Ligand-free reusable nano copper oxide-catalyzed synthesis of 3-amino-1,4-diynes

Article abstract of DOI:10.1039/c5ra18350b

The synthesis of 3-amino-1,4-diynes has been developed by the two-component coupling of N,N-dimethyl formamide dimethyl acetal with terminal alkynes using CuO nanoparticles as an efficient catalyst under mild reaction conditions in ambient air. The procedure is applicable to aryl, alkyl, alkenyl, and heteroaryl alkynes. The CuO nanoparticles are easily recyclable without the loss of significant catalytic activity.

Full text of DOI:10.1039/c5ra18350b

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Ligand-free reusable nano copper oxide-catalyzed synthesis of 3-
amino-1,4-diynes†
Subhajit Mishra,a Sougata Santrab and Alakananda Hajraa*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Synthesis of 3-amino-1,4-diynes have been developed by the two- synthesize 3-amino-1,4-diynes.7 But, the reaction is promoted
component coupling of N,N-dimethyl formamide dimethyl acetal by expensive phosphine ligand and molecular sieves in
with terminal alkynes using CuO nano particle as an efficient nitrogen atmosphere. Despite the advantages of
catalyst under mild reaction conditions in ambient air. The homogeneous metal catalyst, difficulties in recovering and
procedure is applicable to aryl, alkyl, alkenyl, heteroaryl alkynes. recycling severely obstruct its wide use in industry. So finding
The CuO nanoparticles are easily recyclable without the loss of an alternative general and efficient method is always in
significant catalytic activity.
demand.
A tremendous growth in the field of nanoscience and
Propargylamines are synthetically versatile intermediates for
the preparation of various biologically active molecules.1 They
also act as the key intermediate for the construction of
nanotechnology has been observed in the last decade. Metal
nanoparticles have attracted considerable interest in synthetic
organic chemistry due to their high catalytic activity,
reusability and also the benign character in the context of
green chemistry.8 In general, nanoparticles are more effective
compared to the bulk material due to having their high
surface-to-volume ratios which can provide better dispersion
of the active sites and therefore increasing their catalytic
activity.8j In addition, nanoparticles have high zeta potential
which suppress the aggregation of nanoclusters8k and also
show greater activities which avoid the use of ligands.8l These
features of the nano-materials, specially the salts of copper
have been successfully utilized for various organic
transformations.9
isosteres,
β-lactams,
oxotremorine
substrates,
conformationally restricted peptides, and therapeutic drug
molecules.2 This important structural unit is generally used in
organic synthesis as the versatile building blocks for the
synthesis of nitrogen-containing heterocyclic compounds such
as pyrrolidines, pyrroles, aminoindolizines etc.3
Due to the immense biological activities, as well as
remarkable utility in organic synthesis, synthesis of these
scaffolds is a demanding task. Over the past few decades they
have been synthesized mainly by nucleophilic attack of metal
acetylides to imines4 or by using transition metal catalysts.5
However, the efficient methods for the synthesis of 3-amino-
1,4-diynes are very limited.4 Regardless of their efficiency and
reliability, those methods have a major limitation of using
stoichiometric amount of metal in their reactions. The direct
catalytic coupling using terminal alkynes for alkynylation would
be more preferable because it eliminates the need for the
stoichiometric preparation of alkyne anions. But the direct
couplings of terminal alkynes with acetals have been rarely
studied.6 In 2010, Zhang et al. developed a copper-catalyzed
efficient method for the cross-coupling of the C-OMe bond
Very recently, we have developed an environmentally
benign nano-CuO catalyzed “on-water” strategy for the one-
pot synthesis of isoindolo[2,1-a]quinazolines.10a Moreover, we
found that nano In2O3 is an effective catalyst for the synthesis
of propargylamines by the three component coupling of
alkyne, dichloromethane, and amines.10b These results
motivated us to use of nanoparticles as catalyst in organic
transformations. In continuation of our efforts in the field of
nanocatalysis in organic synthesis,10 herein, we are pleased to
report a simple and convenient approach to synthesize 3-
amino-1,4-diynes via a two-component coupling of N,N-
dimethyl formamide dimethyl acetal with various terminal
alkynes using copper oxide nanoparticles as catalyst in 1,2-DCE
under reflux without using any ligand (Scheme 1).‡
adjacent to
a nitrogen atom with terminal alkynes to
aDepartment of Chemistry, Visva-Bharati (A Central University), Santiniketan
731235, India. Email: alakananda.hajra@visva-bharati.ac.in
bUral Federal University, Chemical Engineering Institute, Yekaterinburg, 620002,
Russian Federation.
† Electronic Supplementary Information (ESI) available: Experimental details and
NMR spectra for all compounds, See DOI: 10.1039/x0xx00000x
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Journal Name
Entry Catalyst (mol%)
Solvent (3 mL)
1,2-DCE
1,2-DCE
1,2-DCE
MeCN
Temp. (°C)
reflux
reflux
reflux
reflux
reflux
reflux
90
Yieldb (%)
1
CuO nano (5)
CuO nano (10)
CuO nano (2)
CuO nano (10)
CuO nano (10)
CuO nano (10)
CuO nano (10)
CuO nano (10)
CuO nano (10)
CuO nano (10)
In2O3 nano (10)
ZnO nano (10)
NiO nano (10)
CuBr (10)
68
87
52
-
2
3
4
5
THF
25
-
Scheme 1 CuO nanoparticles-catalyzed synthesis of 3-amino-1,4-diynes.
6
EtOH
7
PEG-400
DMF
-
8
90
-
We started our study by choosing N,N-dimethyl formamide
9
DMSO
90
-
dimethyl acetal (1) and phenylacetylene (2a) as the model
10
11
12
13
14
15
16
17
Toluene
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
90
20
20
15
12
38
<10
<10
-
substrates for this two component reaction using 5 mol% CuO
nano as the catalyst in 1,2-dichloroethane (1,2-DCE) under
reflux for 10 h. To our delight, the desired product 3a was
obtained in 68% yield (entry 1, Table 1). Inspired by this result,
we carried out the reaction employing CuO nano as a catalyst
in different solvent media and the results are summarized in
Table 1. 1,2-DCE appeared to be the best choice among the
common solvents like MeCN, THF, EtOH, PEG-400, DMF,
DMSO, toluene (entries 4-10, Table 1). Increasing the amount
of catalyst (10 mol%) improved the yield to 87%, (entry 2,
Table 1) whereas decreasing the amount of catalyst (2 mol%)
decreased the yield (entry 3, Table 1). Then various metal nano
catalysts such as In2O3, NiO, ZnO were also screened (entry 11-
13, Table 1); nano CuO was found to be the most effective one
among these nano catalysts. Moreover, CuBr, CuO powder and
Cu2O powder were also tested but they were not so effective
like CuO nano (entry 14-16, Table 1). In absence of the
catalyst, no formation of the desired product was observed
(entry 17, Table 1). Finally, optimized reaction conditions were
reflux
reflux
reflux
reflux
reflux
reflux
reflux
CuO powder (10)
Cu2O powder (10)
-
aReaction conditions: 0.5 mmol of 1 and 1.5 mmol of 2a in presence of catalyst in
solvent (3 mL) under heating in air for 10 h; bIsolated yields.
Under the optimized reaction conditions, the scope and
limitations of the present protocol were investigated with a
variety of terminal alkynes, which are summarized in Table 2.
Various phenylacetylenes containing different substituents on
phenyl moiety such as –Me (3b, 3c), –OMe (3d, 3e), -Br (3f) –F
(
3g), led to the corresponding products in good to excellent
yields. Ortho substituted phenylacetylene (3d) furnished the
desired product in good yield. Heteroaryl alkyne like 3-ethynyl
thiophene was well tolerated under the present reaction
conditions without forming any polymerization (3i). Moreover,
aliphatic alkyne such as 1-octyne gave the corresponding N,N-
achieved using N,N-dimethyl formamide dimethyl acetal (1, 0.5
mmol) and phenylacetylene (2a, 1.5 mmol) in presence of 10
mol% of CuO nano in 3 mL of 1,2-DCE solvent under reflux for
10 h (entry 2, Table 1) in ambient air.
dimethyl-1,5-diphenylpenta-1,4-diyn-3-amine
(
3j)
with
excellent yield which also proves the general applicability of
this present protocol. Alkenyl phenylacetylene such as 1-
ethynylcyclohex-1-ene also reacted effectively under the
present optimized conditions (3k). Interestingly, It is notable
that ethynylcyclopropane also reacted successfully under the
present reaction conditions (3l). 1-Phenyl-1-propyne smoothly
participated in this reaction with 90% yield (3m). We are
pleased to find that the present protocol is also effective for
the synthesis of unsymmetrical 3-amino-1,4-diynes (3n and
3o). However, methyl propiolate did not give the desired 3-
amino-1,4-diyne under the present reaction conditions (3p).
The presence of electron-withdrawing groups such as 3-nitro
and 3-cyano phenylacetylene were also failed to proceed the
reaction.
Table 1 Optimization of the reaction conditionsa
2 | J. Name., 2012, 00, 1-3
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Table 2 Substrate scopes of the reactiona,b
The morphology of the CuO nano was determined by
HRTEM. A comparative study of HRTEM of the fresh catalyst
and the recovered catalyst after fourth cycles (Fig. 1) shows
that the catalyst does not undergo substantial leaching or
agglomeration during the recycling process.
N
CuO nano (10 mol%)
N
R
+
1,2-DCE
MeO
N
OMe
R
R
Reflux, 10 h
1
2
3
N
N
3c, 90%
3b
, 92%
3a, 87%
N
N
N
O
O
O
O
Br
Br
3d, 88%
3e, 90%
3f
, 82%
N
N
N
F
F
S
S
F
F
Fig. 1 HRTEM images of (a) fresh CuO nanoparticles and (b) CuO nanoparticles after the
3g, 91%
3i, 90%
3h, 85%
fourth cycle.
N
N
N
A plausible mechanism for the formation 3a is exposed in
Scheme 2. Initially, CuO nanoparticles facilitate the elimination
of the methoxy group of N,N-dimethylformamide dimethyl
3j, 85%
3k, 90%
3l, 65%c
acetal (
the iminium type intermediate
. Then the reacts with phenyl acetylene (2a) to produce the
[alkenyl–CuO] cluster . Next the [alkenyl–CuO] cluster
attacks the iminium intermediate to afford the intermediates
and . The intermediate afforded the final product 3a
through the intermediate The CuO nanoparticles
regenerated from the intermediate by the elimination of
1) through the coordination with oxygen atom to give
N
N
N
C
along with the formation of
B
B
D
D
d
d
3m
3n
3o
, 88%
, 90%
, 85%
C
N
G
E
G
H
.
MeOOC
COOMe
E
3p
, 0%
MeOH. Due to the greater surface to volume ratio of the CuO
nanoparticles in compare to the CuO powder (bulk
counterpart), it facilitates the elimination of the acetal part
aReaction conditions: 0.5 mmol of 1 and 1.5 mmol of 2 in presence of 10 mol%
CuO nano in 1,2-DCE (3 mL) under reflux in air for 10 h; bIsolated yields; cReaction
performed in a sealed vessel under refluxing temperature; dReaction conditions:
0.5 mmol of 1, 0.75 mmol of two different alkynes (2) each, 10 mol% CuO nano,
1,2-DCE (3 mL) under reflux in air for 10 h.
from
1 as well as activates the alkyne with greater
effectiveness to form the alkenyl-CuO cluster which
consecutively aid the reaction towards product formation.
Reusability of the catalyst was also studied to make this
protocol more effective. After completion of the reaction,
DCM (10 mL) was added to the reaction mixture. Then the
insoluble CuO nanoparticles were filtered by Teflon membrane
(PTFE, 0.2 mm pore size). The CuO nanoparticles were
thoroughly washed with the DCM, dried and reused for the
next cycle. The catalyst was found to be effective up to fifth
cycle giving a conversion of 82% in the case of 3a (Table 3).
Table 3 Recycling of the CuO nano for synthesizing 3aa
No of cycles
Yieldsb (%)
Time (h)
10
1
2
3
4
5
87
87
85
84
82
10
10
12
12
Scheme 2 Plausible reaction pathway.
Conclusions
aCarried out with 0.5 mmol of 1 and 1.5 mmol of 2a in the presence of 10 mol%
CuO nano in 1,2-DCE (3 mL) under reflux. bIsolated yields.
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by the two-component coupling of N,N-dimethyl formamide
dimethyl acetal with various terminal alkynes. The reactions
proceed smoothly with high yields without additional external
ligand or additive. The catalyst can be reused up to fifth cycle
without the loss of significant catalytic activity. The notable
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various alkynes including heteroaryl and aliphatic, ligand-free
synthesis, operational simplicity, clean reaction, production of
no hazardous waste, open air reaction conditions and high
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nanoparticles will find widespread applications in academic
laboratories as well as in industry.
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Acknowledgements
A. Hajra acknowledges the financial support from CSIR-India
(Grant No. 02(0168)/13/EMR-II). S. Mishra thanks UGC, New
Delhi for his fellowship (SRF).
Notes and references
‡General procedure for the synthesis of 3-amino-1,4-diynes
3
: A
, 70 µL,
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Graphical Abstract
Ligand-free reusable nano copper oxide-catalyzed synthesis of 3-
amino-1,4-diynes
Subhajit Mishra, Sougata Santra and Alakananda Hajra*
Synthesis of 3-amino-1,4-diynes have been developed by the two-component coupling of
N,N-dimethyl formamide dimethyl acetal with terminal alkynes using CuO nano particle as
an efficient catalyst under mild reaction conditions.