290, 1266, 1165, 1124, 1007, 977, 951,
826, 750 cmꢀ1; H NMR (300 MHz, CDCl3) δ: 7.60ꢀ7.53 (m,
1
(
E
)ꢀ5ꢀchloroꢀ2ꢀ[2ꢀ(phenylsulfonyl)vinyl]benzofuran
(6ba).
2H), 7.49 (d,
J
= 8.1 Hz, 1H), 7.36 (t,
J
= 7.6 Hz, 1H), 7.26ꢀ
Compound 6ba (87 mg, 55%) was obtained as a pale yellow
7.22 (m, 1H), 6.94 (s, 1H) 6.58 (d,
J = 15.7 Hz, 1H), 3.82 (s,
°
3H); 13C NMR (125 MHz, CDCl3) δ: 167.1, 155.5, 152.2,
131.5, 128.3, 126.4, 123.3, 121.7, 118.4, 111.4, 111.2, 51.8;
HRMS calcd for C12H11O3(M+H) 203.0708; found 203.0694.
solid; Mp. 164ꢀ166 C (CH2Cl2ꢀhexane); IR νmax (KBr): 3442,
2924, 2853, 1741, 1624, 1445, 1321, 1149, 1085, 966, 951,
858, 827, 796 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ: 7.96 (d,
8.3 Hz, 2H), 7.67ꢀ7.52 (m, 5H), 7.37ꢀ7.32 (m, 2H), 7.02 (d,
J
J
=
=
(
E
)ꢀethyl 3ꢀ(benzofuranꢀ2ꢀyl)acrylate (7ab). Compound 7ab
(77 mg, 71%) was obtained as a pale yellow solid; Mp. 73ꢀ75
°C16 (CH2Cl2ꢀhexane); IR
max (KBr): 3411, 2922, 2851, 1717,
15.1 Hz, 1H), 6.98 (s, 1H); 13C NMR (75 MHz, CDCl3) δ:
154.0, 151.4, 140.3, 133.6, 129.4, 129.2, 128.8, 128.6, 127.8,
ν
127.3,
121.5,
112.5,
112.3;
HRMS
calcd
for
1643, 1550, 1450, 1367, 1299, 1290, 1257, 1161, 1123, 1022,
978, 949, 872, 826, 753 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ:
C16H11ClO3SNa(M+Na) 341.0015; found 341.0007.
(
E)ꢀ5ꢀchloroꢀ2ꢀ(2ꢀtosylvinyl)benzofuran (6bb). Compound 6bb
7.58 (d,
8.2 Hz, 1H), 7.26ꢀ7.21 (m, 1H), 6.93 (s, 1H), 6.58 (d,
Hz, 1H), 4.28 (q, = 7.2 Hz, 2H), 1.35 (t,
= 7.2 Hz, 3H); 13C
J
= 7.0 Hz, 1H), 7.54 (d,
J
= 15.7 Hz, 1H), 7.35 (t,
J =
°
(
85 mg, 51%) was obtained as a brown solid; Mp. 157ꢀ159 C
max (KBr): 3436, 2924, 2853, 1743, 1626,
1595, 1465, 1300, 1152, 1084, 964, 856, 827, 801, 723 cmꢀ1; 1H
NMR (300 MHz, CDCl3) δ: 7.83 (d, = 8.4 Hz, 2H), 7.56 (d,
= 2.6 Hz, 1H), 7.51 (d, = 15.0 Hz, 1H), 7.37ꢀ7.34 (m, 3H),
7.31 (dd, = 15.0 Hz, 1H),
J
= 15.7
(CH2Cl2ꢀhexane); IR
ν
J
J
NMR (125 MHz, CDCl3) δ 166.7, 155.5, 152.3, 131.2, 128.3,
126.4, 123.3, 121.7, 119.0, 111.4, 111.0, 60.6, 14.3; HRMS
calcd for C13H13O3 (M+H) 217.0865; found 217.0860.
J
J
J
J
= 8.7 Hz, 2.0 Hz, 1H), 7.01 (d, J
(
E
)ꢀmethyl
3ꢀ(5ꢀchlorobenzofuranꢀ2ꢀyl)acrylate
(7ba).
2.44 (s, 3H); 13C NMR (75 MHz, CDCl3) δ: 154.0, 151.5,
144.7, 138.7, 137.3, 130.1, 129.3, 129.2, 128.1, 127.8, 127.2,
121.5, 112.4, 112.0, 21.6; HRMS calcd for C17H14ClO3S(M+H)
333.0352; found 333.0336.
Compound 7ba (67 mg, 57%) was obtained as a white solid;
°
Mp. 160ꢀ162 C (CH2Cl2ꢀhexane); IR
2852, 1729, 1642, 1488, 1441, 1304, 1253, 1089, 1168, 1059,
965, 859, 805cmꢀ1; 1H NMR (300 MHz, CDCl3) δ: 7.55 (d,
2.0 Hz, 1H), 7.53 (d, = 15.7 Hz, 1H), 7.40 (d, J = 8.9 Hz, 1H),
7.31 (dd, = 8.9, 2.0 Hz, 1H), 6.88 (s, 1H), 6.58 (d, J = 15.7
νmax (KBr): 3412, 2923,
J
=
(
E
)ꢀ5ꢀmethoxyꢀ2ꢀ[2ꢀ(phenylsulfonyl)vinyl]benzofuran
(6ca).
J
Compound 6ca (83 mg, 53%) was obtained as a dark yellow
J
°
Hz, 1H), 3.82 (s, 3H); 13C NMR (75 MHz, CDCl3) δ: 166.9,
153.8, 153.6, 131.0, 129.6, 128.9, 126.6, 121.2, 119.5, 112.4,
110.3, 51.9; HRMS calcd for C12H10ClO3 (M+H) 237.0318;
found 237.0312.
crystalline solid; Mp. 180ꢀ182 C (CH2Cl2ꢀhexane); IR νmax
(KBr): 3448, 2924, 2853, 1736, 1620, 1468, 1316, 1287, 1212,
1
1196, 1168, 1154, 1085, 1025, 954, 861, 827 cmꢀ1; H NMR
(500 MHz, CDCl3) δ: 7.96 (d,
1H), 7.57ꢀ7.53 (m, 3H), 7.31 (d,
J
= 8.7 Hz, 2H), 7.65ꢀ7.61 (m,
= 9.0 Hz, 1H), 7.01 (d, J =
J
(
E
)ꢀethylꢀ3ꢀ(5ꢀchlorobenzofuranꢀ2ꢀyl)acrylate
(7bb).
2.7 Hz, 1H), 6.99ꢀ6.96 (m, 3H) 3.83 (s, 3H); 13C NMR (75
MHz, CDCl3) δ: 156.3, 150.8, 150.7, 133.4, 129.3, 129.1,
128.5, 127.7, 127.3, 116.6, 113.3, 112.0, 103.4, 55.8; HRMS
calcd for C17H15O4SNa (M+Na) 337.0510; found 337.0498.
Compound 7bb (70 mg, 56%) was obtained as a white solid;
°
Mp. 123ꢀ125 C (CH2Cl2ꢀhexane); IR
2853, 1738, 1489, 1464, 1260, 1162, 1090, 1034, 805 cmꢀ1; H
NMR (300 MHz, CDCl3) δ: 7.55ꢀ7.49 (m, 2H), 7.40 (d, = 8.9
Hz, 1H), 7.30 (dd, = 8.9, 2.0 Hz, 1H), 6.87 (s, 1H), 6.58 (d,
νmax (KBr): 3432, 2924,
1
J
(E)ꢀ5ꢀmethoxyꢀ2ꢀ(2ꢀtosylvinyl)benzofuran (6cb). Compound
J
J
6cb (82 mg, 50%) was obtained as a brown solid; Mp. 145ꢀ147
= 15.7 Hz, 1H), 4.28 (q,
J = 7.2 Hz, 2H), 1.34 (t, J = 7.2 Hz,
°C (CH2Cl2ꢀhexane); IR νmax (KBr): 3448, 3054, 2921, 2851,
3H); 13C NMR (75 MHz, CDCl3) δ 166.4, 153.8, 153.6, 130.7,
4 | J. Name., 2012, 00, 1-3
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View ArticAle ROnTliInCeLE
DOI: 10.1039/C4RA14948C
129.5, 128.8, 126.5, 121.1, 119.9, 112.4, 110.1, 128.8, 60.7, acetate as eluent to afford the pyrrole derivative
9 (63 mg) and
12.2; HRMS calcd for C13H12ClO3 (M+H) 251.0475; found unreacted 7aa (40 mg).
251.0469.
)ꢀmethyl
Compound 7ca (62 mg, 53%) was obtained as a white solid;
Methylꢀ4ꢀ(benzofuranꢀ2ꢀyl)ꢀ1Hꢀpyrroleꢀ3ꢀcarboxylate
7ca). Compound [63 mg, 52 % (86% brsm)] was obtained as a
brown solid; Mp. 158ꢀ160 C (CH2Cl2ꢀhexane); IR (KBr) νmax
(9).
(
E
3ꢀ(5ꢀmethoxybenzofuranꢀ2ꢀyl)acrylate
(
9
°
:
°
Mp. 98ꢀ100 C (CH2Cl2ꢀhexane); IR νmax (KBr): 3423, 2924, 3286, 2922, 2851, 1693, 1616, 1531, 1458, 1440, 1321, 1288,
2853, 1702, 1638, 1610, 1478, 1436, 1318, 1273, 1206, 1175, 1257, 1208, 1156, 1121, 1083, 1014, 951, 815, 789 cmꢀ1 1H
;
1
1124, 1041, 1024, 963, 938, 851. 817 cmꢀ1; H NMR (300 NMR (300 MHz, CDCl3) δ: 8.68 (br s, 1H), 7.60 (s, 1H), 7.58ꢀ
MHz, CDCl3) δ: 7.53 (d,
1H), 7.01 (d, = 2.5 Hz, 1H), 6.97 (dd,
6.88 (s, 1H), 6.54 (d,
J
= 15.7 Hz, 1H), 7.37 (d,
J
= 8.8 Hz, 7.55 (m, 1H), 7.52 (t,
J = 2.5 Hz, 1H), 7.43 (d, J = 7.7 Hz, 1H),
J
J
= 8.8, 2.5 Hz, 1H), 7.38 (t, J
= 2.5 Hz, 1H), 7.25ꢀ7.16 (m, 2H), 3.87 (s, 3H); 13C
J
= 15.7 Hz, 1H), 3.84 (s, 3H), 3.82 (s, NMR (125 MHz, CDCl3 and (CD3)2SO) δ: 164.3, 153.2, 151.2,
3H); 13C NMR (125 MHz, CDCl3) δ: 167.2, 156.2, 153.0, 129.4, 126.2, 122.8, 121.9, 120.1, 119.1, 114.7, 111.2, 109.8,
150.6, 131.5, 128.8, 118.2, 115.8, 111.9, 111.3, 103.4, 55.8, 102.8, 50.4; HRMS calcd for C14H12NO3(M+H) 242.0817;
51.8; HRMS calcd for C13H13O4(M+H) 233.0814; found found 242.0817.
233.0830.
(
E
)ꢀethylꢀ3ꢀ(5ꢀmethoxybenzofuranꢀ2ꢀyl)acrylate
(7cb).
Acknowledgements
Compound 7cb (68 mg, 53%) was obtained as an offꢀwhite
solid; Mp. 127ꢀ129 C (CH2Cl2ꢀhexane); IR νmax (KBr): 3428,
Financial support from Department of Science and Technology
(DST), India in the form of a Ramanujan fellowship and a fastꢀ
track project to RSM is acknowledged. Financial support in part
from the XIIth five year plan project “Affordable Cancer
Therapeutics (ACT)” (CSC 0301) from the Council of
Scientific and Industrial Research (CSIR), India is also
acknowledged.
°
2923, 2852, 1702, 1633, 1470, 1446, 1432, 1394, 1367, 1314,
1260, 1234, 1203, 1122, 1045, 1026, 960, 934, 848, 806, 766
cmꢀ1 1H NMR (300 MHz, CDCl3) δ: 7.51 (d,
J
= 15.7 Hz, 1H),
= 8.9 Hz, 1H), 7.01ꢀ6.94 (m, 2H), 6.86 (s, 1H), 6.54
= 15.7 Hz, 1H), 4.27 (q, = 7.2 Hz, 2H), 3.84 (s, 3H), 1.34
= 7.2 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ: 166.7,
;
7.36 (d,
(d,
(t,
J
J
J
J
156.1, 153.0, 150.6, 131.2, 128.8, 118.7, 115.6, 111.9, 111.1,
103.3, 60.6, 55.8, 14.2; HRMS calcd for C14H14O4 (M+H)
247.0970; found 247.0957.
Notes and references
a Medicinal Chemistry and Pharmacology Division, CSIRꢀIndian Institute
of Chemical Technology, Hyderabad 500 007, India. Fax: +91ꢀ40ꢀ
27193189. Eꢀmail: srajeevmenon@gmail.com
bCentre for Xꢀray Crystallography, CSIRꢀIndian Institute of Chemical
Technology, Hyderabad 500 007, India.
(
E
)ꢀmethyl
3ꢀ(5ꢀnitrobenzofuranꢀ2ꢀyl)acrylate
(7da).
Compound 7da (52 mg, 42%) was obtained as an offꢀwhite
°
solid; Mp. 163ꢀ165 C (CH2Cl2ꢀhexane); IR νmax (KBr): 3417,
†
Electronic Supplementary Information (ESI) available: [1H and 13C
1721, 1642, 1525, 1454, 1426, 1347, 1317, 1253, 1193, 1175,
NMR spectra of all compounds and crystallographic data for compound
7cb (CCDC 1020845)]. See DOI: 10.1039/b000000x/
1
1133, 1026, 1008, 970, 818, 752 cmꢀ1; H NMR (500 MHz,
CDCl3) δ: 8.53 (d,
J = 2.3 Hz, 1H), 8.29 (dd, J = 9.0, 2.3 Hz,
1H), 7.59ꢀ7.57 (m, 1H), 7.55 (s, 1H), 7.06 (s, 1H), 6.66 (d,
J =
1
(
a
) S. Yamaguchi, N. Tsuchida, M. Miyazawa and Y. Hirai, J. Org.
15.7 Hz, 1H), 3.84 (s, 3H); 13C NMR (125 MHz, (CD3)2SO) δ
165.6, 161.4, 136.4, 130.9, 128.9, 128.8, 126.6, 125.4, 123.6,
123.5, 107.8, 52.4; HRMS calcd for C12H10NO5 (M+H)
248.0559; found 248.0566.
Chem. 2005, 70, 7505; ( ) S. Kim, Y.ꢀW. Chin, B.ꢀN. Su, S. L.
Riswan, B. S. Kardono, J. J. Afriastini, H. Chai, N. R. Farnsworth, G.
A. Cordell, S. M. Swanson, and A. D. Kinghorn, J. Nat. Prod. 2006,
69, 1769; (
C. Frankland and J. A. Field, Tetrahedron Lett. 1999, 40, 5767; (
A. Macias, J. M. G. Molinillo, R. M. Varela, A. Torres and F. R.
Fronczek, J. Org. Chem. 1994, 59, 8261; ( ) S. K. Das, S. K. Dinda,
and G. Panda, Eur. J. Org. Chem. 2009, 204.
b
c
) J. B. P. A. Wijnberg, A. van Veldhuizen, H. J. Swarts, J.
d
) F.
(E)ꢀethyl 3ꢀ(5ꢀnitrobenzofuranꢀ2ꢀyl)acrylate (7db). Compound
e
7db (59mg, 45%) was obtained as an offꢀwhite solid; Mp. 157ꢀ
°
159 C (CH2Cl2ꢀhexane); IR νmax (KBr): 3418, 2924, 2853,
2. D. G. Lloyd, R. B. Hughes, D. M. Zisterer, D. C. Williams, C.
Fattorusso, B. Catalanotti, G. Campaiani, and M. J. Meegan, J. Med.
Chem. 2004, 47, 5612.
3. E. Ciganek, Synlett 1995, 1311.
4. K. Zeitler and I. Mager, Adv. Syn. Catal. 2007, 349, 1851.
1714, 1643, 1520, 1464, 1344, 1269, 1179, 1036 cmꢀ1; 1H NMR
(300 MHz, CDCl3) δ: 8.53 (d,
J
= 2.0 Hz, 1H), 8.29 (dd,
= 9.0 Hz, 1H), 7.55 (d, = 15.9 Hz,
= 15.9 Hz, 1H), 4.30 (q, = 7.2 Hz,
J = 9.0
Hz, 1.9 Hz, 1H), 7.57 (d,
J
J
1H), 7.05 (s, 1H), 6.66 (d,
2H), 1.36 (t,
J
J
5.
(a
) C. Nájera, A. PérezꢀPinar and J. M. Sansano, Tetrahedron 1991,
J
= 7.2 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ:
47, 6337. ( ) J. Zindel and A. de Meijere, Synthesis 1994, 190.
b
166.1, 155.4, 154.2, 144.5, 130.0, 128.7, 121.9, 121.5, 118.1,
111.8, 110.6, 61.0, 14.3; HRMS calcd for C13H12NO5 (M+H)
262.0715; found 262.0722.
6. T. Hirata, Y. Sasada, T. Ohtani, T. Asada, H. Kinoshita, H. Senda
and K. Inomata, Bull. Chem. Soc. Jpn. 1992, 65, 75.
7.
(a
) L. D. Luca, G. Nieddu, A. Porcheddu and G. Giacomelli, Curr.
Med. Chem. 2009, 16, 1 and references cited therein; ( ) M.
Halabalaki, N. Aligiannis, Z. Papoutsi, S. Mitakou, P. Moutsatsou, C.
Sekeris and A.ꢀL. Skaltsounis, J. Nat. Prod. 2000, 63, 1672.
b
Conversion of 7aa into the pyrrole derivative 9
A solution of 7aa (101 mg, 0.5 mmol) and tosylmethyl
isocyanide (108 mg, 0.55 mmol) in anhydrous THFꢀDMSO (1
mL and 2 mL respectively) was added dropwise into a
suspension of sodium hydride (60 % dispersion in mineral oil,
42 mg, 1.1 mmol) in THF (2mL). The mixture was stirred at
room temperature for 6h. The reaction mixture was then treated
with water and extracted with ethyl acetate. The combined
extracts were dried over anhydrous sodium sulfate, solvent was
removed on a rotavapor and the residue obtained was
chromatographed on silica gel using petroleum etherꢀethyl
8.
(
a
) M. W. Khan, M. J. Alam, M. A. Rashid, and R. Chowdhury,
Bioorg. Med. Chem. 2005, 13, 4796; ( ) P. R. Halfpenny, D. C.
Horwell, J. Hughes, J. C. Hunter and D. C. Rees J. Med. Chem. 1990,
33, 286; ( ) I. van Wijngaarden, C. G. Kruse, J. A. M. van der
Heyden, and M. T. M. Tulp, J. Med. Chem. 1988, 31, 1934; ( ) P.
b
c
d
Wipf, J. T. Reeves, R. Balachandran, K. A. Giuliano, E. Hamel and
B. W. Day, J. Am. Chem. Soc. 2000, 122, 9391.
9. S. Wei, X. ꢀG. Wei, X. Su, J. You and Y. Ren, Chem. Eur. J. 2011,
17, 5965.
10. Zeitler’s report4 describe
a schematic diagram without any
experimental data for the assigned structure.
11. CCDC 1020845, for details, see electronic supporting information.
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 5

RSC Advances
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ARTICLE
VJieowuArrtnicalelONnlainme e
DOI: 10.1039/C4RA14948C
12. H. Siderius, B. E. Hugenboom, D. van Leusen, A. M. van Leusen.
Tetrahedron Lett. 1972, 5337.
13. A. ElꢀAwa, M. N. Noshi, X. M. du Jourdin and P. L. Fuchs, Chem.
Rev. 2009, 109, 2315.
14. E. T. Gallagher, D. H. Grayson, Org. Biomol. Chem. 2003, 1, 1374.
15. Wei, S.; Wei, X. ꢀG.; Su, X.; You, J.; Ren, Y. Chem. Eur. J. 2011
,
17, 5965.
16. Matsunaga, N.; Kaku, T.; Ito, F.; Tanaka, T.; Hara, T.; Miki, H.;
Iwasaki, M.; Aono, T.; Yamaoka, M.; Kusaka, M.; Tasaka, A.
Bioorg. Med. Chem. 2004, 12, 2251.
6 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C4RA14948C
Graphical Abstract
Base-mediated cyclocondensation of 2-hydroxybenzaldehydes with 3-bromo-1-(arylsulfonyl)propenes
and 4-bromocrotonates afforded (E)-2-(2-sulfonylvinyl)benzofurans and (E)-2-benzofuranyl-3-acrylates
respectively. Previous reports of benzoxepine formation in the latter case were found to be incorrect.