Access to 2,3-disubstituted benzofurans through one-pot acid-catalyzed nucleophilic substitution/TBAF-mediated oxacycloisomerization

Article abstract of DOI:10.1002/ejoc.201200708

An efficient synthetic strategy for the synthesis of diversely 2,3-disubstituted benzofurans is described. This method is based on the use of propargylic alcohols generated from TBS-protected ortho-hydroxy benzaldehydes as starting materials and allows a library of 2,3-disubstituted benzofurans to be built. The procedure consists of one-pot nucleophilic substitution, TBS-deprotection, and exo-dig cycloisomerization. Copyright

Full text of DOI:10.1002/ejoc.201200708

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DOI: 10.1002/ejoc.201200708
Access to 2,3-Disubstituted Benzofurans through One-Pot Acid-Catalyzed
Nucleophilic Substitution/TBAF-Mediated Oxacycloisomerization
Chada Raji Reddy,*[a] Gaddam Krishna,[a] Nerella Kavitha,[a] Bellamkonda Latha,[a] and
Dong-Soo Shin[b]
Keywords: Synthetic methods / Combinatorial chemistry / Cyclization / Nucleophilic substitution / Oxygen heterocycles /
Alkynes
An efficient synthetic strategy for the synthesis of diversely
2,3-disubstituted benzofurans is described. This method is
based on the use of propargylic alcohols generated from
terials and allows a library of 2,3-disubstituted benzofurans
to be built. The procedure consists of one-pot nucleophilic
substitution, TBS-deprotection, and exo-dig cycloisomeriza-
TBS-protected ortho-hydroxy benzaldehydes as starting ma- tion.
Introduction
Substituted benzofurans are an important class of
heterocycles that display diverse pharmacological activi-
ties.[1] Among these, 2,3-disubstituted benzofurans have
garnered considerable attention as synthetic targets due to
the presence of their skeleton as an integral part of various
biologically active natural products as well as pharmaceuti-
cal compounds.[2] For example (Figure 1), (1) the tetracyclic
meroterpenoid natural product (+)-liphagal (I),[2g] a selec-
tive inhibitor of phosphatidylinositol 3-kinase (PI3K), iso-
lated from the Caribbean sponge Aka coralliphaga; (2)
amiodarone (II),[2a,2f] a clinically used drug for controlling
intractable cardiac arrhythmias; (3) a phenolic compound
(III),[2d] which is an inhibitor of testosterone 5α-reductase,
isolated from the stems of Dalbergia cochinchinensis. In ad-
dition, numerous 2,3-disubstituted benzofurans have been
reported to possess antifungal, antiviral, antidiabetic, and
antiparasitic activities etc.[3] As a result, several methods
have been developed for the synthesis of 2,3-disubstituted
Figure 1. Structures of selected benzofuran-based molecules.
benzofurans.[4] The majority of the reactions involved intra-
molecular cyclization of o-alkynylphenols or o-alk-
ynylphenyl ethers through carbon–oxygen bond forma-
tion.[5]
Although these methods offer some advantages, typically
they require the use of transition metals either in the cycli-
zation reaction or for the preparation of substrates. There-
fore, there is still scope for the development of new meth-
ods, especially those that do not require the use of metal
catalyst.
π-Activated (benzylic, allylic, and propargylic) alcohols
have attracted considerable attention in the direction of
green and atom-economy chemistry, because they generate
only water as a byproduct in the reaction.[6] Furthermore,
their availability and ease of preparation also makes them
as an attractive source. The efficacy of π-activated alcohols
[a] Division of Natural Products Chemistry, CSIR – Indian
Institute of Chemical Technology,
Hyderabad 500007, India
Fax: +91-040-27160512
E-mail: rajireddy@iict.res.in
[b] Department of Chemistry, Changwon National University
Changwon,
641-773, South Korea
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200708.
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in direct nucleophilic SN1-type reactions towards carbon– tion. It was expected that, in the first step, SN1-nucleophilic
carbon, carbon–nitrogen, and carbon–oxygen bond forma- substitution of 1 with various nucleophiles in the presence
tion has been demonstrated under different reaction condi- of an acid catalyst would generate intermediate A. In a sec-
tions, in particular, in the presence of Lewis or Brønsted ond step, desilylation with tetrabutylammonium fluoride
acids.[7] Our recent studies have also been focused in this (TBAF) to give intermediate B followed by subsequent exo-
direction for the synthesis of heterocyclic compounds.[8] For dig oxacycloisomerization would lead to 2,3-disubstituted
instance, C3-alkylation of 4-hydroxycoumarin to give furan- benzofurans 3 (Scheme 1).
ocoumarins,[8a] through N-alkylation of tosylhydrazones
towards pyrazoles,[8b] alkylation of 1,3-dicarbonyl com-
pounds for various oxygenated heterocycles,[8c] and O-alkyl-
Results and Discussion
ation of hydroximides to 2,5-dihydroisoxazoles,[8d] have
been successfully demonstrated. In a continuation of this
To verify the proposed strategy, we chose to use TBS-
work, we were prompted to explore the use of propargylic protected alkynol 1a, derived from TBS-protected salicyl-
alcohols for the synthesis of 2,3-disubstituted benzofurans. aldehyde and phenylacetylene using a known procedure,[12]
A search of the literature showed that a few methods as a model substrate and 1,3,5-trimethoxybenzene (2a) as
have been developed to access substituted benzofurans from the nucleophile for optimization of reaction conditions
hydroxyphenylpropargylic alcohols.[9] The first example of (Table 1). Thus, compound 1a was treated with 2a in the
benzofuran formation from 1-(2-hydroxyphenyl)-2-yn-1-ol presence of BF3·Et2O (5 mol-%) in acetonitrile at room
was observed during the deprotection of methylthiomethyl temperature.[13]
(MTM) ether with HgCl2 in acetonitrile/water under reflux
After the consumption of both starting materials 1a and
conditions.[9a] Bartolo and co-workers have reported tan- 2a (reaction monitored by TLC), TBAF in tetrahydrofuran
dem Pd0-catalyzed carbonylative deallylation/PdII-catalyzed (THF) was added and stirring was continued for 12 h at
heterocyclization leading to 2,3-disubstituted benzofurans room temperature, however, the reaction did not provide
from 1-(2-allyloxyphenyl)-2-yn-1-ols.[9b–9e] Tian et al. have the expected benzofuran 3a, instead the isolated product
demonstrated a single example of the one-pot synthesis of was identified as uncyclized intermediate 3aЈ, which was
benzofuran from 2-(1,3-diphenylprop-2-yn-1-yl)phenol obtained in 97% yield. Thus, the same reaction was con-
using ZnCl2 (10 mol-%) and TMSCl (50 mol-%) at 70 °C ducted by increasing the reaction temperature to reflux af-
in dichloroethane.[10] Xiaobing Xu et al. have observed the ter the addition of TBAF; to our delight, the desired cy-
formation of benzofurans/naphthofurans under the action clized product, benzofuran 3a, was obtained in 94% yield
of 10 mol-% FeCl3 and Na2CO3 at 135 °C, in their study.[11] (Table 1, entry 2). Subsequently, different solvents such as
However, all these reactions require metal catalysts and, CH3NO2 and CH2Cl2 were explored for the above one-pot
furthermore, they do not easily allow the generation of di- reaction and it was found that acetonitrile was optimal
versely substituted benzofurans. Herein, we describe a mild (Table 1, entries 3 and 4). As shown in Table 1, other acid
and general protocol for the synthesis of diversely 2,3-di- catalysts such as B(C6F5)3, pTSA, and 10-camphorsulfonic
substituted benzofurans through a one-pot reaction under acid (CSA) were also tested for initial nucleophilic substitu-
metal-free conditions.
tion and, in all cases, the reaction proceeded to provide the
Based on the knowledge that our group has gained in benzofuran 3a in reasonably good yields (Table 1, entries 5–
the use of π-activated alcohols and on literature reports on 7). It is important to mention that both the nucleophilic
benzofuran synthesis, we envisioned that 2,3-disubstituted substitution and TBAF-promoted tert-butyldimethylsilyl
benzofurans could be accessible from 1-[(tert-butyldimeth- deprotection progressed at room temperature, whereas exo-
ylsilyloxy)phenyl]-2-yn-1-ol derivatives in a one-pot opera- dig oxa-cycloisomerization (benzofuran formation) re-
quired heating to reflux temperature. Furthermore, control
experiments confirmed that the presence of TBAF was es-
sential for the oxacycloisomerization reaction.[14] Although
a few TBAF-mediated heterocyclization reactions are
known, to the best of our knowledge, this is the first exam-
ple for the synthesis of benzofuran formation.[15]
With the standard reaction conditions in hand, we then
examined the scope and generality of the method by synthe-
sizing a library of 2,3-disubstituted benzofurans using a
range of propargylic alcohols 1a–d and carbon nucleophiles
2a–d; the results are summarized in Table 2.
We first explored the use of different nucleophiles for
substitution followed by oxacycloisomerization. The reac-
tions of 1a with electron-rich aromatic nucleophiles, anisole
(2b) and indole (2c), under the established conditions pro-
ceeded to give the corresponding 3-aryl-2-benzylbenzo-
Scheme 1. Proposed strategy for 2,3-disubstituted benzofurans.
furans 3b and 3c in 92 and 88% yields, respectively
2
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Access to 2,3-Disubstituted Benzofurans
Table 1. Optimization of reaction conditions.
(Table 2). Interestingly, the aliphatic nucleophile, allyltri- to our delight, the reaction provided the corresponding
methylsilane (2d), also participated well in the reaction with benzofuran 3p in 86% yield (Scheme 2).
1a, providing the corresponding 3-allyl-2-benzylbenzofuran
3d in 81% yield. This reaction allowed the synthesis of
benzofuran with an sp3-carbon substituent at the 3-posi-
tion, which is a significant advantage of the present method
(product 3d; Table 2, entry 1). Subsequently, various pro-
pargylic alcohols were explored to obtain the corresponding
2,3-disubstituted benzofurans (Table 2). Accordingly, sub-
Scheme 2. Synthesis of 3p.
strate 1b, derived from the reaction of 5-bromo-2-hydroxy-
benzaldehyde with phenylacetylene, was treated with nu-
cleophiles 2a–d to furnish the corresponding benzofurans
In subsequent studies, we also investigated the reactivity
3e–h in good yields (Table 2, entry 2). Similarly, propargylic of propargylic alcohols 1e and 1f, obtained from the reac-
alcohols 1c and 1d also effectively participated in the reac- tion of TBS-protected salicylaldehyde with alkynes derived
tion with 2a–d under the described reaction conditions to from Boc-protected prolinol and Garner’s aldehyde, with
give 2,3-disubstituted benzofurans 3i–o (Table 2, entries 3 allyltrimethylsilane (2d). From these reactions, the corre-
and 4), except for the reaction of 1c with 2c, which gave an sponding 3-allylbenzofurans 3q and 3r were obtained in 74
inseparable mixture of unidentified products. It should be and 61% yields, respectively (Scheme 3). The reaction of 1e
mentioned that, in the case of propargylic alcohol 1c, the with 2d proceeded under the described reaction conditions
exo-dig oxacycloisomerization proceeded at room tempera- [Equation (1), Scheme 3], whereas in the case of 1f, we
ture, which may be due to the presence of electron-with- found that 5 mol-% B(C6F5)3 was a suitable acid catalyst
drawing ester functionality on the alkyne.
for the nucleophilic substitution reaction; see Equation (2)
Later, the reactivity of silylenol ether 2e with 1a was also in Scheme 3), because the acid-labile acetonide group was
tested under the present one-pot reaction conditions and, not stable in the presence of BF3·Et2O.
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C. Raji Reddy, G. Krishna, N. Kavitha, B. Latha, D.-S. Shin
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Table 2. One-pot synthesis of 2,3-disubstituted benzofurans.
Conclusions
We have demonstrated a mild and efficient approach for
the synthesis of 2,3-disubstituted benzofurans starting from
easily accessible 1-[(tert-butyldimethylsilyloxy)pheyl]-2-yn-
1-ol derivatives. The developed strategy is metal free and
proceeds in a one-pot manner involving nucleophilic substi-
tution, TBS-deprotection, followed by exo-dig oxacycloiso-
merization reactions. This approach to diversely 2,3-disub-
stituted benzofurans complements existing routes and al-
lows the synthesis of new benzofuran derivatives with struc-
tural complexity. Importantly sp3-carbon substitution at the
C3 position of the benzofuran can also be achieved.
Scheme 3. Synthesis of 3q and 3r.
4
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Access to 2,3-Disubstituted Benzofurans
(300 MHz, CDCl3): δ = 7.66 (d, J = 2.4 Hz, 1 H, Ar), 7.33 (m, 5
H, Ar), 6.65 (d, J = 8.6 Hz, 1 H, Ar), 5.50 (s, 1 H, CH2-O), 4.53
(s, 2 H, CH2Ar), 3.57 (t, J = 7.1 Hz, 2 H, CH2-OBn), 2.55 (t, J =
6.7 Hz, 2 H, CH2-C), 1.02 (s, 9 H, tBu-Si), 0.25 [d, J = 3.9 Hz, 6
H, Si-(CH3)2] ppm. 13C NMR (75 MHz, CDCl3): δ = 151.9, 137.9,
133.5, 131.8, 130.8, 128.3, 127.6, 125.7, 120.0, 113.5, 83.9, 80.2,
72.9, 68.1, 60.0, 28.5, 25.6, 20.2, –4.2, –4.2 ppm. MS (ESI): m/z =
361 [M + Na]+. C24H31BrO3Si (475.50): calcd. C 60.75, H 6.54;
found C 60.82, H 6.63.
Experimental Section
General: 1H and 13C NMR spectra were recorded in CDCl3 with
300, 500 or 75 MHz spectrometers. Chemical shifts (δ) are reported
in ppm downfield from TMS as internal standard; signal patterns
are indicated as follows: s, singlet; d, doublet; dd, doublet of doub-
let; t, triplet; m, multiplet; br. s, broad singlet. Coupling constants
(J) are given in Hz. FTIR spectra were recorded either as KBr thin
films or neat. For MS and HRMS, m/z ratios are reported as
atomic mass units. All the reagents and solvents were reagent grade
and used without further purification unless specified otherwise.
Technical grade ethyl acetate and petroleum ether used for column
chromatography were distilled prior to use. Column chromatog-
raphy was carried out by using silica gel (60–120 mesh) packed in
glass columns. All the reactions were performed under nitrogen in
flame- or oven-dried glassware with magnetic stirring.
(2S)-tert-Butyl
2-{3-[2-(tert-Butyldimethylsilyloxy)phenyl]-3-hy-
droxyprop-1-ynyl}pyrrolidine-1-carboxylate (1e): Colourless liquid.
[α]2D0 = –41.2 (c = 1.06, CHCl ). IR (neat): νmax = 3406, 2931, 2859,
˜
3
1677, 1400, 1257 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.70–7.53
(br. s, 1 H, Ar), 7.19 (t, J = 7.5 Hz, 1 H, Ar), 6.96 (t, J = 7.5 Hz,
1 H, Ar), 6.81 (d, J = 7.9 Hz, 1 H, Ar), 5.74 (s, 1 H, CH-O), 4.68–
4.44 (m, 1 H, CH-N), 3.52–3.24 (m, 2 H, CH2-N), 2.75–2.63 (br. s,
1 H, OH), 2.12–2.00 (m, 2 H, CH2-CH2), 1.94–1.65 (m, 2 H, CH2-
CH2), 1.43 (s, 9 H, Boc), 1.02 (s, 9 H, tBu-Si), 0.29 (s, 3 H, Si-
CH3), 0.26 (s, 3 H, Si-CH3) ppm. 13C NMR (75 MHz, CDCl3): δ
= 153.9, 152.7, 131.2, 129.0, 128.0, 121.2, 118.2, 86.3, 81.0, 79.5,
60.2, 48.1, 45.5, 33.5, 28.3, 25.6, 23.6, 18.0, –4.2, –4.3 ppm. HRMS
(ESI): calcd. for C24H37NO4SiNa [M + Na]+ 454.2384; found
454.2376.
General Procedure for the Preparation of TBS-protected Alkynol:
To a solution of phenylacetylene (1 mmol) in anhydrous THF
(5 mL) was slowly added nBuLi (1.6 m in THF, 1.5 mmol) at
–78 °C. The reaction mixture was stirred for 45 min, then a solution
of the corresponding TBS protected salicylaldehyde (1 mmol) in
THF (5 mL) was added to the reaction mixture, which was then
stirred at –78 °C for 4 h. After completion of the reaction (moni-
tored by TLC), it was quenched by addition of aq. saturated
NH4Cl (50 mL). The aqueous layer was extracted with ethyl acetate
(2ϫ50 mL). The combined organic layer was washed with brine
(20 mL), dried with Na2SO4, and concentrated under reduced pres-
sure. The crude product was purified by column chromatography.
(4R)-tert-Butyl
4-{3-[2-(tert-Butyldimethylsilyloxy)phenyl]-3-hy-
droxyprop-1-ynyl}-2,2-dimethyloxazolidine-3-carboxylate:
(1f):
Colourless liquid. [α]2D0 = –1.1 (c = 1.0, CHCl ). IR (neat): ν
=
˜
3
max
3447, 2932, 2859, 1701, 1601, 1373, 1378, 1256 cm–1. 1H NMR
(300 MHz, CDCl3): δ = 7.64–7.51 (br. s, 1 H, Ar), 7.15 (t, J =
7.5 Hz, 1 H, Ar), 6.94 (t, J = 7.5 Hz, 1 H, Ar), 6.77 (d, J = 7.5 Hz,
1 H, Ar), 5.69 (s, 1 H, CH-O), 4.72–4.50 (m, 1 H, CH-N), 4.08–
3.96 (m, 2 H, CH2-O), 2.54–2.41 (br. s, 1 H, OH), 1.68–1.38 [m, 15
H, Boc, (CH3)2C], 1.04 (s, 9 H, tBu-Si), 0.28 (s, 3 H, Si-CH3), 0.27
(s, 3 H, Si-CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 152.9,
151.4, 131.0, 129.3, 128.0, 121.3, 121.3, 118.4, 94.3, 84.9, 80.2, 68.6,
60.3, 48.6, 28.3, 25.7, 18.1, 14.1, –4.1, –4.2 ppm. HRMS (ESI):
calcd. for C25H39NO5SiNa [M + Na]+ 484.2490; found 484.2458.
1-[2-(tert-Butyldimethylsilyloxy)phenyl]-3-phenylprop-2-yn-1-ol (1a):
Colourless liquid. IR (KBr): ν
= 3428, 2931, 1598, 1488, 1258,
˜
max
1027, 916, 835, 759, 691 cm–1. 1H NMR (300 MHz, CDCl3): δ =
7.60 (d, J = 8.1 Hz, 1 H, Ar), 7.44–7.13 (m, 6 H, Ar), 6.97 (t, J =
7.5 Hz, 1 H, Ar), 6.80 (d, J = 7.5 Hz, 1 H, Ar), 5.84 (d, J = 6.0 Hz,
1 H, CH-O), 2.61 (d, J = 6.0 Hz, 1 H, OH), 1.05 (s, 9 H, tBu-
Si), 0.30 [d, J = 2.2 Hz, 6 H, Si-(CH3)2] ppm. 13C NMR (75 MHz,
CDCl3): δ = 153.0, 131.6, 131.0, 129.3, 128.3, 128.1, 122.7, 121.4,
88.7, 86.0, 61.3, 29.6, 25.7, –4.1 ppm. MS (ESI): m/z = 361 [M +
Na]+. C21H26O2Si (338.27): calcd. C 74.55, H 7.69; found C 74.67,
H 7.58.
2-[3-Phenyl-1-(2,4,6-trimethoxyphenyl)prop-2-ynyl]phenol
(3aЈ):
Colourless liquid. IR (KBr): ν = 3429, 2939, 1598, 1488, 1217,
˜
max
1
1112, 955, 692 cm–1. H NMR (300 MHz, CDCl3): δ = 7.54 (dd, J
= 7.5, 7.4 Hz, 1 H, Ar), 7.44–7.21 (m, 6 H, Ar), 7.05 (t, J = 7.3 Hz,
2 H, Ar), 6.77 (q, J = 7.5, 13.2 Hz, 2 H, Ar), 6.12 (s, 1 H, Ar), 5.71
(s, 1 H, CH-C=), 3.90 [s, 6 H, (OCH3)2Ar] 3.76 (s, 3 H, (OCH3)-
Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 160.5, 157.7, 154.1,
131.6, 130.1, 128.1, 128.0, 127.6, 125.6, 123.9, 119.6, 116.3, 109.3,
91.8, 89.4, 81.6, 56.0, 55.3, 27.9 ppm. HRMS (ESI): calcd. for
C24H23O4 [M + H]+ 375.1591; found 375.1565.
1-[5-Bromo-2-(tert-butyldimethylsilyloxy)phenyl]-3-phenylprop-2-yn-
1-ol (1b): Colourless liquid. IR (KBr): ν
= 3427, 2931, 1591,
˜
max
1480, 1270, 1030, 914, 842, 690 cm–1. 1H NMR (300 MHz, CDCl3):
δ = 7.89–7.28 (m, 7 H, Ar), 6.72 (d, J = 8.0 Hz, 1 H, Ar), 5.87 (s,
1 H, CH-O), 1.03 (s, 9 H, tBu-Si), 0.28 [d, J = 5.9 Hz, 6 H, Si-
(CH3)2] ppm. 13C NMR (75 MHz, CDCl3): δ = 152.0, 133.2, 132.0,
131.7, 130.8, 128.5, 128.2, 122.3, 120.1, 113.6, 88.0, 86.3, 60.5, 25.7,
18.2, –4.1 ppm. MS (ESI): m/z = 439 [M + Na]+. C21H25BrO2Si
(417.42): calcd. C 60.57, H 6.00; found C 60.49, H 5.96.
General Procedure for the Preparation of 2,3-Disubstituted Benzo-
furans: Nucleophile 2a–d (1 mmol) was added to a solution of TBS-
protected propargylic alcohols 1a–d (1 mmol) in CH3CN (10 mL),
followed by BF3·Et2O (5 mol-%). The resulting mixture was stirred
at room temperature. After disappearance of both starting materi-
als (reaction monitored by TLC), TBAF (1 m in THF, 2 mmol) was
added. The resulting mixture was stirred at room temperature for
15 min, then the temperature was raised to reflux and stirring was
continued for the given time (Table 2). After completion of the re-
action, the solvent was evaporated in vacuo and the crude product
was purified by column chromatography on silica gel (EtOAc/hex-
anes) to afford the corresponding benzofuran 3a–o.
Ethyl 4-[2-(tert-Butyldimethylsilyloxy)phenyl]-4-hydroxybut-2-yno-
ate (1c): Colourless liquid. IR (KBr): ν
= 3481, 2933, 2235,
˜
max
1713, 1489, 1254, 1019, 919, 839, 756 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 7.47 (d, J = 7.9 Hz, 1 H, Ar), 7.23 (t, J = 7.9 Hz, 1
H, Ar), 6.99 (d, J = 6.9 Hz, 1 H, Ar), 6.85 (d, J = 7.9 Hz, 1 H,
Ar), 5.74 (s, 1 H, CH-OH), 4.22 (q, J = 6.2, J = 13.8 Hz, 2 H,
CH2-O), 1.29 (t, J = 6.2 Hz, 3 H, CH3-CH2), 1.04 (s, 9 H, tBu-Si),
0.31 [s, 6 H, Si-(CH3)2] ppm. 13C NMR (75 MHz, CDCl3): δ =
153.3, 153.0, 129.9, 129.0, 128.1, 121.4, 118.4, 86.3, 61.9, 60.9, 25.7,
18.2, 13.9, –4.0 ppm. MS (ESI): m/z = 361 [M + Na]+. C18H26O4Si
(334.49): calcd. C 64.67, H 7.78; found C 64.71, H 7.69.
2-Benzyl-3-(2,4,6-trimethoxyphenyl)benzofuran (3a): White solid;
5-(Benzyloxy)-1-[5-bromo-2-(tert-butyldimethylsilyloxy)phenyl]pent-
m.p. 106–108 °C. IR (KBr): ν
= 2929, 2850, 1596, 1454, 1335,
˜
max
2-yn-1-ol (1d): Colourless liquid. IR (KBr): ν
= 3411, 2932,
1226, 1142, 1126, 975, 749 cm–1. 1H NMR (300 MHz, CDCl3): δ =
˜
max
1590, 1478, 1269, 1107, 1012, 918, 843, 699 cm–1. 1H NMR 7.36 (d, J = 8.1 Hz, 1 H, Ar), 7.24–7.03 (m, 8 H, Ar), 6.17 (s, 2 H,
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Ar), 3.94 (s, 2 H, CH2Ar), 3.85 (s, 3 H, OCH3Ar), 3.64 [s, 6 H,
(300 MHz, CDCl3): δ = 7.44–7.30 (m, 2 H, Ar), 7.28–7.08 (m, 6 H,
(OCH3)2Ar] ppm. 13C NMR (75 MHz, CDCl3): δ = 161.2, 159.3, Ar), 6.00–5.85 (m, 1 H, CH=CH2), 5.13–5.01 (m, 2 H, CH=CH2),
154.3, 153.9, 138.1, 129.8, 128.7, 128.1, 126.0, 122.9, 121.9, 120.4,
110.8, 109.9, 101.6, 90.6, 55.5, 55.3, 33.5 ppm. HRMS (ESI): calcd.
for C24H23O4 [M + H]+ 375.1591; found 375.1565.
4.06 (s, 2 H, CH2Ar), 3.42 (d, J = 6.0 Hz, 2 H, CH2-
CH=CH2) ppm. 13C NMR (75 MHz, CDCl3): δ = 154.1, 152.6,
137.7, 135.5, 129.3, 128.5, 126.5, 123.4, 122.0, 119.3, 115.8, 112.8,
110.8, 32.6, 27.9 ppm. MS (ESI): m/z = 325 [M – H]–.
2-Benzyl-3-(4-methoxyphenyl)benzofuran (3b): White solid; m.p.
131–133 °C. IR (KBr): ν
= 2836, 1600, 1512, 1454, 1246, 1028,
˜
Ethyl 2-[3-(2,4,6-Trimethoxyphenyl)benzofuran-2-yl]acetate (3i):
max
835, 728, 715, 580 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.51
(dd, J = 6.6, 1.8 Hz, 1 H, Ar), 7.42–7.13 (m, 10 H, Ar), 6.96 (dd,
J = 6.7, 2.0 Hz, 2 H, Ar), 4.16 (s, 2 H, CH2Ar), 3.38 (s, 3 H,
OCH3Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 158.8, 154.2,
152.1, 130.1, 128.5, 128.4, 126.5, 123.8, 122.5, 119.6, 114.2,
111.0 ppm. MS (ESI): m/z = 315 [M + H]+. C22H18O2 (314.38):
calcd. C 84.03, H 5.73; found C 84.68, H 5.65.
Colourless liquid. IR (KBr): ν
= 2939, 2840, 1741, 1601, 1454,
˜
max
1227, 1204, 1155, 1033, 813, 748, 639 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 7.45 (d, J = 7.7 Hz, 1 H, Ar), 7.30–7.07 (m, 3 H, Ar),
6.21 (s, 2 H, Ar), 4.16 (q, J = 6.9, 14.1 Hz, 2 H, CH2-O), 3.89 (s,
3 H, OCH3Ar), 3.73 [s, 6 H, (OCH3)2Ar], 3.66 (s, 2 H, CH2C=O),
1.30 (t, J = 6.9 Hz, 3 H, CH3CH2) ppm. 13C NMR (75 MHz,
CDCl3): δ = 169.2, 161.3, 159.0, 154.3, 148.1, 129.2, 123.2,
122.9,120.9, 110.9, 101.0, 90.7, 60.8, 55.5, 55.2, 33.8, 14.0 ppm.
HRMS (ESI): calcd. for C21H23O6 [M + H]+ 371.1489; found
371.1481.
3-(2-Benzylbenzofuran-3-yl)-1H-indole (3c): Brick-red solid; m.p.
124–126 °C. IR (KBr): ν
= 3397, 2922, 1717, 1598, 1448, 1263,
˜
max
1084, 924, 805, 736, 580, 507 cm–1. H NMR (300 MHz, CDCl3):
δ = 8.17 (s, 1 H, NH), 7.14 (d, J = 7.5 Hz, 1 H, Ar), 7.48–7.37 (m,
3 H, Ar), 7.28–7.06 (m, 10 H, Ar), 4.17 (s, 2 H, CH2Ar) ppm. 13C
NMR (75 MHz, CDCl3): δ = 154.4, 152.8, 138.2, 136.2, 128.5,
126.4, 123.6, 123.0, 122.3, 120.4, 120.3, 119.9, 111.3, 111.0, 107.5,
33.0 ppm. MS (ESI): m/z = 324 [M + H]+. C23H17NO (323.39):
calcd. C 85.44, H 5.26, N 4.33; found C 85.33, H 5.23, N 4.64.
1
Ethyl 2-[3-(4-Methoxyphenyl)benzofuran-2-yl]acetate (3j): Colour-
less liquid. IR (KBr): ν
= 2922, 2852, 1512, 1453, 1247, 1029,
˜
max
772, 746 cm–1. H NMR (300 MHz, CDCl3): δ = 7.21–7.15 (dd, J
= 1.7, 7.7 Hz, 1 H), 7.11–7.05 (m, 2 H, Ar), 7.00–6.95 (m, 1 H,
Ar), 6.83–6.78 (m, 1 H, Ar), 6.70–6.62 (m, 3 H, Ar), 4.08 (q, J =
7.1, 14.1 Hz, 2 H, CH2-O), 3.85 (s, 3 H, OCH3Ar), 3.78 (s, 2 H,
CH2C=O), 1.19 (t, J = 6.98 Hz, 3 H, CH3CH2) ppm. 13C NMR
(75 MHz, CDCl3): δ = 169.2, 146.3, 131.4, 130.1, 129.1, 124.2,
122.7, 120.7, 120.5, 119.8, 111.7, 61.4, 55.3, 33.8, 33.4, 29.6,
14.1 ppm. HRMS (ESI): calcd. for C19H18NaO4 [M + Na]+
333.1097; found 333.1123.
1
3-Allyl-2-benzylbenzofuran (3d): Pale-yellow liquid. IR (KBr): ν
˜
max
= 2136, 1639, 1454, 1256, 1089, 913, 745, 708 cm–1. 1H NMR
(300 MHz, CDCl3): δ = 7.43–7.11 (m, 9 H, Ar), 6.01–5.36 (m, 1 H,
CH=CH2), 5.13–5.02 (m, 2 H, CH2=CH), 4.07 (s, 2 H, CH2Ar),
3.00 (dd, J = 6.0, 1.5 Hz, 2 H, CH2-C) ppm. 13C NMR (75 MHz,
CDCl3): δ = 154.1, 152.7, 137.7, 135.5, 129.4, 129.3, 126.4, 123.4,
122.0, 119.3, 115.8, 112.8, 110.8, 32.5, 27.9 ppm. MS (ESI): m/z =
247 [M – H]–. C18H16O (248.32): calcd. C 87.09, H 6.45; found C
87.14, H 6.49.
Ethyl 2-(3-Allylbenzofuran-2-yl)acetate (3k): Colourless liquid. IR
(KBr): ν
= 2925, 1741, 1454, 1248, 1186, 1030, 746 cm–1. 1H
˜
max
NMR (300 MHz, CDCl3): δ = 7.40 (dd, J = 14.6, 7.8 Hz, 2 H, Ar),
7.25–7.10 (m, 2 H, Ar), 5.94 (m, 1 H, HC=C), 5.16–5.02 (m, 2 H,
CH2C=C), 4.16 (q, J = 7.5, 14.3 Hz, 2 H, CH2C=), 3.71 (s, 2 H,
CH2C=O), 3.42 (d, J = 6.0 Hz, 2 H, CH2-O), 1.27 (t, J = 7.5 Hz,
3 H, CH3CH2) ppm. 13C NMR (75 MHz, CDCl3): δ = 168.9, 154.2,
146.7, 135.1, 129.0, 123.8, 122.2, 119.4, 115.9, 114.7, 110.9, 61.2,
32.8, 27.7, 14.0 ppm. HRMS (ESI): calcd. for C15H16O3 [M +
Na]+ 267.0992; found 267.0986.
2-Benzyl-5-bromo-3-(2,4,6-trimethoxyphenyl)benzofuran (3e): Yel-
low solid; m.p. 136–138 °C. IR (KBr): ν
= 2932, 2838, 1736,
˜
max
1593, 1453, 1337, 1219, 1130, 1041, 969, 805, 701, 618 cm–1. 1H
NMR (300 MHz, CDCl3): δ = 7.36–7.15 (m, 8 H, Ar), 6.23 (s, 2
H, Ar), 3.96 (s, 2 H, CH2Ar), 3.87 (s, 3 H, OCH3Ar), 3.66 [s, 6 H,
(OCH3)2Ar] ppm. 13C NMR (75 MHz, CDCl3): δ = 161.5, 159.2,
155.5, 153.1, 137.6, 131.9, 128.6, 128.1, 126.2, 125.7, 123.1, 115.1,
112.2, 109.7, 100.8, 90.7, 55.5, 55.3, 33.5 ppm. HRMS (ESI): calcd.
for C24H22BrO4 [M + H]+ 453.0696; found 453.0688.
2-[3-(Benzyloxy)propyl]-5-bromo-3-(2,4,6-trimethoxyphenyl)benzo-
furan (3l): Green solid; m.p. 152–154 °C. IR (KBr): ν
= 2941,
˜
max
2838, 1729, 1598, 1502, 1453, 1352, 1228, 1153, 1126, 1097, 967,
805, 748, 699, 623, 523 cm–1. 1H NMR (500 MHz, CDCl3): δ =
7.29–7.18 (m, 8 H, Ar), 6.17 (s, 2 H, Ar), 4.38 (s, 2 H, CH2Ar), 3.85
(s, 3 H, OCH3Ar), 8.70 [s, 6 H, (OCH3)2Ar], 3.45 (t, J = 6.9 Hz, 2
H, CH2=CH2), 2.71 (t, J = 6.9 Hz, 2 H, CH2Ar), 1.99 (m, 2 H,
CH2-CH2) ppm. 13C NMR (75 MHz, CDCl3): δ = 161.3, 159.0,
157.3, 141.0, 138.5, 128.2, 127.4, 127.3, 125.3, 122.9, 115.0, 112.0,
90.6, 72.7, 69.5, 55.5, 55.3, 27.4, 24.2 ppm. HRMS (ESI): calcd. for
C27H27NaBrO5 [M + Na]+ 533.0939; found 533.0950.
2-Benzyl-5-bromo-3-(4-methoxyphenyl)benzofuran (3f): Colourless
liquid. IR (KBr): ν
= 2924, 2852, 1596, 1511, 1450, 1250, 1171,
˜
max
717 cm–1. H NMR (300 MHz, CDCl3): δ = 7.62 (d, J = 1.5 Hz, 1
H, Ar), 7.38–7.17 (m, 9 H, Ar), 6.97 (d, J = 9.1 Hz, 2 H, Ar), 4.14
(s, 2 H, CH2Ar), 3.85 (s, 3 H, OCH3Ar) ppm. 13C NMR (75 MHz,
CDCl3): δ = 159.1, 153.5, 153.0, 137.5, 130.9, 130.1, 128.6, 128.4,
126.6, 123.8, 122.4, 117.5, 115.7, 114.4, 112.5, 55.3, 32.8 ppm. MS
(ESI): m/z = 391 [M – H]–. C22H17BrO2 (393.28): calcd. C 67.34,
H 4.33; found C 67.54, H 4.78.
1
2-[2-(Benzyloxy)ethyl]-5-bromo-3-(4methoxyphenyl)benzofuran
(3m): Yellow liquid. IR (KBr): νmax = 2925, 1725, 1596, 1511, 1452,
˜
3-(2-Benzyl-5-bromobenzofuran-3-yl)-1H-indole (3g): Red solid;
1248, 1174, 1105, 765 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.59
(d, J = 1.5 Hz, 1 H, Ar), 7.36–7.17 (m, 9 H, Ar), 6.91 (dd, J = 6.7,
2.2 Hz, 2 H, Ar), 4.39 (s, 2 H, CH2Ar), 3.82 (s, 3 H, OCH3Ar),
3.47 (t, J = 6.0 Hz, 2 H, CH2-O), 2.96 (t, J = 7.5 Hz, 2 H, CH2-
CH), 2.06 (m, 2 H, CH2-CH2) ppm. 13C NMR (75 MHz, CDCl3):
δ = 158.9, 155.4, 152.7, 138.3, 131.1, 130.0, 128.2, 127.5, 126.3,
124.0, 122.1, 116.5, 115.6, 114.3, 112.2, 72.8, 69.0, 55.2, 28.1,
23.4 ppm. MS (ESI): m/z = 473 [M + Na]+. C25H23BrO3 (451.36):
calcd. C 66.66, H 5.11; found C 66.73, H 5.13.
m.p. 152–154 °C. IR (KBr): ν
= 3405, 2923, 2856, 1722, 1617,
˜
max
1446, 1332, 1262, 1085, 927, 800, 734 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 8.21 (s, 1 H, NH), 7.56 (s, 1 H, Ar), 7.50 (d, J =
7.7 Hz, 1 H, Ar), 7.40 (d, J = 8.1 Hz, 1 H, Ar), 7.31 (s, 2 H, Ar),
7.29–7.09 (m, 8 H, Ar), 4.15 (s, 2 H, CH2Ar) ppm. 13C NMR
(75 MHz, CDCl3): δ = 154.4, 153.1, 137.8, 136.1, 131.6, 128.5,
128.4, 126.5, 123.1, 122.9, 122.5, 120.2, 119.9, 105.5, 112.4, 11.3,
106.7, 33.0 ppm. HRMS (ESI): calcd. for C23H15BrNO [M – H]–
400.0343; found 400.0341.
3-Allyl-2-benzyl-5-bromobenzofuran (3h): Yellow liquid. IR (KBr):
ν
˜
3-{2-[3-(Benzyloxy)propyl]-5-bromobenzofuran-3-yl}-1H-indole (3n):
max = 2922, 1602, 1454, 1256, 1089, 913, 746, 707 cm–1. 1H NMR Dark-brown liquid. IR (KBr):νmax = 3446, 2924, 2854, 1729, 1459,
˜
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20708
/KAP1
Date: 07-08-12 18:45:06
Pages: 9
Access to 2,3-Disubstituted Benzofurans
1
1378, 1271, 1122, 1072, 741 cm–1. H NMR (300 MHz, CDCl3): δ
search grant from the Korea Ministry of Environment, South Ko-
rea as an Eco-Innovation project (412-111-008), is gratefully ac-
knowledged.
= 8.31 (s, 1 H, NH), 7.54 (s, 2 H, Ar), 7.48 (d, J = 7.7 Hz, 1 H,
Ar), 7.37 (d, J = 8.3 Hz, 1 H, Ar), 7.31 (s, 2 H, Ar), 7.28–7.06 (m,
7 H, Ar), 4.13 (s, 2 H, CH2Ar), 3.44 (t, J = 5.8 Hz, 2 H, CH2-
CH=CH2), 2.97 (t, J = 7.1 Hz, 2 H, CH2Ar), 2.05 (m, 2 H, CH2-
CH2) ppm. 13C NMR (75 MHz, CDCl3): δ = 156.2, 153.0, 138.3,
136.2, 131.9, 128.2, 127.5, 127.4, 126.1, 123.1, 122.7, 122.5, 120.1,
120.0, 115.4, 112.2, 111.3, 72.7, 69.1, 28.2, 29.6 ppm. MS (ESI):
m/z = 460 [M + H]+. C26H22BrNO2 (460.37): calcd. C 67.97, H
4.79, N 3.05; found C 67.54, H 4.78, N 3.03.
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lina II, M. R. Boyd, J. Nat. Prod. 1998, 61, 351; c) M. Halaba-
laki, N. Aligiannis, Z. Papoutsi, S. Mitakou, P. Moutsatsou, C.
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Shirota, V. Pathak, S. Sekita, M. Satake, Y. Nagashima, Y. Hi-
rayama, Y. Hakamata, T. Hayashi, J. Nat. Prod. 2003, 66, 1128;
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Esbenshade, A. A. Hancock, M. D. Cowart, Bioorg. Med.
Chem. Lett. 2005, 15, 2559; f) S. Basaria, D. S. Cooper, Am. J.
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Romagnoli, P. Baraldi, M. Carrion, C. Cara, O. Cruz-Lopez,
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[3] a) Z. Yang, H. B. Liu, C. M. Lee, H. M. Chang, H. N. C.
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3-Allyl-2-(benzyloxymethyl)-5-bromobenzofuran (3o): Colorless li-
quid. IR (KBr): ν
= 2924, 2851, 1720, 1637, 1602, 1451, 1360,
˜
max
1266, 1198, 1102, 916, 801, 738 cm–1. 1H NMR (500 MHz, CDCl3):
δ = 7.50 (d, J = 1.9 Hz, 1 H, Ar), 7.32–7.2 (m, 7 H, Ar), 5.94–5.85
(m, 1 H, CH2=CH2), 5.10–5.04 (m, 2 H, CH2=CH2), 4.47 (s, 2 H,
CH2Ar), 3.46 (t, J = 5.9 Hz, 2 H, CH2Ar), 3.32 (d, J = 5.9 Hz, 2
H, CH2-CH=), 2.85 (t, J = 6.9 Hz, 2 H, CH2-CH=), 2.01 (m, 2 H,
CH2-CH2) ppm. 13C NMR (300 MHz, CDCl3): δ = 155.8, 152.7,
138.3, 135.2, 131.5, 128.3, 127.6, 127.5, 125.9, 121.9, 115.9, 115.1,
112.0, 111.8, 72.9, 69.0, 29.6, 28.1, 27.6, 22.9 ppm. MS (ESI): m/z
= 407 [M + Na]+.
2-(2-Benzylbenzofuran-3-yl)-1-phenylethanone (3p): White solid;
m.p. 110–113 °C. IR (KBr): ν
= 2925, 2863, 1724, 1676, 1589,
˜
max
1444, 1332, 1208, 1093, 985, 877, 744, 685, 581 cm–1. 1H NMR
(300 MHz, CDCl3): δ = 7.74 (dd, J = 6.7, 1.5 Hz, 2 H, Ar), 7.55–
7.33 (m, 5 H, Ar), 7.28–7.10 (m, 7 H, Ar), 4.20 (s, 2 H, CH2C=O),
4.41 (s, 2 H, CH2Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 196.2,
154.1, 153.8, 137.0, 136.3, 133.2, 128.6, 128.5, 128.2, 126.6, 123.6,
122.4, 119.1, 110.9, 110.0, 33.9, 32.9 ppm. HRMS (ESI): calcd. for
C23H18NaO2 [M + Na]+ 349.1199; found 349.1207.
(S)-tert-Butyl 2-[(3-Allylbenzofuran-2-yl)methyl]pyrrolidine-1-carb-
oxylate (3q): Colorless liquid. [α]2D0 = –19.5 (c = 2.0, CHCl3). IR
(neat): ν
= 2929, 1692, 1640, 1935 cm–1. 1H NMR (500 MHz,
˜
max
CDCl3): δ = 7.46 (d, J = 6.6 Hz, 1 H, Ar), 7.39 (d, J = 7.6 Hz, 1
H, Ar), 7.25–7.14 (m, 2 H, Ar), 6.00–5.91 (m, 1 H, HC=C), 5.15–
5.03 (m, 2 H, C=CH2), 4.23–4.08 (m, 1 H, CH-N), 3.45–3.09 (m,
5 H, CH2-N, CH2-C=C, N-CH-CH2-Ar), 2.97–2.71 (m, 1 H, N-
CH-CH2-Ar), 1.91–1.57 (m, 4 H, CH2-CH2), 1.47 (s, 9 H,
Boc) ppm. 13C NMR (125 MHz, CDCl3): δ = 154.4, 154.1, 151.9,
135.6, 129.3, 123.3, 122.0, 119.3, 115.7, 113.4, 110.7, 79.4, 56.5,
46.2, 29.6, 28.5, 27.9, 22.6 ppm. MS (ESI): m/z = 364 [M + Na]+.
(R)-tert-Butyl
4-[(3-Allylbenzofuran-2-yl)methyl]-2,2-dimethylox-
azolidine-3-carboxylate (3r): Colorless liquid. [α]2D0 = –25.0 (c = 1.1,
1
CHCl ). IR (neat): ν
= 2927, 1697, 1638, 1385 cm–1. H NMR
˜
3
max
(300 MHz, CDCl3): δ = 7.46 (d, J = 7.9 Hz, 1 H, Ar), 7.39 (d, J =
7.9 Hz, 1 H, Ar), 7.25–7.14 (m, 2 H, Ar), 6.03–5.91 (m, 1 H,
HC=C), 5.15–5.04 (m, 2 H, C=CH2), 4.32–4.13 (m, 1 H, CH-N),
3.95–3.84 (m, 2 H, CH2-O), 3.47–3.39 (m, 2 H, CH2-C=), 3.22 (m,
1 H, N-CH-CH2-Ar), 2.98–2.88 (m, 1 H, N-CH-CH2-Ar), 1.68–
1.44 [m, 15 H, (Boc), (CH3)2C] ppm. 13C NMR (75 MHz, CDCl3):
δ = 154.2, 151.3, 151.1*, 135.6, 135.4*, 129.1, 123.5, 123.4*, 122.1,
122.0*, 119.4, 115.8, 115.7*, 113.8, 113.7*, 110.8, 80.2, 79.9*, 66.7,
66.4*, 56.8, 56.5*, 29.6, 29.3*, 28.4, 27.8*, 27.5, 26.9*, 24.4,
23.2* ppm (*asterisk denotes conformer peaks). MS (ESI): m/z =
394 [M + Na]+.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of H and 13C NMR spectra for all compounds.
1
Acknowledgments
G. K., N. K., and B. L. thank the Council of Scientific and Indus-
trial Research (CSIR), New Delhi for research fellowships. A re-
Eur. J. Org. Chem. 0000, 0–0
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Job/Unit: O20708
/KAP1
Date: 07-08-12 18:45:06
Pages: 9
C. Raji Reddy, G. Krishna, N. Kavitha, B. Latha, D.-S. Shin
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Received: May 28, 2012
Published Online: ᭿
8
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20708
/KAP1
Date: 07-08-12 18:45:06
Pages: 9
Access to 2,3-Disubstituted Benzofurans
Heterocyclic Chemistry
C. Raji Reddy,* G. Krishna, N. Kavitha,
B. Latha, D.-S. Shin ......................... 1–9
Access to 2,3-Disubstituted Benzofurans
through One-Pot Acid-Catalyzed Nucleo-
philic Substitution/TBAF-Mediated Oxa-
cycloisomerization
A one-pot method for the synthesis of di-
versely 2,3-disubstituted benzofurans from
propargylic alcohols is described. The
strategy involves acid-catalyzed nucleo-
philic substitution followed by TBAF-me-
diated desilylative exo-dig-oxacycloisomeri-
zation.
Keywords: Synthetic methods / Combina-
torial chemistry / Cyclization / Nucleo-
philic substitution / Oxygen heterocycles /
Alkynes
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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9