Efficient cyclization of 2-phenoxyalkanals to 2-alkylbenzo[b]furans

Article abstract of DOI:10.1080/00397910500182747

A new and efficient route to 2-alkylbenzo[b]furans via acid-catalyzed cyclization of 2-phenoxyalkanals under mild conditions over amberlyst-15 resin has been described. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1080/00397910500182747

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Efficient Cyclization of
2‐Phenoxyalkanals to
2‐Alkylbenzo[b]furans
a
M. Witczak a & H. Kwiecień
a Department of Organic Synthesis and Drug
Technology, Institute of Organic Chemical
Technology, Szczecin University of Technology,
Szczecin, Poland
Published online: 18 Aug 2006.
To cite this article: M. Witczak & H. Kwiecie (2005) Efficient Cyclization of
2‐Phenoxyalkanals to 2‐Alkylbenzo[b]furans, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 35:16,
2223-2230
To link to this article: http://dx.doi.org/10.1080/00397910500182747
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Synthetic Communicationsw, 35: 2223–2230, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500182747
Efficient Cyclization of 2-Phenoxyalkanals
to 2-Alkylbenzo[b]furans
´
M. Witczak and H. Kwiecien
Department of Organic Synthesis and Drug Technology, Institute
of Organic Chemical Technology, Szczecin University of Technology,
Szczecin, Poland
Abstract: A new and efficient route to 2-alkylbenzo[b]furans via acid-catalyzed cycli-
zation of 2-phenoxyalkanals under mild conditions over amberlyst-15 resin has been
described.
Keywords: Amberlyst, benzofurans, cyclization
The benzo[b]furan ring system occurs in a large number of biologically active
natural and synthetic compounds.[1] 2-Alkylbenzo[b]furans are intermediates
in the production of therapeutic agents used for treatment of pathological
syndromes of the cardiovascular system such as hypertension and arrhyth-
mia.[2] Many 2-alkylbenzo[b]furans derivatives exhibit various pharmaco-
dynamic properties, and a large number of synthetic approaches to these
compounds have been reported.[3] The majority of the syntheses are based
on formation of the furan ring from various phenolic substrates, except for
the following methods that start from benzofuran: acylation followed by
reduction of the acyl derivative with hydrazine[4] and direct alkylation.[5]
Among the procedures based on formation of the furan moiety from phenolic
substrates, the palladium-catalyzed heteroannulation of 2-halophenols with
terminal or internal alkynes is the most often applied.[6–9] Commonly used
Received in Poland March 22, 2005
Address correspondence to H. Kwiecien, Department of Organic Synthesis and
´
Drug Technology, Institute of Organic Chemical Technology, Szczecin University
´
of Technology, Al. Piastow 42, 71-065, Szczecin, Poland. Tel.: þ48 914494103;
E-mail: halina.kwiecien@ps.pl
2223

´
M. Witczak and H. Kwiecien
2224
precursors of 2-alkylbenzo[b]furans are 2-formylphenoxyketones[10] and 2-(2-
formylphenoxy)alkanoic acids,[11–13] both prepared from salicylaldehyde.
2-Alkylbenzo[b]furans were also obtained by cyclization of 2-alkoxybenzyl-
triphenylphosphonium bromides.[14] Most of the cyclization methods suffer
complicated reaction conditions, for example, high temperature and
dangerous reagents. In addition, a stoichiometric or an excess amount of the
reagents is often needed.
The first attempt to cyclize 2-phenoxyacetaldehyde diethylacetal with
sulphuric acid or zinc chloride in acetic acid was performed by
Stoermer,[15] but the yield of benzo[b]furan formation was low. Previously
we cyclized 2-phenoxyhexanal to 2-butylbenzo[b]furan, but the reaction
required drastic conditions, the yields were low, and undesirable polymeric
products were also formed.[13]
Considerably better results of benzo[b]furan synthesis have been
achieved when O,O-diacetals of aryloxyacetaldehyde were cyclized at
1008C with polyphosphoric acid in the presence of phosphorus (V)
oxide[16,17] or with amberlyst-15 resin in boiling chlorobenzene.[18]
Recently, during our investigation of the acetalization of 2-phenoxyalka-
nals, we ascertained that the diacetals easily underwent cyclization to 2-alkyl-
benzo[b]furans in a nonpolar solvent such as benzene or toluene over
amberlyst-15 resin.[19]
Herein we have investigated the cyclization of 2-phenoxyalkanals 1a–g
(Scheme 1). The aldehydes have been obtained by Rosenmund reduction
of the corresponding 2-phenoxyalknoyl chlorides. The reduction led to the
formation of 2-phenoxyalkanal as the main product and to a mixture of Z, E
diastereoisomers of phenyl-alkenyl and phenyl-alkyl ethers as by-
products.[20] The optimization of the parameters catalyst and poison for the
starting chloride weight ratio of the reduction allowed us to obtain 2-phenox-
yalkanals in 70–75% yield. The product was isolated by distillation of the
crude reduction mixture under reduced pressure.[21]
To optimize the cyclization parameters, the reaction of the model 2-(4-
methoxyphenoxy)butanal 1c was investigated. The process was carried out
Scheme 1.

Cyclization of 2-Phenoxyalkanals
2225
in benzene or toluene, using homogenous sulphuric acid and heterogeneous
amberlyst-15 resin as catalysts. The best results and high yield of cyclization
were achieved when the reaction mixture was heated in boiling benzene for
20–30 min (Scheme 1, Table 1).
When the cyclization of compound 1c was performed in benzene, in the
presence of a catalytic amount of sulphuric acid, 2-ethyl-5-methoxybenzo[b]-
furan 2c was formed in 50–60% yields. When the aldehyde was treated with a
larger than catalytic amount of sulphuric acid or when the reaction was
performed at higher temperature (1208C) or for a longer time (more than
2 h), the yield of 2c was decreasing because of the polymerization processes
(Table 1).
In the established, optimal reaction conditions, the cyclization of other
aldehydes was carried out to give suitable 2-alkylbenzo[b]furans in a high
yield (Table 2). All of the obtained 2-alkylbenzo[b]furans 2a–g, after fil-
tration of the resin, neutralization of the reaction mixture, and removal of
the solvent, were pure enough to be used in a further synthesis. The crude
samples were distilled under reduced pressure, and afterward their structure
1
was determined with GC/MS and H NMR spectroscopy.
An efficient cyclization of 2-phenoxyalkanals to 2-alkylbenzo[b]furans,
as a green chemistry process, carried out in mild conditions over the
amberlyst-15 resin has been presented. The atom economy of the cyclization
of 2-phenoxybutanal is 90%, whereas the atom economy of the 2-(2-formyl-
phenoxy)hexanoic acid cyclization to 2-butylbenzo[b]furan only amounts to
41%. The obtained 2-butylbenzo[b]furan 2b is an intermediate in amiodarone
production.[2]
EXPERIMENTAL
1H NMR spectra were recorded with TM Bruker DPX 400 spectrometer for a
solution in CDCl3 using TMS as internal standard. The analyses of the
reaction products were carried out on a GC/MS Agilent Technologies
6890N apparatus equipped with a mass-sensitive detector Agilent Technol-
ogies 5973Network and 30 m ꢀ 0.25 mm capillary column filled up with a
0.25 m film of a 5% PhMe polysiloxane. Helium was used as a carrier gas
at a flow rate of 1.2 ml min21. The column temperature was programmed:
initial temperature 608C (hold for 3 min); ramp rate 108C min21; final
temperature 2808C (hold for 10 min). The injection port and the transfer
line temperatures were 2508C and 2808C, respectively.
Starting Materials
Amberlyst-15 resin was purchased from Fluka. 2-Phenoxyalkanals (1a–g)
were prepared from the corresponding 2-phenoxyalkanoyl chlorides.[20]

´
M. Witczak and H. Kwiecien
2226

Cyclization of 2-Phenoxyalkanals
2227
Table 2. Cyclization of 2-phenoxyalkanals (1a–g) to 2-alkylbenzo[b]furans (2a–g)
2-Phenoxyalkanals 1
2-Alkylbenzo[b]furans 2
Yields (%)
96
a
b
94
c
95
94
d
e
93
f
95
93
g
Cyclization of 2-Phenoxyalkanals (1a–g) to 2-Alkylbenzo[b]furans
(2a–g), General Procedure
Amberlyst-15 resin (0.75 g) was added to the solution of 2-phenoxyalkanals
(2 mmol) in benzene (15 ml), and the mixture was heated under reflux with
stirring for 20 min. The resin was filtered off; the solution was washed with

´
M. Witczak and H. Kwiecien
2228
aqueous sodium bicarbonate and with water and then dried over MgSO4. The
solvent was evaporated and a crude 2-alkylbenzo[b]furan was distilled under
reduced pressure. The following benzo[b]furans have been obtained:
2-Ethylbenzo[b]furan (2a): bp 54–568C/2 Torr; lit.[21] bp 698C/5 Torr.
2-Butylbenzo[b]furan (2b): bp 80–828C/3 Torr; lit.[13] bp 114–1168C/8
Torr.
1
2-Ethyl-5-methoxybenzo[b]furan (2c): bp 112–1148C/6 Torr; H NMR
(400 MHz, CDCl3): d 1.29 (3H, t, J ¼ 7.4 Hz, CH3), 2.75 (2H, J ¼ 7.4 Hz,
CH2), 3.79 (3H, s, OCH3), 6.28 (1H, s, aromatic proton), 6.78–6.74 (1H,
J ¼ 8.5, 2.6 Hz, dd, aromatic protons), 6.94 (1H, d, J ¼ 2.6 Hz, 1H,
aromatic proton), 7.27 (1H, d, J ¼ 8.4 Hz, aromatic proton); GC
(t ¼ 13.23 min); MS, m/z (%) ¼ 176-Mþ (70), 161 (100), 146 (10), 131
(4), 103 (6), 77 (9), 63 (4), 39 (2). Anal. calcd. for C11H12O2 (176.22): C,
74.98; H, 6.86; found: C, 74.82; H, 6.97.
2-Ethyl-5-t-butylbenzo[b]furan (2d): bp 115–1168C/8 Torr; 1H NMR
(400 MHz, CDCl3): d 1.30 (3H, t, J ¼ 7.5 Hz, CH3), 2.75 (2H, q,
J ¼ 7.5 Hz, CH2), 1.36 (9H, s, CH3), 6.32 (1H, d, J ¼ 0.6 Hz, aromatic
proton), 7.25–7.33 (2H, m, aromatic protons), 7.47 (1H, d, J ¼ 1.8 Hz,
aromatic proton); GC (t ¼ 14.12 min); MS m/z (%) ¼ 202-Mþ (36), 187
(100), 171 (7), 159 (9), 131 (16), 115 (8), 91 (7), 72 (6), 57 (7), 41 (2), 39
(2). Anal. calcd. for C14H18O (202.29): C, 83.12; H, 8.97; found: C, 83.02;
H, 9.06.
1
4,6-Dimethyl-2-ethylbenzo[b]furan (2e): bp 99–1008C/10 Torr; H NMR
(400 MHz, CDCl3): d 1.30 (3H, t, J ¼ 7.5 Hz, CH3), 2.42 (3H, s, CH3), 2.39
(s, 3H, CH3), 2.76 (2H, q, J ¼ 7.5 Hz, CH2), 6.31 (1H, d, J ¼ 0.7 Hz,
aromatic proton), 7.04 (1H, s, aromatic proton), 7.18 (1H, s, aromatic
proton); GC (t ¼ 12.49 min); MS, m/z (%) ¼ 174-Mþ (50), 159 (100), 144
(5), 128 (8), 115 (12), 91 (6), 72 (2), 51 (2), 39 (2). Anal. calcd. for
C12H14O (174.24): C, 82.72; H, 8.10; found: C, 82.65; H, 8.15.
1
6,7-Dimethyl-2-ethylbenzo[b]furan (2f): H NMR (400 MHz, CDCl3): d
1.30 (3H, t, J ¼ 7.5 Hz, CH3), 2.39 (3H, s, CH3), 2.46 (3H, s, CH3), 2.76
(2 h, q, J ¼ 7.5 Hz, CH2), 6.31 (1H, d, J ¼ 0.7 Hz, aromatic proton), 7.18
(1H, s, aromatic proton), 7.48 (1H, s, aromatic proton); GC (t ¼ 13.35 min);
MS, m/z (%) ¼ 174-Mþ (49), 159 (100), 160 (11), 128 (8), 115 (7), 128
(4), 144 (4), 158 (2), 64 (2), 51 (2). Anal. calcd. for C12H14O (174.24): C,
82.72; H, 8.10; found: C, 82.61; H, 8.19.
1
5-Methoxy-2-propylbenzo[b]furan (2 g): H NMR (400 MHz, CDCl3): d
1.29 (3H, t, J ¼ 7.4 Hz, CH3), 2.01–1.94 (2H, m, CH2), 2.72 (2H, q,

Cyclization of 2-Phenoxyalkanals
2229
J ¼ 7.4 Hz, CH2), 3.80 (3H, s, OCH3), 6.28 (1H, s, aromatic proton), 6.75–
6.69 (1H, dd, J ¼ 8.5, 2.6 Hz, aromatic proton), 6.91 (1H, d, J ¼ 2.6 Hz,
aromatic proton), 7.24 (1H, d, J ¼ 8.4 Hz, aromatic proton); GC
(t ¼ 14.94 min); MS, m/z (%) ¼ 190-Mþ (39), 161 (100), 162 (12), 118
(8), 146 (5), 89 (2), 76 (2), 63 (2), 50 (2). Anal. calcd. for C12H14O
(190.24): C, 75.76; H, 7.42; found: C, 75.68; H, 7.49.
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