676
LETTER
A Microwave-Enhanced, Solventless Mannich Condensation on CuI-Doped
Alumina
G. W. Kabalka,* L. Wang, R. M. Pagni
Departments of Chemistry and Radiology, The University of Tennessee, Knoxville, Tennessee 37996-1600 U.S.A.
Fax (865)974-2997; Phone (865)974-3260; E-mail: kabalka@utk.edu
Received 15 February 2001
formaldehyde on CuI-doped alumina in the absence of
Abstract: Terminal alkynes react with secondary amines and para-
solvents which produces the corresponding aminomethy-
formaldehyde to afford Mannich adducts in the presence of cuprous
lated adducts in good yields. The process is highly effi-
cient, does not require pre-forming the iminium species,
and is not hampered by the heterogeneity of the reaction,
Scheme 1.
iodide on alumina under microwave irradiation and solvent free
conditions.
Key words: Mannich condensation, microwave irradiation, alumi-
na, aminoalkynes
CuI/Al2O3
R1C
CH + (CH2O)n + HNR2R3
R1C
The Mannich reaction is a classic example of a three-com-
ponent condensation reaction.1 In general, formaldehyde
or (para-formaldehyde), an amine, and an “active-hydro-
gen” component such as an enolizable ketone or terminal
alkyne are allowed to react to afford the corresponding
-aminoketone or -aminoalkyne. The latter Mannich
adduct contains at least two potential sites for further
modification, the amine and the alkyne.2 In addition,
-aminoalkynes have a wide range of applications includ-
ing use as pharmaceutical intermediates3 and as general
synthetic building blocks.4
The traditional Mannich methods for synthesizing -ami-
noalkynes often require drastic reaction conditions and
generally utilize dioxane. The organic solvent and the
metal catalyst can be difficult to handle and pose a number
of waste handling problems.
MW
CCH2NR2R3
Scheme 1
The results are summarized in the Table. The data indicate
that under microwave irradiation and solvent free condi-
tions, aliphatic and aromatic terminals alkynes react
smoothly with iminium species formed in situ in the pres-
ence of cuprous iodide and alumina. A variety of second-
ary amines, such as dibenzylamine, dibutylamine,
piperidine, 1-phenylpiperazine and morpholine partici-
pate in a reaction with para-formaldehyde to afford the
desired Mannich adducts.
During the investigation, we found that piperazine reacts
with 1-octyne and para-formaldehyde (excess) to afford
the diaminomethylation adduct. 1,9-Decadiyne reacts
with dibutylamine and para-formaldehyde (excess) to
generate the bis-aminoalkyne. Interestingly, benzylamine
(a primary amine) was found to react with 1-decyne and
para-formaldehyde (excess) to produce the bis-Mannich
condensation product, Scheme 2.
The chemoselectivity of the reaction was investigated.
When a mixture of acetophenone and 4-ethynyltoluene
served as competitive acidic substrates for the Mannich
reaction, only the -aminoalkyne was formed. As antici-
pated, the Mannich reaction of 4-acetyl-1-ethynylbenzene
generated only the -aminoalkyne product.
The synthesis of dibenzyl(undec-2-ynyl)amine is repre-
sentative. Dibenzylamine (0.197 g, 1.00 mmol), and 1-de-
cyne (0.138 g, 1.00 mmol) were added to a mixture of
cuprous iodide (0.572 g, 3.00 mmol), para-formaldehyde
(0.090 g, 3.00 mmol) and alumina (1.00 g) contained in a
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 (punctured by an 18 gauge
We have found alumina to be a particularly useful reagent
in organic synthesis because it can be modified in a vari-
ety of ways which enhance its reactivity. It also obviates
a number of environmental problems.5 For example, using
a commercially available alumina potassium fluoride
mixture to which we added palladium powder, we were
able to carry out Suzuki and Sonogashira coupling reac-
tions on a wide variety of aromatic moieties without the
use of solvents.6
Microwave irradiation of organic reactions has gained in
popularity in recent years since it was found to accelerate
a wide variety of transformations.7 In recent years a num-
ber of reports have appeared in which reactants are coated
onto surfaces which themselves absorb little or no micro-
wave energy; in these instances, the reactive species ab-
sorb the microwave energy but the bulk temperature of the
reaction mixture tends to rise only modestly. This results
in relatively large energy savings as well as making it pos-
sible to carry out reactions in relatively simple glassware,
such as open beakers and flasks.8
We now wish to report a microwave-enhanced Mannich
condensation of terminal alkynes with amines and para-
Synlett 2001, No. 5, 676–678 ISSN 0936-5214 © Thieme Stuttgart · New York
Kabalka
