Copper-catalyzed one-pot synthesis of propargylamines via C-H activation in PEG

Article abstract of DOI:10.1002/aoc.1707

An efficient and convenient three-component A³ coupling reaction of aldehyde, amine and alkyne via C-H activation with CuI alone as the catalyst in PEG is developed, providing a wide range of propargylamines with yields ranging from moderate to

Full text of DOI:10.1002/aoc.1707

Full Paper
Received: 22 June 2010
Revised: 9 July 2010
Accepted: 10 July 2010
Published online in Wiley Online Library: 1 September 2010
(wileyonlinelibrary.com) DOI 10.1002/aoc.1707
Copper-catalyzed one-pot synthesis
of propargylamines via C–H activation in PEG
Qiang Zhanga, Jiu-Xi Chena∗, Wen-Xia Gaoa, Jin-Chang Dinga,b
and Hua-Yue Wua∗
An efficient and convenient three-component A3 coupling reaction of aldehyde, amine and alkyne via C–H activation with CuI
alone as the catalyst in PEG is developed, providing a wide range of propargylamines with yields ranging from moderate to
excellent. Additionally, the catalyst system was recovered and reused several times without evident loss in activity. Copyright
c
ꢀ 2010 John Wiley & Sons, Ltd.
Supporting information may be found in the online version of this article.
Keywords: three-component A3 coupling; propargylamine; C–H activation; CuI; PEG
Introduction
cosmetics, is potentially recyclable and is water-miscible, which
facilitates its removal from reaction products.[37–39] On the other
hand, PEG is inexpensive, completely non-halogenated and easily
degradable. The use of PEG as a reaction solvent has received
considerable attention in synthetic organic chemistry. Its potential
as reaction media and promoter for organic reactions has
attracted the attention of organic chemists in recent years.[40–44]
However, it is surprising that the A3 coupling reaction in PEG is
still unexplored so far.
Recent studies in our group have focused on metal-catalyzed
organic reactions,[45–54] and herein we report an efficient recy-
clable one-pot synthesis of propargylamines via C–H activation
catalyzed by CuI in PEG.
Propargylamines are versatile building blocks for organic
synthesis and are generally used as precursors for the synthesis
of N-containing heterocyclic compounds such as quinolines,[1]
pyrroles,[2] pyrrolidines,[3] indolizines[4] and oxazoles,[5] and as
well as key intermediates for the synthesis of natural product.[6–9]
Traditionally, similar to the addition of carbanions to the carbonyl
group of aldehydes and ketones, the addition of organometallic
reagents such as lithium acetylides or Grignard reagents to the C
EQBOND N bonds of imines or their derivatives is an important and
efficient process to afford propargylamine derivatives.[10–12] How-
ever, these reagents must be used in stoichiometric amounts, are
highly moisture sensitive, and require harsh reaction conditions.
An alternative atom-economical approach to their synthesis is to
perform this type of reaction by coupling of aldehydes, amines
and alkynes (A3 coupling) via C–H activation, where water is the
only theoretical by-product.[13–17] Recent progress in this area has
been reported in order to expand the scope of this A3 coupling
using homogeneous catalysts and heterogenous catalysts.[18–32]
However, it is a considerable drawback that an expensive metal
catalyst (silver, gold, iridium and indium, etc.) is often lost at the
end of the reaction. Hence, a process for recycling the catalyst
system is of importance. To achieve the recyclability of the
metal catalyst, Li[33] and Alper[34] used room-temperature ionic
liquid-immobilized catalysts. However, ionic liquids, especially
imidazolium-based systems containing BF4 or PF6 anions, are
toxic in nature because they liberate hazardous HF, and their high
cost and disposability make their utility limited.[35] Recently, Yun
and co-workers also reviewed the environmental fate and toxicity
of ionic liquids.[36] However, many of these methodologies are
associated with one or more disadvantages such as prolonged
reaction time, unsatisfactory yield, harsh reaction conditions, use
of hazardous organic solvents and excess costly reagents.
Results and Discussion
The model reaction of benzaldehyde (1a), morpholine (2a)
and phenylacetylene (3a) was conducted to screen the optimal
reaction conditions and the results are listed in Table 1. Initially, we
examined a series of copper salts such as CuCl, Cu2O, CuBr, CuSO4,
CuCl2, Cu(OAc)2·H2O and CuI (Table 1, entries 1–7). The three-
componentcouplingreactionproceededsmoothlyandgenerated
the desired product 4-(1,3-diphenylprop-2-ynyl)morpholine (4a)
in 92% yield, representing one of the best results when 10 mol%
of CuI was used as catalyst without any cocatalyst or activator than
other copper salts tested [such as CuCl (87%), Cu2O (40%), CuBr
(88%), CuSO4 (53%), CuCl2 (64%), Cu(OAc)2·H2O (42%)] in PEG
under nitrogen atmosphere (Table 1, entry 7). In contrast, only
∗
Correspondence to: Jiu-Xi Chen and Hua-Yue Wu, College of Chemistry
and Materials Engineering, Wenzhou University, Wenzhou 325035, People’s
Republic of China. E-mail: jiuxichen@wzu.edu.cn;huayuewu@wzu.edu.cn
In recent years, PEG has become prominent as an alternative
green reaction media with unique properties such as thermal
stability, commercial availability, non-volatility, immiscibility with
a number of organic solvents and recyclability in synthetic chem-
istry. In general, PEG is non-toxic, being used in food products and
a
CollegeofChemistryandMaterialsEngineering,WenzhouUniversity,Wenzhou
325035, People’s Republic of China
b
Wenzhou Vocational and Technical College, Wenzhou, 325035, People’s
Republic of China
c
Appl. Organometal. Chem. 2010, 24, 809–812
Copyright ꢀ 2010 John Wiley & Sons, Ltd.

Q. Zhang et al.
Table 1. Conditions screeninga
Scheme 1. Reuse of the catalyst.
Entry
Catalyst
Solvent
Yield (%)b
1
2
CuCl
Cu2O
CuBr
CuSO4
CuCl2
Cu(OAc)2·H2O
CuI
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
[Bmim]PF6
H2O
87
Furthermore, this method was also successful with various
amines such as piperidine and pyrrolidine to afford the cor-
responding propargylamines 4n and 4o in good yields under
standard conditions (Table 2, entries 14 and 15). In all cases, no
propargylic alcohol (an adduct between the aldehyde and alkyne)
was obtained under similar reaction conditions, which might be
attributed to a rapid formation of the carbon–nitrogen bond
from aldehydes and amines.
Finally, we investigated the recycling of PEG in a subsequent
reaction, for example, the synthesis of 4a from the reaction of
benzaldehyde, morpholine and phenylacetylene (Scheme 1). The
remaining PEG containing CuI could be recycled and reused for
five runs without noticeably decreasing the productivity. In the
next run there was no need for further additions of copper salt.
40
3
88
4
53
5
64
6
42
7
92
8
CuI
81
9
CuI
27
38
10
11
12
CuI
THF
CuI
CH3CN
42
–
PEG-400
No reaction
a All reactions were run with benzaldehyde 1a (1 mmol), morpholine
2a (1.2 mmol), phenylacetylene 3a (1.5 mmol) and catalyst (10 mol%)
in 1 ml of solvent at 100 ◦C for 12 h under N2 atmosphere.
b Isolated yields.
Conclusion
In summary, we have developed a copper-catalyzed method for
the one-pot synthesis of propargylamines by three-component
A3 coupling reaction of aldehyde, amine and alkyne via C–H
activation in good yields in the presence of CuI in PEG under
nitrogen atmosphere. Work to probe the detailed mechanism and
apply the reaction in organic synthesis is currently underway.
a trace of 4a was obtained in the absence of CuI (Table 1, entry
8). On the other hand, the effect of solvents was tested. Among
all the solvents screened (H2O, THF, CH3CN, PEG and ionic liquid
[Bmim]PF6), PEG was determined to be the most effective medium
for the generation the desired product (Table 1, entries 8–12).
With the optimal conditions in hand, we chose a variety
of diverse aldehydes, amines and alkynes possessing the of
functional groups to understand the scope and generality of
copper-catalyzed A3 coupling reaction in PEG and the results are
summarized in Table 2.
As shown in Table 2, aromatic aldehydes bearing either
electron-donating or electron-withdrawing groups on the
aromatic ring were investigated. The substitution groups on
the aromatic ring had no obvious effect on the yield under
the optimal conditions. Various aldehydes 1a–1h reacted
effectively with morpholine and phenyl acetylene to produce the
corresponding propargylic amines in good yields (Table 2, entries
1–8). It should be noted that the products of 4e and 4f had
the bromo group untouched (Table 2, entries 5 and 6). Similarly,
aromatic heterocyclic aldehydes such as furan-2-carboxaldehyde
(1i) and thiophene-2-carboxaldehyde (1j) were also equally
effective for this conversion and the desired products of4i and
4j were obtained in 87 and 85% yields, respectively (Table 2,
entries 9 and 10). Reactions involving aliphatic aldehydes such
as n-butyl aldehyde (1k) gave higher yields (Table 2, entry 11).
While unwanted trimerization of aliphatic aldehydes is a major
limitation of the A3 coupling reactions catalyzed by homogeneous
catalysts,[18–34] almost no trimer could be detected with aliphatic
aldehydes when using CuI as the catalyst in PEG.
Experimental
All chemicals were either purchased or purified by standard
techniques without special mention. IR spectra were recorded
on a Bruker-EQUINOX55 spectrometer. The products were
identified by NMR on a Bruker-300 spectrometer or a Bruker-500
spectrometer using CDCl3 as the solvent with tetramethylsilane
(TMS) as an internal standard at room temperature. Elemental
analysis was determined on a Carlo-Erba 1108 instrument. All
reactions were conducted using standard Schlenk techniques.
Column chromatography was performed using EM Silica gel 60
(300–400 mesh). For analytical data and spectra (1H and 13C NMR)
of all compounds see Supporting Information.
General Synthetic Procedure for One-pot Synthesis
of Propargylamines
A mixture of CuI (0.05 mmol), aldehyde (0.5 mmol), amine
(0.6 mmol), alkyne (0.75 mmol) and PEG-400 (1 ml) was stirred
for 12 h at 100 ◦C under nitrogen atmosphere. After completion of
thereaction(monitoredbyTLC), themixturewasdilutedwithethyl
acetate (20 ml), washed with water (20 ml) and the aqueous layer
wasthenextractedwithethylacetate(3×10 ml).Thecombinedor-
ganiclayerwasdriedoverMgSO4 andconcentratedundervacuum.
Further purification was carried out by column chromatography
on silica gel eluting with ethyl acetate–petroleum ether. After ex-
traction with ethyl acetate, the catalyst in the aqueous phase was
On the other hand, several terminal alkynes were examined for
the coupling using benzaldehyde and morpholine as the model
substrates.Alkyneswithelectron-donatinggroupsonthearomatic
ring such as 1-ethynyl-4-methylbenzene (3b) and 1-ethynyl-4-
methoxybenzene(3c)gavegoodyields(Table 2,entries12and 13).
c
wileyonlinelibrary.com/journal/aoc
Copyright ꢀ 2010 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2010, 24, 809–812

Copper-catalyzed one-pot synthesis of propargylamines
Table 2. Copper-catalyzed one-pot synthesis of propargylamine derivativesa
Entry
R1
Amine
R4
Product
Yield (%)b
1
2
Ph (1a)
4-FC6H4 (1b)
4-ClC6H4 (1c)
2,4-Cl2C6H3 (1d)
4-BrC6H4 (1e)
2-BrC6H4 (1f)
4-MeC6H4 (1g)
4-MeOC6H4 (1h)
2-furyl (1i)
2-thienyl (1j)
CH3CH2CH2 (1k)
1a
Morpholine (2a)
Ph (3a)
4a
4b
4c
4d
4e
4f
92
88
91
87
91
88
87
86
87
85
96
85
88
91
94
2a
3a
3
2a
3a
4
2a
3a
5
2a
3a
6
2a
3a
7
2a
3a
4g
4h
4i
8
2a
3a
9
2a
3a
10
11
12
13
14
15
2a
3a
4j
2a
2a
3a
4-MeC6H4 (3b)
4-MeOC6H4 (3c)
3a
4k
4l
1a
2a
4m
4n
4o
1a
Pyrrolidine (2b)
Piperidine (2e)
1a
3a
a All reactions were run with aldehyde 1 (1 mmol), amine 2 (1.2 mmol), alkyne 3 (1.5 mmol) and CuI (10 mol%) in PEG-400 (1 ml), 100 ◦C for 12 h under
N2 atmosphere.
b Isolated yields.
concentratedinovenat130 ◦Cfor6 handthesolutionoftherecov-
ered CuI and PEG-400 could be reused in the next batch reaction.
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4-(3-(4-Methoxyphenyl)-1-phenylprop-2-ynyl)morpholine(4m)
IR (KBr): 2954, 2851, 16.05, 1508, 1450, 1290, 1245, 1171, 1114,
1071, 1030, 1001, 970, 864, 830, 805, 747, 713, 698 cm−1; 1H NMR
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Acknowledgments
We are grateful for financial support from the National Key
Technology R&D Program (no. 2007BAI34B00), the Natural Science
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