Unexpected one-step synthesis of 3-benzoyl-2-phenylbenzofurans under Wittig conditions

Article abstract of DOI:10.1016/j.tetlet.2018.03.048

The reaction of 2-hydroxybenzyltriphenylphosphonium bromide with substituted benzoyl chlorides under Wittig conditions, led to 2-phenylbenzofuran derivatives 4a–p and the unexpected formation of 3-benzoyl-2-phenylbenzofuran derivatives 5a–p. Benzoyl chlorides possessing electron-withdrawing groups afforded 3-benzoyl-2-phenylbenzofuran derivatives in higher yields than those with electron-donating groups. This reaction represents a simple and regioselective, one-pot route towards the preparation of deactivated 3-benzoyl-2-phenylbenzofuran compounds which are difficult to obtain by the direct acylation of 2-phenylbenzofurans.

Full text of DOI:10.1016/j.tetlet.2018.03.048

Accepted Manuscript
Unexpected one-step synthesis of 3-benzoyl-2-phenylbenzofurans under Wittig
conditions
Michela Begala, Pierluigi Caboni, Maria João Matos, Giovanna Lucia Delogu
PII:
S0040-4039(18)30362-9
https://doi.org/10.1016/j.tetlet.2018.03.048
TETL 49817
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Accepted Date:
16 February 2018
17 March 2018
Please cite this article as: Begala, M., Caboni, P., Matos, M.J., Delogu, G.L., Unexpected one-step synthesis of 3-
benzoyl-2-phenylbenzofurans under Wittig conditions, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/
j.tetlet.2018.03.048
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Unexpected one-step synthesis of 3-benzoyl-2-phenylbenzofurans under Wittig
conditions
Michela Begalaa,*,†, Pierluigi Cabonia, Maria João Matosb and Giovanna Lucia Delogua,†
a
b
Department of Life and Environmental Science, University of Cagliari, Via Ospedale 72, 09124 Cagliari, Italy
Department of Organic Chemistry, University of Santiago de Compostela, Campus Vida, 15782 Santiago de Compostela, Spain

1
Tetrahedron Letters
Unexpected one-step synthesis of 3-benzoyl-2-phenylbenzofurans under Wittig
conditions
Michela Begalaa, †, Pierluigi Cabonia, Maria João Matosb and Giovanna Lucia Delogua,†
,
a
b
Department of Life and Environmental Sciences, University of Cagliari, Via Ospedale 72, 09124 Cagliari, Italy
Department of Organic Chemistry, University of Santiago de Compostela, Campus Vida, 15782 Santiago de Compostela, Spain
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The reaction of 2-hydroxybenzyltriphenylphosphonium bromide with substituted benzoyl
chlorides under Wittig conditions, led to 2-phenylbenzofuran derivatives 4a-p and the
unexpected formation of 3-benzoyl-2-phenylbenzofuran derivatives 5a-p. Benzoyl chlorides
possessing electron-withdrawing groups afforded 3-benzoyl-2-phenylbenzofuran derivatives in
higher yields than those with electron-donating groups. This reaction represents a simple and
regioselective, one-pot route towards the preparation of deactivated 3-benzoyl-2-
phenylbenzofuran compounds which are difficult to obtain by the direct acylation of 2-
phenylbenzofurans.
Available online
Keywords:
Wittig reaction
2-phenylbenzofurans
3-aroylbenzofurans
Introduction
Many synthetic methods to prepare 3-acylbenzofurans
introduce the C3-substituent to the preformed benzo[b]furan ring
at the end of the synthsis.5c,6 Among these, the simplest and most
straightforward method is the Friedel-Crafts reaction using acyl
chlorides.7 However, this method suffers from limitations, e.g.
the use of excess Lewis acid, the formation of gaseous HCl and
poor regioselectivity, especially when strongly deactivated acyl
chlorides are used. In fact, during the Friedel-Crafts acylation of
2-phenylbenzofuran with nitrobenzoyl chloride, many positions
of the benzofuran ring were also acylated, leading to a complex
mixture of regioisomers where the expected derivative was
formed as a minor product.8
3-Aroyl[b]benzofurans represent the structural cores of a large
number of bioactive molecules in current pharmaceutical use or
development. Representative examples of this family include
amiodarone (A), a clinically used drug for controlling intractable
cardiac arrhythmias,1 LY 320135 (B), a potent cannabinoid CB1
receptor antagonist,2 benzbromarone (C), an uricosuric agent,3
and SKF-64346 (D), an amyloid binding agent with
neuroprotective and antitumor activities4 (Fig. 1).
Br
I
O
OH
Br
O
O
CN
OMe
O
O
2-Aryl-3-benzoylbenzofuran derivatives bearing strongly
electron-withdrawing groups on both phenyl rings, such as NO2
and CN, could provide convenient intermediates in the
preparation of more complicated compounds.9 However, no
methods for the synthesis of such deactivated benzo[b]furans
have been described. Thus, the development of synthetic routes,
especially those that allow access to deactivated analogues, is of
considerable interest.
N
O
N
I
O
MeO
O
O
O
MeO
LY-320135 (B)
benzbromarone (C)
amiodarone (A)
SKF 64346 (D)
Figure 1. Representative 3-aroyl[b]benzofurans of pharmacological
interest.
Herein, we report a simple and regioselective, one-pot route
As a result, numerous approaches towards the synthesis of 3-
acylbenzofurans have been disclosed in the literature; however,
most are only suitable for the preparation of 2-aryl-3-benzoyl
benzofuran derivatives bearing electron-donating groups.5
for
the
preparation
of
deactivated
2-phenyl-3-
benzoylbenzo[b]furans via ylide acylation under Wittig
conditions.
———
 Corresponding author.
e-mail address: michelabegala@unica.it (M. Begala).
† This author equally contributed to the work.

2
Tetrahedron Letters
the formation of secondary products was not mentioned.11 These
Results and Discussion
findings encouraged us to investigate the formation of 2-phenyl-
3-acylbenzofurans under Wittig conditions.
In the course of a program directed towards the synthesis of
novel monoamine oxidase (MAO) inhibitors,10 we planned to
synthesize 2-phenylbenzofurans using an intramolecular Wittig
procedure due to the accessibility and simplicity of this
methodology.11
Initially, triphenylphosphonium salt 2 was treated with
benzoyl chloride 3a (1.0 equiv.) and triethylamine in dry toluene
for 2 hours at 110 °C. The obtained products were easily purified
by silica gel chromatography, using a mixture of hexane/ethyl
acetate (9:1) as the eluent system.
Under these conditions, 5a was isolated as the minor product
along with 2-phenylbenzofuran 4a. A higher ratio of compound
5a was achieved by altering the ratio of reagents. Upon
increasing the equivalents of both benzoyl chloride 3a and
triethylamine (3.0 equiv.), the total yield remained practically
unchanged, whereas the ratio of 4a and 5a significantly changed
from 9:1 to 1.5:1 (Table 1, entry 1). Unfortunately, attempts to
prepare a single benzofuran derivative by varying the other
reaction parameters failed. Next, we investigated the effect of
various benzoyl chlorides on the ratio of 4 and 5 after purification
(Table 1).
The desired Wittig reagent was readily prepared in high yield
from 2-hydroxybenzyl alcohol
1 and triphenylphosphine
hydrobromide (Method A, Table 1).12-13 Compounds 4 and 5a-p
were prepared from the appropriate triphenylphosphonium salt 2
and the commercially available aroyl chlorides 3a-p.14-21
However, while developing this procedure, GC/MS analysis
of the reaction mixture using triphenylphosphonium salt 2 and
benzoyl chloride 3a, revealed that, together with the desired
product of cyclization 4a, the unexpected side-product 5a was
present. This product, after purification and extensive analysis by
NMR and mass spectrometry, was determined to be 2-phenyl-3-
benzoylbenzofuran (see ESI for full spectroscopic data).
Although the Wittig reaction has been described in several
papers regarding the preparation of 2-arylbenzofuran derivatives,
Table 1. Synthetic route towards 2-phenylbenzofurans 4a-p and 3-benzoyl-2-phenylbenzofurans 5a-p (Method A). Effect of various
benzoylchlorides on the ratio of 4 and 5.a
Yield (%)b
(ratio 4:5)
Entry
Product
Product
O
93 (9:1)c
88 (1.5:1)
1
O
+
+
O
5a
O2N
O
4a
O
O2N
4b
2
3
-
O
O2N
5b
NO2
O
O
+
38 (1:5)
NO2
4c
O
NO2
5c

3
NO2
NO2
O
NO2
O
4
5
+
+
16 (1:5)
O
4d
5d
NC
O
O
-
NC
F3C
Br
4e
O
NC
5e
CN
O
O
6
+
27 (1:3)
CN
CN
4f
O
CN
CN
5f
O
O
7
8
+
+
46 (1:2)
CN
O
4g
5g
F3C
O
O
-
4h
O
F3C
5h
CF3
O
O
9
+
21 (1:5)
CF3
4i
O
CF3
CF3
5i
O
CF3
O
10
11
+
+
18 (1:3)
CF3
O
4j
5j
Br
O
O
-
4k
O
5k
Br
Br
O
O
12
+
49 (1:1.5)
Br
4l
O
Br
5l

4
Tetrahedron
Br
Br
O
Br
O
13
14
+
46 (1:1.3)
25 (2:1)
O
4m
5m
MeO
O
O
MeO
+
O
MeO
4n
5n
OMe
O
O
15
16
+
+
34 (5.5:1)
29 (2.5:1)
OMe
4o
O
OMe
OMe
5o
O
OMe
O
OMe
O
4p
5p
a Reagents and conditions: 2 (1 equiv.), benzoyl chloride 3a-p (3 equiv.); b Total yield of products 4 and 5. c Reagents and conditions: 2 (1
equiv.), benzoyl chloride 3a (1 equiv.).
Route A
-Ph3PO
P+Ph3Br-
P+Ph3Br-
P+Ph3
O
PhCOCl
Et3N
-HBr
4a
OH
O
O
Et3N, toluene
Route B
PhCOCl
2
P+Ph3Cl-
O
O
II
I
O
O
O
III
P+Ph3
Et3N
O
-HCl
-Ph3PO
O
O
O
O
5a
IV
Scheme 1. Proposed reaction mechanism.

5
O Cl
Br
R
NBS, CCl4, AIBN
PPh3
O
O
Py, 0°C
OH
O
O
R
R
R
75%
95%
O Cl
O
P+Ph3Br-
+
O
Et3N, toluene,110°C
O
O
4a
5a
O
R
50%
ratio 4a:4b = 4:1
14%
I
60%
Scheme 2. Preparation of compounds 4a and 5a from intermediate I (Method B).
Compounds 4a-p and 5a-p were prepared using
Acknowledgments
triphenylphosphonium salt 2 (1 equiv.), benzoylchlorides 3a-p (3
equiv.) and triethylamine. In general, the electronic nature of the
substituents on the phenyl ring has a strong influence on the
reaction. Benzoyl chlorides possessing electron-withdrawing
groups gave the corresponding 3-acyl derivatives 5 as the major
products. However, ortho-substituted benzoyl chlorides with
electron-withdrawing groups (NO2, CN, CF3 and Br), failed to
form the acylation product (Table 1, entries 2, 5, 8, and 11).
A plausible mechanism is depicted in Scheme 1. According to
the literature,11 the phosphonium salt 2 is O-acylated in the
presence of triethylamine to afford the corresponding o-
(benzoyloxy)benzyl)-triphenyl-phosphonium salt I. Then, salt I is
converted to the desired phosphorane II using triethylamine as a
base. Subsequently, phosphorane II could either directly cyclize
to give 2-phenylbenzofuran 4a (Route A) or react with a second
molecule of the acyl chloride to afford the α-ketophosphonium
salt III (Route B). Compound III then readily eliminates HCl to
give the stabilized C-acylated ylide IV. In the final step,
intramolecular nucleophilic attack of the ylide carbanion onto the
carboxylate group leads to 3-aroylbenzofuran 5a.
The formation of intermediate I was supported by the fact
that, under the same conditions, this compound prepared from o-
cresol,22,23 reacts with benzoyl chloride (2 equiv.) to afford a
mixture of 2-phenylbenzofuran 4a and 3-benzoyl-2-
phenylbenzofuran 5a (Method B, Scheme 2). It should be noted
that this synthetic approach cannot be considered a convenient
route to the preparation of compounds 4a and 5a as it requires
three additional synthetic steps and toxic reagents, when
compared with Method A (Table 1).
The authors gratefully acknowledge financial support from the
Fondazione di Sardegna - Università degli Studi di Cagliari
(Convenzione triennale per gli esercizi 2015-2017; Annualità
2015; Progetti di Ricerca di Interesse Dipartimentale (PRID)).
The authors are grateful to Roberto Mascia for technical
assistance. MJM thanks Xunta da Galicia for the Postdoctoral
fellowship (ED481B 2014/086-0).
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Conclusion
A series of 2-phenylbenzofurans and unexpected 3-benzoyl-2-
phenylbenzofurans were synthesized under Wittig conditions.
This operationally simple procedure, requires short reaction times
and does not involve the use of expensive reagents. The principal
advantage of this synthetic method consists of the synthesis of 3-
benzoyl-2-phenylbenzofuran
derivatives
with
electron-
withdrawing groups, which are difficult to obtain by the direct
acylation of the 2-phenylbenzofurans.
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6
Tetrahedron
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Supporting Information
Details of the experimental procedure and spectral data for
new compounds. This material is available free of charge in the
online version [http://].

7
Highlights
•The Wittig reaction affords 3-benzoyl-2-
phenylbenzofurans from triphenylphosphonium
salt and commercially available aroyl chlorides
•A variety of new deactivated 3-benzoyl-2-
phenylbenzofurans were obtained
•The present protocol offers direct and facile
access to 3-benzoyl-2-phenylbenzofurans and
good tolerance towards strongly deactivated
functional groups