Mild and efficient synthesis of propargylamines by copper-catalyzed Mannich reaction

Article abstract of DOI:10.1016/j.tetlet.2004.09.079

Terminal alkynes can be condensed with aqueous formaldehyde and primary or secondary amines to give secondary and tertiary propargylamines. The reaction is best carried out in DMSO under CuI catalysis. Terminal alkynes undergo mild and efficient aminomethylation with aqueous formaldehyde and secondary amines under CuI catalysis. In most cases high to nearly quantitative yields of tertiary propargylamines are obtained in DMSO solution at room temperature. Aromatic, aliphatic and silylated acetylenes as well as alkynols can be used. Primary amines are less reactive and satisfactory yields of secondary propargylamines are obtained only with phenylacetylene.

Full text of DOI:10.1016/j.tetlet.2004.09.079

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8281–8283
Mild and efficient synthesis of propargylamines by
copper-catalyzed Mannich reaction
Lothar W. Bieber* and Margarete F. da Silva
´ ´
Departamento de Quımica Fundamental, Universidade Federal de Pernambuco, Cidade Universitaria, 50670-901 Recife, PE, Brazil
Received 27 August 2004; revised 8 September 2004; accepted 10 September 2004
Abstract—Terminal alkynes undergo mild and efficient aminomethylation with aqueous formaldehyde and secondary amines under
CuI catalysis. In most cases high to nearly quantitative yields of tertiary propargylamines are obtained in DMSO solution at room
temperature. Aromatic, aliphatic and silylated acetylenes as well as alkynols can be used. Primary amines are less reactive and
satisfactory yields of secondary propargylamines are obtained only with phenylacetylene.
Ó 2004 Elsevier Ltd. All rights reserved.
Propargylamines 3 are compounds of interesting biolog-
ical properties and important synthetic intermediates.1,2
The most attractive synthetic access is the classical Man-
nich reaction,3 a three component procedure between
terminal alkynes 1, formaldehyde and secondary amines
2; initially restricted to arylacetylenes, the reaction has
been extended to some less activated alkynes by the
introduction of copper catalysts.4 However, rather harsh
conditions, moderate yields and complex workup and
purification procedures still have limited a wider appli-
cation. Also a recent microwave-enhanced, solventless
reaction on alumina does not represent an attractive
alternative because of the need of large excess of formal-
dehyde and copper(I) iodide.5 In contrast to the lack of
efficient Mannich procedures with formaldehyde itself,
recently several related reactions starting from aliphatic
and aromatic aldehydes via enamines,6 N,O-acetals,7
iminium salts and their precursors8 have been reported,
some of them even under asymmetric catalysis.6,9 Most
of these procedures require dry aprotic solvents, but
solid-phase methodologies10 and several aqueous proce-
dures catalyzed by Cu, Ag or Au have also been
described.11
nyl alkynes,13 prompted us to examine similar condi-
tions for the aminomethylation of terminal alkynes.
DMSO/H2O
R
R
CH2NR'R''
+ CH2O + HNR'R''
[CuI]
3
1
2
In our first experiments, phenylacetylene, morpholine
and aqueous formaldehyde were reacted at 30°C in
commercial, DMSO in the presence of 0.02equiv of cop-
per(I) iodide. After 2h, the alkyne was almost consumed
and the desired tertiary amine 3 could be isolated in
nearly quantitative yield (Table 1, entry 1). Other cop-
per(I) salts were less effective with yields decreasing from
CuCN to CuBr and CuCl; surprisingly, also CuCl2 gave
3, albeit in moderate yield, probably because of in situ
reduction by formaldehyde (entries 2–5). With CuSO4,
Cu2O and metallic copper and in the absence of catalyst
no reaction at all occurred (entries 6–9). AuCl3 and AgI,
which have been reported to catalyze similar transform-
ations with aromatic and higher aliphatic aldehydes in
refluxing water,11b,c produced only trace amounts of
product under our conditions (entries 10 and 11). Vari-
ation of the solvent brought no further improvement:
acetonitrile was less efficient than DMSO, water and
methanol gave only a few percent of yield and dioxane
or carbon tetrachloride did not afford any product at
all (entries 12–16). Paraformaldehyde in the absence of
additional water can also be used, but required 20h at
room temperature probably because of the slow depo-
lymerization (entries 17 and 18).
Recent progress in two different copper(I)-catalyzed
reactions, the mild and efficient Barbier-type alkylation
of iminium ions12 and the direct synthesis of phenylsele-
Keywords: Aminomethylation; Terminal alkynes; Primary and second-
ary amines.
*
Corresponding author. Tel.: +55 81 21268441; fax: +55 81
21268442; e-mail: bieberlothar@hotmail.com
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.09.079

8282
L. W. Bieber, M. F. da Silva / Tetrahedron Letters 45 (2004) 8281–8283
Table 1. Mannich reaction of phenylacetylene with formaldehyde and
morpholine14
Table 2. Synthesis of propargylamines 314
Entry
R
R0, R00
Solvent Time Yield
(h)
Entry
Catalyst
Solvent
Time (h)
Yielda (%)
(%)
1
CuI
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
MeCN
H2O
2
2
95
77
60
23
59
—
—
—
—
17
2
1
Ph
Ph
Me, Mea,b
Et, Et
c-C6H11, c-C6H11 DMSO 20
DMSO 10
DMSO 10
95
98
96
92
98
98
93
73
70
72
86
98
89
96
95
93
2
CuCN
CuBr
CuCl
CuCl2
CuSO4
Cu2O
Cu0
2
3
2
3
Ph
Ph
4
2
4
(CH2)4
(CH2)5
DMSO 10
DMSO 10
DMSO 10
DMSO 20
DMSO 20
DMSO 20
DMSO 20
DMSO 72
DMSO 20
5
2
5
Ph
Ph
6
2
6
(CH2)2O(CH2)2
Ph, Me
7
2
7
Ph
Ph
8
2
8
Me, Ha,b,c
n-Bu, Hc
PhCH2, Hc
Me, Mea,b
Et, Et
9
—
2
9
Ph
Ph
10
11
12
13
14
15
16
17b
18b
AuCl3
AgI
CuI
2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
2
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Oct
CH2OH
CH2OH
CH2OH
2
71
5
CuI
CuI
2
c-C6H11, c-C6H11 DMSO 72
MeOH
Dioxane
CCl4
2
2
(CH2)4
(CH2)5
DMSO 20
DMSO 20
DMSO 20
CuI
CuI
2
—
—
4
2
(CH2)2O(CH2)2
Ph, Me
Ph, Me
CuI
CuI
DMSO
DMSO
2
20
DMSO
DMSO
H2O
4d,e 83
93
4d
72
72
78
70
96
67
87
80
82
67
71
60
(CH2)4
(CH2)5
a Determined by 1H NMR in the crude extract (1mL of CCl4 con-
taining 0.05mmol of cyclohexane as internal quantitative reference).
b 1mmol of paraformaldehyde was used in the absence of additional
water.
H2O
c-C6H11, c-C6H11 DMSO 20
CMe2OH Et, Et
CMe2OH (CH2)4
CMe2OH (CH2)5
H2O
H2O
H2O
72
72
72
CMe2OH c-C6H11, c-C6H11 DMSO 20
SiMe3
SiMe3
Me, Mea,c,f
(CH2)2O(CH2)2
DMSO 72
DMSO 72
In the following experiments the procedure was adjusted
to different amines and alkynes. Several secondary
amines gave excellent yields with phenylacetylene,
including the highly hindered dicyclohexylamine;
dimethylamine was used as the hydrochloride and
potassium bicarbonate was added as auxiliary base
(Table 2, entries 1–6). Also the less basic N-methylaniline
produced a high yield after 20h (entry 7). Even primary
amines, previously found unreactive, gave preparative
results of secondary propargylamines 3 (entries 8–10).
g
a The hydrochloride was used.
b 1mmol of KHCO3 was added as auxiliary base.
c 1mmol of amine was used.
d Reaction temperature 80°C.
e Performed in a sealed tube.
f 1mmol of paraformaldehyde and 1mmol of K2HPO4 as auxiliary
base were used.
g 0.75mmol of acetic acid were also added.
lated before in the Zn-Barbier reaction12 and in the
TiCl3-promoted reaction with diazonium salts or tert-
butyl hydroperoxide.15
1-Hexyne was less reactive with secondary amines and
needed longer reaction times to achieve complete trans-
formation (entries 11–16). No reaction was observed
with N-methylaniline at 30°C, but a satisfactory yield
was obtained at 80°C in a sealed tube; the less volatile
decyne gave similar results at atmospheric pressure
(entries 17 and 18). Alkynols too showed good reactivity
(entries 19–25). Especially when both substrates 1 and 2
were hydrophilic (entries 19 and 20), water instead of
DMSO improved the yields by a factor of 2–3. Under
careful pH-control, the reaction was also successful with
the acid and base-sensitive trimethylsilyl acetylene. This
was achieved by the addition of a weak inorganic base
(K2HPO4) in the case of the hydrochloride of dimethyl-
amine (entry 26) or by buffering free morpholine with
1.5equiv of acetic acid (entry 27).
In summary, the method allows the easy, mild and effi-
cient synthesis of a large number of differently substi-
tuted propargylamines characterized by high atom
economy, low environmental impact and use of non-
toxic solvents and reagents. The possibility to react
unprotected primary amines and alkynols allows further
reactions on these sites. Present studies with suitable
benzyl, allyl or silyl-protected secondary amines are
underway and can open an easy access also to primary
propargylamines.
Acknowledgements
The described reactions can be regarded as examples of
the Mannich reaction, which involves enols or carbani-
ons as intermediates in the classical version. In the pre-
sent study, a terminal acetylene is used as CH-acidic
component under weakly basic conditions. However,
in view of the need for a copper catalyst and the excep-
tionally mild reaction conditions, a radical intermediate
should also be considered. A radical addition of phenyl,
acetyl and alkyl radicals to iminium ions has been postu-
We gratefully acknowledge financial support from
CNPq.
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