Microwave-mediated solvent free Rap-Stoermer reaction for efficient synthesis of benzofurans

Article abstract of DOI:10.1016/j.tetlet.2006.11.077

The Rap-Stoermer reaction of salicylaldehydes with diverse phenacyl bromide and phenacyl iodides proceeded cleanly to afford various functionalized benzofurans in excellent yields under base-mediated solvent free microwave irradiation conditions.

Full text of DOI:10.1016/j.tetlet.2006.11.077

Tetrahedron Letters 48 (2007) 431–434
Microwave-mediated solvent free Rap–Stoermer reaction
for efficient synthesis of benzofurans
Maddali L. N. Rao,* Dheeraj K. Awasthi and Debasis Banerjee
Department of Chemistry, Indian Institute of Technology, Kanpur 208 016, India
Received 5 October 2006; revised 30 October 2006; accepted 10 November 2006
Available online 1 December 2006
Abstract—The Rap–Stoermer reaction of salicylaldehydes with diverse phenacyl bromide and phenacyl iodides proceeded cleanly to
afford various functionalized benzofurans in excellent yields under base-mediated solvent free microwave irradiation conditions.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Benzofurans are highly valuable molecular motifs often
found in various natural products. Major interest asso-
ciated with these molecules stems from their diverse
range of pharmacological properties.1,2 Despite the
availability of multi-step methods for the synthesis of
benzofurans,2 a straightforward approach for their syn-
thesis from easily available starting materials is always
advantageous. The Rap–Stoermer reaction provides
opportunity for the direct preparation of benzofurans
via base-mediated reaction of salicylaldehydes with a-
haloketones.3a,b The unique potential associated with
the Rap–Stoermer reaction originates from its starting
materials and hence a wide variety of substituted
benzofurans can be easily synthesized depending on
the functionality present in the salicylaldehyde and
(or) a-haloketones. Unfortunately, the reported proce-
dures involving solvent and heating conditions were
not efficient giving lower yields in several cases.3
Recently reported solid state studies on the Rap–Stoer-
mer reaction provided valuable insights into the mecha-
nistic details of this reaction.3d
and to perform the Rap–Stoermer reaction under clean
conditions, we have studied this reaction under solvent-
free microwave irradiation conditions for the efficient
synthesis of benzofurans in short reaction times.
The Rap–Stoermer reaction was normally performed
using alkaline base in alcoholic medium, which often
produced poor to moderate yields of benzofuran
products.3a,b In order to investigate this method under
solvent free microwave conditions, we examined the
efficiency of various bases on the reaction of salicylalde-
hyde with phenacyl bromide (Table 1).
Table 1. Screening of the reaction of salicylaldehyde with phenacyl
bromidea
O
CHO
OH
base
+
Br
microwave
O
O
Entry
Base
MW (W)
Time (min)
Conv. (%)b
1
2
3
4
5
6
7
8
9
NaOAc
KOAc
Na2CO3
K2CO3
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
850
850
850
850
850
850
600
600
600
600
0.5
0.5
0.5
0.5
0.5
0.25
0.5
1
17
15
<1
89
97
85
54
85
93
95
The application of microwaves in organic synthesis is a
widely accepted tool to achieve clean reaction conditions
in the context of green and sustainable alternative meth-
ods.4,5 In particular, reactions using solvent-free condi-
tions would be more attractive to perform under
microwave irradiation. So, to obviate the use of solvent
1.5
2
10
Keywords: Benzofurans; Rap–Stoermer reaction; Microwave; Solvent
free conditions.
a Conditions: salicylaldehyde (1 equiv), phenacyl bromide (1 equiv),
base (2.2 equiv).
b Based on GC analysis.
*
Corresponding author. Tel./fax: +91 512 2597532; e-mail:
maddali@iitk.ac.in
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.11.077

432
M. L. N. Rao et al. / Tetrahedron Letters 48 (2007) 431–434
a,b,c
Table 2. Synthesis of benzofurans
R1
O
R1
CHO
OH
R
K3PO4
MW
+
X
O
R
R2
R2
O
Entry
Salicylaldehyde
Phenacyl halide (equiv)
MW (W)
Time (min)
Benzofuran
Yield (%)
O
R
CHO
OH
O
X
R
O
1
2
3
4
5
6
7
R = H (1.0); X = Br
R = Br (1.5); X = Br
R = Br (1.0); X = Br
R = Me (1.1); X = Br
R = OMe (1.2); X = Br
R = H (1.2); X = I
600
850
600
600
600
600
600
2.0
2.0
3.0
2.5
1.5
1.0
0.5
R = H
93
90
91
94
93
93
91
R = Br
R = Br
R = Me
R = OMe
R = H
R = Me (1.2); X = I
R = Me
Cl
R
Cl
CHO
OH
O
O
8
9
R = H (1.1); X = Br
R = Br (1.5); X = Br
R = Me (1.0); X = Br
R = OMe (1.2); X = Br
R = H (1.2); X = I
600
850
600
600
600
600
600
2.5
3.0
2.0
1.5
1.0
1.0
1.5
R = H
R = Br
98
93
92
92
93
90
92
10
11
12
13
14
R = Me
R = OMe
R = H
R = Me
R = OMe
R = Me (1.2); X = I
R = OMe (1.2); X = I
Br
R
Br
CHO
OH
O
O
15
16
17
18
19
20
21
22
R = H (1.1); X = Br
R = Br (1.0); X = Br
R = Me (1.1); X = Br
R = OMe (1.2); X = Br
R = H (1.2); X = I
R = Br (1.5); X = I
R = Me (1.2); X = I
R = OMe (1.5); X = I
600
600
600
600
600
600
600
600
1.0
1.5
1.0
2.0
0.5
1.5
1.0
2.0
R = H
R = Br
R = Me
R = OMe
R = H
R = Br
R = Me
R = OMe
92
91
94
95
93
88
87
78
I
I
CHO
OH
R
O
I
I
O
23
R = H (1.1); X = Br
600
1.5
R = H
64
Br
Br
CHO
OH
R
O
Br
Br
O
24
25
26
27
R = H (1.5); X = Br
R = Br (1.5); X = Br
R = Me (1.5); X = Br
R = OMe (1.5); X = Br
850
850
850
850
0.5
2.0
0.5
1.0
R = H
R = Br
R = Me
R = OMe
74
79
78
92

M. L. N. Rao et al. / Tetrahedron Letters 48 (2007) 431–434
433
Table 2 (continued)
Entry
Salicylaldehyde
Phenacyl halide (equiv)
MW (W)
Time (min)
Benzofuran
Yield (%)
R
CHO
OH
O
O
28
29
30
31
32
33
34
35
R = H (1.5); X = Br
R = Br (1.5); X = Br
R = Me (1.2); X = Br
R = OMe (1.2); X = Br
R = H (1.2); X = I
R = Br (1.5); X = I
R = Me (1.2); X = I
R = OMe (1.5); X = I
600
850
600
600
600
600
600
600
0.5
2.0
0.5
1.0
1.0
3.0
0.5
1.5
R = H
R = Br
R = Me
R = OMe
R = H
R = Br
R = Me
R = OMe
90
91
92
91
90
91
91
91
a In all cases K3PO4 (2.2 equiv) was used as the base.
b Isolated yields obtained after column chromatography. All the products were characterized by 1H, 13C NMR, IR and mass spectral analysis.
c A domestic microwave oven (Samsung M183DN, 2450 MHz) was used for irradiation.
In this study, sodium acetate, potassium acetate and
sodium carbonate failed to deliver good conversions
(entries 1–3) to benzofuran. Potassium phosphate and
potassium carbonate were found to be efficient giving
high conversions in short reaction times (entries 4 and
5). Further scrutiny with potassium phosphate as base
and by varying the microwave power, it was found that
the exposure time could be easily tuned without affecting
the overall conversions (entries 6–10).
furans obtained in short reaction times. In addition, the
2-aroyl benzofurans formed using this method are also
important as the corresponding carbinols (reduction
products) are known to have hypolipidemic activity.3b
Acknowledgements
The authors thank CSIR, India, and IIT Kanpur
for financial support. D.K.A. and D.B. thank UGC,
India, and IIT Kanpur, respectively, for research
fellowships.
To expand the scope of this reaction, a variety of func-
tionalized salicylaldehydes were employed along with
electronically diverse phenacyl halides (bromides and
iodides) and the results are summarized in Table 2.
The reactivity of diverse salicylaldehydes with phenacyl
bromides and iodides was found to be efficient affording
the corresponding benzofurans in excellent yields. It is
worth mentioning that the change of electronics in phen-
acylbromide and iodides did not affect the overall reac-
tivity, and high yields of benzofurans were obtained.
Despite being thermally labile, phenacyl iodides also
reacted well under solvent free microwave conditions
giving high yields of benzofurans. The excellent reactiv-
ity observed with various phenacyl iodides was almost
similar to that observed with the corresponding phenac-
yl bromides. In addition, the reactivity of various mono
and di-substituted salicylaldehydes was found to be
efficient under the present conditions. Importantly, the
various functionalized benzofurans that were obtained
would be useful precursors for the synthesis of a variety
of natural products possessing a benzofuran nucleus. In
addition, the high yields of benzofuran obtained in very
short reaction times are a reflection of the advantage
and suitability associated with the Rap–Stoermer reac-
tion under solvent free microwave irradiation.
References and notes
1. (a) Cruz, M. del C.; Tamariz, J. Tetrahedron 2005, 61,
10061–10072, and references cited therein; (b) Bellur, E.;
Langer, P. J. Org. Chem. 2005, 70, 7686–7693; (c) Chen, C.;
Dormer, P. G. J. Org. Chem. 2005, 70, 6964–6967; (d) Kao,
C.-L.; Chern, J.-W. J. Org. Chem. 2002, 67, 6772–6787; (e)
Khan, M. W.; Alam, M. J.; Rashid, M. A.; Chowdhury, R.
Bioorg. Med. Chem. 2005, 13, 4796–4805; (f) Hayakawa, I.;
Shioya, R.; Agatsuma, T.; Furukawa, H.; Naruto, S.;
Sugano, Y. Bioorg. Med. Chem. Lett. 2004, 14, 455–458; (g)
Tsuji, E.; Ando, K.; Kunitomo, J.; Yamashita, M.; Ohta,
S.; Kohno, S.; Ohishi, Y. Org. Biomol. Chem. 2003, 1,
3139–3141; (h) Smith, R. A.; Chen, J.; Mader, M. M.;
Muegge, I.; Moehler, U.; Katti, S.; Marrero, D.; Stirtan, W.
G.; Weaver, D. R.; Xiao, H.; Carley, W. Bioorg. Med.
Chem. Lett. 2002, 12, 2875–2878; (i) Kao, C.-L.; Chern,
J.-W. Tetrahedron Lett. 2001, 42, 1111–1113; (j) Ando, K.;
Tsuji, E.; Ando, Y.; Kuwata, N.; Kunitomo, J.; Yamashita,
M.; Ohta, S.; Kohno, S.; Ohishi, Y. Org. Biomol. Chem.
2004, 2, 625–635.
2. Selected benzofuran methods: (a) Youn, S. W.; Eom, J. I.
Org. Lett. 2005, 7, 3355–3358; (b) Sanz, R.; Miguel, D.;
Martinez, A.; Perez, A. J. Org. Chem. 2006, 71, 4024–4027;
(c) Xie, X.; Chen, B.; Lu, J.; Han, J.; She, X.; Pan, X.
Tetrahedron Lett. 2004, 45, 6235–6237; (d) Gill, M.
Tetrahedron 1984, 40, 621–626; (e) Hennings, D. D.; Iwasa,
S.; Rawal, V. H. Tetrahedron Lett. 1997, 38, 6379–6382; (f)
Herndon, J. W.; Zhang, Y.; Wang, H.; Wang, K. Tetra-
hedron Lett. 2000, 41, 8687–8690; (g) Kundu, N. G.; Pal,
M.; Mahanty, J. S.; De, M. J. Chem. Soc., Perkin Trans. 1
In summary, a microwave-mediated solvent free Rap–
Stoermer reaction has been reported for the synthesis
of benzofurans from a variety of salicylaldehydes and
phenacyl halides.6 Some of the advantages and high-
lights of the present microwave protocol include, solvent
free clean reaction conditions and high yields of benzo-

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M. L. N. Rao et al. / Tetrahedron Letters 48 (2007) 431–434
1997, 2815–2820; (h) Kraus, G. A.; Zhang, N.; Verkade, J.
2006, 47, 5497–5501; (g) Jung, M. E.; Maderna, A. J. Org.
Chem. 2004, 69, 7755–7757; (h) Kabalka, G. W.; Mereddy,
A. R. Tetrahedron Lett. 2005, 46, 6315–6317; (i) Kabalka,
G. W.; Zhou, L.-L.; Naravane, A. Tetrahedron Lett. 2006,
47, 6887–6889; (j) Xie, X.; Chen, B.; Lu, J.; Han, J.; She, X.;
Pan, X. Tetrahedron Lett. 2004, 45, 6235–6237; (k) Kumar,
G. D. K.; Saenz, D.; Lokesh, G. L.; Natarajan, A.
Tetrahedron Lett. 2006, 47, 6281–6284.
G.; Nagarajan, M.; Kisanga, P. B. Org. Lett. 2000, 2, 2409–
2410; (i) Cruz, M. del C.; Tamariz, J. Tetrahedron Lett.
2004, 45, 2377–2380; (j) Gil, M. V.; Roman, E.; Serrano, J.
A. Tetrahedron Lett. 2000, 41, 10201–10205; (k) Bellur, E.;
Freifeld, I.; Langer, P. Tetrahedron Lett. 2005, 46, 2185–
2187; (l) Thielges, S.; Meddah, E.; Bisseret, P.; Eustache, J.
Tetrahedron Lett. 2004, 45, 907–910; (m) Bogdal, D.;
Warzala, M. Tetrahedron 2000, 56, 8769–8773.
5. For reviews on microwaves in organic synthesis, see: (a)
Perreux, L.; Loupy, A. Tetrahedron 2001, 57, 9199–9223;
(b) Lidstrom, P.; Tierney, J.; Wathey, B.; Westman, J.
Tetrahedron 2001, 57, 9225–9283.
3. (a) Buu-Hoi, N. P.; Saint-Ruf, G.; Loc, T. B.; Xuong, N. D.
J. Chem. Soc. 1957, 2593–2596, and references cited therein;
(b) Pestellini, V.; Giolitti, A.; Pasqui, F.; Abelli, L.;
Curtrufo, C.; Salvia, G. D.; Evangelista, S.; Meli, A. Eur.
Med. Chem. 1988, 23, 203–206; (c) Fitton, A. O.; Smalley,
R. K. Practical Heterocyclic Chemistry; Academic Press,
1968; p 15; (d) Yoshizawa, K.; Toyota, S.; Toda, F.;
Csoregh, I. Green Chem. 2003, 5, 353–356.
4. Recent microwave-mediated reactions: (a) Yin, W.; Ma, Y.;
Xu, J.; Zhao, Y. J. Org. Chem. 2006, 71, 4312–4315; (b)
Bashiardes, G.; Safir, I.; Mohamed, A. S.; Barbot, F.;
Laduranty, J. Org. Lett. 2003, 5, 4915–4918; (c) Viana, G.
H. R.; Santos, I. C.; Alves, R. B.; Gil, L.; Marazano, C.;
Gil, R. P. F. Tetrahedron Lett. 2005, 46, 7773–7776; (d)
Kabalka, G. W.; Mereddy, A. R. Tetrahedron Lett. 2006,
47, 5171–5172; (e) Villemin, D.; Cheikh, N.; Mostefa-Kara,
B.; Bar, N.; Choukchou-Braham, N.; Didi, M. A. Tetra-
hedron Lett. 2006, 47, 5519–5521; (f) Bras, G. L.; Provot,
O.; Peyrat, J.-F.; Alami, M.; Brion, J.-D. Tetrahedron Lett.
6. Representative procedure: In a typical experiment,
a
15 mL open glass vial with a 20 mm diameter, was
charged with salicylaldehye (0.122 g, 1 mmol), phenacyl
bromide (0.199 g, 1 mmol) and potassium phosphate
(0.467 g, 2.2 mmol). The mixture was stirred gently with
a spatula for a few seconds and was subjected to
domestic microwave irradiation (Samsung, M183DN,
2450 MHz) at 600 W for 2 min. After cooling, the crude
solid mixture was quenched with 5% dilute HCl and
extracted with ethyl acetate (2 · 15 mL). The organic
extract was dried over MgSO4 and concentrated. The
crude product was subjected to column chromatography
on silica gel using hexane–ethyl acetate as eluent and the
pure benzofuran (0.206 g, 93%) was isolated. The product
1
was characterized by H, 13C NMR, IR and mass spectral
analysis.