Synthesis of propargylamines by three-component coupling of aldehydes, amines and alkynes catalyzed by magnetically separable copper ferrite nanoparticles

Article abstract of DOI:10.1055/s-0029-1217362

An efficient three-component coupling of aldehydes, amines and alkynes has been developed to prepare propargylamines in nearly quantitative yields using magnetically separable copper ferrite nanoparticles as catalyst. Structurally divergent aldehydes and

Full text of DOI:10.1055/s-0029-1217362

LETTER
1791
Synthesis of Propargylamines by Three-Component Coupling of Aldehydes,
Amines and Alkynes Catalyzed by Magnetically Separable Copper Ferrite
Nanoparticles
S
ynthesis of Propargyl
.
amines using
L
Copper Ferrite
a
Nanopartic
k
les shmi Kantam,*a Jagjit Yadav,a Soumi Laha,a Shailendra Jhab
a
b
gylamines.6 Carreira and Fischer demonstrated the prepa-
Abstract: An efficient three-component coupling of aldehydes,
amines and alkynes has been developed to prepare propargylamines
in nearly quantitative yields using magnetically separable copper
ferrite nanoparticles as catalyst. Structurally divergent aldehydes
ration of propargylamines by the reaction of aldimines
with trimethylsilyl acetylene by using commercially
available and air-stable [IrCl(Cod)]2.7 Wei and Li reported
and amines were converted into the corresponding propargyl- the A3 coupling reaction through C–H bond activation in
amines. The reaction does not require any co-catalyst.
water using gold, silver and silver in ionic liquids without
using any noble metal co-catalyst.8 Though the yields
Key words: copper ferrite nanoparticles, propargylamines, three-
component coupling, reusability
were good, the scope is generally limited for cyclic
amines in the silver-catalyzed reaction, and inert condi-
tions are invariably used for the gold- and silver-catalyzed
reactions in order to obtain good yields. More recently, Tu
and co-workers developed a microwave (MW) promoted
CuI catalyzed A3 coupling reaction.9 A chiral version of
the A3 coupling reaction for the formation of chiral prop-
argylamines is also reported using copper and gold com-
plexes as chiral catalysts under homogeneous
conditions.10 Recently, we reported the A3 coupling reac-
tion using heterogeneous catalysts such as copper sup-
ported on hydroxyapatite,11 layered double hydroxide
supported gold,12 and zinc dust13 for the preparation of
propargylamines.
Despite the advantages of homogeneous metal catalysts,
difficulties in recovering the catalyst from the reaction
mixture severely inhibits their wide use in industry. Het-
erogeneous catalysis supplies the opportunity for easy
separation and recycling of the catalyst, easy purification
of product and the possibility of continuous or multiple
processing of compounds. Magnetic nanoparticles that
can be magnetized in the presence of an external magnet
have been studied extensively for various biological ap-
plications such as magnetic resonance imaging, drug de-
livery, biomolecular sensors, bioseparation and magneto-
thermal therapy.1 Recent reports show that magnetic
nanoparticles are efficient supports and can facilitate cat-
alyst separation from the reaction medium after magneti-
zation with a permanent magnetic field.2
As part of our ongoing research aimed at the development
of reusable catalysts for various organic transforma-
tions,14 we herein explore the activity of copper ferrite
nanoparticles for the A3 coupling reaction to generate pro-
pargylamines without using any co-catalyst or additive
(Scheme 1).
One-pot multicomponent coupling reactions (MCR)
where several organic moieties are coupled in one step is
an attractive synthetic strategy.3 Three-component cou-
pling of aldehydes, amines and alkynes (A3 coupling) is
one of the best examples of MCR, and has received much
attention in recent times. The resultant propargylamines
obtained by A3 coupling reactions are versatile synthetic
intermediates for biologically active compounds such as
b-lactams, conformationally restricted peptides, isosteres,
natural products and therapeutic drug molecules.4 Tradi-
tionally, propargylamines are prepared by amination of
propargylic halides, propargylic phosphates or propargyl-
ic triflates.5 However, these reagents are used in stoichio-
metric amounts, are highly moisture sensitive and require
strictly controlled reaction conditions. Recently, mild
metal-catalyzed reactions based upon the nucleophilic ad-
dition of metal acetylides generated in situ, to imines and
enamines have been reported for the synthesis of propar-
Scheme 1
Initially, in order to identify and develop the best magnet-
ically separable catalyst for the synthesis of propargyl-
amines by A3 coupling reaction, Fe3O4 and different
substituted ferrites, MFe2O4 (M = Cu2+, Co2+, Ni2+) were
synthesized by co-precipitation methods as described in
the literature15,16 and screened in the presence of benzal-
dehyde, piperidine and phenylacetylene. The results are
summarized in Table 1. It was found that Fe3O4, CoFe2O4
and NiFe2O4 gave lower yields, while CuFe2O4 nanopar-
ticles afforded excellent yields in short periods of time
(Table 1, entries 1, 7, 8 and 9). When the CuFe2O4 nano-
particle-catalyzed A3 coupling reaction was carried out in
SYNLETT 2009, No. 11, pp 1791–1794
Advanced online publication: 12.06.2009
DOI: 10.1055/s-0029-1217362; Art ID: D00609ST
x
x
.x
x
.2
0
0
9
© Georg Thieme Verlag Stuttgart · New York

1792
M. L. Kantam et al.
LETTER
solvents other than toluene, such as anhydrous THF, diox- of the CuFe2O4 nanoparticle-promoted A3 coupling reac-
ane, acetonitrile or 1,2-dichloroethane (DCE), a signifi- tion was illustrated when a variety of structurally diver-
cant decrease in yield was noticed. When water was used gent aldehydes and amines possessing a wide range of
as a solvent, only a trace amount of product was observed functional groups were used.17 As summarized in Table 3,
even after prolonged reaction time. The optimum ratio of both aromatic and aliphatic aldehydes were able to under-
aldehyde, amine and alkyne was found to be 1:1.2:1.3, re- go addition to afford the corresponding propargylic
spectively. The catalytic activity of the CuFe2O4 nanopar- amines effectively. The results in Table 3 indicate that ar-
ticles was evident when no product was obtained in the omatic aldehydes bearing different functional groups such
absence of catalyst. The feasibility of repeated use of as chloro, bromo, or methoxy were able to affect the A3
CuFe2O4 was also examined. In Table 2, results from the coupling. Trace amount of product was obtained when 4-
investigation of CuFe2O4 for three consecutive cycles of nitrobenzaldehyde was used as a substrate, increasing the
the same reaction are presented. After each cycle, nano- reaction time did not increase the yield.
particles were magnetically separated, washed, air-dried
The aliphatic aldehyde (Table 3, entry 8) displayed high
and used directly for the next cycle of reaction without
reactivity and the corresponding propargylamine was ob-
further purification. No significant loss of catalytic activ-
tained in high yields. Heteroaromatic aldehydes such as
ity was observed for CuFe2O4 in the A3 coupling reac-
furfuraldehyde and 3-pyridinecarboxaldehyde reacted
with piperidine and phenylacetylene to afford the corre-
tions.
sponding propargylamines in good yields (Table 3, en-
tries 9 and 10).
Table 1 Three-Component Coupling of Benzaldehyde, Piperidine
and Phenylacetylene with Various Catalysts and Solventsa
Table 3 Three-Component Coupling between Piperidine, Phenyl-
acetylene and Various Aldehydes Catalyzed by CuFe2O4 Nanoparti-
clesa
Entry
Catalyst
CuFe2O4
CuFe2O4
CuFe2O4
CuFe2O4
CuFe2O4
CuFe2O4
Fe3O4
Solvent
toluene
MeCN
THF
Time (h) Yield (%)b
1
2
3
4
5
6
7
8
9
4
6
86
25
Entry Aldehyde
Product
Time Yield
(h) (%)b
10
10
6
tracec
trace
31
dioxane
DCE
CHO
N
1
2
3
4
5
6
4
4
86
88
Ph
H2O
10
4
trace
15
Ph
toluene
toluene
toluene
CHO
NiFe2O4
CoFe2O4
4
trace
trace
N
4
Cl
4-ClC6H4
a Reaction conditions: Benzaldehyde (1 mmol), piperidine (1.2
mmol), phenylacetylene (1.3 mmol), solvent (4 mL), CuFe2O4 nano-
particles (15 mg, 6.5 mol%), 80 °C, N2 atmosphere.
b Isolated yield.
Ph
CHO
N
12 trace
c Reflux temperature.
O2N
4-O2NC6H4
4-MeOC6H4
4-NCC6H4
Ph
Table 2 Recycling of the Catalytic System for the Three-Compo-
nent Coupling of Benzaldehyde, Piperidine and Phenylacetylenea
CHO
Run
1
Catalyst recovery (%)
Isolated yield (%)
N
15 85
–
86
81
78
MeO
NC
Br
Ph
2
93
91
3
CHO
N
7
5
90
84
a Reaction conditions: Benzaldehyde (1 mmol), piperidine (1.2
mmol), phenylacetylene (1.3 mmol), toluene (4 mL), CuFe2O4 nano-
particles (15 mg, 6.5 mol% of copper), 80 °C, 4 h, N2 atmosphere.
Ph
Atomic absorption spectroscopy (AAS) was employed to
determine the copper content of CuFe2O4 nanoparticles,
and it was found to be 27.32%. The leaching of the metal
after the first cycle was determined by AAS and was
found to be negligible (0.258%). The general applicability
CHO
N
4-BrC6H4
Ph
Synlett 2009, No. 11, 1791–1794 © Thieme Stuttgart · New York

LETTER
Synthesis of Propargylamines using Copper Ferrite Nanoparticles
1793
Table 3 Three-Component Coupling between Piperidine, Phenyl-
acetylene and Various Aldehydes Catalyzed by CuFe2O4 Nanoparti-
clesa (continued)
Table 4 Three-Component Coupling between Benzaldehyde and
Various Amines and Alkynes Catalyzed by CuFe2O4 Nanoparticlesa
Entry Amine
Product
Time Yield
(h) (%)b
Entry Aldehyde
Product
Time Yield
(h) (%)b
O
O
CHO
1
4
85
N
N
7
8
9
15 89
N
H
Ph
OMe
2-MeOC6H4
Ph
Ph
Ph
N
2
4
7
81
71
CHO
N
N
H
5
5
91
81
Ph
Ph
Ph
Ph
N
Ph
( )
3
Ph
N
Ph
H
N
Ph
CHO
CHO
( )3
Ph
( )
O
O
3
N
( )3
4
5
12 87
15 65
N
H
3
Ph
Ph
Ph
Ph
N
N
10
5
83
Ph
N
Ph
Ph
H
N
Ph
Ph
N
a Reaction conditions as exemplified in the typical experimental pro-
cedure.17
N
6
7
8
8
75
71
b Isolated yield.
Ph
N
H
Different amine substrates, such as morpholine, pyrroli-
dine and dibutylamine gave very good yields of the cou-
pling products in the A3 coupling reaction of
benzaldehyde and phenylacetelene (Table 4, entries 1, 2
and 4). On the other hand, aromatic amines, such as diben-
zylamine or phenylbenzylamine gave moderate yields of
the product (Table 4, entries 3 and 5). There was not much
difference in the yield when the aryl group of the phenyl-
acetylene was substituted with a 4-methoxy or 4-methyl
group (Table 4, entries 6 and 7).
OMe
N
Ph
N
H
a Reaction conditions as exemplified in the typical experimental pro-
cedure.17,
b Isolated yield.
Figure 1 shows two TEM images of the CuFe2O4 catalyst
before and after use. It can be observed that the synthe-
sized particles are spherical, about 10–12 nm in size, and
that the morphology and size of the particles do not
change considerably even after recycling.
It is assumed that the A3 coupling reaction proceeds by
terminal alkyne C–H bond activation by the CuFe2O4
nanoparticles.8 The copper acetylide intermediate thus
generated will react with the iminium ion prepared in situ
from the aldehyde and the amine and form the corre-
sponding propargylamine, water and CuFe2O4 nanoparti-
cles. Thus, the regenerated CuFe2O4 nanoparticles
participate further in the reaction and complete the cata-
lytic cycle.
Figure 1 TEM figures of copper-ferrite nanoparticles: (a) before
use, (b) after use
Synlett 2009, No. 11, 1791–1794 © Thieme Stuttgart · New York

1794
M. L. Kantam et al.
LETTER
(10) (a) Li, Z.; Li, C. J. Org. Lett. 2004, 6, 4997. (b) Lo, K.-Y.
V.; Liu, Y.; Wong, M.-K.; Che, C.-M. Org. Lett. 2006, 8,
1529. (c) Fernandez, E.; Maeda, K.; Hooper, M. W.; Brown,
J. M. Chem. Eur. J. 2000, 6, 1840. (d) Gommermann, N.;
Knochel, P. Chem. Commun. 2005, 4175. (e) Bisai, A.;
Singh, V. K. Org. Lett. 2006, 8, 2405.
In summary, an efficient CuFe2O4 nanoparticle-catalyzed
three-component coupling of aldehydes, amines and
alkynes has been achieved in toluene. Both aliphatic as
well as aromatic aldehydes and amines can be used. The
catalyst is magnetically separated and reused for several
cycles with only a slight decrease in activity.
(11) Choudary, B. M.; Sridhar, C.; Kantam, M. L.; Sreedhar, B.
Tetrahedron Lett. 2004, 45, 7319.
(12) Kantam, M. L.; Prakash, B. V.; Reddy, C. R. V.; Sreedhar,
Acknowledgment
B. Synlett 2005, 15, 2329.
(13) Kantam, M. L.; Balasubrahmanyam, V.; Kumar, K. B. S.;
Venkanna, G. T. Tetrahedron Lett. 2007, 48, 7332.
(14) (a) Choudary, B. M.; Kantam, M. L.; Ranganath, K. V. S.;
Mahender, K.; Sreedhar, B. J. Am. Chem. Soc. 2004, 126,
3396. (b) Choudary, B. M.; Ranganath, K. V. S.; Pal, U.;
Kantam, M. L.; Sreedhar, B. J. Am. Chem. Soc. 2005, 127,
13167. (c) Choudary, B. M.; Ranganath, K. V. S.; Yadav, J.;
Kantam, M. L. Tetrahedron Lett. 2005, 46, 1369.
J.Y. and S.L. thank CSIR, New Delhi for the award of research fel-
lowships.
References and Notes
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(16) Typical procedure for the preparation of CuFe2O4
nanoparticles: CuFe2O4 nanoparticles were prepared by a
soft chemical method – co-precipitation of Fe2+ and Cu2+
cations in strong alkaline media at room temperature.15a
Dilute water solutions of FeCl2·4H2O and CuCl2·2H2O
mixed in the ratio 2:1 with intensive stirring were used for
that purpose. In a water solution, the chlorides of these
elements exist in a complex form. When a concentrated
solution of NaOH with pH 13 is added, the complexes turn
into hydroxides and a black precipitate of CuFe2O4 is
produced. After decanting, the precipitate is rinsed with
distilled water until pH 7 and then dried.
(17) Typical procedure for A3 coupling reaction: A mixture of
benzaldehyde (1 mmol), piperidine (1.2 mmol), phenyl-
acetylene (1.3 mmol) and CuFe2O4 nanoparticles (15 mg, 6.5
mol% of copper) in toluene (4 mL) was stirred in a round-
bottomed flask at 80 °C under N2 atmosphere. After
completion of the reaction, which was monitored by TLC,
the reaction mixture was magnetically concentrated with the
aid of a magnet to separate the catalyst and the catalyst was
washed several times with Et2O. The reaction mixture was
concentrated under reduced pressure to afford the crude
product which, after chromatography on silica gel, gave the
corresponding propargylamine, N-(1,3-diphenyl-2-propyn-
yl)piperidine.1H NMR (200 MHz, CDCl3): d = 7.64–7.56
(m, 2 H), 7.50–7.42 (m, 2 H), 7.36–7.18 (m, 6 H), 4.76 (s,
1 H), 2.55–2.52 (m, 4 H), 1.63–1.54 (m, 4 H), 1.51–1.42 (m,
2 H). ESI MS: m/z = 276 (M + H)+.
Synlett 2009, No. 11, 1791–1794 © Thieme Stuttgart · New York