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).
References and notes
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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.
7. Twyman, L. J.; Allsop, D. Tetrahedron Lett. 1999, 40, 9383-9384.
8. Thévenin, M.; Thoret, S.; Grellier, P.; Dubois, J. Bioorg. Med.
Chem. 2013, 21(17), 4885-4892.