Microwave-promoted, solvent-free, three-component coupling of aldehyde, alkyne, and amine catalyzed by AgNO3

Article abstract of DOI:10.1080/00397910601131320

An efficient three-component coupling reaction of alkyne, aldehyde, and amine was carried out in one pot smoothly under the catalysis of AgNO3 and microwave irradiation. The scope of reaction substrates was extended. Moreover, the reaction can be performe

Full text of DOI:10.1080/00397910601131320

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Microwave‐Promoted, Solvent‐Free,
Three‐Component Coupling of Aldehyde,
Alkyne, and Amine Catalyzed by AgNO
3
a
a
a
a
Tingting He , Zhenggen Zha , Chongfeng Pan & Zhiyong Wang
a
Hefei National Laboratory for Physical Science at Microscale and
Department of Chemistry, University of Science and Technology of China,
Hefei, China
Published online: 10 Mar 2007.
To cite this article: Tingting He , Zhenggen Zha , Chongfeng Pan & Zhiyong Wang (2007):
Microwave‐Promoted, Solvent‐Free, Three‐Component Coupling of Aldehyde, Alkyne, and Amine Catalyzed by
AgNO , Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
3
Chemistry, 37:5, 849-858
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Synthetic Communications , 37: 849–858, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910601131320
Microwave-Promoted, Solvent-Free,
Three-Component Coupling of Aldehyde,
Alkyne, and Amine Catalyzed by AgNO3
Tingting He, Zhenggen Zha, Chongfeng Pan, and
Zhiyong Wang
Hefei National Laboratory for Physical Science at Microscale and
Department of Chemistry, University of Science and Technology of
China, Hefei, China
Abstract: An efficient three-component coupling reaction of alkyne, aldehyde, and
amine was carried out in one pot smoothly under the catalysis of AgNO3 and
microwave irradiation. The scope of reaction substrates was extended. Moreover, the
reaction can be performed under solvent-free condition, affording propargylamine
derivatives with high yields.
Keywords: microwave, propargylamine, silver catalyst, solvent free, three-component
coupling
INTRODUCTION
Nowadays multicomponent coupling reactions in one pot are a popular
[
strategy in organic synthesis, among which the direct addition of terminal
1]
[2]
alkyne to imines to afford propargylamines has received much attention.
Propargylamines are important both as synthetic intermediates for the prepa-
ration of many polyfunctional amino derivatives and as biologically active
[
compounds such as conformationally restricted peptide isosteres, oxotre-
3]
morine analogues, and b-lactams. Although a lot of reports involved employ-
[6]
[
ments of iridium complexes, copper salts, gold salts, and silver salts
2a]
[4]
[5]
Address correspondence to Zhiyong Wang, Hefei National Laboratory for Physical
Science at Microscale and Department of Chemistry, University of Science and Tech-
nology of China, Hefei 230026, China. E-mail: zwang3@ustc.edu.cn
8
49

8
50
T. He et al.
as catalysts to construct this unit, many of these catalysts have their limitations
for reaction substrates. For example, gold salt catalysts were often much more
reactive to aromatic aldehydes than aliphatic aldehydes whereas silver salts
showed a reversal of reactivity of aliphatic and aromatic aldehydes.
Moreover, most of the reactions need to be performed under an inert atmos-
phere and these reactions often proceeded slowly in water. All of these limit-
ations attracted us to study this three-component reaction. On the other hand,
organic synthesis promoted by microwave irradiation (MWI) has received
[7]
considerable attention in recent years. MWI can circumvent the need for
prolonged heating and generally accelerate the rate of chemical reactions,
[
often with increased yields. Moreover, the microwave-assisted reactions
8]
[9]
are believed to meet the demands of “green chemistry,” one of which
targets is to explore alternative reaction conditions and reaction media
to accomplish the desired chemical transformations with minimum
by-products and waste generation as well as the elimination of the use of
[10]
volatile and toxic organic solvents.
RESULTS AND DISCUSSION
Recently, we investigated this three-component reaction of alkyne, aldehyde,
and amine in the presence of silver nitrate under microwave irradiation. A
simple and fast solvent-free synthetic method was developed for propargyla-
mine derivatives, giving the corresponding product with high yields regardless
of whether the starting materials are aromatic aldehydes and alkynes or not
(
Scheme 1).
First of all, different salts were screened for this three-component coupling
reaction. To a flask, benzaldehyde (2 mmol), phenylacetylene (2.5 mmol),
diethylamine (2.5 mmol), and the corresponding salt (0.06 mmol) (AuCl3,
AuBr , AgI, AgBr, AgCl, Ag O, AgNO , Ag SO , or AgF) were added.
3
2
3
2
4
Then the mixture was stirred, and the reaction was carried out under MWI at
08C. After 10 min under MWI, the reaction was finished, and the experimental
9
results are listed in Table 1. As shown in Table 1, AgNO showed the best
3
catalytic ability in catalyzing the reaction, giving the desired product with
the highest yield (56%) under this condition (Entry 7, Table 1). Therefore
silver nitrate (AgNO ) was chosen as the catalyst. To the mixture of
3
Scheme 1. Microwave-assisted solventless synthesis of propargylamine. R ¼ Aryl,
Alkyl; R , R ¼ Akyl; R ¼ Aryl, Akyl.
1
2
3

Aldehyde, Alkyne, and Amine Coupling
851
Table 1. Optimization of the reaction condition
Amount of
catalyst
(mmol%)
Temperature
(8C)
Entry
Catalyst
AuCl
Yield (%)
1
2
3
4
5
6
7
8
9
3
3
3
3
3
3
3
3
3
3
5
8
5
5
90
90
14
17
21
23
27
19
26
56
30
68
68
89
89
AuBr3
AgI
90
90
AgBr
AgCl
Ag O
90
90
2
AgNO
AgF
Ag SO
3
90
90
90
90
2
4
1
1
1
1
0
1
2
3
AgNO
AgNO
3
3
90
AgNO3
AgNO
105
120
3
benzaldehyde (2 mmol), phenylacetylene (2.5 mmol), and diethylamine
2.5 mmol) were added different amounts of AgNO3 catalyst, and the
(
reactions were conducted at the same reaction conditions (908C, 10 min) to
determine the optimum amount of the catalyst. When the amount of silver
nitrate was increased from 3% to 5% mol, the corresponding reaction yield
was enhanced from 56% to 68% (Entry 10, Table 1). Increasing the amount
of the catalyst further had little influence on the reaction yield (Entry 11,
Table 1). After many trials, 5 mol% of the silver nitrate was the best
dosage for the catalyst in this reaction. Afterward, the reaction was carried
out at different temperature to optimize the reaction temperature. Low tempe-
rature effected low yield, and the reaction temperature beyond 1208C created
many by-products. The experimental result showed that 1058C was a good
compromise between the high yield and the generation of the reaction
by-products.
The scope of the reaction substrates was then investigated. The experi-
mental results showed that both aromatic aldehydes and aliphatic aldehydes
worked very well in this three-component coupling reaction to afford the
desired products with high yields (Entries 1–11, Table 2). Interestingly, it
was found that aliphatic aldehydes reacted more rapidly than aromatic
aldeydes, obtaining the corresponding product with nearly quantitative yield
(Entries 8 and 9, Table 2). No trimerization of aliphatic aldehydes were
observed in the reaction, which usually was a limitation of the three-
[4,5]
component coupling catalyzed by Au or Cu in water.
Also, the electronic
properties of the substituents on the aromatic ring had little influence on the
reaction rate and yield. For instance, the aldehydes bearing electron-donating

8
52
T. He et al.
Table 2. AgNO
amine
3
-catalyzed three-component coupling of aldehyde, alkynene, and
Time Yield
(min) (%)
Entry
1
Aldehyde
Amine Alkynene
Et NH
Product
2
10
480
10
89
36
80
a
1
Et NH
2
2
3
4
Et NH
2
Et NH
2
10
10
84
82
2
Et NH
5
6
Et NH
2
10
12
83
79
Et
2
NH
7
Et
Et
2
NH
NH
12
76
8
9
2
8
8
97
99
(CH O)
2
Et NH
2
n
(
continued)

Aldehyde, Alkyne, and Amine Coupling
853
Table 2. Continued
Time Yield
(min) (%)
Entry
Aldehyde
Amine Alkynene
Product
10
10
11
12
Et
2
NH
10
500
10
80
29
83
90
a
Et
2
NH
(CH O)
2
Et NH
2
n
10
a
Under the condition of conventional heating at 1058C in the presence of 5 mol%
of AgNO
3
.
groups were more reactive partners in this reaction (Entries 3–5, Table 2) than
the aldehydes bearing electron-withdrawing groups (Entries 2 and 7, Table 2).
Subsequently, different amines and alkynes were examined to expand the
scope of amine and alkyne substrates. When the 1-ethynyl-benzene was
replaced with pent-1-nye in this coupling reaction, the reaction was carried
out smoothly, giving the corresponding product with a high yield. On the
other hand, the replacement of diethylamine by piperidine had little
influence on this coupling reaction (Entry 12, Table 2). All the experimental
results demonstrated that this new method has good applicability.
To examine the effect of microwave irradiation, further investigations
were performed. Without MWI, the three-component coupling under conven-
a
tional heating required more than 8 h, affording much lower yields (Entries 1
a
and 10 ). It indicated that MWI was necessary for speeding up the coupling.
On the basis of these experimental results, together with some literature
[
8–10]
results
a tentative mechanism was proposed. At first, the MWI and
silver ion catalysis activated the C-H bond of alkyne, which results in the
formation of silver acetylide and the iminium ion. The silver acetylide inter-
mediate was then added to iminium ion to generate the corresponding propar-
gylamine, and the released Ag (I) catalyzed the next cycle in the reaction. The
proposed mechanism is described in Scheme 2.

8
54
T. He et al.
Scheme 2. Tentative mechanism for the silver-catalyzed reaction under microwave
irradiation.
In summary, an efficient three-component coupling of aldehyde, alkyne,
and amine catalyzed by AgNO has been successfully achieved under MWI
3
and solvent-free conditions. The reaction procedure is facile, simple, and
economical. The employment of this new method extended the scope of the
reaction substrates. Different aldehydes, alkynes, and amines, such as
aromatic aldehydes, aliphatic aldehydes, aromatic alkynes, aliphatic
alkynes, aliphatic amine, and cyclic amine, can be the reaction substrate,
generating a diverse range of propargylamines with high yields.
EXPERIMENTAL
Infrared (IR) spectra were run on a Bruker spectrometer and are expressed in
2
centimeters . NMR spectra were recorded on a Bruker AVMCE-300 MHz
1
in CD Cl solutions. High-resolution mass spectra were obtained with a
3
Micromass GCT TOF mass spectrometer.
General Procedure
A mixture of aldehyde (2.0 mmol), amine (2.5 mmol), alkyne (2.5 mmol), and
AgNO (0.1 mmol, 17 mg) were placed in a 10-ml crimp-sealed thick-wall
3
reaction tube equipped with a magnetic stirrer. The reaction tube was
placed in Emrys Creator from Personal Chemistry, which was operated at
1
2
058C for 10 min with 2 min prestirring (pressure ꢀ1.3 bars, power
00 W). After completion of the reaction, the product was extracted into
ethyl acetate and dried over anhydrous MgSO . The solvent was removed
4
under reduced pressure, and the residue was purified by chromatography on
a silica-gel column with petroleum ether/ethyl acetate as eluent to afford
the final product as light yellow oil or dark red oil. The pure compounds
1
13
were identified by H NMR, C NMR, IR, and HRMS.

Aldehyde, Alkyne, and Amine Coupling
855
Data
1
Compound 1a: H NMR (300 MHz, CDCl ), d, ppm, 7.69–7.67 (m, 2H, Ar-
3
H), 7.50–7.48 (m, 2H, Ar-H), 7.34–7.22 (m, 6H, Ar-H), 5.05 (s, 1H, -C-H),
1
3
2
NMR (75 MHz, CDCl ) d, ppm, 140.0, 131.9, 128.5, 128.4, 128.2 (two
.67–2.52 (m, 4H, 2ꢀ-CH-H), 1.08 (t, 6H, 2ꢀ -CH -H, J ¼ 7.1 Hz);
C
2
3
signals overlap), 127.4, 123.6, 87.6, 86.3, 57.2, 44.7, 13.7; IR (neat) vmax,
2
cm , 3061, 2969, 2932, 2821, 1599, 1490, 1449, 1050, 756, 692; HRMS
1
þ
(
EI) calcd. for C H N (M ): 263.1674; found: 263.1680.
1
9 21
1
Compound 2a: H NMR (300 MHz, CDCl ), d, ppm, 7.64–7.61 (m, 2H, Ar-
3
H), 7.51–7.49 (m, 2H, Ar-H), 7.34–7.30 (m, 5H, Ar-H), 4.99 (s, 1H, -C-H),
1
3
2
.67–2.47 (m, 4H, 2ꢀ -CH-H), 1.07 (t, 6H, 2ꢀ -CH -H, J ¼ 7.1 Hz);
C
NMR (75 MHz, CDCl ) d, ppm, 139.1, 133.4, 132.3, 130.1, 128.8, 128.6
2
3
(two signals overlap), 123.6, 88.3, 86.0, 57.0, 45.1, 13.7; IR (neat) vmax,
cm , 3057, 2969, 2932, 2822, 1597, 1488, 1470, 1383, 1287, 1091, 1016,
2
1
3
5
þ
7
55, 690; HRMS (EI) calcd. for C H
9 20
ClN (M ) 297.1284; found:
1
2
97.1289.
1
Compound 3a: H NMR (300 MHz, CDCl ), d, ppm, 7.61–7.52 (m, 4H, Ar-H),
3
7
2
.34–7.32 (m, 3H, Ar-H), 7.12–7.18 (m, 2H, Ar-H), 5.06 (s, 1H, -C-H), 2.74–
.53 (m, 4H, 2ꢀ -CH-H), 2.38 (s, 3H, Ar-CH -H), 1.12 (t, 6H, 2ꢀ -CH -H,
2
2
1
3
J ¼ 7.1 Hz); C NMR (75 MHz, CDCl ) d, ppm, 136.9, 136.9, 131.8, 128.8,
3
128.3 (two signals overlap), 128.0, 123.6, 87.4, 86.5, 56.9, 44.6, 21.1, 13.7;
IR (neat) vmax, cm , 3054, 2969, 2820, 1598, 1509, 1490, 1051, 756, 691;
21
þ
HRMS (EI) calcd. for C H N (M ): 277.1830; found: 277.1836.
20 23
1
Compound 4a: H NMR (300 MHz, CDCl ), d, ppm, 7.59–7.56 (m, 2H, Ar-
3
H), 7.51–7.48 (m, 2H, Ar-H), 7.31–7.29 (m, 3H, Ar-H), 6.89–6.86 (m, 2H,
Ar-H), 4.99 (s, 1H, -C-H), 3.80 (s, 3H, Ar-O-CH -H), 2.67-2.49 (m, 4H, 2ꢀ
2
3
1
-
CH-H), 1.07 (t, 6H, 2ꢀ -CH -H, J ¼ 7.1 Hz); C NMR (75 MHz, CDCl )
2
3
d, ppm, 158.9, 132.0, 131.8, 129.5, 128.3, 128.0, 123.6, 113.5, 87.4, 86.6,
5
2
6.6, 55.2, 44.5, 13.7; IR (neat) vmax, cm , 2968, 2834, 1610, 1509, 1490,
1
1
464, 1247, 1171, 1038, 833, 756, 691; HRMS (EI) calcd. for C H NO
2
0 23
þ
(M ): 293.1780; found: 293.1783.
1
Compound 5a: H NMR (300 MHz, CDCl ), d, ppm, 7.49–7.47 (m, 2H, Ar-
3
H), 7.32–7.30 (m, 3H, Ar-H), 7.19–7.18 (m, 2H, Ar-H), 6.78 (d, 1H, Ar-H,
J ¼ 8.6 Hz), 5.95 (s, 2H, Ar-O-CH-H), 4.94 (s, 1H, -C-H), 2.69–2.46
1
3
(
m, 4H, 2ꢀ -CH-H), 1.07 (t, 6H, 2ꢀ -CH -H, J ¼ 7.1 Hz); C NMR
2
(
75 MHz, CDCl ) d, ppm, 147.7, 146.9, 134.1, 131.9, 128.4, 128.2, 123.5,
3
1
cm , 2969, 2931, 1598, 1503, 1487, 1439, 1234, 1041, 938, 756, 691;
21.7, 109.0, 107.8, 101.1, 87.6, 86.4, 57.0, 44.6, 13.7; IR (neat) vmax,
2
1
þ
HRMS (EI) calcd. for C H NO (M ): 307.1572; found: 307.1580.
2
0
21
2
1
Compound 6a: H NMR (300 MHz, CDCl ), d, ppm, 8.51 (d, 1H, Ar-H,
3
J ¼ 8.0 Hz), 8.00 (d, 1H, Ar-H, J ¼ 8.0 Hz), 7.83–7.78 (m, 2H, Ar-H),

8
56
T. He et al.
7
2
.54–7.45 (m, 5H, Ar-H), 7.34–7.31 (m, 3H, Ar-H), 5.73 (s, 1H, -C-H), 2.80–
1
3
.58 (m, 4H, 2ꢀ -CH-H), 1.07 (t, 6H, 2ꢀ -CH -H, J ¼ 7.2 Hz); C NMR
2
(
75 MHz, CDCl ) d, ppm, 134.8, 134.1, 132.0, 128.7, 128.6, 128.5, 128.4,
3
1
IR (neat) vmax, cm , 3051, 2968, 2931, 2818, 1726, 1598, 1509, 1489,
28.1, 127.4, 125.8, 125.6, 125.1, 125.0, 123.7, 88.3, 86.6, 56.0, 45.0, 13.5;
1
2
1
C H N (M ): 313.1830; found: 313.1826.
443, 1383, 1293, 1259, 1046, 784, 756, 691; HRMS (EI) calcd. for
þ
2
3 23
1
Compound 7a: H NMR (300 MHz, CDCl ), d, ppm, 8.92 (dd, 1H, Ar-H,
3
J ¼ 0.8, 1.4 Hz), 8.53 (dd, 1H, Ar-H, J ¼ 1.2, 4.7 Hz), 7.99–7.96 (m, 1H,
Ar-H), 7.52–7.49 (m, 2H, Ar-H), 7.35–7.33 (m, 3H, Ar-H), 7.32–7.28
m, 1H, Ar-H), 5.06 (s, 1H, -C-H), 2.68–2.52 (m, 4H, 2ꢀ -CH-H), 1.08
2 3
(
1
3
(
t, 6H, 2ꢀ -CH -H, J ¼ 7.1 Hz); C NMR (75 MHz, CDCl ) d, ppm,
1
50.1, 148.6, 135.8, 135.5, 131.8, 128.3, 128.3, 123.0, 122.90, 88.2, 84.6,
2
5.1, 44.6, 13.6; IR (neat) vmax, cm , 3413, 2970, 2218, 1671, 1576, 1474,
1
5
þ
1287, 1054, 756, 692; HRMS (EI) calcd. for C H N (M ): 264.1626;
found: 264.1631.
1
8 20
1
Compound 8a: H NMR (300 MHz, CDCl ), d, ppm, 7.42 (m, 2H, Ar-H), 7.28
3
(
m, 3H, Ar-H), 3.68 (t, 1H, -C-H, J ¼ 6.8 Hz), 2.72 (m, 2H, -CH-H), 2.49
(
m, 2H, -CH-H), 1.71 (m, 2H, -CH-H), 1.69 (m, broad, 2H, -CH-H), 1.52
m, broad, 6H, 3ꢀ -CH-H), 1.10 (t, 6H, 2ꢀ -CH -H, J ¼ 7.2 Hz), 0.90
(
2
1
3
(
t, 3H, -CH -H, J ¼ 6.5 Hz); C NMR (75 MHz, CDCl ) d, ppm, 131.8,
2
3
1
28.3, 127.8, 123.9, 89.3, 84.7, 53.9, 45.0, 34.4, 31.9, 29.2, 26.9, 22.8, 14.2,
2
3.9; IR (neat) vmax, cm , 3057, 2929, 2856, 1598, 1489, 1467, 1380,
1
1
þ
1
found: 271.2304.
197, 1068, 755, 691; HRMS (EI) calcd. for C H N (M ): 271.2300;
1
9 19
1
Compound 9a: H NMR (300 MHz, CDCl ), d, ppm, 7.44–7.42 (m, 2H, Ar-
3
H), 7.30-7.25 (m, 3H, Ar-H), 3.64 (s, 2H, -CH-H), 2.63 (q, 4H, 2ꢀ -CH-H,
1
3
J ¼ 7.1 Hz), 1.12 (t, 6H, 2 ꢀ -CH -H, J ¼ 7.1 Hz); C NMR (75 MHz,
2
CDCl ) d, ppm, 131.7, 128.2, 127.9, 123.8, 85.0, 84.5, 47.3, 41.5, 12.7; IR
3
2
neat) vmax, cm , 3058, 2971, 2934, 2819, 2185, 1598, 1489, 1460, 1381,
1
(
þ
1
1
321, 1066, 691; HRMS (EI) calcd. for C H N (M ): 187.1361; found:
3 17
1
87.1366.
1
Compound 10a: H NMR (300 MHz, CDCl ), d, ppm, 7.62–7.59 (m, 2H, Ar-
H), 7.34–7.28 (m, 2H, Ar-H), 7.25–7.22 (m, 1H, Ar-H), 4.80 (s, 1H, -C-H),
3
2
.55–2.40 (m, 4H, 2ꢀ-CH-H), 2.31–2.26 (m, 2H, -CH-H), 1.63–1.56 (m, 2H,
1
3
-
CH-H), 1.06–1.00 (m, 9H, 3ꢀ-CH -H); C NMR (75 MHz, CDCl ) d, ppm,
2
3
140.7, 128.5, 128.0, 127.1, 87.4, 76.3, 56.7, 44.6, 22.7, 21.0, 13.7 (two signals
overlap); IR (neat) vmax, cm , 3061, 2966, 2821, 2257, 1601, 1491, 1451,
2
1
þ
1381, 1196, 724, 697; HRMS (EI) calcd. for C H N (M ): 229.1830;
found: 229.1822.
1
4 23
1
Compound 11a: H NMR (300 MHz, CDCl ), d, ppm, 3.39–3.37 (m, 2H,
3
-
CH-H), 2.54 (q, 4H, 2ꢀ -CH-H, J ¼ 7.2 Hz), 2.20–2.14 (m, 2H, -CH-H),

Aldehyde, Alkyne, and Amine Coupling
857
1
.56–1.48 (m, 2H, -CH-H), 1.06 (t, 6H, 2ꢀ-CH -H, J ¼ 7.2 Hz), 0.98 (t, 3H, -
2
1
3
CH -H, J ¼ 7.3 Hz); C NMR (75 MHz, CDCl ) d, ppm, 84.7, 74.4, 47.1,
2
3
2
0.9, 22.4, 20.7, 13.4, 12.5; IR (neat) vmax, cm , 2970, 2819, 2260, 1461,
1
4
1
1
þ
379, 1322, 1202, 1091, 981, 764; HRMS (EI) calcd. for C H N (M ):
1
0 19
53.1517; found: 153.1509.
1
Compound 12a: H NMR (300 MHz, CDCl ), d, ppm, 7.64–7.62 (m, 2H, Ar-
3
H), 7.52–7.49 (m, 2H, Ar-H), 7.35–7.31 (m, 6H, Ar-H), 4.80 (s, 1H, -C-H),
2
.57 (t, 4H, 2ꢀ -CH-H, J ¼ 5.4 Hz), 1.66–1.55 (m, 4H, 2ꢀ -CH-H), 1.52–
1
.44 (m, 2H, -CH-H); C NMR (75 MHz, CDCl ) d, ppm, 138.6, 131.9,
3
1
3
1
28.7, 128.4, 128.2 (two signals overlap), 127.6, 123.5, 88.1, 86.1, 62.5,
2
1
0.8, 26.3, 24.6; IR (neat) vmax, cm , 3060, 2933, 2853, 2805, 1598, 1490,
5
þ
1
found: 275.1679.
451, 1095, 755, 692; HRMS (EI) calcd. for C H N (M ): 275.1674;
2
0 21
ACKNOWLEDGMENT
The authors are grateful to National Nature Science Foundation of China (Nos.
0472078 and 30572234) for their support.
2
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