An efficient synthesis of propargylamines using a silica gel anchored copper chloride catalyst in an aqueous medium

Article abstract of DOI:10.1016/j.tetlet.2007.08.116

The design and development of a silica gel anchored copper chloride heterogeneous catalyst for the synthesis of propargylamines using an amine, an aldehyde, and an alkyne through C-H activation in water is described. Both aliphatic and aromatic aldehydes and amines are used for the reaction. The catalyst was recovered quantitatively by simple filtration and reused several times.

Full text of DOI:10.1016/j.tetlet.2007.08.116

Tetrahedron Letters 48 (2007) 7882–7886
An efficient synthesis of propargylamines using a silica gel
anchored copper chloride catalyst in an aqueous medium
*
B. Sreedhar, P. Surendra Reddy, C. S. Vamsi Krishna and P. Vijaya Babu
Inorganic and Physical Chemistry Division, Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 007, India
Received 25 December 2006; revised 19 August 2007; accepted 30 August 2007
Available online 5 September 2007
Abstract—The design and development of a silica gel anchored copper chloride heterogeneous catalyst for the synthesis of propar-
gylamines using an amine, an aldehyde, and an alkyne through C–H activation in water is described. Both aliphatic and aromatic
aldehydes and amines are used for the reaction. The catalyst was recovered quantitatively by simple filtration and reused several
times.
Ó 2007 Elsevier Ltd. All rights reserved.
Transition metal catalyzed multi-component reactions
are a powerful synthetic tools to access complex struc-
tures from simple precursors by one-pot procedures.
The three-component coupling of aldehydes, alkynes,
using Cu–HAP and LDH–AuCl under heterogeneous
3
conditions.
1
2
Even though some of the above reported procedures are
general, environmentally friendly and applicable to both
aliphatic and aromatic aldehydes and amines, there are
no reports on the recyclability of the catalyst in water.
3
and amines (A coupling) is one of the best examples
1
of such a process and has received much attention.
3
The resultant propargylamines obtained by A coupling
reactions are important synthetic intermediates for
potential therapeutic agents and polyfunctional amino
derivatives. Traditionally, these compounds are synthe-
The immobilization and chemical modification of
homogeneous catalysts to form heterogeneous ana-
logues of well-defined structures anchored to an insolu-
ble matrix is an area of current interest. The
development of heterogeneous catalysts for the synthesis
of fine chemicals in industrial processes is advantageous
over homogeneous catalysts, since heterogeneous cata-
lysts are easy to separate, and can potentially be
2
sized by nucleophilic attack of lithium acetylides or
3
Grignard reagents on imines or their derivatives. How-
ever, these reagents are stoichiometric, highly moisture
sensitive, and require strictly controlled reaction condi-
tions. Besides, sensitive functionalities such as esters
are not tolerated. Thus there is a need for a general
and efficient synthetic protocol that is applicable to a
wide range of propargylamines. Several transition metal
1
3
reused. The synthesis of mesoporous silica has greatly
expanded the possibilities for the design of open pore
4
5
6
14
catalysts such as silver salts, gold salts, copper salts, Ir
structures. As a result of their large surface area,
7
8
complexes and Cu/Ru bimetallic systems under homo-
geneous conditions have all been used for this reaction
and later their chiral equivalents were also reported.
well-defined pore size and pore shape, these materials
have great potential in industrial processes. The pore
walls of mesoporous materials are easily modified with
either purely inorganic or with hybrid, semi-organic,
9
In our earlier reports we described the ultrasound
assisted synthesis of propargylamines using CuI as
1
5
functional groups.
1
0
3
catalyst.
Recently, an A coupling reaction was
reported using immobilization of silver and copper salts
in an ionic liquid. Our group has reported the same
In the present work, silica gel anchored copper chlo-
ride was synthesized using 3-mercaptopropyltrimeth-
1
1
16
oxysilane as a spacer in order to explore its activity in
3
A coupling reactions.
Keywords: Propargylamines; Silica gel anchored copper chloride;
Mesoporous silica; Terminal alkynes and imines.
*
Corresponding author. Tel./fax: +91 40 27160921; e-mail:
sreedharb@iict.res.in
The three-component coupling of benzaldehyde, piperi-
dine, and phenylacetylene using the Si(CH ) SO CuCl
2
3
3
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.08.116

B. Sreedhar et al. / Tetrahedron Letters 48 (2007) 7882–7886
7883
1
2
R
R
a slight decrease in activity (Table 1). Having established
the reusability of the catalyst, we carried out the cou-
pling reactions of a variety of aldehydes, amines, and
alkynes to understand the scope and generality of the
catalyst, and the results are shown in Tables 2–4.
N
O
R1
R
2
SO3CuCl
H
N
H
+
+
R1
o
R1
H2O, 100 C.
Scheme 1.
Initially various aldehyde substrates were added with
piperidine and phenylacetylene. The aldehydes used
for this study included aromatic, aliphatic and hetero-
catalyst in water at 100 °C afforded the desired propar-
gylamine in 86% yield (Scheme 1). The reaction pro-
ceeded very well in water as well as in other organic
1
7
solvents such as toluene, THF, DMF, and acetonitrile.
Table 1. Recovery and reuse of Si(CH
component coupling reaction of an aldehyde, an amine and an alkyne
2 3 3
) SO CuCl for the three-
At room temperature, only a trace amount of the prod-
uct was formed and the reaction devoid of the catalyst
gave no product despite prolonged reaction times. The
optimum ratio of aldehyde, amine and alkyne was found
to be 1:1.2:1.5.
a
Entry
Run
Isolated yield (%)
1
2
3
4
1
2
3
4
86
80
75
75
With optimal reaction conditions in hand, we further
3
a
examined the reusability of the catalyst for the A cou-
Reaction conditions: aldehyde (1 mmol); amine (1.2 mmol); alkyne
pling reaction. It is worth noting that the catalyst was
recovered quantitatively and reused four times with only
(1.5 mmol); 50 mg of catalyst (5 mol %) and H O (3 mL) at 100 °C
for 10 h.
2
a
Table 2. Three-component coupling reaction of various aldehydes, with piperidine, and phenylacetylene
b
Entry
Aldehyde
Product
Time (h)
Yield (%)
CHO
N
1
10
86
79
Ph
Ph
N
CHO
2
12
Cl
p-ClC H
6
4
Ph
CHO
N
3
4
5
6
14
12
16
8
75
75
72
98
92
MeO
p-MeOC H
6
4
Ph
CHO
N
m-BrC H
6
4
Br
Ph
Ph
CHO
N
p-MeC H
6
4
N
CHO
CHO
Ph
N
7
8
8
8
Ph
CHO
N
95
Ph
(continued on next page)

7884
B. Sreedhar et al. / Tetrahedron Letters 48 (2007) 7882–7886
Table 2 (continued)
b
Entry
Aldehyde
Product
Time (h)
Yield (%)
CHO
N
9
10
10
80
85
N
Py
Ph
N
O
1
0
CHO
O
Ph
a
18
Reaction conditions as exemplified in the typical experimental procedure.
Isolated yields after column chromatography.
b
a
Table 3. Three-component coupling reaction of benzaldehyde, various amines and phenylacetylene
b
Entry
Amine
Product
Time (h)
10
Yield (%)
N
H
N
1
92
54
Ph
Ph
Ph
O
O
N
2
16
N
H
Ph
(
)
( )
3
3
N
(
)
( )
3
H
3
4
3N
12
12
85
68
Ph
Ph
N
N
H
Ph
Ph
COOEt
COOEt
N
c
5
10
52
N
H
Ph
Ph
a
b
c
18
Reaction conditions as exemplified in the typical experimental procedure.
Isolated yields after column chromatography.
Products obtained in a diastereomeric ratio of 78:22.
a
Table 4. Three-component coupling reaction of benzaldehyde, piperidine, and various alkynes
b
Entry
Alkyne
Product
Time
8
Yield
H3C
1
N
92
Ph
p-CH3C6H4
p-OCH3C6H4
p-OCH3C10H6
P-C5H11C6H4
C6H13
N
2
3
4
5
H3CO
H3CO
8
10
10
24
86
71
80
60
Ph
N
Ph
N
4
Ph
N
4
Ph
a
Reaction conditions as exemplified in typical experimental procedure.
Isolated yields after column chromatography.
b

B. Sreedhar et al. / Tetrahedron Letters 48 (2007) 7882–7886
7885
cyclic examples, and the results are shown in Table 2.
Irrespective of the electronic nature of the substituent,
aromatic aldehydes reacted smoothly to give the
corresponding products in good yields (Table 2, entries
3. (a) Ryan, C. W.; Ainsworth, C. J. Org. Chem. 1961, 26,
547; (b) Tubery, F.; Grierson, D. S.; Husson, H.-P.
1
Tetrahedron Lett. 1987, 28, 6457; (c) Jung, M. E.; Huang,
A. Org. Lett. 2000, 2, 2659; (d) Murai, T.; Mutoh, Y.;
Ohta, Y.; Murakami, M. J. Am. Chem. Soc. 2004, 126,
1
6
–5). On the other hand, aliphatic aldehydes (entries
–8) reacted rapidly and gave excellent yields without
5
968.
4
5
. Wei, C. M.; Li, Z.; Li, C. J. Org. Lett. 2003, 5, 4473, and
references cited therein.
. Wei, C. M.; Li, C. J. J. Am. Chem. Soc. 2003, 125, 9584.
any trimerization. In addition, heteroaromatic alde-
hydes displayed high reactivity and gave good yields of
products (entries 9–10).
6. (a) Kabalka, G. W.; Wang, L.; Pagni, R. M. Synlett 2001,
76; (b) Shi, L.; Tu, Y. Q.; Wang, M.; Zhang, F. M.; Fan,
6
To expand the scope of amine substrates, we used benz-
aldehyde and phenylacetylene as model substrates and
examined various secondary amines in the A coupling
reaction. The order of reactivity for these amines in
terms of yields and the reaction time was pyrrol-
idine > piperidine > dialkylamines > morpholine. Cyclic
amines gave the desired product in excellent yields
except morpholine (Table 2, entry 2). On the other hand,
C. A. Org. Lett. 2004, 6, 1001; (c) Gommermann, N.;
Koradin, C.; Polborn, K.; Knochel, P. Angew. Chem., Int.
Ed. 2003, 42, 5763; (d) Syeda, H. Z. S.; Halder, R.; Karla,
S. S.; Das, J.; Iqbal, J. Tetrahedron Lett. 2002, 43, 6485.
. Fischer, C.; Carreira, E. M. Org. Lett. 2001, 3, 4319.
. Li, C. J.; Wei, C. Chem. Commun. 2002, 268.
. Koradin, C.; Polborn, K.; Knochel, P. Angew. Chem., Int.
Ed. 2002, 41, 2535.
3
7
8
9
1
0. Sreedhar, B.; Surendra Reddy, P.; Veda Prakash, B.;
(
S)-ethyl prolinoate gave the desired product in 52%
Ravindra, A. Tetrahedron Lett. 2005, 46, 7019.
yield with a diastereomeric ratio of 78:22.
11. (a) Li, Z.; Wei, C.; Chen, L.; Varma, R. S.; Li, C. J.
Tetrahedron Lett. 2004, 45, 2443; (b) Park, B. S.; Alper, H.
Chem. Commun. 2005, 1315.
Several terminal alkynes were examined for the coupling
using benzaldehyde and piperidine as the model sub-
strates (Table 3). p-Methyl and p-methoxy-substituted
phenylacetylenes were more reactive compared to p-pen-
tyl-substituted phenylacetylene and p-methoxynapthyl
acetylene (Table 4, entries 1–4). It is noteworthy that
with an aliphatic alkyne, the reaction was slow affording
a lower yield (Table 4, entry 5).
1
2. (a) Choudary, B. M.; Sridhar, Ch.; Kantam, M. L.;
Sreedhar, B. Tetrahedron Lett. 2004, 45, 7319; (b) Kan-
tam, M. L.; Prakash, B. V.; Venkat Reddy, C. R.;
Sreedhar, B. Synlett 2005, 2329.
1
3. (a) Vos, D. E.; Vankelecom, I. F. K.; Jacobs, P. A. In
Chiral Catalyst Immobilization and Recycling; Wiley:
Weinheim, 2000; (b) Inaki, Y.; Kajita, Y.; Hisao, H.;
Yoshida, K.; Ito, K.; Hattori, T. Chem. Commun. 2001,
2
358.
To conclude, we have developed a simple and efficient
method for the synthesis of propargylamines via C–H
activation using silica gel anchored CuCl in water with-
out using any organic solvent or co-catalyst. This proto-
col is an environmentally friendly process and can be
used to generate a diverse range of acetylenic amines
in good to excellent yields. The simple procedure for cat-
alyst preparation, easy recovery and reusability of the
catalyst is expected to contribute to its utilization for
the development of benign chemical process and
products.
14. (a) Beck, J. S.; Kresge, C. T.; Leonowicz, M. E.; Roth, W.
C.; Virtuli, J. C.; Schmitt, K. D.; Chu, C. T. W.; Olson, D.
H.; Sheppard, E. W. J. Am. Chem. Soc. 1992, 114, 10834;
(
b) Kresge, C. T.; Leonowicz, M. E.; Roth, W. C.; Virtuli,
J. C.; Beck, J. S. Nature 1992, 359, 710; (c) Virtuli, J. C.;
Beck, J. S. Curr. Opin. Solid State Mater. Sci. 1996, 1, 76.
5. (a) Burkett, S. L.; Sims, S. D.; Mann, S. Chem. Commun.
1
1
996, 1961; (b) Feng, X.; Fryxell, G. E.; Wang, L. Q.;
Kim, A. Y.; Liu, J.; Kermer, K. M. Science 1997, 276, 923;
(c) Sreekanth, P.; Sang-Wook, K.; Hyeon, T.; Kim, B. M.
Adv. Synth. Catal. 2003, 345, 936.
16. Catalyst preparation and XPS, TGA–MS, AAS, and
FTIR characterization data is given in the Supplementary
data.
1
7. Organic solvents such as DMF, toluene, THF, and
acetonitrile gave the 1-(1,3-diphenyl-prop-2-ynyl)-piperi-
dine in 90%, 95%, 92%, and 85% yields at their reflux
temperatures in 10 h.
Acknowledgement
P.S.R. wishes to thank the Council of Scientific and
Industrial Research, New Delhi, for the award of Senior
Research Fellowship.
1
8. Typical procedure for the A
of benzaldehyde (106 mg, 1 mmol), piperidine (102 mg,
.2 mmol), phenylacetylene (153 mg, 1.5 mmol) and 50 mg
3
coupling reaction: A mixture
1
of catalyst (0.05 mol %) was taken in a round-bottomed
flask and stirred at reflux temperature. After completion of
the reaction (monitored by TLC) the catalyst was removed
by filtration. After removing the solvent, the crude
material was chromatographed on silica gel to afford the
pure product. All products gave satisfactory spectroscopic
data. Spectroscopic data for all new compounds are
reported.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/
j.tetlet.2007.08.116.
1
-(3-Phenyl-1-propyl-prop-2-ynyl)-piperidine (Table 2,
1
entry 6): H NMR (300 MHz, CDCl
H, J = 6.7), 1.40–1.68 (m, 10H), 2.44–2.55 (m, 4H), 3.45
t, 1H, J = 7.36), 7.23–7.25 (m, 3H), 7.36–7.39 (m, 2H).
3
): d (ppm) 0.97 (t,
References and notes
3
(
1
2
. Wei, C.; Li, Z.; Li, C. J. Synlett 2004, 1472.
. (a) Naota, I.; Takaya, H.; Murahashi, S. I. Chem. Rev.
1
3
3
C NMR (75 MHz, CDCl ): d (ppm) 13.92, 20.16, 24.44,
2
1
6.06, 35.52, 58.21, 85.50, 87.90, 123.34, 127.71, 128.13,
31.62. ESI-MS (m/z): 241 (M) . Anal. Calcd for
1
3
998, 98, 2599; (b) Dyker, G. Angew. Chem., Int. Ed. 1999,
8, 1698.
+

7886
B. Sreedhar et al. / Tetrahedron Letters 48 (2007) 7882–7886
17
C H23N: C, 84.59; H, 9.60; N 5.80. Found: C, 84.54; H, 1-[3-(4-Methoxy-phenyl)-1-phenyl-prop-2-ynyl]-piperidine
1
9.63; N, 5.81.
3
(Table 4, entry 2): H NMR (300 MHz, CDCl ): d (ppm)
1
-(1-Isobutyl-3-phenyl-prop-2-ynyl)-piperidine (Table 2,
1.42–1.63 (m, 6H), 2.51–2.56 (m, 4H), 3.81 (s, 3H), 4.75 (s,
1
entry 7): H NMR (300 MHz, CDCl
3
): d (ppm) 1.10 (d,
1H), 6.81 (d, 2H, J = 8.8), 7.23–7.43 (m, 5H), 7.59 (d, 2H,
1
3
6
1
H, J = 6.6), 1.41–1.49 (m, 2H), 1.55–1.63 (m, 4H), 1.83–
.97 (m, 1H), 2.33–2.45 (m, 2H), 2.56–2.65 (m, 4H), 2.94
3
J = 8. 8). C NMR (75 MHz, CDCl ): d (ppm) 24.33,
25.79, 50.55, 55.23, 62.40, 83.96, 88.02, 13.85, 127.62,
1
3
+
(
t, 1H, J = 7.6), 7.23–7.27 (m, 3H), 7.37–7.41 (m, 2H).
C
128.10, 128.72, 133.20, 159.47. ESI-MS (m/z): 305 (M) .
NMR (75 MHz, CDCl
3
): d (ppm) 14.22, 20.42, 24.48,
Anal. Calcd for C21H23NO: C, 82.58; H, 7.59; N, 4.59.
2
1
C
6.27, 30.29, 50.44, 57.30, 86.15, 87.53, 123.44, 127.93,
Found: C, 82.54; H, 7.63; N, 4.56.
1-[3-(6-Methoxy-naphthalen-2-yl)-1-phenyl-prop-2-ynyl]-
piperidine (Table 4, entry 3): H NMR (300 MHz,
+
28.29, 131.84. ESI-MS (m/z): 255 (M) . Anal. Calcd for
25N: C, 84.65; H, 9.87; N, 5.48. Found: C, 84.63; H,
1
18
H
9
4
2
0
.91; N, 5.47.
3
CDCl ): d (ppm) 1.42–1.49 (m, 2H), 1.57–1.68 (m, 4H),
-(3-Phenyl-1-piperidin-1-yl-prop-2-ynyl)-pyridine (Table
2.57–2.64 (m, 4H), 3.91 (s, 3H), 5.28 (s,1H), 7.04–7.91 (m,
1
13
, entry 9): H NMR (300 MHz, CDCl ): d (ppm) 0.85–
11H). C NMR (75 MHz, CDCl ): d (ppm) 24.28, 26.18,
3
3
.88 (m, 2H), 1.39–1.48 (m, 4H), 2.45–2.50 (m, 4H), 4.79
50.82, 55.29, 62.23, 87.10, 90.81, 105.82, 118.18, 124.16,
(
s, 1H), 7.28–7.32 (m, 5H), 7.48 (d, 2H, J = 4.6), 7.63 (d,
127.54, 128.27, 128.34, 129.03, 129.60, 131.52, 132.95,
156.79. ESI-MS (m/z): 355 (M) . Anal. Calcd for
13
+
2
2
1
H, J = 7.55). C NMR (75 MHz, CDCl
3
): d (ppm)
4.56, 26.27, 50.73, 62.39, 86.02, 88.22, 123.42, 127.47,
C H NO: C, 84.47; H, 7.09; N, 3.94. Found: C, 84.43;
2
5
25
28.03, 128.45, 128.52, 131.85, 138.67. ESI-MS (m/z): 276
H, 7.13; N, 3.92.
1-[3-(4-Pentyl-phenyl)-1-phenyl-prop-2-ynyl]-piperidine
+
(
M) . Anal. Calcd for C19
H
20
2
N : C, 84.57; H, 7.29; N,
1
1
(
0.14. Found: C, 84.54; H, 7.32; N, 10.13.
1,3-Diphenyl-prop-2-ynyl)-diisopropyl-amine (Table 3,
(Table 4, entry 4): H NMR (300 MHz, CDCl ): d (ppm)
3
0.87 (t, 3H, J = 6.5), 1.22–1.27 (m, 4H), 1.40–1.59 (m, 8H),
1
entry 4): H NMR (300 MHz, CDCl
6
3
): d (ppm) 1.04 (d,
2.45–2.49 (m, 2H), 2.53–2.61 (m, 4H), 4.71 (s, 1H), 7.02 (d,
1
3
H, J = 6.6), 2.95–3.02 (m, 1H), 4.92 (s, 1H), 7.40–7.26
2H, J = 7.9), 7.22–7.34 (m, 5H) 7.53 (d, 2H, J = 7.7).
C
1
3
(
(
8
1
m, 6H),7.55–7.50 (m, 2H), 7.67–7.62 (m, 2H), C NMR
75 MHz, CDCl ): d (ppm) 20.66, 23.83, 46.59, 50.41,
5.82, 91.62, 123.90, 126.75, 127.78, 127.84, 128.29,
NMR (75 MHz, CDCl ): d (ppm) 13.97, 18.77,22.55,
3
3
24.41, 26.13, 28.47, 28.97, 31.32, 43.23, 50.59, 61.96, 84.52,
87.82, 127.15, 127.23, 127.83, 128.23, 128.52, 128.91,
+
+
29.00, 131.30, 142.14. ESI-MS (m/z): 291 (M) . Anal.
130.33, 139.21, 142.23. ESI-MS (m/z): 345 (M) . Anal.
Calcd for C H N: C, 86.55; H, 8.65; N, 4.81. Found: C,
Calcd for C H N: C, 86.90; H, 9.04; N, 4.05. Found: C,
21
25
25 31
8
6.53; H, 8.69; N, 5.78.
86.87; H, 9.08; N, 4.02.
1-(1-Phenyl-non-2-ynyl)-piperidine (Table 4, entry 5): H
NMR (300 MHz, CDCl ): d (ppm) 0.89–0.93 (m, 3H),
1
1-(1-Phenyl-3-p-tolyl-prop-2-ynyl)-piperidine (Table 4,
1
entry 1): H NMR (300 MHz, CDCl ): d (ppm) 1.41–
3
3
1
.63 (m, 2H), 1.54–1.63 (m, 4H), 2.51–2.56 (m, 4H), 2.38
1.30–1.68 (m, 14H), 2.28–2.33 (m, 2H), 2.40–2.44 (m, 4H),
1
3
(
s, 3H), 4.76 (s, 1H), 7.1 (d, 2H, J = 8.0), 7.23–7.40 (m,
4.49 (s, 1H), 7.27–7.42 (m, 5H). C NMR (75 MHz,
CDCl ): d (ppm) 13.97, 22.40, 24.26, 25.88, 30.98, 31.27,
1
3
5H), 7.61 (d, 2H, J = 8.8). C NMR (75 MHz, CDCl
3
): d
3
(
1
ppm) 21.22, 24.17, 25.90, 53.27, 62.07, 84.93, 87.63,
21.41, 128.38, 128.65, 128.77, 128.94, 137.78, 138.31.
35.68, 50.44, 62.40, 78.52, 80.48, 127.54, 128.08, 128.67,
131.71. ESI-MS (m/z): 283 (M) . Anal. Calcd for
+
+
ESI-MS (m/z): 289 (M) . Anal. Calcd for C21
H23N: C,
C
20
H
29N: C, 84.75; H, 10.31; N, 4.94. Found: C, 84.71;
87.15; H, 8.01; N, 4. 84. Found: C, 87.14; H, 8.07; N, 4.80.
H, 10.37; N, 4.91.