Copper(I) halide catalyzed three-component coupling reaction of aldehyde, pyrrolidine and stannyl- and silylacetylene

Article abstract of DOI:10.1055/s-0028-1087553

An efficient three-component coupling reaction of aldehyde, pyrrolidine and tributylstannylacetylene or triphenylsilylacety-lene to generate propargylamines has been developed by using copper(I) halides as promoters. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1087553

LETTER
441
Copper(I) Halide Catalyzed Three-Component Coupling Reaction of
Aldehyde, Pyrrolidine and Stannyl- and Silylacetylene
Copper(I) Halide
C
d
atalyzedTh
a
ree-Compo
m
nent CouplingReaction Shih-Yuan Lee,* Ge-An Chen, Yu-Ting Chang, Shu-Fang Chu
Department of Chemistry, Tamkang University, Tamsui, Taipei 25137, Taiwan
Fax +886(2)26223830; E-mail: adamlee@mail.tku.edu.tw
Received 23 September 2008
pose of three-component coupling reactions to generate
the desired acetylenic propargylamines. However, tribu-
tylstannylacetylene has not been investigated due to the
instability of stannyl group under the reported reaction
conditions.4
Abstract: An efficient three-component coupling reaction of alde-
hyde, pyrrolidine and tributylstannylacetylene or triphenylsily-
lacety-lene to generate propargylamines has been developed by
using copper(I) halides as promoters.
Key words: three-component coupling reaction, propargylamine,
tributylstannylacetylene, triphenylsilylacetylene
In this report, we investigated the use of copper(I) halides
as reagents for the A3-coupling reaction because they are
readily available and much cheaper than gold,6a silver,6b
ruthenium,6c iridium3b or other additives. Various cop-
per(I) halides were examined for the A3-coupling reaction
of benzaldehyde (1.0 equiv), pyrrolidine (1.0 equiv) and
tributylstannylacetylene (1.1 equiv). The results showed
that an unexpected dialkyne5 1 was formed as the major
product together with the destannylated propargylamine 2
(Table 1). Copper(I) species, especially CuI, showed
much better catalytic property than those of copper(II)
complexes. Various amount of CuI (0.1 equiv to 1.0
equiv) was introduced and investigated, and a 50 mol% of
CuI to substrate was shown to give the best results. On the
basis of these results, together with several literature pre-
cedents,6 it is believed that the A3-coupling reaction pro-
ceeded via a terminal alkyne C–H bond and activated by
copper(I) species. The copper acetylide intermediate thus
generated can react with the iminium ion prepared in situ
from the aldehyde and pyrrolidine, to form the corre-
sponding propargylamine. Dialkyne 1 was generated from
the Hay coupling reaction2 of propargylamine 2 which
might be produced by the destannylation reaction of
Propargylamines are compounds that have the interesting
biological properties and can provide important synthetic
intermediates in natural products.1 Multicomponent reac-
tion is a powerful and useful synthetic tool to produce
complex molecular structures from simple precursors by
a one-pot procedure.2 Propargylamine can be synthesized
by a three-component (A3) coupling reaction of aldehyde,
amine and alkyne through the activation of a terminal
alkynyl C–H bond, where the acetylenic moiety is of val-
ue in organic synthesis. The three-component coupling re-
action between terminal alkyne, aldehyde and secondary
amine, initially restricted to arylacetylene, has been ex-
tended to some less activated alkynes by the introduction
of transition metal complexes as catalysts.3 Propargyl-
amines with terminal acetylenic functionality are impor-
tant synthetic intermediates, however the reliable methods
for their synthesis are relatively few. Thus, there is a need
for a general yet efficient synthetic protocol to use a wide
range of propargylamine derivatives. Silyl- and stannyl-
acetylenes are alternative synthetic precursors for the pur-
Table 1 Optimization of Copper Promoter
O
CuX (50 mol%)
N
N
N
+
+
+
H
Bu3Sn
N
THF, r.t.
Ph
H
Ph
Ph
1
2
Entry
CuX
Time
41 h
60 h
40 h
48 h
44 h
Yield (%) of 1
Yield (%) of 2
1
2
3
4
5
CuCl
7
21
52
0
4
3
5
0
0
CuBr
CuI
CuBr2
Cu(OAc)2
15
SYNLETT 2009, No. 3, pp 0441–0446
x
x.
x
x.
2
0
0
9
Advanced online publication: 21.01.2009
DOI: 10.1055/s-0028-1087553; Art ID: W14808ST
© Georg Thieme Verlag Stuttgart · New York

442
A. S.-Y. Lee et al.
LETTER
Table 2 Optimization of Amine
O
CuI (50 mol%)
THF, r.t.
N
N
N
+
+
+
H
Bu3Sn
N
Ph
H
Ph
Ph
1
2
Entry
Amine
Time
24 h
21 h
43 h
40 h
43 h
44 h
Yield (%) of 1
Yield (%) of 2
1
2
3
4
5
6
n-BuNH2
PhNH2
0
0
0
0
0
5
0
0
i-Pr2NH
pyrrolidine
imidazole
Ph2NH
0
52
0
0
stannyl propargylamine. Thus, a reaction mixture of com- was interesting to observe that the destannylated propar-
pound 2, CuI (0.5 equiv) and pyrrolidine (1.0 equiv) was gylamine 2 was obtained as the only product when 1.5
further tested under the reaction conditions and dialkyne equivalents of tributylstannylacetylene were used in this
1 (84%) was obtained (Scheme 1). It should be noted that A3-coupling reaction (Table 3). When a higher amount of
self-coupling reaction did not occur and starting materials tributylstannylacetylene was introduced, no yield im-
were recovered when pyrrolidine was absent.
provement of propargylamine 2 was resulted. With the
use of the destannylated propargylamine, no other addi-
tive was needed for this A3-coupling reaction system, and
the experimental procedure was simple to perform.
pyrrolidine (1.0 equiv)
N
CuI (50 mol%)
N
N
To understand the scope of this new reaction, various al-
dehydes were studied as the substrates (Table 4). A repre-
sentative coupling procedure is given as follows: a
mixture of aldehyde (1.0 mmol) and pyrrolidine (1.0
mmol) was added to a mixture of tributylstannylacetylene
(1.5 mmol) and CuI (0.5 mmol) in anhydrous THF (5 mL)
and the reaction mixture was stirred at room temperature.
After the indicated time, water (10 mL) was added and the
resulting mixture was extracted with CH2Cl2 (3 × 20 mL).
The combined organic layer was washed with brine (30
mL), dried (MgSO4), filtered, and then the organic solvent
was removed under a reduced pressure. The desired prod-
uct was isolated by short-path silica gel column chroma-
tography.
THF, r.t., 24 h
84%
Ph
Ph
Ph
1
Scheme 1 Self-coupling raction of Propargylamine
Different amines were investigated but pyrrolidine was
the only one that could drive this coupling reaction
(Table 2). No reaction occurred when primary amines,
such as n-butylamine and aniline and secondary amines,
such as diisopropylamine, diphenylamine and imidazole
were introduced under the reaction conditions.
In the previous studies, 1.2–1.5 equivalents of terminal
alkyne were usually used in the A3-coupling reaction.
Thus, the coupling process was investigated with different
molar ratios of tributylstannylacetylene to substrate. It
Table 3 Optimization of Tributylstannylacetylene Introduction Amount
O
CuI (50 mol%)
N
N
N
+
+
H
Bu3Sn
THF, r.t.
+
N
H
Ph
Ph
Ph
1
2
1.0 equiv
1.0 equiv
Entry
Acetylene (equiv)
Time
43 h
43 h
40 h
44 h
Yield (%) of 1
Yield (%) of 2
1
2
3
4
1.1
1.3
1.5
2.0
52
30
0
5
18
80
50
0
Synlett 2009, No. 3, 441–446 © Thieme Stuttgart · New York

LETTER
Copper(I) Halide Catalyzed Three-Component Coupling Reaction
443
Table 4 CuI-Promoted A3-Coupling of Tributylstannylacetylene with Aldehyde and Pyrrolidine
O
CuI (50 mol%)
+
+
Bu3Sn
N
N
THF, r.t.
R
H
H
R
1.5 equiv 1.0 equiv 1.0 equiv
Entry
R
Time
27 h
23 h
Yield (%)
40a
1
2
Et
98
3
4
5
25h
98
91
91
24 h
26 h
F
6
7
8
26 h
24 h
25 h
83
90
88
Cl
Br
MeO
O
9
23 h
22 h
48
64
10
S
11
12
13
25 h
27 h
24 h
13
58
30
N
H
N
Ts
N
a The low yield was obtained due to the high volatility of the product.
As shown in Table 4, reactions using aliphatic aldehydes role did not generate any desired product and starting
(entries 1–3), electron-poor (entries 5–7) or electron-rich material was recovered under the reaction conditions.
(entry 8) benzaldehydes, or heteroaromatic aldehydes (en-
The terminal alkynyl propargylamine could be obtained
tries 9–13) gave the desired products in good to moderate
from an A3-coupling reaction of tributylstannylacetylene,
yields. Aliphatic aldehydes having an a-hydrogen (entries
pyrrolidine and aldehyde. We are also interested in the
1–3) displayed high reactivity and gave clean reaction
formation of masked terminal alkynyl propargylamine
product under standard reaction conditions. Furthermore,
and silylacetylene might be a good choice for the A3-cou-
heteroaromatic aldehyde such as pyrrole also gave the de-
pling reaction as it allows for a subsequent cleavage to the
sired product (entry 11). However, protected N-acetylpyr-
terminal alkyne.7 Therefore, we further investigated this
Synlett 2009, No. 3, 441–446 © Thieme Stuttgart · New York

444
A. S.-Y. Lee et al.
LETTER
Table 5 Optimization of Copper Promoter
O
CuX (50 mol%)
THF, r.t.
N
N
N
+
+
+
Ph3Si
H
N
Ph
H
Ph
Ph
SiPh3
1
3
1.1 equiv
1.0 equiv
1.0 equiv
Entry
CuX
Time
Yield (%) of 1
Yield (%) of 3
1
2
3
4
CuCl
CuBr
CuI
41 h
25 h
25 h
44 h
3
0
0
4
8
29
10
0
Cu(OAc)2
Table 6 Optimization of Reaction Conditions
O
CuBr (50 mol%)
THF, r.t.
N
N
N
+
+
+
Ph3Si
H
N
Ph
Ph
H
Ph
SiPh3
1.0 equiv
1
3
1.5 equiv
1.8 equiv
Entry
Energy source
r.t.
Time
Yield (%) of 1
Yield (%) of 3
1
2
3
32 h
0
0
1
39
80
79
MW (15 W)
MW (30 W)
90 min
90 min
A3-coupling reaction by using triphenylsilylacetylene as action. A much higher yield of silyl propargylamine
the masked terminal alkyne. A reaction mixture of (80%) was obtained when 15 watts of microwave power
triphenylsilylacetylene, pyrrolidine and benzaldehyde was used after 90 minutes irradiation (Table 6). A trace
with different copper promoters was investigated and the amount of dialkyne 1 was also produced when the micro-
results showed that CuBr was the best choice for the reac- wave irradiation was increased to 30 watts under the reac-
tion (Table 5). Promoters of CuCl and Cu(OAc)2 generat- tion conditions.
ed small amount of dialkyne 1 after prolong reaction time.
Using triphenylsilylacetylene, the same series of alde-
CuBr as a promoter produced the highest yield of silyl hydes was also investigated for A3-coupling reaction un-
propargylamine at room temperature after 25 hours stir- der microwave irradiation (Table 7). Product yields of
ring. The formation of silyl propargylamine increased reactions using triphenylsilylacetylene with aliphatic al-
slightly when 1.5 equivalents of triphenylsilylacetylene dehydes (entries 1–3), electron-poor (entries 5–7) or elec-
and 1.8 equivalents of pyrrolidine were introduced at tron-rich (entry 8) benzaldehydes were lower than those
room temperature after 32 hours stirring. Recently, micro- of using tributylstannylacetylene. Heteroaromatic alde-
wave radiation has been used to promote three-component hydes (entries 9–11) also reacted with pyrrolidine and
coupling reaction of aldehyde, alkyne, and amine for the triphenylsilylacetylene to give products in higher yields
generation of propargylamine.6,8 Thus, we employed mi- than those treated with tributylstannylacetylene.
crowave as energy source to promote this A3-coupling re-
Synlett 2009, No. 3, 441–446 © Thieme Stuttgart · New York

LETTER
Copper(I) Halide Catalyzed Three-Component Coupling Reaction
445
Table 7 CuBr-Promoted A3-Coupling Reaction of Triphenylsilylacetylene with Aldehyde and Pyrrolidinea
O
CuBr (50 mol%)
N
+
+
Ph3Si
N
H
THF, 80 °C,
MW (15 W)
R
H
R
SiPh3
1.5 equiv
1.8 equiv
1.0 equiv
Entry
R
Time
Yield (%)
1
2
90 min
90 min
77
60
Et
3
90 min
83
4
5
6
7
8
90 min
90 min
90 min
90 min
90 min
80
48 + 18b
65
F
Cl
Br
64
65
MeO
O
9
90 min
90 min
53
60
10
S
11
12
13
90 min
90 min
90 min
30
77
43
N
H
N
Ts
N
a A reaction mixture of triphenylsilylacetylene (1.5 mmol), CuBr (0.5 mmol), aldehyde (1.0 mmol), pyrrolidine (1.8 mmol) and anhyd THF (5
mL) in a pressure tube with a threaded Teflon cap was microwave irradiated with 15 W power at 80 °C (CEM Discovery microwave reactor).
b The yield of desilylated propargylamine.
In summary, an efficient three-component coupling reac- Supporting Information for this article is available online at
tion of aldehyde, pyrrolidine and tributylstannyl- or tri- http://www.thieme-connect.com/ejournals/toc/synlett.
phenylsilylacetylenes to generate the corresponding
propargylamines has been achieved by using copper(I)
Acknowledgment
halides as promoters. In addition, no other additive was
needed for this A3-coupling reaction system, and the ex-
We would like to thank Taiwan’s National Science Council (NSC
95-2113-M-032-003-MY3) and Tamkang University for their
perimental process was quite simple to perform.
financial support.
Synlett 2009, No. 3, 441–446 © Thieme Stuttgart · New York

446
A. S.-Y. Lee et al.
LETTER
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