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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
Choudary, Boyapati M.
