Study on the A3-coupling reaction catalyzed by readily available copper-containing minerals. Synthesis of propargylamines

Article abstract of DOI:10.1016/j.tetlet.2019.151544

The highly atom efficient three-component reaction of aldehydes, secondary amines and acetylenes to form propargylamines (A³-coupling) has been studied with twelve readily available copper-containing minerals. It was found that the reaction could easily be performed in the presence of malachite, brochantite, chrysocolla and azurite in toluene at reflux. The desired products were obtained in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2019.151544

Journal Pre-proofs
Study on the A3-coupling reaction catalyzed by readily available copper-con-
taining minerals. Synthesis of propargylamines
Mátyás Milen, Gábor Györke, András Dancsó, Balázs Volk
PII:
S0040-4039(19)31343-7
DOI:
https://doi.org/10.1016/j.tetlet.2019.151544
TETL 151544
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
7 November 2019
12 December 2019
17 December 2019
Please cite this article as: Milen, M., Györke, G., Dancsó, A., Volk, B., Study on the A3-coupling reaction catalyzed
by readily available copper-containing minerals. Synthesis of propargylamines, Tetrahedron Letters (2019), doi:
https://doi.org/10.1016/j.tetlet.2019.151544
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Study on the A3-coupling reaction catalyzed by readily available copper-containing
minerals. Synthesis of propargylamines
Mátyás Milen*, Gábor Györke, András Dancsó and Balázs Volk
Egis Pharmaceuticals Plc., Directorate of Drug Substance Development, P. O. Box 100, H-1475
Budapest, Hungary.
GRAPHICAL ABSTRACT
ABSTRACT
The highly atom efficient three-component reaction of aldehydes, secondary amines and acetylenes to
form propargylamines (A3-coupling) has been studied with twelve readily available copper-containing
minerals. It was found that the reaction could easily be performed in the presence of malachite,
brochantite, chrysocolla and azurite in toluene at reflux. The desired products were obtained in good to
excellent yields.
KEYWORDS
Copper-containing minerals, Catalysis, A3-coupling, Multicomponent reaction

Introduction
Propargylamines are valuable intermediates and have found broad applications in organic synthesis for
the construction of various nitrogen-containing heterocycles [1,2]. Moreover, the propargylamine
moiety can be found in commercially available drugs: rasagiline and deprenyl are irreversible inhibitors
of the monoamine oxidase-B (MAO-B) enzyme and are used for the treatment of Parkinson's disease
and Alzheimer's disease [3‒6], while racemic oxybutynin is a muscarine receptor antagonist drug which
was developed for the treatment of overactive bladder [7,8] (Fig. 1). Therefore, the synthesis of this type
of compounds has attracted considerable attention.
Figure 1. Marketed drugs containing a propargylamine structural unit.
The classical method for the assembly of propargylamines is based on the nucleophilic addition of a
metal acetylide, formed by the reaction of the corresponding acetylene derivative with an
organometallic reagent, to an imine. The disadvantages of this traditional process are the use of an
equimolar amount of an expensive and moisture-sensitive organometallic reagent [9‒11]. About two
decades ago, Li and Wei described an efficient CuBr-RuCl3-catalyzed reaction of an aldehyde, an amine
and an alkyne (also known as A3-coupling) for the preparation of propargylamines (Scheme 1), where
the transition metal catalyst was only applied in a catalytic amount (30 mol% CuBr and 3 mol% RuCl3)
[12]. Subsequently, several modifications of this three-component reaction have been developed [1]. In
general, the A3-coupling is catalyzed by salts and complexes of transition metals, such as copper, silver,
gold, iron, indium, iridium, mercury, manganese, nickel, cobalt, zirconium, bismuth and rhenium
[13‒15]. Among these, copper-catalyzed A3-coupling reactions have been the most investigated, with
catalysts ranging from Cu(0) nanoparticles [16], and simple Cu(I) or Cu(II) halogenides to special
copper-containing complexes [17].
Scheme 1. Transition metal-catalyzed A3-coupling protocol.

Naturally occurring clays or their modified forms are widely used to catalyse various types of organic
reactions [18,19]. Both elemental copper and synthetic copper salts have long been known as catalysts
in a number of organic transformations, for example C‒H bond functionalizations [20,21], aerobic
oxidations of organic molecules [22], azide‒alkyne 1,3-dipolar cycloadditions [23] and cross-coupling
reactions [24‒26]. Yu and co-workers reported [3+3] cycloadditions of C,N-cyclic azomethine imines
catalyzed by basic copper carbonate [Cu2CO3(OH)2]; however, the origin of the latter was not disclosed
by the authors [27]. It is also noteworthy that calcination of naturally occurring copper-containing
minerals (malachite, rosasite, aurichalcite) can be applied for the manufacturing of synthetic copper-
containing catalysts, notably silica-nanosphere-embedded copper oxide and graphene oxide-supported
copper oxide [28‒33]. Nevertheless, to the best of our knowledge, the catalytic role of naturally
occurring copper ores has not been studied in organic synthesis.
Herein, we report an A3-coupling reaction catalyzed by readily available copper-containing minerals.
The direct use of minerals in their native form makes their transformation into synthetic copper
compounds unnecessary, thereby rendering this approach environmentally friendly.
Results and Discussion
Based on literature data [34,35], the first experiments were conducted in toluene at reflux using
benzaldehyde (1a, 2.0 mmol), morpholine (2a, 2.0 mmol, 1.0 eq) and phenylacetylene (3a, 2.4 mmol,
1.2 eq, Table 1). The reaction time was 2.5 h and the amount of various powdered copper-containing
minerals used was 40 mg (ca. 4.1–25 mol%, depending on the catalyst). Sulfide minerals were found to
be ineffective in this A3-coupling reaction (Table 1, entries 1‒5). Among copper silicates, the catalytic
effect of dioptase and chrysocolla was studied. With dioptase, product 4a was isolated in 72% yield
(Entry 6). In the case of chrysocolla, an even higher yield (86%) was observed (Entry 7). The outcome
of the reaction was practically identical when brochantite, a copper sulfate-type mineral was used (Entry
8). Next, the activity of copper carbonate minerals, including aurichalcite, rosasite, malachite and
azurite was investigated (Entries 9–12). Whereas aurichalcite (Entry 9) and rosasite (Entry 10)
proceeded in an unsatisfactory manner, malachite and azurite were found to be equally efficient when
compared with brochantite and chrysocolla (Entries 11, 12). Malachite is one of the most important,
inexpensive and abundant copper ores, therefore further optimization of the model reaction was
performed with this mineral.

Table 1. Optimization of the reaction conditions.a
Entry
1
Copper-containing mineral
covellit (CuS)
Quantity of catalyst (mg)
Time (h)
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
5
Yield 4a (%)b
40
40
40
40
40
40
40
40
40
40
40
40
60
20
10
5
0
2
chalcocite (Cu2S)
1
3
chalcopyrite (CuFeS2)
bornite (Cu5FeS4)
0
4
0
5
bournonite (PbCuSbS3)
dioptase (Cu6Si6O18 • 6 H2O)
chrysocolla [(Cu,Al)2H2Si2O5(OH)4 • n H2O]
brochantite [Cu4(SO4)(OH)6]
aurichalcite [(Zn,Cu)5(CO3)2(OH)6]
rosasite [(Cu,Zn)2(CO3)(OH)2]
malachite [Cu2(CO3)(OH)2]
azurite [Cu3(CO3)2(OH)2]
malachite
0
6
72
86
80
22
32
83
80
79
81
80
80
80
93
94
0
7
8
9
10
11
12
13
14
15
16
17
18
19
20
malachite
malachite
malachite
malachite
1
malachite
5
malachite
5
20
-
-
20
a Reagents and conditions: 1a (2.0 mmol), 2a (2.0 mmol), 3a (2.4 mmol), toluene (10 mL), copper-containing mineral, reflux. b Isolated
yield based on benzaldehyde and morpholine.
In addition to toluene, other solvents including acetonitrile, methanol, water, 2-methyltetrahydrofuran
and 2,2,2-trifluoroethanol were examined at reflux for 2.5 h in the presence of 40 mg malachite.
However, in these solvents product 4a could only be detected in trace amounts by HPLC-MS (results
not shown in Table 1). When using solvent-free conditions (110 °C, 2.5 h) in the presence of malachite,
propargylamine 4a was obtained in 63% yield (result not shown in Table 1).
Next, the effect of the amount of catalyst and reaction time was tested. Increasing the amount of
malachite from 40 mg to 60 mg did not afford better results (Table 1, entry 13). When reducing the
amount of malachite gradually to 1 mg, product 4a was still obtained in good yield (Entries 14‒17);

thus, the catalyst was also effective in very small amounts (down to ca. 0.45 mol%, calculated for the
Cu ion). Nevertheless, for practical reasons, 5 mg of malachite was employed in further investigations.
Increasing the reaction time from 2.5 h to 5 h or 20 h led to higher yields (93% and 94%, respectively;
entries 18, 19).
It is also noteworthy that no product (4a) was detected in the control experiment in the absence of
catalyst (Table 1, entry 20). The presumed role of the catalyst is to form a copper acetylide in the first
step that reacts with the iminium ion, leading to the formation of the targeted propargylamine, as
suggested by Van der Eycken and co-workers [1].
Although in our model reaction (with 1a, 2a and 3a) 2.5 hours were sufficient to produce the product
(4a) in good yield, other substrates led to slower conversions, therefore we considered 20 hours as the
optimal reaction time. With the optimized conditions in hand, we explored the substrate scope of this
three-component condensation (Table 2). First, the reaction of benzaldehydes with varied substitution
patterns (1b‒i) with morpholine (2a) and phenylacetylene (3a) was tested. Aldehydes with either
electron-withdrawing or electron-donating groups attached to the benzene ring (1b‒i) were suitable
substrates and provided the corresponding products (4b‒i) in good yields (Table 2, entries 2‒9). The
reaction of bulkier naphthalene-2-carbaldehyde (1j) and 9H-fluorene-2-carbaldehyde (1k) also
proceeded smoothly to afford the desired products (4j and 4k) in 91% and 87% yields, respectively
(Entries 10, 11). The use of heteroaromatic carbaldehydes bearing a thiophenyl, furanyl, thiazolyl or
pyridinyl moiety was also successful to give products 4l‒p (Entries 12‒16). Lower yields were obtained
when 5-fluoro-1-benzothiophene-2-carbaldehyde (1q) and 1-methylpyrrol-2-carboxaldehyde (1r) were
employed (Entries 17, 18). The reaction was also successfully extended to the aliphatic aldehyde
heptanal which gave propargylamine derivative 4s in 88% yield (Entry 19).

Table 2. Study of the substrate scope for the A3-coupling.a
Entry
1
1
a
b
c
R1
Ph
2
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
b
c
R2R3
3
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
b
c
R4
Ph
Yield 4 (%)
94/87b/89c/94d (4a)
84/76e (4b)
91/79e (4c)
85 (4d)
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)4-
2
2-F3CC6H4
3-BrC6H4
4-F3CC6H4
4-NCC6H4
4-i-PrC6H4
4-MeOC6H4
4-PhOC6H4
2,3-diF-C6H3
naphthalen-2-yl
9H-fluoren-2-yl
thiophen-2-yl
thiophen-3-yl
5-methylfuran-2-yl
1,3-thiazol-4-yl
pyridin-3-yl
5-F-benzothiophen-3-yl
1-Me-1H-pyrrol-2-yl
hexyl
Ph
3
Ph
4
d
e
Ph
5
Ph
65 (4e)
6
f
Ph
76 (4f)
7
g
h
i
Ph
83/21e (4g)
92/92d (4h)
81 (4i)
8
Ph
9
Ph
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
j
Ph
91 (4j)
k
l
Ph
87 (4k)
Ph
80 (4l)
m
n
o
p
q
r
Ph
78 (4m)
Ph
85 (4n)
Ph
94 (4o)
Ph
92 (4p)
Ph
51 (4q)
Ph
36 (4r)
s
Ph
88 (4s)
a
a
a
a
a
a
o
a
a
o
a
Ph
4-MeC6H4
4-O2NC6H4
hexyl
octyl
Ph
93 (4t)
Ph
47 (4u)
Ph
d
e
83 (4v)
Ph
77 (4w)
Ph
a
a
a
a
a
a
a
59 (4x)
Ph
-(CH2)5-
Ph
95 (4y)
1,3-thiazol-4-yl
Ph
c
-(CH2)5-
Ph
67 (4z)
d
e
-(CH2)6-
Ph
87 (4aa)
96/88b/92c/98d (4ab)
89 (4ac)
71 (4ad)
Ph
-(CH2)2NMe(CH2)2-
-(CH2)2NMe(CH2)2-
Buf
Ph
1,3-thiazol-4-yl
e
Ph
Ph
f
Ph
a
Reagents and conditions: 1 (2.0 mmol), 2 (2.0 mmol), 3 (2.4 mmol), malachite (5 mg), PhMe (10 mL), reflux, 20 h. b Azurite (5 mg)
c
d
e
f
was used. Brochantite (5 mg) was used. Chrysocolla (5 mg) was used. The reaction time was 5 h. Dibutylamine was used.

Subsequently, the reaction of 4-substituted phenylacetylenes with benzaldehyde (1a) and morpholine
(2a) was investigated. 4-Methylphenylacetylene (3b) showed good reactivity giving product 4t in 93%
yield (Entry 20). However, 4-nitrophenylacetylene (3c) containing a strongly electron-withdrawing
group produced the desired propargylamine (4u) only with a moderate yield of 47% (Entry 21). In
addition, the reaction could be performed with aliphatic acetylenes, oct-1-yne (3d) and dec-1-yne (3e),
giving the desired products 4v and 4w in 83% and 77% yield, respectively (Entries 22, 23).
To further examine the scope of this three-component reaction, several other secondary amines were
tested, in addition to morpholine. Pyrrolidine (2b), piperidine (2c), hexamethyleneimine (2d) and 1-
methylpiperazine (2e) were also well tolerated, and the products (4x‒ac) were obtained in 59‒96% yield
(Entries 24‒29). Dibutylamine (2f), an acyclic secondary amine, was also reacted with benzaldehyde
(1a) and phenylacetylene (3a) to give product 4ad (Entry 30). An attempted extension of the reaction to
aniline as an aromatic amine, with benzaldehyde (1a) and phenylacetylene (3a), led to Schiff-base
formation, but no further reaction with 3a took place under the applied conditions. Among the target
compounds described in Table 2, 4a,c‒g,j,l,m,s‒y,aa,ab,ad are known in the literature (see references in
the ESI), while 4b,h,i,k,n‒r,z,ac are new compounds.
In addition to malachite, the three-component reaction of various substrates was also successfully
performed in the presence of azurite (Entries 1, 28), brochantite (Entries 1, 28) or chrysocolla (Entries 1,
8, 28) under the optimized conditions, and the expected products (4a, 4h, 4ab) were isolated in high
yields.
Besides its green characteristics, low cost and high abundance [36–38], a further advantage of malachite
is its thermal stability. According to our observations, no degradation takes place, and it does not lose its
catalytic activity when heated at reflux in toluene. When malachite was kept at 110 °C for 20 h, and the
reagents (1a, 2a, 3a) were added afterwards, the reaction time and yield of 4a remained practically
unchanged. This is in line with the reported thermogravimetric analysis indicating that malachite only
begins to degrade at a temperature as high as 250 °C with the loss of water [39].
The malachite catalyzed A3-coupling reaction of benzaldehyde (1a), morpholine (2a) and
phenylacetylene (3a) was further optimized. A detailed summary of the experimental results obtained
with an equimolar amount of phenylacetylene, reduced quantity of toluene and malachite, reaction on 20
mmol scale, or distillation instead of chromatography can be found in the ESI.
Attempted filtration and recovery of the catalyst were not successful due to its partial dissolution in the
reaction mixture and to the colloidic character of the solid residue. Nevertheless, the procedure
7

described here remains highly economical thanks to the ready availability of malachite and the
remarkably low amount used.
Conclusion
In summary, the A3 multicomponent reaction of aromatic and aliphatic aldehydes, various secondary
amines and acetylenes was examined in the presence of commercially available copper-containing
minerals in their natural form. The best catalytic effect was obtained with brochantite, malachite, azurite
and chrysocolla. The optimization and extension of this novel and highly economical A3-reaction were
studied in detail with malachite, an inexpensive and naturally abundant mineral. Thus, a number of
propargylamine derivatives were prepared in good yields in a green procedure. Investigation of other
organic reactions catalyzed by copper-containing minerals is currently in progress in our laboratory.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
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9

 Application of copper-containing mineral catalysts in organic synthesis
 A novel strategy in the field of Cu-catalyzed organic reactions
 Efficient synthesis of propargylamines
10