48 Current Organic Chemistry, 2010, 14, 48-64
1385-2728/10 $55.00+.00 © 2010 Bentham Science Publishers Ltd.
2-Acetylbenzofurans: Synthesis, Reactions and Applications
Mohamed A. Metwallya, Bakr F. Abdel-Wahab
b and Gamal A. El-Hiti*
c
a Department of Chemistry, Faculty of Science, University of Mansoura, P.O. Box 23, Mansoura, Egypt
b Applied Organic Chemistry Department, National Research Center, Dokki, Giza, Egypt
c School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff CF10 3AT, UK
Abstract: This review deals with synthesis and reactions of 2-acetylbenzofurans. Some of these reactions have been applied successfully
to the synthesis of biologically important compounds. The main purpose of this review is to present a survey of the literature on
2-acetylbenzofurans chemistry and provides useful and up-to-date data for their applications since such compounds have not been previ-
ously reviewed.
1. INTRODUCTION
2-Acetylbenzofuran, known as 2-benzofuryl methyl ketone, was
named as 1-(benzofuran-2-yl)ethanone using the IUPAC system.
2-Acetylbenzofurans have been employed successfully as starting
materials for the production of biologically active compounds. Due
to the wide spectrum of activities shown by benzofuran moiety,
various substituted benzofurans with various substituents at differ-
ent positions have been synthesized. Also, reactions of benzofuran
derivatives were studied and have been applied to the synthesis of
more complex valuable materials.
2. METHODS OF SYNTHESIS
2.1. Friedel-Craft Acetylation
Friedel–Crafts acetylation of benzofuran (1) provides a funda-
mental method for the preparation of 2-acetylbenzofuran (2a),
which is a useful intermediate for the synthesis of many valuable
compounds. Benzofuran itself is known to be sensitive to the ordi-
nary Friedel-Crafts acetylation in the presence of AlCl3 as a catalyst
[1,2]. However, benzofuran (1) can be acetylated at high tempera-
ture using acetic anhydride in the presence of phosphoric acid.
However, such method suffers from low product yield and the reac-
tion succeeds only when the anhydride was employed as the solvent
[3]. For example, treatment of benzofuran (1) with acetic anhydride
in acetic acid in the presence of phosphoric acid as a catalyst, at
130 °C for 4 h, gave 2-acetylbenzofuran (2a; Scheme 1) in moder-
ate yields (33-55%) [3].
O O
Ac
2a1
Ac2O
Catalyst
Scheme 1.
Also, catalytic Friedel–Crafts acetylation of 1 has been
achieved with acetic anhydride in the presence of metal triflates as
catalysts in acetonitrile as a solvent [4]. 2-Acetylbenzofurane (2a)
was produced in the yield of 30-72% along with a small proportion
of 3-acetylbenzofuran as a side product [4].
*Address correspondence to this author at the School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff CF10 3AT, UK; Tel: +442920870601; Fax: +442920874030; E-mail: [email protected]
Generally, Friedel-Crafts acetylation of 1 suffer serious disad-
vantages, including some or all of the following: the requirement
for large quantities of mineral or Lewis acids as activators, which
on work-up may be hydrolysed with generation of large quantities
of corrosive and toxic waste by-products; poor yields or production
of mixtures of regioisomers. Major efforts are therefore being made
to develop clean and environmentally friendly processes for the
production of 2a via Friedel-Crafts acetylation of benzofuran (1).
It is well recognized that zeolite catalysts can play an important
role in the development of greener synthesis of 2a through their
abilities to act as recyclable heterogeneous catalysts, support rea-
gents, entrain by-products and avoid aqueous work-ups. Indeed,
zeolites have been used as catalysts for the acetylation of 1 under
mild conditions [5-8]. It was found that acetylation of 1 with acetic
anhydride at 60 °C for 10 h in the presence of zeolite Y produced
2a in 43% yield [5]. However, the sustainability of the process that
improved the yield of 2a was still low.
2.2. From 1-(benzofuran-2-yl)ethanol
Oxidation of 1-(benzofuran-2-yl)ethanol (3) with dimethyldiox-
irane (three mole equivalents) at 0 °C for 12 h gave
2-acetylbenzofuran (2a) in 38% yield (Scheme 2) [9]. Since 2a was
produced in only low yield, expoxidation of the enol ether bond
could take place. It is believed that dimethyldioxirane oxidation of
3 initially afforded the corresponding epoxide, which subsequently
could arrange 2a via 1,2-migration.
O
2a (38%)
O OH
Me
3
O O
MeMe Me
O0 °C, 12 h
Scheme 2.
2.3. From 2-(trimethylsilyl)benzofuran
2-Acetylbenzofuran (2a) was synthesized in 88% yield from the
reaction of 2-(trimethylsilyl)benzofuran (4), available quantitatively
from 1 itself via lithiation followed by reaction with chlorotrimeth-
ylsilane at low temperature, with acetyl chloride in the presence of
titanium chloride at -78 °C (Scheme 3) [10,11].
2.4. From 2-hydroxybenzaldehydes
The yield of 2a obtained from direct acetylation of benzofuran
is always low. This problem could be overcome by incorporation of
2-Acetylbenzofurans: Synthesis, Reactions and Applications Current Organic Chemistry, 2010, Vol. 14, No. 1 49
the 2-acetyl group in the starting materials, in which benzofuran
ring was constructed during reaction. Indeed, reactions of
2-hydroxybenzaldehydes 5 with chloroacetone in the presence of
alcoholic potassium hydroxide gave the corresponding 2-acetyl-
benzofuran derivatives 2 (Scheme 4) [12-16]. For example, treat-
ment of salicylaldehyde with chloroacetone in the presence of alco-
holic KOH produced 2a in 67% yield after purification [12].
CHOR1
R2 OH O
Ac
R1
R2
25 R1 = R2 = H, OMe
AcCH2Cl
alc. KOH
Scheme 4.
2.5. From -oxoacyloxybenzylphosphonium Salt
Intramolecular Witting reaction of (2-(2-oxopropanoyloxy)
benzyl)triphenyl-phosphonium salt (6) afforded 2-acetylbenzo-
furans 2 but as a mixture with 3-methylcoumarin (7; Scheme 5)
[17].
2.6. From (Z)-3-(3,5-dimethoxyphenoxy)-4-(dimethylamino)but-
3-en-2-one
Intramolecular cyclization of (Z)-3-(3,5-dimethoxyphenoxy)-4-
(dimethylamino)but-3-en-2-one (8) catalyzed by ZnCl2, at room
temperature for 48 h, afforded 2-acetyl-4,6-dimethoxybenzofuran
(2b), the naturally occurring compound known as calebertin, in
60% yield (Scheme 6) [18].
ZnCl2
DCM, 48 hO
Ac
OMe
MeO
8 2b (60%)
O
OMe
MeO
Ac
NMeMe
Scheme 6.
Reaction of 3,5-dimethoxyphenol (9; Fig. 1) with chloroacetone
in the presence of K2CO3, under reflux conditions for 12 h in ace-
tone, gave the corresponding ether 10 (Fig. 1) in 72% yield which
on reaction with N,N-dimethylformamide-dimethyl acetal (DMF-
DMA) at 80 °C for 6 h gave 8 in 82% yield [18].
9
OH
OMe
MeO
10
O
OMe
MeO Ac
Fig. (1).
Also, compound 2b could be produced but in only low yield
(19%) from direct reaction of 9 (Fig. 1) with DMF-DMA in aceto-
nitrile at 90 °C for 48 h [18]. The yield was improved to 35% when
the reaction was carried out under microwave conditions in the
presence of zinc chloride as a catalyst [18].
2.7. From 2-acetylbenzofuranhydrazone
Hydrolytic cleavage of 2-acetylbenzofuranhydrazone (11) un-
der acidic conditions in the presence of 4-chlorobenzaldehyde is a
convenient method for the regeneration of 2a (Scheme 7) along
with formation of bis(4-chlorobenzylidene)hydrazine as a side-
product [19].
3. REACTIONS
3.1. Reduction
Catalytic hydrogenation of 2a was found to be dependent on the
type of reducing agent. For example, hydrogenation of 2a using
platinum/hydrogen or sodium borohydride afforded 2-(1-
hydroxyethyl)benzofuran (3; Scheme 8) in high yield [20,21].
However, use of Raney nickel catalyst produced 1-(2,3-
dihydrobenzofuran-2-yl)ethanol (12) in 81-90% yields [20]. Also, it
was found that hydrogenation of 2a in the presence of colloidal
platinum resulted in a mixture of 3, 12, 13 and 2-ethyl-2,3-
dihydrobenzofuran [20]. On the other hand, Wolf-Kishner reduction
of 2a gave 2-ethylbenzofuran (13; Scheme 8) [15,22].
2-Acetylbenzofuran (2a) was reduced selectively with bo-
rane/oxazaborolidine, generated in situ from triisopropoxyborane
and (1S,3S,4R,6R)-4-amino-3,7,7-trimethylbicyclo[4.1.0]heptan-3-
ol, to afford (S)-1-(benzofuran-2-yl)ethanol (14, Scheme 9) in 98%
ee [23]. Also, reduction of 2a with borane/oxazaborolidines, gener-
ated in situ from (1S,2R)-norephedrine or (S)-diphenylvalinol, re-
sulted in the production of 14 but in a lower enantiomeric excess.
O
Ac
2a (88%)
O
SiMe3
4 (100%)
AcCl, TiCl4
-78 °CO
1
n-BuLi, -78 °C
Me3ClSi, -78 °C
Scheme 3.
R2
R1
OCOAc
CH2PPh3X R1
R2
O
Ac
O
Me
R2
R1
6 2 7
+
R1 = R2 = H, Br; R2 = NO2
O
Scheme 5.
50 Current Organic Chemistry, 2010, Vol. 14, No. 1 Metwally et al.
O2a
O
Me
O OH
Me
O
NH
BOPri
, BH3/THF
0 °C, 4 h
14
Scheme 9.
3.2. Oxidation
Oxidation of 2a with selenium dioxide in aqueous dioxane, un-
der reflux conditions for 3 h, gave 2-( , -dihydroxyacetyl)benzo-
furan (15) which could be dehydrated to give 2-(benzofuran-2-yl)-
2-oxoacetaldehyde (16; Scheme 10) [24].
Benzofuran acetic acids 17 can be conveniently synthesized
from reactions of 2 with sulfur in the presence of morpholine fol-
lowed by hydrolysis of the resulting thiomorpholides (Scheme 11)
[25].
3.3. Halogenation
Bromination of 2a with bromine in acetic acid, dioxane/ether or
carbon disulfide as a solvent gave 1-(benzofuran-2-yl)-2-
bromoethanone (18; Scheme 12) [26-29].
O
2a
Br
O O
18
Br2
AcOH or CS2
Me
O
Scheme 12.
Bromination of 5-chloro-3-methyl-2-acetylbenzofuran (2c) with
bromine in acetic acid as a solvent gave 5-chloro-3-methyl-2-
bromoacetylbenzofuran (19; Scheme 13) [30].
O
2c
Br
O O
19
Br2
AcOH
Cl
Me Me
ClMe
O
Scheme 13.
1-(1-Benzofuran-2-yl)-2-chloroethanone (20; Scheme 14) was
synthesized from 2a by chlorination with thionyl chloride. From the
X-ray study, it was found that the benzofuran ring and the carbonyl
group are coplanar. Also, the carbonyl group was found to be in a
syn position relative to both the O atom of the benzofuran ring and
the C-l atom [31].
O
2a
O
Me
N NH2
ClHCl/H2O/EtOH
reflux, 30 min
O
Me
+ CHO
11
Scheme 7.
O
2a
O OH
Me
3
Wolf-Kishner
O
Et
13
Pd/H2 or
NaBH4
Me
O
Raney-Ni
O OH
Me
12 Scheme 8.
O
2a
O O
OH
HO
O O
CHO
15 16
- H2OSeO2Me
O
Scheme 10.
R = H, Cl, F, Me, Me3C, OMe, Ph, PhCH2, cyclohexyl
O
R
Me
1, S/morphline
2, Hydrolsis O
COOHR
Me
172
Me
O
Scheme 11.
2-Acetylbenzofurans: Synthesis, Reactions and Applications Current Organic Chemistry, 2010, Vol. 14, No. 1 51
O
2a
Cl
O O
20
Me
O
SOCl2
Scheme 14.
Treatment of 2a with TIPSOTf in the presence of iPr2NEt in di-
chloromethane gave the corresponding ether 21 (Scheme 15) in
98% yield. Chlorination of 21 with N-chlorosuccinimide (NCS; 1.1
equivalents) in THF under reflux conditions gave the corresponding
chloro derivative 22 (Scheme 15) in 99% yield but as a mixture of
two geometric isomers. 1-(1-Benzofuran-2-yl)-2-chloroethanone
(20; Scheme 15) was isolated in 67% yield after desilylation of 22
with aqueous HF (48%) in acetonitrile as a solvent [32].
Direct -iodination of 2a with elemental iodine in the presence
of 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis
(tetrafluoroborate) afforded 1-(benzofuran-2-yl)-2-iodoethanone
(23; Scheme 16) [33].
O
2a
Me
O
I
O O
23
I2
Scheme 16.
Reaction of 2a with hydrobromic acid in the presence of lithium
aluminum hydride gave 2-(1-bromoethyl)benzofuran (24; Scheme
17) [34].
O
2a
Me
O O
Me
Br
24
HBr
LiAlH4
Scheme 17.
Reaction of N-(2-acetylbenzofuran-3-yl)acetamide (25) with
bromine in THF or phenyltrimethylammonium tribromide
(Me3NPhBr3) gave N-(2-(2-bromoacetyl)benzofuran-3-yl)aceta-
mide (26; Scheme 18) in 51 or 59% yield, respectively. While,
reaction of 25 with two equivalents of sulfuryl chloride (SO2Cl2) in
acetic acid gave N-(2-chlorobenzofuran-3-yl)acetamide (27;
Scheme 18) in 78% yield after purification [35]. Compound 27 was
obtained in 51% yield when excess chlorine in chloroform was used
as the chlorinating reagent [36].
On the other hand, 1-(3-methylbenzofuran-2-yl)ethanone (2d)
was easily halogenated with SO2Cl2 in chloroform or Me3NPhBr3 in
THF to give the corresponding haloacetyl derivatives 28 (Scheme
19) in high yields after crystallization [35].
O
Me
O
O
Me
X
2d
SO2Cl2
or Me3N+Ph Br3-
28 X = Cl, Br
Me
O
Scheme 19.
Reaction of 2a with ethylene glycol in benzene and in the pres-
ence of 4-tolylsulfonic acid afforded 2-(2-methyl-1,3-dioxolan-2-
yl)benzofuran (29) which on bromination with bromine in chloro-
form gave 2-(2-(dibromomethyl)-1,3-dioxolan-2-yl)benzofuran (30;
Scheme 20) [36].
O
2a
Me
O
TIPSOTF
iPr2NEt, CH2Cl2 O OTIPS
NCS, THF
O OTIPS
Cl48% aq. HF
MeCN O O
Cl
21 (98%)
22 (99%) 20 (67%) Scheme 15.
O
NHAc
Me3N+Ph Br3-
or Br2O
O
NHAc
Br
2526 (51-59%)
O
Cl
NHAc
27 (78%)
Me
O
SO2Cl2
AcOH
Scheme 18.
52 Current Organic Chemistry, 2010, Vol. 14, No. 1 Metwally et al.
3.4. Nitration
Nitration of 2a with a mixture of nitric acid and acetic anhy-
dride was mostly successful at the 5 and 6-positions and in some
instances at the 4-position and possibly at the 7-position to give the
corresponding nitro derivatives 31-34 (Fig. 2), respectively. In
some cases, the acetyl group at the 2-position was replaced by the
nitro group to produce 2-nitrobenzofuran (35; Fig. 2) [37].
Bachelet et al. [38] reported the synthesis of 1-(4-methoxy-5-
nitrobenzofuran-2-yl)ethanone (36) but as a mixture with 1-(4-
methoxy-7-nitrobenzofuran-2-yl)ethanone (37) from nitration reac-
tion of 2-acetyl-4-methoxybenzofuran (2e) with a mixture of nitric
acid and acetic anhydride (Scheme 21).
3.5. Acetylation
2-Acetylbenzofurans 2 (R = 4-OMe, 5-OMe, 6-OMe, 7-OMe)
could be acetylated, but not regioselectively, at the 4-, 5- and 7-
postions or at the 4- and 7-positions [39]. However, regioselective
acetylation of 2a with acetic anhydride at 60 °C in the presence of
zeolite HY (Si/Al = 16) as a catalyst gave 3-(benzofuran-2-
carbonyl)pentane-2,4-dione (38) as the main product (Scheme 22)
as a result of two consecutive acetylation steps on the side chain
[40]. Other minor products were also obtained but the purity of 38
was high (ca. 96%) and the conversion of 2a was ca. 50%.
O
2a
Me
O
Ac
Ac
OO
38
Ac2O, 60 °C
HY
Scheme 22.
3.6. Mannich Reaction
Mannich reaction of 2a with various amines followed by reduc-
tion with NaBH4 gave the corresponding benzofuranoaminopropan-
1-ols 39 (Scheme 23) [41].
O
2a
Me
O O OH
NR2
39
NR2 = 4-phenylpiperazino, piperidino, morpholino, 4-(2-methylphenyl)piperazino
i, HCHO, R2NH
ii, NaBH4
Scheme 23.
3.7. Schmidt Rearrangement
Schmidt rearrangement of 2-acetylbenzofuran (2a) gave
N-methylbenzofuran-2-carboxamide (40; Fig. 3) [34,42].
O
O
NHMe
40 Fig. (3).
3.8. Claisen Condensation
Claisen condensation of 2a with diethyl oxalate in the presence
of sodium methoxide gave ethyl 4-(benzofuran-2-yl)-2,4-
dioxobutanoate (41, Scheme 24) [43].
Recently, compound 41 was used as intermediate for the syn-
thesis of biologically active heterocycles such as 5-(benzofuran-2-
yl)-pyrazole-3-carboxamides 42 (Fig. 4) and 3-(5-(benzofuran-2-
yl)-1-phenyl-1H-pyrazol-3-yl)-4-(2-chloro-4-
nitrobenzylideneamino)-1H-1,2,4-triazole-5(4H)-thione (43; Fig. 4)
[44,45].
3.9. Reaction with Grignard Reagents
The reaction of 2a with a Grignard reagent followed by dehy-
dration gave 2-(1-propenyl)benzofuran (44; Fig. 4) [46].
HO
HO
O
29 302a
O O
O
Me
O O
O
B Br
benzene
Me
O
Br2
CHCl3
Scheme 20.
O
Ac
O2N
O
Ac
NO2
O
Ac
NO2
O
NO2
31 32 33 34 35
O
Ac
O2N
Fig. (2).
O
Ac
2e
+HNO3
Ac2O
OMe
O
Ac
36
OMe
O2N
O
Ac
37
OMe
NO2 Scheme 21.
2-Acetylbenzofurans: Synthesis, Reactions and Applications Current Organic Chemistry, 2010, Vol. 14, No. 1 53
3.10. Aldol Condensations
Reaction of 2-acetylbenzofuran (2a) with aldehydes took place
smoothly and easily to produce the corresponding condensation
product that could be easily cyclised to produce various heterocyc-
lic compounds [47-50]. For example, treatment of 2a with various
aldehydes in solvent-free reactions under microwave irradiation
conditions [48] or in the presence of a strong base [49] gave the
corresponding chalcones 45 (Scheme 25). Also, (E)-1-(benzofuran-
2-yl)-3-phenylprop-2-en-1-one (45, R = Ph; Scheme 25) was ob-
tained from reaction of 2a with benzaldehyde in DMF and in the
presence of chlorotrimethylsilane (three molar equivalents), as a
promoter and water-acceptor agent, at 100 °C in a sealed tube [47].
RCHO
O O O
R
452a
Me
O
R = alkyl, aryl Scheme 25.
Condensation of 45 with guanidine hydrochloride, thiourea and
urea, in the presence of a strong base or under microwave condi-
tions, afforded the corresponding 4-substituted 6-(benzofuran-2-
yl)pyrimidines 46 (Scheme 26) [48,49].
Also, it was found that condensation of 45 with hydrazines gave
the corresponding pyrazolines 47 (Scheme 27) [51-57].
3-Aryl-1-(benzofuran-2-yl)prop-2-en-1-ones 45 also undergo
condensation with heterocyclic hydrazines to give the correspond-
ing hydrazones 48 (Scheme 28) [58-60].
On the other hand, condensation of 45 with mefenamic acid hy-
drazide gave the corresponding pyrazolines 49 (Scheme 29) [58-
60].
Cyclocondensation of 45 with different hydrazides resulted in
the formation of benzofuran-2-pyrazolines 50 (Scheme 30) [61,62].
Similarly, condensation of 45 with o-phenylenediamine or
2-aminothiophenol gave the corresponding benzodiazepines 51
(Scheme 31) [51-57].
O2a
O O
O
CO2Et
41
O
EtO O
OEtMe
O MeONa
Scheme 24.
O N N
R
O
NH
N
O
O
42 R = H, Ph
ON
N
Ph
N
HN
N S
N Cl
NO243
O
44
Me
Fig. (4).
O O
R
H2N NH2
X
N
N
XH
R
O
45 46
MW or base
R = alkyl, aryl; X = NH.HCl, S, O Scheme 26.
O O
Ar
RNHNH2
O NN
R
Ar
45 47R = H, Me, Ph, 4-NO2C6H4 Scheme 27.
O O
Ar
45
Het-NHNH2
O N
Ar
NH
Het
48 Scheme 28.
54 Current Organic Chemistry, 2010, Vol. 14, No. 1 Metwally et al.
North and Oxford [63] have synthesized 1-(benzofuran-2-yl)-3-
(5-methyl-1-trityl-1H-imidazol-4-yl)prop-2-en-1-one (53) by stir-
ring 2a with 5-methyl-1-trityl-1H-imidazole-4-carbaldehyde (52) in
ethanolic potassium hydroxide for overnight (Scheme 32).
Bianchi and Barzaghi [64] reported the successful synthesis of
4-(benzofuran-2-yl)-4-oxobut-2-enoic acid (54) from reaction of 2a
with glyoxalic acid in acetic acid (Scheme 33).
Condensation of 2a with 2-(2,2-dimethylhydrazono)propanal
(55) gave 1-(benzofuran-2-yl)-4-(2,2-dimethylhydrazono)pent-2-
en-1-one (56; Scheme 34) [65].
3.11. Synthesis of Quinolines
Substituted quinoline 57 was prepared using Friedländer syn-
thesis from reaction of 2a with 2-aminobenzophenone in DMF and
O O
Ar
45
ON
N
Ar
N
O
F
N
Et
O
NH
mefenamic acid
hydrazide
49
Scheme 29.
O O
Ar
45
Ar1
O
NH
NH2
O
Ar
NNH
OAr150
Scheme 30.
O O
Ar
45
NH2
XH
O
N
Ar
X
R2
R1
R1, R2 = H, Me, Cl, X = NH, S 51
R1
R2
Scheme 31.
NNCPh3
Me
O
+
O O NNCPh3
Me
2a 52 53
KOH
EtOH
O
O
Me
Scheme 32.
O
2a
O
Me O
O
OH
AcOHO O
54
O
HO
Scheme 33.
2-Acetylbenzofurans: Synthesis, Reactions and Applications Current Organic Chemistry, 2010, Vol. 14, No. 1 55
in the presence of chlorotrimethylsilane as a promoter and water-
acceptor agent (Scheme 35) [66].
Also, reaction of 2a with isatin in alkaline medium, by the
Pfitzinger reaction, gave quinoline-4-carboxylic acid (58, Scheme
36) [67].
3.12. Reactions with Arylidene Nitriles
Reactions of 2a with a mixture of 3,4-dimethoxybenzaldehyde
and ethyl cyanoacetate in the presence of ammonium acetate, in dry
ethanol under reflux conditions for 3 h, afforded 3-cyano-4-(3,4-
dimethoxyphenyl)-6-(1-benzofuran-2-yl)-lH-pyrid-2-one (59;
Scheme 37) in 30% yield after purification [68].
Similarly, reaction of 2a with a mixture of aromatic aldehydes
and malononitrile in the presence of ammonium acetate, in dry
ethanol under reflux conditions for 3-4 h, gave the corresponding
2-amino-4-aryl-6-(benzofuran-2-yl)nicotinonitrile 60 (Scheme 38)
in 25-30% yields after crystallization [68].
Treatment of 2a with 2-(3,4,5-trimethoxybenzylidene)malono-
nitrile, in the presence of sodium alkoxide, gave the corresponding
6-(benzofuran-2-yl)-2-alkoxy-4-(3,4,5-trimethoxyphenyl)nicotino-
nitriles 61 (Scheme 39) [69].
3.13. Reactions with Schiff’s Bases
Reactions of 2a with Schiff bases 62 gave the corresponding
3-aryl-1-(benzofuran-2-yl)benzo[f]quinolines 63 (Scheme 40) [70].
O
2a
O
Me
NN Me
MeMe
N
N
Me
Me
O
Me
O
56
+
O
55
Scheme 34.
O
2a
O
Me
O
Ph
NH2
N
O
Ph
+
57
Me3SiCl
DMF
Scheme 35.
O
2a
O
Me
+
N
O
OH
ONH
O
O
58
base
Scheme 36.
O
2a
O
Me
+ + NC CO2Et
NH4OAc
O HN
CN
59 (30%)
CHO
OMe
OMe
O
OMeMeO
Scheme 37.
O N
Ar
NH2
CN
Ar = Ph, 4-ClC6H4, 4-MeOC6H4
O
2a
O
Me
+ +
NH4OAc
NC CN
60 25-30%)
ArCHO
Scheme 38.
56 Current Organic Chemistry, 2010, Vol. 14, No. 1 Metwally et al.
3.14. Reactions with DMF-DMA
Condensation of 2a with dimethylformamide-dimethylacetal
(DMF-DMA) afforded 1-(benzofuran-2-yl)-3-(dimethylamino)pro-
p-2-en-1-one (64; Scheme 41). Addition of cyanoacetamide to 64 in
the presence of sodium methoxide gave 3-cyano-6-(benzofuran-2-
yl)pyridin-2(1H)-one (65; Scheme 41) [71].
Recently, Abdelhamid et al., reported the synthesis of 3-acyl-4-
(1-benzofuran-2-ylcarbonyl)pyrazoles 66 via reaction of 64 with the
appropriate hydrazonoyl chlorides (Scheme 42) [72].
3.15. Reaction with Guanidine
4,6-Di(benzofuran-2-yl)-6-methyl-1,6-dihydropyrimidin-2-
amine (67) can be synthesized from the reaction of equimolar
amounts of 2a and guanidine (Scheme 43) [73].
3.16. Reactions with Amines, Hydroxylamine, Hydrazines and
Hydrazides
Schiff's bases 68 were produced from reaction of 2 (R = H, Me)
with aromatic amines, which on treatment with chloroacetyl chlo-
ride in dioxane produced azetidinones 69 (Scheme 44) [74].
O
2a
O
Me
+
O N
OR
CN
OMe
OMeMeO
NC
NC
MeOOMe
OMe
61
RONa
ROH
R = Me, Et, Pr
Scheme 39.
O
2a
O
Me N Ar
+
O
N
Ar
62
63Ar = 3-pyridinyl, 2-quinolinyl, (un)substituted phenyl
Scheme 40.
O
2a
O
Me
O O
N
Me
Me
HN
O
CNNC CONH2
NaOMe O
64 65
DMF-DMA
DMF
Scheme 41.
NN
OO
O
R
Ar
O O
N
Me
Me
64
Cl
O R
N
HN
Ar
66 Scheme 42.
+H2N NH2
N
NH
NH2
O
OMe
67
NH
O
2a
O
Me
Scheme 43.
2-Acetylbenzofurans: Synthesis, Reactions and Applications Current Organic Chemistry, 2010, Vol. 14, No. 1 57
Reaction of 2a with hydroxylamine hydrochloride in the pres-
ence of sodium acetate, in ethanol under reflux conditions for 3 h,
gave the corresponding oxime 70 in 95% yield (Scheme 45) after
crystallization [23]. Oxime 70 could be converted to its benzyl ether
71, in 90% yield, on treatment with sodium hydride followed by
reaction with benzyl chloride at room temperature for 18 h (Scheme
45). Reduction of 71 with borane/oxazaborolidine, generated in-situ
from (1S,2R)-norephedrine, gave (R)-(+)-N-(1-(benzofuran-2-
yl)ethyl)-O-benzylhydroxylamine (72) in 64% yield with 75% ee
(Scheme 45). In contrast, borane/oxazaborolidine, generated in-situ
from (1R,2S,3R,4S)-3-amino-1,7,7-trimethylbicyclo[2.2.1]heptan-2-
ol, reduced 71 to 72 in 92% ee [23]. Compound 72 was converted
into its N-benzyloxyurea derivative 73 in 95% yield, which was
readily debenzylated by palladium catalyzed hydrogenolysis to
produce (R)-1-(1-(benzofuran-2-yl)ethyl)-1-hydroxyurea (74) in
83% yield with 92% ee, which was raised up to 99% ee by crystal-
lization [23]. Compound 74 was the first 5-lipoxygenase inhibitor.
Treatment of 2a with 2-aminoethanol hydrochloride gave the
corresponding oxime 75 (Scheme 46) [75].
2-Acetylbenzofurans 2 on treatment with phenyl hydrazine
[74], ethyl hydrazinecarboxylate [76] and thiosemicarbazides [77],
in ethanol containing acetic acid under reflux conditions, gave the
corresponding condensation products 76 in good to excellent yields
(Scheme 47). Treatment of 76 (R1 = Ph) with Vilsmeier reagent
underwent cyclization to produce the corresponding substituted
pyrazoles [47].
+
O
2a
Me
OEtOH/AcOH
ClCH2COCl
Me
N
ArO
68
ArNH2
R
O
N
Me
R
Ar
69
O
R
Scheme 44.
O
2a
O
Me H2NOH.HCl
AcONa
reflux, 3 h
O
1, NaH, DMF, 0 ˚C
2, BnCl, RTN
Me
OH O N
Me
OBn
70 (95%) 71 (90%)
HNBH
O
PhMe
, THF, 0 ˚C, 6 h
RT, 24 h
aq. HCl, RT, 18 h O HN
Me
OBn
72 (64%); 75% ee
73 (95%)
O
Me
N C
BnO
NH2
O
1, ClSO2NCO, THF, -78 ˚C, 2 h
2, H2O, RT, 18 h
74 (83%); 99% ee
O
Me
N C
HO
NH2
O
H2, Pd(OH)2/C, MeOH, RT, 2 h
Scheme 45.
O
2a
Me
ONH2.HCl
HO
O
N
Me
HO
75 Scheme 46.
O
2
Me
O
R
O
N
Me
NHR1
76
R1NHNH2
AcOH/EtOH
R = H, Me; R1 = Ph, CO2Et, CSNHNHAr Scheme 47.
58 Current Organic Chemistry, 2010, Vol. 14, No. 1 Metwally et al.
Compound 76 (R1 = CSNHNHAr) was used as a precursor for
the synthesis of many valuable compounds. For example, treatment
of 76 with chloroacetone in dry dioxane under reflux conditions for
2-3 h gave the corresponding N-(1-benzofuran-2-yl-ethylidene)-N'-
(4-methyl-3-aryl-3H-thiazol-3-ylidene)hydrazines 77 (Scheme 48)
in 54-67% yield [77]. Similarly, treatment of 76 (R1 =
CSNHNHAr) with chloroacetic acid in glacial acetic acid and so-
dium acetate under reflux conditions for 4-5 h afforded the corre-
sponding 2-((1-benzofuran-2-yl-ethylidene)hydrazono)-3-substi-
tuted-thiazolidin-4-ones 78 (Scheme 48) in 55-85% yield after crys-
tallization from acetone [77].
3.17. Synthesis of (benzofuran-2-yl)indolin-2-one
Reaction of 2a with isatin in ethanol and in the presence of di-
ethylamine as a catalyst at room temperature gave 3-(2-
(benzofuran-2-yl)-2-oxoethyl)-3-hydroxyindolin-2-one (79;
Scheme 49) in 86% yield. Dehydration of 79, on heating in ethano-
lic hydrochloric acid solution for 30 min, gave 3-(2-(benzofuran-2-
yl)-2-oxoethylidene)indolin-2-one (80; Scheme 49) in 78% yield
[25,78]. Treatment of 80 with Na2S2O4 in aqueous ethanol gave
3-(2-(benzofuran-2-yl)-2-oxoethyl)indolin-2-one (81; Scheme 49)
in 63% yield [78].
3.18. Reaction with 1-[(methylthio)methyl]-1H-benzotriazole
Lithiation of 1-[(methylthio)methyl]-1H-benzotriazole (82)
with n-BuLi under anhydrous conditions in THF at -78 °C for 1 h
followed by reaction of the lithium reagent 83 thus obtained in-situ
with 2a at -78 °C for 1 h gave 2-benzotriazolyl alcohol 84 (Scheme
50) in 72% yield [79].
O Me
N NH
S
NH
Ar
Cl COOH
O
Me
NN N
S
O
Ar
76
78 (55-58%)
O Me
N N
N
S
Ar
Me
77 (54-67%)
MeCOCH2Cl
dioxane
Ar = n-Bu, Ph, Bn, 4-MeC6H4
Scheme 48.
+
O
2a
NH
O
OEt2NH
EtOHO O
HN
HO
O
79 (86%)
EtOH/HCl
heat (-H2O)
O O
NH
O
80 (78%)
Me
O
O O
NH
O
81 (63%)
Na2S2O4
H2O/EtOH
Scheme 49.
2aN
NN
SMe
NN
N
OH
MeO
84 (72%)
n-BuLi
82
N
NN
SMe
83Li
MeS
Scheme 50.
2-Acetylbenzofurans: Synthesis, Reactions and Applications Current Organic Chemistry, 2010, Vol. 14, No. 1 59
3.19. Reformatsky Reaction
Reformatsky reaction of 2a with methyl bromoacetate in dry
benzene containing Zn under reflux conditions gave the corre-
sponding -hydroxyester 85 which was dehydrated to produce , -
unsaturated ester 86 (Scheme 51) in high yield [80,81].
Ethyl 2-bromo-2-methylpropanoate was reacted with 2a to give
ethyl 3-(benzofuran-2-yl)-3-hydroxy-2,2-dimethylbutanoate (87;
Scheme 52). Dehydration of 87 followed by hydrolysis gave
3-(benzofuran-2-yl)-2,2-dimethylbut-3-enoic acid (88; Scheme 52)
[81].
3.20. Reaction with Trimethylsilyl Chloride
Reaction of 2-acetylbenzofuran (2a) with chlorotrimethylsilane
in DMF and in the presence of triethylamine gave (1-(benzofuran-
2-yl)vinyloxy)trimethylsilane (89; Scheme 53) [82]. Reaction of 89
with a mixture of iodosobenzene and boron trifluoride in DCM, at
-40 °C for 1 h and at room temperature for another 1 h, gave
1,4-di(benzofuran-2-yl)propane-1,3-dione (90; Scheme 53) in 63%
yield after crystallization from chloroform [82].
3.21. Reaction with Dichloroacetamide
Reaction of 1-(benzofuran-2-yl)-2-bromoethanone (17) with
2,2-dichloroacetamide gave N-(2-(benzofuran-2-yl)-2-oxoethyl)-
2,2-dichloroacetamide (91; Scheme 54) [83].
3.22. Formation of Benzofuran-2-ethanolamines
Chlorination of the acetyl group in compounds 2 followed by
reduction of the carbonyl group, to produce the corresponding alco-
hols, and then elimination of HCl from the produced chlorohydrins
gave the corresponding oxiranes 92 (Scheme 55) [64,65]. Reactions
of 92 with aliphatic amines gave the corresponding benzofuran-2-
ethanolamines 93 (Scheme 55) [84,85].
O
2a
Me
O
Br CO2Et
O Me
HOCO2Et
O Me
CO2Et
85 86
- H2O
Scheme 51.
O
2a
Me
O
Br
Me
Me
CO2Et
Me
Me
CO2Et
O OH
Me
OMe
Me
CO2H88
1, dehydration
2, hydrolysis
87 Scheme 52.
O
2a
Me
O
Me3SiCl
Et3NO
89
OSiMe3
O
O
(PhIO)n-BF3.Et2O
90 (63%)
O
O
Scheme 53.
O O O O
NH
O Cl
Cl
Br
O
H2NCl
Cl
9117
Scheme 54.
O
2
R1NH2
R1, Chlorination
2, [H]
3, - HCl
O
92
RO
O
93
R
OH
NHR1
R = 5,6-di-Me, 6,7-(CH2)3, 7-Et; R1 = Pr, iPr, tBu
O
Me
Scheme 55.
60 Current Organic Chemistry, 2010, Vol. 14, No. 1 Metwally et al.
3.23. Synthesis of Pyridazines
Reaction of 2a with methyl 3,3,3-trifluoropyruvate (MeTFP)
gave the aldol product 94 which was reacted readily with hydrazine
hydrate in acetic acid to give 4-trifluoromethyl-(2H)-pyridazin-3-
one (95, Scheme 56) [86].
3.24. Miscellaneous Reactions
Reaction of 2a with dimethyl sulfoxide, in the presence of cop-
per(II) oxide and iodine, gave 1,4-di(benzofuran-2-yl)-2-
(methylthio)but-2-ene-1,4-dione (96) in 65% yield (Scheme 57)
[87]. Compound 96 could be used as precursor for the synthesis of
various heterocycles. For example, 96 was converted to (Z)-2,2'-(3-
(methylthio)furan-2,5-diyl)dibenzofuran (97) in 69% yield on re-
duction with SnCl2 in acid medium (Scheme 57) which on reduc-
tive desulfuration using Raney nickel gave 2,5-di(benzofuran-2-
yl)furan (98) in 90% yield (Scheme 57). Treatment of 96 with KI in
an acid medium gave 99 in 80% yield. Reactions of 99 with ammo-
nium formate and Lawesson’s reagent gave 100 and 101 in 80 and
88% yield, respectively (Scheme 57) [87].
Zaitsev, et al. reported the synthesis of 2-(benzofuran-2-yl)-1H-
pyrrole (103) from reaction of 2-acetylbenzofuranoxime (70) with
acetylene under pressure in KOH/DMSO system via intermediate
102 (Scheme 58) [88].
4. APPLICATIONS
The chemistry of 2-acetylbenzofurans has attracted many re-
searchers due to their biological activities and their potential appli-
cations as pharmacological agents. Also, such compounds are
widely distributed in nature, e.g., ailanthoidol and have been re-
ported to have antiviral, antioxidant and antifungal activities [89].
Many compounds that synthesised from 2-acetylbenzofurans have
shown antitumor, antiflammatory and fungicidal activities
[52,53,86,90]. Furthermore, compounds containing benzofuran
moiety also have in-vitro antibacterial activities. Examples include
bacterial enzymes involved in the methionine cycle (e.g. me-
thionine aminopeptidase and deformylase), enzymes involved in
peptidoglycan synthesis (e.g. UDP-N-acetylmuramyl-L-alanine
ligase) and chorismate synthase [45,50].
2-Acetylbenzofurans are flavor agents and flavor modifiers that
added to coffee and food. They are used for treatment of hyperu-
ricemia [91,92], while, 5,6-dimethoxy-2-acetylbenzofuran are used
as herbicide [93]. 4-(Benzofuran-2-yl)-2-(3,5-dimethyl-1H-pyrazol-
1-yl)thiazole (104; Fig. 5) have been reported to show antimicrobial
activities [70]. While, 4-aryl-6-(benzofuran-2-yl)pyrimidines 46 (X
= NH, S, O; Scheme 26) have shown antitumor and antibacterial
activities [55].
1,2,4-Oxadiazoles 105 (Fig. 5) was found to inhibit the ro-
tamase activity of FKBP12 binding protein on a substrate L-1605
peptide in the presence of -chymotrypsin with IC50 of 0.035 M
[94]. Pyridoquinoxalines 106 (Fig. 6) used as antiviral agents for
treatment of herpes, varicella zoster, cytomegalovirus and Epstein-
Barr virus infections [95].
Chiral benzofuran derivatives 107 (Fig. 7) are used for treat-
ment of cardiac arrhythmias [96].
O
2a
Me
O
O
F3C O
OMe
O
NHN
CF3
O
95
N2H4.H2O
AcOHO O
OH
CO2Me
CF3
94
Scheme 56.
Ar
OSMe
O
Ar
96 (65%)
O
2a
Me
O
Cu2O, I2
DMSO
SnCl2
H+ Ar Ar
97 (69%)
O
SMe
KI, HCl
Ar
OSMe
O
Ar
99 (80%)
Raney-Ni
Ar Ar
98 (90%)
O
Ar Ar
100 (80%)
NH
SMe
HCO2NH4
Ar Ar
101 (88%)
S
SMe
Lawesson's reagent
Ar = 2-benzofuryl
Scheme 57.
O
Me
N OH O
Me
N O O NH
HC CH
KOH/DMSO
75 °C, 5min
- H2O
70 102 103
Scheme 58.
2-Acetylbenzofurans: Synthesis, Reactions and Applications Current Organic Chemistry, 2010, Vol. 14, No. 1 61
Methyl 2-{3-[4-(2-(dimethylamino)ethoxy)-3,5-diiodobenzoyl)
benzofuran-2-yl]}acetate (108; Fig. 8) is useful in regulating car-
diac arrhythmia, including atrial fibrillation, in animals and humans
[97]. While, 1-[benzofuran-2-yl(phenyl)methyl]-1H-imidazole and
its 4-fluoro derivative (109; Fig. 8) were used as inhibitors of aro-
matase (P 450 AROM) [98].
N-{[2-(Benzofuran-2-yl(phenyl)methylene)hydrazinyl](imino)
methyl}-4-nitrobenzamide (110; Fig. 9) is useful as class-III antiar-
rhythmic agents [99].
O
Ph
N
HN NH
HN
O
NO2
110
Fig. (9).
OS
NN
N
Me
Me
104 NO
F
F
R3
R1R2
N
ON
O
O
O
105 R1 = R2 = C3-8 cycloalkyl; R2 = H; R3 = H, OH
Fig. (5).
N
N
O
NH
O
R1
R2
O
N
MeOH
O
106 R1 = F, Cl; R2 = alkyl, hydroxyalkyl, alkoxyalkyl
Fig. (6).
OO
O
R1
X1
X2
O
NEt2
O
Me
107 X1, X2 = I, F, Br, Cl
R1 = H, alkyl, alkenyl, aryl, alkylaryl,
alkenylaryl, heteroaryl, alkylheteroaryl,
alkenylheteroaryl, cycloalkyl, heterocycloalkyl,
alkylheteroycloalkyl, alkylcycloalkyl
Fig. (7).
O
O
OMe
O
ON
Me
MeI
I
108
N
N
X
O
109 X = H, F
Fig. (8).
62 Current Organic Chemistry, 2010, Vol. 14, No. 1 Metwally et al.
1-(7-(Dodecyloxy)benzofuran-2-yl)ethanone (111; Fig. 10) and
1-(7-(tridecyloxy)benzofuran-2-yl)ethanone (112; Fig. 10) exhib-
ited a specific activity against respiratory syncytial virus in HeLa
[100].
1-(Benzofuran-2-yl)-3-(5-methyl-1-trityl-1H-imidazol-4-
yl)prop-2-en-1-one (53; Scheme 32) is useful as serotonin antago-
nists [60]. Also, benzofuran acetic acids 17 (Scheme 11; R = H, Cl,
F, Me, Me3C, MeO, Ph, PhCH2, cyclohexyl) are useful as analge-
sics and inflammation inhibitors [101]. Substituted 3-(benzofuran-
2-yl)-4,5-dihydro-1H-pyrazoles 113 (Fig. 11) are used as potential
antiinflammatory agents [65]. While, substituted 2-benzofuranyl
derivatives 114 (Fig. 11) are used as antitubercular agents [58].
O
R1
NN
R2
R3
113
O O
R1
114
R
Fig. (11).
2-(1-(Benzofuran-2-yl)ethyl)-7-chloro-2,3-dihydropyridazino[4,
5-b]quinoline-1,4,10(5H)-trione (115; Fig. 12) was found to have
potent activity at the glycine site of the NMDA receptor [102].
Cl NH
O
NH
N
O
O
Me
O
115 Fig. (12).
CONCLUSIONS
The chemistry of 2-acetylbenzofuran has exhibited promise on
a number of fronts; the full evaluation of its utility in heterocycles
synthesis was not sufficiently investigated. The aim of this review
was to demonstrate the wide synthetic application of
2-acetylbenzofuran in organic synthesis and especially the produc-
tion of biologically useful compounds.
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Received: 09 July, 2009 Revised: 08 Seprember, 2009 Accepted: 11 September, 2009
