Hydroxyapatite supported copper catalyst for effective three-component coupling

Article abstract of DOI:10.1016/j.tetlet.2004.08.004

The coupling of three-components, namely an aldehyde, an alkyne and an amine to prepare propargylamines was performed using copper exchanged hydroxyapatite (CuHAP) as the catalyst under mild reaction conditions and in the absence of any co-catalyst. A variety of aldehydes and amines were converted to the corresponding propargylamines, demonstrating the versatility of the reaction. CuHAP was recovered quantitatively by simple filtration and reused several times.

Full text of DOI:10.1016/j.tetlet.2004.08.004

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7319–7321
Hydroxyapatite supported copper catalyst for effective
three-component coupling
*
Boyapati M. Choudary, Chidara Sridhar, Mannepalli L. Kantam and Bojja Sreedhar
Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 15 June 2004; revised 20 July 2004; accepted 2 August 2004
Available online 20 August 2004
Abstract—The coupling of three-components, namely an aldehyde, an alkyne and an amine to prepare propargylamines was per-
formed using copper exchanged hydroxyapatite (CuHAP) as the catalyst under mild reaction conditions and in the absence of any
co-catalyst. A variety of aldehydes and amines were converted to the corresponding propargylamines, demonstrating the versatility
of the reaction. CuHAP was recovered quantitatively by simple filtration and reused several times.
Ó 2004 Elsevier Ltd. All rights reserved.
Metal mediated C–C bond formations are among the
1
most important reactions in organic synthesis. Copper
the reaction mixture severely obstructs its wide use in
industry. Thus, development of improved syn-
thetic methods for the preparation of propargylamines
remains an active research area.
is an essential trace element in all living systems. Due
to its redox properties, copper, as a co-factor in many
proteins, catalyzes single electron transfer reactions.
Propargylamines are important synthetic intermediates
for potential therapeutic agents and polyfunctional
Heterogeneous catalysis is particularly attractive as it
allows production and ready separation of large quanti-
ties of products with the use of a small amount of cata-
lyst. Apatites are metal basic phosphates for which the
chemical formula is M (PO ) (OH) [M = divalent
2
amino derivatives. However, the standard practice for
carrying out such reactions involves the amination of
propargylic halides, propargylic phosphates or propar-
1
0
4 6
2
3
gylic triflates. Recently a range of efficient and mild
metal] and the most typical apatite is calcium hydroxy-
apatite Ca (PO ) (OH) (CaHAP). CaHAP attracted
metal-catalyzed reactions based upon the nucleophilic
addition of in situ generated metal acetylides to imines
and enamines have been reported for the synthesis of
1
0
4 6
2
wide attention due to its versatile applications in the
field of bioceramics, chromatographic adsorbents and
acid base catalysis. It has been well established that
4
propargylamines. Wei and Li have reported the highly
efficient three-component coupling reaction through
C–H activation in water using gold, silver and silver in
2
+
the Ca sites of CaHAP can be replaced by divalent
2
+
2+
2+
2+
7
cations such as Sr , Ba , Pb , Cd etc. Kaneda
and co-workers demonstrated the utility of CaHAP as
a solid support for Ru and Pd to perform many organic
transformations that including oxidation of alcohols
5
ionic liquids without using any noble metal co-catalyst.
Nevertheless, the scope is generally limited for cyclic
amines in the case of the silver catalyzed reaction, and
inert conditions are invariably used for the gold and sil-
ver catalyzed reactions in order to obtain good yields.
Very recently Tu and co-workers developed microwave
augmented three-component coupling reactions of wider
scope using CuI as a catalyst, a reaction, which other-
8
and Heck and Diels–Alder reactions.
Herein we designed and developed a method involving
CuHAP for the three-component coupling of aldehydes,
amines and alkynes to generate propargylamines with-
out using any co-catalyst or additive (Scheme 1).
6
wise requires five days under thermal conditions.
Despite these advantages of homogeneous metal cata-
lyst, difficulties in recovering the expensive catalyst from
Calcium hydroxyapatite [Ca (PO ) (OH) ] was synthe-
1
0
4 6
2
9
sized according to the literature procedure. CaHAP
1g) was stirred with aqueous copper acetate (400mg,
(
*
Corresponding author. Tel./fax: +91 402716 09 21; e-mail addresses:
choudary@iict.res.in; bmchoudary@yahoo.com
2mmol in 25mL water) at 80°C for a period of 10h.
The slurry obtained was filtered, washed with deionized
0
040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.004

7320
B. M. Choudary et al. / Tetrahedron Letters 45 (2004) 7319–7321
2
3
NR R
occurred during the reaction and provides evidence for
heterogeneity throughout the reaction.
CuHAP
1
2 3
R4
R -CHO
+
R R NH
+
H
R1
CH CN
3
reflux
R4
R1 = aryl and cyclohexyl
We chose a variety of structurally divergent aldehydes
and amines possessing a wide range of functional groups
for our study to understand the scope and the generality
of the CuHAP promoted three-component coupling
reactions and the results are summarized in Table 2.
5
5-92%
2
3
R , R = dialkyl and dibenzyl
4
R = alkyl and phenyl
Scheme 1.
The amines used for this study include aliphatic, alicy-
clic and aromatic examples. Among the various amines
tested, the aliphatic amines piperidine (Table 2, entry 1),
pyrrolidine (Table 2, entry 2), morpholine (Table 2,
entry 3), dibutylamine (Table 2, entry 4) and the aromatic
amine, phenylbenzylamine (Table 2, entry 5), gave very
good yields of the coupling product in the three-compo-
nent system composed of benzaldehyde (Table 2, entries
water and dried overnight at 110°C, yielding copper ex-
changed hydroxyapatite as a blue powder, which was
characterized by XPS, SEM-EDAX and IR. XPS analy-
sis of the CuHAP catalyst indicated the same binding
energy values for Ca, P and O as in CaHAP. A narrow
scan of Cu 2p3/2 for CuHAP showed the binding energy
peak at 934.9 (the binding energy of Cu in Cu(II) is
1
0
around 935eV), which indicates copper in the +2 state
in CuHAP. The copper content was measured as
1
1
–6) or cyclohexylcarboxaldehyde (Table 2, entries 7–
1) and phenylacetylene. On the other hand dibenzyl-
À1
1
.25mmolg using SEM-EDAX.
amine (Table 2, entry 6) gave the corresponding coupled
product in only moderate yield. The order of reactivity
for these amines in terms of yields and the reaction time
is piperidine > pyrrolidine > dibutylamine > morpho-
line > phenylbenzylamine > dibenzylamine. (S)-Proline
methyl ester gave the corresponding chiral propargyl-
amine in good yield (Table 2, entry 12). It is significant
that these reactions are faster than that reported using
In an effort to develop a better catalytic system, various
metal hydroxyapatites were screened in the three-com-
ponent reaction composed of benzaldehyde, piperidine
and phenylacetylene in acetonitrile under reflux and
the results are summarized in Table 1. FeHAP gave lower
yields, while CuHAP and homogeneous Cu(OAc)2
afforded very good yields. When the reaction was con-
ducted with Cu powder, a lower yield was obtained even
after longer reaction times. The order of efficiency is Cu-
5
c
silver in ionic liquids. Aryl aldehydes possessing an
electron-withdrawing group afforded better yields
(
Table 2, entries 13–15) than that with an electron-
HAP > Cu(OAc) > RuHAP > Cu > FeHAP. The sol-
2
donating group (Table 2, entry 16). It is worth noting
that 4-nitrobenzaldehyde gave only traces of the coupled
product (Table 2, entry 17). When alkylacetylenes were
used in place of phenylacetylene, the corresponding
propargylamines were isolated in excellent yields (Table
vent also has a pronounced effect in these reactions.
Acetonitrile provided optimum yields, whereas toluene
and water offered lower yields. The optimum ratio of
aldehyde, amine and alkyne was found to be 1:1.2:1.3.
The controlled three-component reaction conducted
under identical conditions and devoid of CuHAP gave
no coupled product, despite prolonged reaction times.
CuHAP was recovered quantitatively by simple filtra-
tion and reused several times showing consistent activity
even after the fourth cycle (Table 1, entry 3). Moreover
the absence of copper in the filtrate was confirmed by
AAS, which reiterates that no leaching of copper
2
, entries 18–19).
In conclusion, we have developed a simple and efficient
method for the three-component coupling of aldehydes,
amines and alkynes in acetonitrile through C–H bond
activation at reflux temperature to yield propargyl-
amines with moderate to very good yields using CuHAP
as catalyst. The catalyst can be readily recovered and
reused thus making this procedure more environmen-
tally acceptable whilst no catalyst leaching was ob-
served. We believe that this methodology will find
widespread use in organic synthesis for the preparation
of propargylamines.
Table 1. Three-component coupling of benzaldehyde, piperidine and
a
phenylacetylene with different catalysts
N
CHO
catalyst
+
+
Typical procedure for three-component coupling reaction
with CuHAP. CuHAP (100mg) was added to a mixture
of benzaldehyde (1mmol), piperidine (1.2mmol) and
phenylacetylene (1.3mmol) in acetonitrile (3mL) at
reflux, and the mixture was stirred for 6h. The progress
of the reaction was monitored by TLC and on comple-
tion the reaction mixture was filtered and the filtrate
concentrated under reduced pressure to afford the crude
product, which after chromatography on silica gel gave
the corresponding propargylamine, N-(1,3-diphenyl-2-
propynyl)piperidine.
N
acetonitrile, reflux
H
b
Entry
Catalyst
Yield (%)
1
2
3
FeHAP
RuHAP
CuHAP
25
60
85
8
c
0
4
5
Cu(OAc)
Cu powder
2
80
45
a
Benzaldehyde (1mmol), piperidine (1.2mmol), phenylacetylene
1.3mmol), catalyst (100mg), acetonitrile, reflux, 6h.
(
1
b
c
Based on isolated yields.
Yield after fourth cycle.
H NMR (200MHz, CDCl ) d 7.67–7.62 (m, 2H), 7.55–
3
7.50(m, 2H), 7.4 0– 7.26 (m, 6H), 4.8 (s, 1H), 2.61–2.50

B. M. Choudary et al. / Tetrahedron Letters 45 (2004) 7319–7321
Table 2. Three-component coupling of aldehydes, amines and alkynes using CuHAP as catalyst
NR R3
7321
2
CuHAP
1
2 3
R4
R -CHO
+
R R NH
+
H
R1
CH CN
3
reflux
R4
1
2
Amine (R , R )
3
4
R
a,b
Entry
R
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
Ph
Ph
Piperidine
Pyrrolidine
Morpholine
Dibutyl
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
6
6
85
85
70
80
65
Ph
Ph
6
5
Ph
R
2
= Ph, R
3
= PhCH
2
8
Ph
Dibenzyl
Piperidine
1060
4
Cyclohexyl
Cyclohexyl
Cyclohexyl
R
87
80
70
74
80
85
90
Morpholine
Dibenzyl
6
8
1
1
1
1
1
1
1
1
0Cyclohexyl
2
=Ph, R
Dibutyl
3
=PhCH
2
6
1
2
3
4
5
6
7
Cyclohexyl
Ph
4
L-Proline methyl ester
Piperidine
4
4-ClC
6
H
4
5
3,4-Cl
3,4-Cl
2
C
C
6
H
3
Dibenzyl
Piperidine
1055
8
2
6
H
3
85
55
5
4-MeOC
4-NO
6
H
4
Piperidine
Piperidine
18
12
2
C
6
H
4
18
Ph
Piperidine
4
80
19
Cyclohexyl
Piperidine
4
92
a
Isolated yields.
Identification of the products was by NMR and mass spectrometric analysis.
b
(
(
(
(
m, 4H), 1.70–1.50 (m, 4H), 1.50–1.40 (m, 2H). MS
Nakamura, S. I.; Murahashi, S. I. J. Org. Chem. 1994, 59,
282–2284; (c) Czerneck, S.; Valery, J. M. J. Carbohydr.
Chem. 1990, 9, 767.
+
70eV) m/z (%) 275 (M , 18.75%), 274 (8.75%), 202
2
11.25%), 198 (72.5%), 191 (100%), 115 (7.5%), 84
7.5%).
4
. (a) Fischer, C.; Carreira, E. M. Org. Lett. 2001, 3,
4
2
1
319–4321; (b) Li, C. J.; Wei, C. Chem. Commun. 2002,
68–269; (c) Wei, C.; Li, C. J. J. Am. Chem. Soc. 2002,
24, 5638–5639; (d) Koradin, C.; Polborn, K.; Knochel, P.
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5
Ch.S. thanks the Council of Scientific and Industrial Re-
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6
7
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