A facile solvent-free one-pot three-component Mannich reaction of aldehydes, amines and terminal alkynes catalysed by CuCl2

Article abstract of DOI:10.3184/030823407X191994

A solventless Mannich condensation of aldehydes, amines, and terminal alkynes catalysed by 10 mol% of CuCl₂ was investigated. The components were simply mixed and heated together under vacuum, without any need of solid-support or solvent. This results in the formation of Mannich products in high yields.

Full text of DOI:10.3184/030823407X191994

JOURNAL OF CHEMICAL RESEARCH 2007
FEBRUARꢀ, 129–132
RESEARCH PAPER 129
A facile solvent-free one-pot three-component Mannich reaction of
aldehydes, amines and terminal alkynes catalysed by CuCl
2
a
a
b
Ali Sharifi *, Mojtaba Mirzaei and M. Reza Naimi-Jamal *
a
Chemistry & Chemical Engineering Research Centre of Iran, P.O. Box 14335-186, Tehran, Iran
bOrganic Chemistry Research Lab., Faculty of Chemistry, Iran University of Science and Technology, 16846 Tehran, Iran
A solventless Mannich condensation of aldehydes, amines, and terminal alkynes catalysed by 10 mol% of CuCl was
2
investigated. The components were simply mixed and heated together under vacuum, without any need of solid-
support or solvent. This results in the formation of Mannich products in high yields.
Keywords: Mannich reaction, aldehydes, alkynes, solvent-free synthesis, copper salt
Multi-component reactions are some of the most important
reactions in organic synthesis. The Mannich reaction is a
well-known example of a three-component reaction in which
an aldehyde (usually formaldehyde), ammonia or a primary
or secondary amine and a compound having an acidic C–H
bonding site such as an enolisable ketone, an electron rich
aromatic, a nitro compound or a terminal alkyne are condensed
to afford the corresponding products which are usually called
been clearly investigated. As it has been proved in recent
years that using some auxiliaries in such reactions is NOT
7
necessary, we were interested to explore the necessity and
efficiency of solid supports, and to study the scope of the
method for other aldehydes than formaldehyde (including
enolisable ones). We have investigated, therefore, the reaction
of phenylacetylene, piperidine and p-chlorobenzaldehyde as
a model reaction in the presence of SiO , alumina (acidic and
2
1
Mannich bases. The products are used extensively in industry,
basic) or Montmorillonite K-10 (Scheme 1).
To a mixture of p-chlorobenzaldehyde (1.0 mmol),
phenylacetylene (1.2 mmol) and piperidine (1.2 mmol) in a
pharmacology and organic synthesis.2
The classic method for the Mannich reaction suffers from
some disadvantages and limitations such as low yields,
restriction to non-enolisable aldehydes and drastic reaction
1
0 ml flask, 1.0 g. of the corresponding solid-support was
added (Table 1). The flask was evacuated and heated to 80°C
for the given time. The results are summarised in Table 1.
Interestingly, the best result was obtained when using only
conditions such as refluxing of the reagents in toxic solvents
like dioxane, acetonitrile, toluene, etc.1a Modern variations of
the Mannich reaction have been developed in past decades
1
0 mol% of CuCl catalyst (instead of 3 equivalents as used in
to overcome these drawbacks, including the use of pre- or in
2
4
b
1,3
other methods ) and no solid support at all. It seemed that the
presence of a solid support was not strictly necessary.
situ prepared imminium salts, microwave-assisted methods
4
on solid supports and more recently, performing the reaction
5
in aqueous solution. The latter meets the increasing interest
A wide range of potential catalysts such as FeCl3, ZnCl2,
CeCl .7H O, CoCl .6H O, BiCl , CuI and CuCl were tested
nowadays in developing environmentally-benign methods
removing the need for organic solvents as reaction media.
The one-pot variations among others, profit from the ease
of the methodology, simple laboratory equipment and the
possibility of using non-modified reagents.3
3
2
2
2
3
2
in the model reaction. The last was the most effective one and
was chosen for further investigations (Table 2).
These results have encouraged us to investigate the
usefulness of this methodology for other substrates. Table 3
contains a summary of the results. All of the known products
Solid–solid, solid–melt and melt reactions have recently
been developed as eco-friendly procedures which afford
high yields and do not require any auxiliaries such as solid-
supports, organic solvents, or microwave acceleration. These
methods have been successfully used in different type of
4
a–4p were been characterised with comparison of their
physical or spectral data with those in the literature. The new
products 4q–4s exhibit satisfactory elemental analysis and
spectroscopic data.
6
reactions including protection, condensation and elimination.
For example, it has been reported that the Knoevenagel
reaction is viable if the reagents are mixed and heated in an
evacuated vessel. In this respect and towards our goal of
H
N
CHO
7
N
developing new solventless methods of preparation of organic
compounds, we were interested in developing a new method
for the Mannich reaction which combines the advantages of
solvent-free methods, one-pot procedures, and avoids the
need for solid-supports.
+
+
Solid support, 80 °C
Cl
Cl
Scheme 1 Solvent-free reaction of phenyl-acetylene,
piperidine and p-chlorobenzaldehyde.
We now wish to report a one-pot, three-component Mannich
reaction catalysed by CuCl , simply by heating a mixture
2
of the reagents in an ordinary laboratory oven. No reaction
solvent, no solid support or acceleration by microwave
irradiation is needed.
Very recently, there has been a report on a microwave-
enhanced, solventless Mannich condensation of terminal
alkynes and secondary amines with para-formaldehyde on
Table 1 Effect of different solid-supports on sample Mannich
condensation reaction
Solid-support
Time/h
Yield/%
SiO2
SiO2
3
20
3
20
3
20
3
20
3
9
30
34
60
16
72
15
85
95
Al O (basic)
cuprous iodide doped alumina which gave the corresponding
2
3
Mannich products in good yields.4b Despite of the usefulness
Al2O3 (basic)
Al O (acidic)
2
3
of the method, it is restricted to using of para-formaldehyde
and the rôle of alumina (1 g per 1 mmol of aldehyde) has not
Al O (acidic)
2
3
Montmorillonite K10
Montmorillonite K10
1
0 mol% CuCl2
*
Correspondent. E-mail: sharifi@ccerci.ac.ir; naimi@iust.ac.ir
PAPER: 06/4388

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30 JOURNAL OF CHEMICAL RESEARCH 2007
Table 2 Effect of different catalysts on sample Mannich
Mannich products. This solventless approach provides ready
access to propargylamines and is applicable both to non-
enolisable aldehydes such as benzaldehyde and its derivatives
condensation reaction (Scheme 1)a
Entry
Catalyst
Yield/%
(
entries 1–4, 11–19), and formaldehyde (entries 7–10), as
1
2
3
4
5
6
7
FeCl3
14
37
3
well as enolisable aldehydes, such as n-hexanal and n-octanal
(entries 5 and 6). Both primary amines like aniline and
secondary amines including sterically hindered dibenzylamine
afforded good yields.
In summary, we have reported here an environmentally
friendly Mannich condensation of terminal alkynes, aldehydes
and amines by simply mixing the reagents and only 10 mol%
ZnCl2
CeCl .7H O
3
2
CoCl .6H O
7
2
2
BiCl3
8
87
95
CuI
CuCl2
aAfter 3 h at 80°C with 10 mol% catalyst.
of CuCl catalyst and heating at temperatures up to 80°C in
The method is very efficient, as a wide range of different
aldehydes (not only formaldehyde), and amines with
phenylacetylene (2a), 1-octyne (2b), and or 1-heptyne (2c)
were successfully condensed to afford the corresponding
2
an evacuated vessel affording the desired products in high
yields. No reaction solvent, no solid support or acceleration
by microwave irradiation was needed.
Table 3 Mannich condensation of aldehydes, alkynes and amines
Entry
Aldehyde
Alkyne
Amine
Product
Temp/°C
Yield/%
a
1
2
3
4
1
1a: C H CHO
2a: C H C∫CH
N
60
43
85
6
5
6
5
N
H
80
Ph
Ph
3a
Ph
4a8
4b5b
4c9
2
3
1b: p-CF C H CHO
2a
2a
3a
N
60
80
53
56
3
6
4
p-CF C H
4
3
6
N
1c: p-CH OC H CHO
3a
3a
80
92
3
6
4
Ph
p-CH OC H
4
3
6
N
4
5
1d: p-CH C H CHO
2a
2a
80
80
88
90
3
6
4
Ph
p-CH C H
4
4d9
3
6
Ph
Ph
(PhCH ) N
2 2
Ph
1e: n-C H11CHO
5
N
H
n-H11C5
3b
4e4a
N
6
1f: n-C H15CHO
2a
2a
3a
Ph
80
75
7
n-H15C7
4f10
7
8
1g: (CH O)n
3a
3b
80
80
95
92
2
N
Ph
4g10
Ph
N
Ph
1g
1g
2b: n-C H13C∫CH
6
n-C H 4h4b
6
13
(
PhCH ) N
2
2
9
2a
3a
80
83
Ph 4i4b
PAPER: 06/4388

JOURNAL OF CHEMICAL RESEARCH 2007 131
Table 3 Continued
Entry
Aldehyde
Alkyne
Amine
Product
Temp/°C
80
Yield/%
100
a
1
2
3
4
10
11
12
1g
2a
2a
2a
N
H
N
Ph 4j11
3c
H
Ph
Ph
N
1a
80
80
80
93
Ph
Ph
Ph
N
3d
4k8
4l12
NH2
H
1h: p-ClC H CHO
3d
6
4
p-ClC H
6
4
Ph
Ph
1
1
3
4
1a
2a
2a
3b
N
80
80
75
95
Ph
4m5b
Ph
O
O
N
1h
N
H
Ph
4n9
p-ClC H4
3e
6
N
15
16
17
1h
1a
2a
2a
3a
80
80
80
85
80
90
Ph
Ph
4o5b
p-ClC H
6
4
N
N
4p5c
3f
Ph
H
O
1i: o-ClC H CHO
2c: n-C H11C∫CH
3e
N
6
4
5
n-C H
5
11
o-ClC H
4q
6
4
O
N
1
1
8
9
1j: p-BrC H CHO
2b
2a
3e
80
80
94
68
6
4
n-C H
6
13
p-BrC H
4r
6
4
N
N
H
1h
Ph
3g
p-ClC H
4s
6
4
aThe structures of the all known products were being characterised with comparison of their spectroscopic data with those reported
in the cited literature.
Experimental
General procedure for the preparation of Mannich bases from
aldehydes, alkynes and amine
Aldehyde (1 mmol), alkyne (1.2 mmol), and amine (1.2 mmol)
were poured in a 10 ml flask at room temperature. After addition
Melting points were determined on a hot stage or oil bath
1
13
apparatus without correction. H NMR and C NMR spectra were
recorded on a Bruker 500 MHz in CDCl3 using TMS as internal
standard. The GC Analysis was performed with a Varian CP-3800
instrument. Elemental analyses were performed using a Thermo
Finnigan Flash EA 1112 instrument. GC-MS spectra were obtained
on a Fisons 8000 Trio instrument at ionisation potential of 70 ev.
The structures of the all known products were being characterised
with comparison of their spectroscopic data with those reported in
the literature.4
of CuCl (0.1 mmol) and mixing, the flask was evacuated (0.2 bar)
2
and heated to 80°C for 3 h in a laboratory oven. The progress
of reaction was monitored by GC. The reaction mixture was
washed with petrol and filtered, and the solvent was evaporated
on a rotary evaporator. The residue was purified with a short silica
gel column (eluent:light petroleum ether/ethyl acetate, 10:1), when
necessary.
,5,8-12
PAPER: 06/4388

1
32 JOURNAL OF CHEMICAL RESEARCH 2007
4
-(1-(2-chlorophenyl)oct-2-ynyl)morpholine (4q):
A
yellow
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4
1
obtained in 94% yield; H NMR (CDCl ): d = 0.94 (t, 3H, J = 7 Hz),
3
1
2
4
1
1
1
.31–1.39 (m, 4H), 1.45–1.50 (m, 2H), 1.60 (quint, 2H, J = 7.2 Hz),
.35 (dt, 2H, J = 2, 7.0 Hz), 2.54 (t, 4H, J = 4.5 Hz), 3.73 (m, 4H),
3
4
5
6
.52 (t, 1H, J = 2 Hz), 7.49 (s, 4H). 13C NMR (CDCl ): d = 14.5,
3
9.2, 23.0, 29.0, 29.3, 31.7, 50.0, 61.4, 67.5, 75.1, 89.8, 121.9, 130.7,
+
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(
2
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1
9
26
Found: C, 62.5 ,H, 7.1, N, 3.8.
-(1-(4-chlorophenyl)-3-phenylprop-2-ynyl)-2-methylpiperidine
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1
1
(
4s): A yellow oil was obtained in 68% yield; H NMR (CDCl ):
3
d = 1.29 (d, 3H, J = 6 Hz), 1.34–1.45 (m, 3H), 1.53–1.57 (m, 1H),
1
1
.70–1.74 (m, 2H), 2.24–2.30 (t, 1H, J = 11.2 Hz), 2.42–2.46 (m,
5
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1
3
(
3
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3
7
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+
1
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8
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2
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2
1
22
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9
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Received 4 January 2007; accepted 23 February 2007
Paper 07/4388 doi: 10.3184/030823407X191994
11
PAPER: 06/4388