Microwave-assisted copper(I) catalyzed A3-coupling reaction: Reactivity, substrate scope and the structural characterization of two coupling products

Article abstract of DOI:10.1016/j.catcom.2017.09.020

The application of highly efficient catalyst [{Cu(μ ? I)₂Cu}(PPh₃)₄] for the synthesis of biologically and pharmaceutically important propargylamine derivatives through microwave assisted A³-coupling reaction is

Full text of DOI:10.1016/j.catcom.2017.09.020

Accepted Manuscript
Microwave-assisted copper(I) catalyzed A3-coupling reaction:
Reactivity, substrate scope and the structural characterization of
two coupling products
Vitthalrao S. Kashid, Maravanji S. Balakrishna
PII:
DOI:
Reference:
S1566-7367(17)30402-8
doi:10.1016/j.catcom.2017.09.020
CATCOM 5202
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Catalysis Communications
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25 July 2017
1 September 2017
21 September 2017
Please cite this article as: Vitthalrao S. Kashid, Maravanji S. Balakrishna , Microwave-
assisted copper(I) catalyzed A3-coupling reaction: Reactivity, substrate scope and the
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ACCEPTED MANUSCRIPT
Microwave-assisted copper(I) catalyzed A3-coupling reaction:
reactivity, substrate scope and the structural characterization of
two coupling products
Vitthalrao S. Kashid, Maravanji S. Balakrishna*
Phosphorus Laboratory, Department of Chemistry, Indian Institute of Technology Bombay,
Mumbai-400 076, India
*Corresponding author. Fax: +91 22 5172 3480, +91 22 2576 7152.
E-mail addresses: krishna@chem.iitb.ac.in, msb_krishna@iitb.ac.in (M.S. Balakrishna).

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ABSTRACT
The application of highly efficient catalyst [{Cu(µI)2Cu}(PPh3)4] for the synthesis of
biologically and pharmaceutically important propargylamine derivatives through microwave
assisted A3-coupling reaction is described. The A3-coupling reaction performed under
microwave conditions with a catalyst loading of 0.1 mol% produced propargylamines in
almost quantitative isolated yields. Most of the reactions were completed within 5 minutes.
Various alkynes, amines and aldehydes were employed to produce propargylamines in
excellent yields.
Keywords: Microwave; Copper(I); A3-Coupling; Catalyst; Propargylamine.

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1. Introduction
The coupling of an alkyne, an aldehyde and an amine to generate propargylic amines by
CH activation of terminal alkyne is popularly known as A3-coupling reaction or three
components reaction (Scheme 1) [1]. Due to the enormous utility of propargylamines in the
synthesis of biologically important molecules such as dibenzoazocines/dibenzoazepines [2],
triazolodiazepines [3], 1,4-diamino-2-butynes [4], furoquinoxalines, β-lactams and
oxotremorine analogues [5], one-pot A3-coupling reaction involving mild reaction conditions
and cheap catalysts is a boost to the pharmaceutical and drug industries [6]. In this context,
A3-coupling reactions have been studied by several groups employing various metal catalysts,
including calcium [7], magnesium [8], ruthenium [9], rhodium [10], iron [11], cobalt [12],
nickel [13], zinc [14], iridium [15], indium [5], copper [16, 17], silver [18, 19] and gold [20]
under thermal as well as microwave assisted conditions (Table 1). Further, nanoparticles of
coinage metals [21, 22], solid surface support [23], ionic liquids [24] and doping [25]
methodologies have also been used in these reactions. Though, A3-coupling reaction has been
extensively studied, the reports on microwave assisted reactions are scarce [1-4, 26, 27]. In
this paper we report A3-coupling reaction carried out under microwave condition catalyzed
by simple and cheaper copper(I) catalyst, [{Cu(µI)2Cu}(PPh3)4] in very low concentration.
The catalyst showed excellent conversion (upto 100%) within five minutes and the isolated
yields of the products were also quantitative.
(R= H/alkyl/aryl/hetero atom substituted; R’= H/alkyl/aryl; R”= H/alkyl/aryl)
Scheme 1. General scheme of A3-coupling reaction.
Table 1 Some reported catalysts and the A3-coupling reaction conditions
Sr.
No.
Catalyst used
Types of
reaction
Duration of
reaction
References

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1.
2.
3.
[{Rh(µ-Cl)(H)2(IPr)}2]
AuBr3
Thermal
Thermal
Thermal
5-96 h
20 h
2-6 h
[10]
[28]
[29]
[AuI(L1)]SbF6
4.
5.
6.
7.
8.
9.
PANF-NHC-Ag Complex
Silver(I)–XPhos Complexes
Au-NPs
Thermal
Thermal
12 h
0.1-24 h
[30]
[19]
[31]
[32]
[33]
[2, 4]
[4]
Thermal
variable time
variable time
variable time
25 min
Ag-NPs
Thermal
Fe-NPs
Thermal
CuBr (20 mol%)
Microwave
Microwave
Microwave
10. CuI (30 mol%)
30 min
11. GO-CuCl2 (20 mol%)
20 min
[27]
2. Results and discussion
Previously, several groups have reported A3-coupling reaction using precious metals
such as rhodium, gold, silver, nanoparticles (NPs) of coinage metals and as simple catalysts
as copper(I) halides. Some of these catalysts and reaction conditions are listed in Table 1.
Most of these reactions have been carried out under thermal conditions with temperature
o
ranging from 60-100 C over a period of 12-96 h or using microwave radiations over a period
of 20-30 min. In the present investigation, copper(I) complex, [{Cu(µI)2Cu}(PPh3)4] works
well with aromatic as well as aliphatic alkynes, aldehyde (paraformaldehyde) and secondary
amines. Variables such as solvents, temperature, catalysts and catalyst loading were
optimized by carrying out A3-coupling reaction under microwave power of 80 W as shown in
Scheme 1.
Initially, the reaction of phenylacetylene, para-formaldehyde and N-ethylbenzylamine in
o
1:1.1:1 molar ratio was performed in acetonitrile at 85 C for 30 min using 5 mol% CuX (X
= Cl, Br and I) as catalyst did not show any conversion which may be due to the less
reactivity of CuX aggregates which remain intact in the absence of Lewis bases (Table 2,

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CuI: entry 1, CuBr: entry 2, CuCl: entry 3) [26]. The same reaction when carried out using 5
mol% catalyst [{Cu(µI)2Cu}(PPh3)4] in toluene at 110 oC for 30 min showed 50%
o
o
conversion (Table 2, entry 4), whereas in water at 100 C and in acetonitrile at 85 C, the
conversions were 70% (Table 2, entry 5) and 100% (Table 2, entry 6), respectively. Under
similar reaction condition, 0.1 mol% catalyst also showed the same result (Table 2, entry 7).
However on further decreasing the catalyst loading to 0.01 mol% only 40% conversion
(Table 2, entry 8) was observed. Reaction performed under the above condition without any
catalyst showed no conversion (Table 2, entry 9). The same reaction carried out under
conventional thermal condition showed about 57% conversion within 1 h and it took nearly 6
h for the complete conversion (Table 2 entry 10). Thus, based on the above trials, the best
optimized conditions for A3-coupling reaction depicted in entry 7 was adopted (i.e. 0.1 mol%
[{Cu(µI)2Cu}(PPh3)4], time: 5 min. and temperature: 85 oC).
Table 2 Optimization of coupling reaction conditionsa
Entry
Catalyst
Solvent
Temp.
oC
85
Time
Conv.
(%)b
00
Yield
(%)c
00
1
2
3
4
5
CuI
CuBr
CH3CN
CH3CN
CH3CN
Toluene
H2O
30 min
30 min
30 min
30 min
30 min
85
85
00
00
50
70
00
00
50
70
CuCl
110
100
[{Cu(µI)2Cu}(PPh3)4]
[{Cu(µI)2Cu}(PPh3)4]
6
7d
8e
9
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
85
85
85
85
85
30 min
5 min
5 min
30 min
6 h
100
100
40
100
100
40
[{Cu(µI)2Cu}(PPh3)4]
[{Cu(µI)2Cu}(PPh3)4]
[{Cu(µI)2Cu}(PPh3)4]
No catalyst
00
00
10f
100
--
[{Cu(µI)2Cu}(PPh3)4]
aReaction conditions: alkyne (1 equivalent), paraformaldehyde (1.1 equivalent), 2o amines (1
equivalent), catalyst (5 mol %), solvents (2 mL); in a microwave vessel (10 mL) power (80
W); bConversion was determined by GC and GC-MS. cIsolated yields after column

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chromatography, dCatalyst loading upto 0.1 mol%, eCatalyst loading upto 0.01 mol%.
fReaction was performed under thermal condition
In order to investigate the generality of the optimized reaction conditions, different types
of substrates such as secondary amines (N-ethylbenzylamine, morpholine, diisopropylamine,
piperazine, N-methylpiperazine, diphenylamine) with different types of substituted acetylenes
(phenylacetylene, 1-Pentyne and trimethylsilylacetylene (ethynyltrimethylsilane)) were
reacted with aldehyde (Table 3, Entry 1-19); excellent conversions were observed with very
good isolated yields of the products (Table 3). The substrate scope is wide for amines and
alkynes but in the case of aldehydes no product was formed with benzaldehyde (Table 3,
Entry 12). However, on increasing the catalyst loading from 0.1 to 10 mol%, reaction of
PhC≡CH, PhCHO and N-ethyl,benzyl amine showed 22% conversion, whereas the same
reaction with morpholine and diethylamine showed quantitative conversions (Table 3, entry
12). In order to examine the durability of the catalyst, the same catalyst was used in five
successive catalytic cycles and no change in the catalytic efficiency was observed. Only in
the 6th and 7th the cycles, the conversions were reduced by only 5-7%.
The overall conversion was in the range of 72-100% with good isolated yields and all the
1
products have been characterized by H NMR, 13C{1H} NMR, mass spectrometry and
molecular structures of two of the products have been confirmed by single crystal X-ray
analysis.
Table 3 A3-coupling reaction of terminal alkynes with secondary amines and aldehydes
(para-formaldehyde and benzaldehyde)a
Entry Alkyne
Amine
Product
Code Con. Yieldb
(%)
%

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1
A3-1
A3-2
100
100
97
95
2
3
A3-3
100
98
4
A3-4
A3-5
100
100
96
99
5d
6
7
8
A3-6
A3-7
A3-8
100
100
100
97
92
98
9 d,f
10
A3-9
100
98
96
HN
NH
A3-10 100
11
A3-11 100
A3-12 22
91
-
A3-
12A
100
100
-
-
12 c
A3-
12B

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13 d,f
14f
A3-13 100
A3-14 100
98
99
15f
16
17
18
A3-15 100
A3-16 100
A3-17 100
A3-18 100
96
93
94
97
(CH3)3Si C CH
19 d,f
Insoluble polymer
A3-19 80
72
[a] optimized conditions; [b] Isolated yields of product; [c] C6H5CHO (1.1 equiv),
conversions are based on GCMS; [d] alkyne, formaldehyde and piperazine, in 1:1.1:0.5 molar
ratio; [f] new compounds.
2.1 Possible catalytic cycle for A3-coupling reaction
The catalytic cycle (Fig. 1) shows a plausible mechanism for A3-coupling reaction. Firstly
an amine and an aldehyde form imine by condensation, and alkyne and copper(I) form an
alkenylcopper complex. The mixture of these two compounds is termed as A. Intermediate A
shows concerted mechanism of nucleophilic alkyne attack on activated imine carbon to form
a CC bond resulting in the intermediate B. Finally decomplexation results in the formation
of propargylamine (C) and the regeneration of copper(I) catalyst as suggested by Van der
Eycken [1].

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Microwave
Fig. 1. Proposed catalytic cycle for microwave assisted [{Cu(µI)2Cu}(PPh3)4] catalyzed A3-
coupling reaction.
2.2 Molecular structures of A3-5 and A3-13 (deprotected)
The molecular structures of products A3-5 and A3-13 (deprotected) are confirmed by
single crystal X-ray analyses. The slow diffusion of petroleum ether into the saturated
solution of A3-5 and A3-13 (deprotected) in ethyl acetate yielded colourless crystals suitable
for single crystal X-ray analysis. The centrosymmetrically substituted piperazine compound
adopts chair conformation and both the acetylene and the substituted acetylene arms are trans
to each other. The average NC bond distances of CH2N in both the structures are 1.463(2)
Å. The average NCC bond angle in piperazine and acetylene molecules is 114.62(14)°.
The bond length and bond angles are shown in Fig. 2.
Fig. 2. Solid state molecular structure of A3-5 and A3-13 (deprotected). All hydrogen atoms
and solvent molecule have been omitted for clarity. Thermal ellipsoids are drawn at the 50%

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probability level. Selected bond distances (Å) and bond angles (deg): (A3-5): N1C9 =
1.462(2) N1C11 = 1.472(2), N1C10 = 1.467(2), C7C8 = 1.203(2), C8C9 = 1.485(2),
C9N1C11 = 111.78(13), C9N1C10 = 111.82(13), C10N1C11 = 109.78(13),
C7C8C9 = 175.77(17). A3-13 (deprotected): N1C5 = 1.466(2), N1C4 = 1.465(2),
N1C3 = 1.464(2), C1C2 = 1.190(3), C2C3 = 1.483(3), C4N1C5 = 109.59(15),
C3N1C5 = 111.85(14), C3N1C4 = 112.31(15), C1C2C3 = 177.49(19).
3. Experimental section
3.1 General Procedure for A3-Coupling Reaction
The reactions were performed in a closed vessel containing a mixture of alkyne (1
equivalent), amine (1.0 equivalent), (CH2O)n (1.1 equivalent), and catalyst (0.1 mol %) in
acetonitrile (2 mL). The microwave irradiation power of 80 W was applied to reach a
temperature of 85 °C. After a specified reaction time, the reaction mixture was filtered and
dried under reduced pressure. The residue was diluted with H2O (8 mL) and Et2O (8 mL), and
twice extracted with Et2O (6 mL) and the combined organic fractions were dried over MgSO4
or Na2SO4 and the solvent was removed under reduced pressure. The crude products were
purified by column chromatography using petroleum ether/ethyl acetate mixture as eluent.
Yields were calculated against alkyne.
3.2 X-ray crystallography
A crystal of each of the compounds in the present work suitable for single crystal X-ray
diffraction studies was mounted in a Cryoloop with a drop of Paratone oil and placed in the
cold nitrogen stream of the kryoflex attachment of the Rigaku Saturn 724+ (4×4 bin mode)
diffractometer (See Supporting Information). Data were collected at different temperatures
(Table S1), using graphite-monochromated MoKα radiation (λα = 0.71073 Å) using the ω-
scan technique. The data were reduced by using Crystal Clear- SMExpert 2.1 b24 software.
Crystal data and summary of data collection for compounds are given in crystallographic data
(Table S1). The structures A3-5 and A3-13 (deprotected) were solved by direct methods and

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refined by least-squares against F2 utilizing the software packages SHELXL-97/2013 [34].
All non-hydrogen atoms were refined anisotropically. Crystallographic data for the structures
reported in this paper have been deposited with the Cambridge Crystallographic Data Centre
as supplementary publication no. CCDC 1560999 (compound A3-5), 1561000 (compound
A3-13- deprotected).
4. Conclusions
In Summary, we have developed a simple and efficient method for A3-coupling or three
component reaction using copper(I) complex, [{Cu(µI)2Cu}(PPh3)4] under microwave
irradiation conditions. The utility of cheap triphenylphosphine-copper complex and its easy
synthetic method and low catalyst loading (0.1 mol%) has broadened the scope of A3-
coupling reactions. Despite low catalyst loading, the same catalyst remained efficient even
after 5 cycles and only in the 6 and 7th cycles the catalytic efficiency was reduced by a
margin of 6-7%. Further, this method works smoothly for both aromatic and aliphatic
alkynes, and both cyclic and acyclic secondary amines. Five novel products have been
isolated and some of them can serve as valuable synthons for the synthesis of new types of
ligands and click-products with rich coordination chemistry. Further studies into applications
of this methodology is in progress.
Acknowledgments
We are grateful to the Science & Engineering Research Board, New Delhi, India, for
financial support of this work through grant No.SB/S1/IC-08/2014. VSK (JRF/SRF) thanks
UGC, New Delhi, research fellowships and IRCC, IIT Bombay for financial support. We also
thank the Department of Chemistry Instrumentation Facilities, IIT Bombay, for spectral,
analytical data and single crystal X-ray diffraction facilities.
Appendix A. Supplementary data

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Supplementary
data
to
this
article
can
be
found
online
at
https://www.journals.elsevier.com/catalysis-communications
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Graphical abstract
Microwave-assisted copper(I) catalyzed A3-coupling reaction: reactivity,
substrate scope and the structural characterization of two coupling
products
A3-coupling reaction of an alkyne, aldehyde and amine carried out under microwave
o
condition (85 C and 80 W) catalyzed by 0.1 mol% [{Cu(µI)2Cu}(PPh3)4] in 5 min. is
described.

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Research highlights





Simple and easy to prepare catalyst: [{Cu(µI)2Cu}(PPh3)4]
Low cost and a very low catalyst loading (o.1 mol%)
Lesser reaction time (5 minutes) as compare to traditional thermal conditions
Scope for substrates of various alkynes and secondary amines
Excellent conversion and isolated yields of all products