A novel route to 2-(dialkylaminomethyl)benzo[b]furans via a microwave-enhanced, solventless Mannich condensation-cyclization on cuprous iodide doped alumina

Article abstract of DOI:10.1016/S0040-4039(01)01226-6

A microwave-enhanced, solventless Mannich condensation-cyclization sequence involving the reaction of o-ethynylphenol with secondary amines and para-formaldehyde on cuprous iodide doped alumina in the absence of solvents has been developed. The procedure generates 2-(dialkylaminomethyl)benzo[b]furans in good yields.

Full text of DOI:10.1016/S0040-4039(01)01226-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6049–6051
A novel route to 2-(dialkylaminomethyl)benzo[b]furans via a
microwave-enhanced, solventless Mannich
condensation–cyclization on cuprous iodide doped alumina
George W. Kabalka,* Lei Wang and Richard M. Pagni
Departments of Chemistry and Radiology, The University of Tennessee, Knoxville, TN 37996-1600, USA
Received 23 May 2001; accepted 8 June 2001
Abstract—A microwave-enhanced, solventless Mannich condensation–cyclization sequence involving the reaction of o-ethynylphe-
nol with secondary amines and para-formaldehyde on cuprous iodide doped alumina in the absence of solvents has been
developed. The procedure generates 2-(dialkylaminomethyl)benzo[b]furans in good yields. © 2001 Elsevier Science Ltd. All rights
reserved.
Benzo[b]furans and their derivatives have received atten-
tion in recent years because of their occurrence in natural
substances and their physiological activity.1 They are
widely used as anti-tumor agents,2 as ligands for the
adenosine A1 receptor,3 and as calcium entry blockers.4
General routes to benzo[b]furans involve reductive
cyclization of ketoesters by low-valent titanium,5 photo-
chemical induced rearrangement of phosphate esters,6
palladium-catalyzed Suzuki coupling of appropriate
boronic acids with organic halides or triflates,7 and
palladium-catalyzed Sonogashira coupling of o-iodophe-
nols and terminal alkynes.8 No reports have appeared
describing the synthesis of 2-substituted-benzo[b]furans
using Mannich condensation reactions.
also obviates a number of environmental problems.9 For
example, using a commercially available alumina potas-
sium fluoride mixture to which we added palladium
powder or cupric chloride, we were able to carry out
Suzuki, Sonogashira, and Glaser coupling reactions on
a wide variety of aromatic moieties without the use of
solvents.10
Microwave irradiation of organic reaction has gained in
popularity in recent years since it was found to accelerate
a wide variety of transformations.11 A number of reports
have appeared in which reactants are coated onto sur-
faces which themselves absorb little or no microwave
energy; in these instances, the reactive species absorb the
microwave energy but the temperature of the reaction
mixture tends to rise only modestly. This results in
relatively large energy savings as well as making it
possible to carry out reactions in relatively simple glass-
ware, such as open beakers and flasks.12
The traditional Mannich methods for synthesizing b-
aminoketones or b-aminoalkyne often require drastic
reaction conditions and utilize solvents such as dioxane
or N,N-dimethylformamide. In addition, metal catalysts
are required which can be difficult to handle and pose,
along with the solvent, a number of waste handing
problems.
We wish to report a microwave-enhanced Mannich
condensation–cyclization
sequence
involving
o-
ethynylphenol, secondary amines and para-formalde-
hyde on CuI-doped alumina in the absence of solvents,
which generates 2-(dialkylaminomethyl)benzo[b]furans
in good yields (Scheme 1).
We have found alumina to be a particularly useful
reagent in organic synthesis because it can be modified
in a variety of ways which enhance its reactivity. Alumina
R
R
CuI/Al2O3
HNR1R2
(CH2O)n
+
+
NR1R2
solventless
O
OH
M.W.
Scheme 1.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01226-6

6050
G. W. Kabalka et al. / Tetrahedron Letters 42 (2001) 6049–6051
Table 1. Mannich condensation–cyclization reaction of o-ethnylphenol and its derivatives with secondary amines and para-
formaldehyde
Table 1 contains the results of our study. Under
microwave irradiation and solvent free conditions, o-
ethynylphenol (as well as o-ethynyl-p-methylphenol
and p-acetyl-o-ethynylphenol), react smoothly with
para-formaldehyde and a variety of secondary amines
to afford the desired 2-(dialkylaminomethyl)benzo-
[b]furans in good yields. Interestingly, when o-
ethynylphenol (2 equiv.) was allowed to react with
para-formaldehyde (excess) and piperazine (1 equiv.), a
bis-Mannich condensation–cyclization product was
formed (40% yield, Scheme 2). A general procedure is
illustrated for the preparation of 2-(dialkyl-
aminomethyl)benzo[b]furans: o-ethynylphenol (0.118 g,
1.00 mmol) and a secondary amine (1.00 mmol) were
added to a mixture of cuprous iodide (0.572 g, 3.00
mmol), para-formaldehyde (0.09 g, 3.00 mmol) and
alumina (1.00 g) contained in a clean, dry, 10 mL
round-bottomed flask. The mixture was stirred at room
temperature to ensure efficient mixing. The flask was
then fitted with a septum which had been punctured by
an 18 gauge needle (to serve as a pressure relief valve),
placed in the microwave oven and irradiated at 30%
power for 5 min. [Caution: heating volatile materials in
commercial microwave ovens for extended periods can
be hazardous.] After cooling, ether (4 mL) was added
and the slurry stirred at room temperature to ensure
CuI/Al2O3
(CH2O)n
+
HN
NH
+
N
N
solventless
M.W.
O
O
OH
Scheme 2.

G. W. Kabalka et al. / Tetrahedron Letters 42 (2001) 6049–6051
6051
product removal from the surface. The mixture was
vacuum filtered using a sintered glass funnel and the
product purified by flash chromatography (hexane/
EtOAc as eluent) to afford the desired 2-(dialkylamino-
methyl)benzo[b]furan.
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In conclusion, a reliable, rapid, and environmentally
benign method for synthesizing 2-(dialkylamino-
methyl)benzo[b]furans has been developed which
involves the use of a solvent-free mixture of cuprous
iodide and alumina under microwave irradiation condi-
tions. The process is highly efficient, does not require
preforming the iminium species, and is not hampered
by the heterogeneity of the reaction.
Acknowledgements
9. (a) Kabalka, G. W.; Pagni, R. M. Tetrahedron 1997, 53,
7999; (b) McGinnis, M. B.; Vagle, K.; Green, J. F.; Tan,
L.-C.; Palmer, R.; Siler, J.; Pagni, R. M.; Kabalka, G. W.
J. Org. Chem. 1996, 61, 3496; (c) Sponholtz, III, W. R.;
Pagni, R. M.; Kabalka, G. W.; Green, J. F.; Tan, L.-C.
J. Org. Chem. 1991, 56, 5700; (d) Pala Wilgus, C.;
Downing, S.; Molitor, E.; Bains, S.; Pagni, R. M.;
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We wish to thank the US Department of Energy and
the Robert H. Cole Foundation for support of this
research.
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