Iridium-catalyzed coupling of simple primary or secondary amines, aldehydes and trimethylsilylacetylene: Preparation of propargylic amines

Article abstract of DOI:10.1039/b404430d

The coupling of amines, aldehydes and trimethylsilylacetylene was found to be promoted in the presence of a catalytic amount of [IrCl(cod)]₂; 1:1:1 or 1:2:2 coupling products were obtained by allowing primary amine to react with aldehyde and trimethylsilylacetylene.

Full text of DOI:10.1039/b404430d

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Iridium-catalyzed coupling of simple primary or secondary amines,
aldehydes and trimethylsilylacetylene: preparation of propargylic amines
Satoshi Sakaguchi, Tomoya Mizuta, Masuyuki Furuwan, Takashi Kubo and Yasutaka Ishii*
Department of Applied Chemistry, Faculty of Engineering & High Technology Research Center, Kansai
University, Suita, Osaka 564-8680, Japan. E-mail: ishii@ipcku.kansai-u.ac.jp
Received (in Corvallis, OR, USA) 23rd March 2004, Accepted 14th May 2004
First published as an Advance Article on the web 8th June 2004
The coupling of amines, aldehydes and trimethylsilylacetylene
was found to be promoted in the presence of a catalytic amount
of [IrCl(cod)]2; 1 : 1 : 1 or 1 : 2 : 2 coupling products were
obtained by allowing primary amine to react with aldehyde and
trimethylsilylacetylene.
seems that 5aa is produced through the formation of 4aa as an
intermediate. Thus, after optimization of the reaction conditions,
5aa was found to be obtained in satisfactory yield. When 1a (0.25
mmol), 2a (1.5 mmol) and 3 (0.75 mmol) were allowed to react
under the influence of [IrCl(cod)]2 in 1,4-dioxane at 75 °C for 15 h,
5aa was produced in 81% yield based on 1a used [eqn. (2)].† By the
use of cyclopentyl methyl ether (CPME) as a solvent, the reaction
was completed within 6 h at 100 °C yielding 5aa (83%). To the best
of our knowledge, this is the first example of 1 : 2 : 2
multicomponent coupling reaction of simple amine, aldehyde and
TMS-acetylene catalyzed by an iridium complex.
The addition of terminal acetylenes to the CNN bond is an important
reaction for the preparation of propargylic amines which act as
synthetic intermediates of biologically active compounds.1 Al-
though many catalytic methods for the addition of alkynes to the
CNO bond forming propargylic alcohols have been developed so
far, work on the synthesis of propargylic amines by the reaction of
terminal alkynes with the CNN bond through catalytic C–H
activation of alkynes is still rare.2 It has been reported that terminal
acetylenes are coupled with nitrones in the presence of a catalytic
amount of CuI or Zn(OTf)2 to give 1-aza-1-buten-3-ynes or
propargylic N-hydroxylamines, respectively.3–5 However, few
papers on the transition metal-catalyzed addition of terminal
alkynes to simple imines have appeared. In 2001, Carreira and
Fischer demonstrated the preparation of propargylic amines by the
reaction of aldimines with trimethylsilylacetylene catalyzed by
[IrCl(cod)]2.6 More recently, Li and Wei showed that the three-
component coupling of amines, aldehydes and alkynes via C–H
bond activation was facilitated by AuBr3 or AgI catalyst in water to
afford the corresponding propargylic amines.7
In the course of our studies on the development of iridium-
catalyzed organic syntheses,8 we have reported a new-type of C–H
bond activation adjacent to the nitrogen atom of imines by
[IrCl(cod)]2, leading to three-component coupling products of
amines, aldehydes and simple alkynes such as 1-octyne.8a We also
briefly described that a propargylic amine was obtained by
treatment of amine and aldehyde with trimethylsilylacetylene in
place of 1-octyne in the presence of a catalytic amount of
[IrCl(cod)]2 [eqn. (1)].9 Although we did not focus on the latter
reaction of propargylic amines, the works of Carreira and Li
prompted us to report our results on the study of the iridium-
catalyzed reaction of amines, aldehydes and trimethylsilylacety-
lene. Here we wish to report a 1 : 1 : 1 or 1 : 2 : 2 coupling reaction
of simple primary amines, aldehydes and trimethylsilylacetylene
catalyzed by [IrCl(cod)]2. Furthermore, propargylic amines could
also be synthesized by the three-component coupling of secondary
amines, aldehydes and TMS-acetylene.
(2)
On the basis of these results, the coupling of several primary
amines, aldehydes and 3 catalyzed by [IrCl(cod)]2 was examined.
The representative results are summarized in Table 1.
In a similar manner to the reaction of 1a, 2a and 3, propylamine
(1b), isobutylamine (1c) and benzylamine (1d) were reacted with
2a or propionaldehyde (2b) and 3 under the influence of the iridium
catalyst to produce the corresponding 1 : 2 : 2 coupling products,
5bb, 5ca and 5da, in 75–83% yields, respectively (runs 1 to 3).
Although the reaction of 2-aminobutane (1e) with 2a and 3 at 60 °C
for 6 h gave a 1 : 1 : 1 coupling product, propargylic amine 4ea, in
good yield (84%), it is difficult to obtain 5ea as a major product in
the reaction even at higher temperature (100 °C) probably due to the
Table 1 Results of the coupling reaction of primary amines, 2a and 3
catalyzed by [IrCl(cod)]2
Run
1b
Amine
Methoda
Product (Yield, %)
B
B
4bb ( < 1)
4ca ( < 1)
5bb (83)
The reaction of n-butylamine (1a) (0.25 mmol), n-butyraldehyde
(2a) (0.25 mmol) and trimethylsilylacetylene (TMS-acetylene) (3)
(0.25 mmol) in the presence of a catalytic amount of [IrCl(cod)]2 (5
mol% with respect to 1a) in THF at 60 °C for 6 h afforded butyl(1-
propyl-3-trimethylsilyl-2-propynyl)amine (4aa) in 78% yield along
with N-butylydene butylamine (15%) [eqn. (1)].
2
5ca (75)
5da (75)
3
B
4da (5)
4
5
6
A
B
A
4ea (84)
4ea (34)
4fa (82)
5ea ( < 1)
5ea (30)
5fa ( < 1)
1e
(1)
a Method A: Amine (0.25 mmol), 2a (0.25 mmol) and 3 (0.25 mmol) were
allowed to react in the presence of a catalytic amount of [IrCl(cod)]2 (0.025
mmol) in THF (2 mL) at 60 °C for 6 h; Method B: Amine (0.25 mmol), 2a
(1.5 mmol) and 3 (0.75 mmol) were allowed to react in the presence of a
catalytic amount of [IrCl(cod)]2 (0.025 mmol) in 1,4-dioxane (2 mL) at 75
°C for 15 h. b Propionaldehyde (2b) was used in place of 2a.
Interestingly, a trace amount of the 1 : 2 : 2 coupling product of
1a, 2a and 3, N,N-bis(1-propyl-3-trimethylsilyl-2-propynyl)butyla-
mine (5aa), was detected as a side product. As discussed later, it
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T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

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steric hindrance of 1e (runs 4 and 5). Similarly, 2-amino-
2-methylpropane (1f) coupled with 2a and 3 to give a three-
component coupling product 4fa (82%) (run 6), but almost no 1 : 2
: 2 coupling product of 1f, 2a and 3 was formed even at 100 °C.
Carreira reported the iridium-catalyzed synthesis of propargylic
amines by employing aldimines and 3 as starting materials.6
However, the reaction has been limited to the aldimines prepared
independently by the reaction of benzylamine with aldehydes.
Therefore, our results provide a simple procedure for the prepara-
tion of propargylic amines by the coupling of simple primary
amines with aldehydes and TMS-acetylene.
generated in situ from amine 1 and aldehyde 2, with TMS-acetylene
3 under the influence of an iridium complex affords a 1 : 1 : 1
coupling product of 1, 2 and 3, propargylic amine 4. 4 is then
converted into enamine B by the reaction with aldehyde 2.
Subsequently, the enamine B couples with 3 in the presence of the
Ir complex giving a 1 : 2 : 2 coupling product 5.
According to the proposed reaction pathway, it is thought that the
iridium-catalyzed coupling of secondary amines with aldehydes
and 3 will produce the corresponding propargylic amines through
the in situ generation of enamines. Recently, Knochel and co-
workers reported the CuBr-catalyzed addition of terminal alkynes
to enamines.10 Thus, we next examined the three-component
coupling reaction of secondary amines, aldehydes and 3 catalyzed
by [IrCl(cod)]2 (Table 2).
Although it is difficult to clarify a detailed reaction mechanism
of the present coupling, we would like to propose a plausible
reaction pathway (Scheme 1). The coupling reaction of aldimine A,
As expected, various secondary amines were found to react with
aldehydes and 3 in the presence of a catalytic amount of
[IrCl(cod)]2 to give the corresponding propargylic amines in good
to excellent yields. For example, the reaction of dibutylamine (6a)
with 2a and 3 (6a : 2a : 3 = 1 : 6 : 3 molar ratio) catalyzed by
[IrCl(cod)]2 (10 mol%) in THF at 60 °C for 6 h produced dibutyl(1-
propyl-3-trimethylsilyl-2-propynyl)amine (7aa) in 97% yield (run
1). The coupling of diisobutylamine (6c) with 2a and 3 proceeded
smoothly under these reaction conditions, but the isolated yield of
the product 7ca was somewhat low (run 3). This may be due to the
instability of 7ca during the isolation with column chromatography.
In the CuBr-catalyzed synthesis of propargylic amine by the
reaction of enamines with alkynes, the reaction was limited to N,N-
diallyl or N,N-dibenzyl substituted enamines.10 In the present
iridium-catalyzed reaction, the simple secondary amines and
aldehydes could be employed as the starting materials.
In conclusion, we have established an alternative synthetic route
to propargylic amines by the reaction of amines, aldehydes and
TMS-acetylene using an iridium complex as a catalyst.
Scheme 1 A plausible reaction pathway for the Ir-catalyzed coupling
reaction of amine 1, aldehyde 2 and TMS-acetylene 3.
This work was partially supported by MEXT.KAKENHI
(no.15750095) and Daicel Chemical Industries Ltd.
Table 2 Results of the coupling reaction of secondary amines, aldehydes
and 3 catalyzed by [IrCl(cod)]2
a
Notes and references
Yield
Run Amine
1
Aldehyde Product
(%)b
† Representative procedure: To a 1,4-dioxane solution (2.0 mL) of
dichlorobis(1,5-cyclooctadiene)diiridium [IrCl(cod)]2 (0.025 mmol) were
added amine (0.25 mmol), aldehyde (1.5 mmol) and 3 (0.75 mmol) under
Ar. Then, the reaction mixture was stirred at 75 °C for 15 h. The reaction
was quenched with wet ether, and products were isolated by column
chromatography (230–400 mesh Al2O3, hexane), and purified by distilla-
tion under reduced pressure. After the reaction, the GC and GC-MS
analyses were performed. The yields of products were estimated from the
peak areas based on the internal standard technique using GC.
2a
(97)c
6a
7aa
7ba
7ca
2
3
4
2a
2a
2a
(97)
6b
6c
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9 We8b and Carreira6 were independently reported the [IrCl(cod)]2-
catalyzed coupling reaction of amines, aldehydes (or aldimines) with
trimethylsilylacetylene to give propargylic amines.
(99)
(90)
(86)
6d
7da
5
6
6a
6a
2b
2c
7ab
7ac
a Amine (1 mmol), aldehyde (6 mmol) and 3 (3 mmol) were allowed to react
in the presence of a catalytic amount of [IrCl(cod)]2 (0.1 mmol) in THF (8
mL) at 60 °C for 6 h. b Isolated yield. c GC yield.
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