Efficient synthesis of propargylamines from terminal alkynes, dichloromethane and tertiary amines over silver catalysts

Article abstract of DOI:10.1039/c3ob41878b

A simple, efficient and highly functional group compatible method for the synthesis of propargylamines from terminal alkynes, dichloromethane and tertiary amines using silver catalysts has been developed.

Full text of DOI:10.1039/c3ob41878b

Organic &
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Efficient synthesis of propargylamines from
terminal alkynes, dichloromethane and tertiary
amines over silver catalysts†
Cite this: Org. Biomol. Chem., 2014,
12, 247
Received 15th September 2013,
Accepted 5th November 2013
Xiuling Chen,a Tieqiao Chen,a Yongbo Zhou,*a Chak-Tong Au,a,b Li-Biao Hana and
Shuang-Feng Yin*a
DOI: 10.1039/c3ob41878b
www.rsc.org/obc
A simple, efficient and highly functional group compatible method propargylamines, we believe that the protocol has a great deal
for the synthesis of propargylamines from terminal alkynes, of applicability.
dichloromethane and tertiary amines using silver catalysts has
been developed.
ð1Þ
Propargylamines have attracted considerable attention over the
First, phenylacetylene, dichloromethane and triethylamine
were chosen as model reactants for the optimization of reac-
tion conditions, and selected results are shown in Table 1.
Using 5 mol% AgOAc as a catalyst, we screened parameters
such as the amounts of CH2Cl2 and Et3N (Table 1, entries 1–4),
and the best result is obtained under the conditions of
1 mmol of phenylacetylene, 15 mmol of CH2Cl2 and 3 mmol of
Et3N in 1 mL dioxane at 120 °C for 12 h. The effect of AgOAc
loading was also investigated. When 1 mol% of AgOAc is used,
only 62% yield of 3a is obtained (Table 1, entry 5). However,
past few decades due to their wide applications in medical and
synthetic chemistry.1,2 Conventional synthetic procedures for
the preparation of propargylamines involve the use of stoichio-
metric amounts of alkynylmetal reagents which are highly
moisture-sensitive, and the harsh conditions hinder their wide
application.3 Direct oxidative cross-coupling of tertiary amines
with terminal alkynes represents an alternative route for the
synthesis of propargylamines,4 but the approach is far from
ideal due to the use of dangerous peroxides and extra addi-
tives. Recently, the three-component coupling reaction of
alkynes and aldehydes (or dihalomethanes) with primary (or
secondary) amines provided a more efficient and attractive
method to produce propargylamines.5,6 Although these proto-
cols represent approaches that are more straightforward for
the synthesis of propargylamines, the reactions are limited to
primary (secondary) amines, and some functional groups such
as the carbonyl group are generally sensitive to these amines.
Compared with primary and secondary amines, tertiary
amines are inexpensive, commercially available and relatively
stable to many functional groups. Herein, for the first time a
silver-catalyzed reaction of alkyne, dichloromethane and ter-
tiary amine is reported for the formation of propargylamines
in high to excellent yields via the selective cleavage of C–N
bonds (eqn (1)). The method is highly tolerant to functional
groups and can be applied to both aromatic and aliphatic
alkynes. As an alternative method for the production of
Table 1 Optimization of the reaction conditionsa
Entry
CH2Cl2 (mmol)
Et3N (mmol)
Catalyst
Yieldb (%)
1
2
3
1
3
7
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgNO3
Ag2CO3
AgOSO2CF3
AgBF4
Trace
10
38
98
62
98
40
88
80
80
90
70
92
85
Trace
4
15
15
15
15
15
15
15
15
15
15
15
15
5c
6d
7e
8
9
10
11
12
13
14
15
AgClO4
AgOSO2C4F9
AgCl
aState Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry
and Chemical Engineering, Hunan University, Changsha 410082, China.
E-mail: zhouyb@hnu.edu.cn, sf_yin@hnu.edu.cn; Fax: (+) 86-731-88821171
—
a Reaction conditions: phenylacetylene (1.0 mmol), CH2Cl2
(1–15 mmol), Et3N (3 mmol), dioxane (1 mL), N2, 120 °C, 12 h, a
sealed tube. b Reported yields were based on phenylacetylene and
determined by GC using dodecane as an internal standard. c AgOAc
(1 mol%). d AgOAc (7 mol%). e 100 °C.
bDepartment of Chemistry, Hong Kong Baptist University, Kowloon Tong Hong Kong,
China
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c3ob41878b
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further increase of AgOAc to 7 mol% does not improve the alkyl chain length, the lower the yield. For unsymmetrical amines,
yield of 3a (Table 1, entry 6). The reaction is found to be sensi- a high selectivity to C–N bond cleavage is observed over the ter-
tive to temperature, e.g. at 100 °C, only 40% 3a is produced tiary amines. For example, a high selectivity to N–Me cleavage is
under similar conditions (Table 1, entry 7). Other silver cata- observed using the substrate of dimethylcyclohexylamine 2f and
lysts are also effective for this three-component coupling reac- the yield of product 3f is 89% (Table 2, entry 6). The high selecti-
tion (Table 1, entries 8–14). It should be noted that the vity to C–N bond cleavage is also detected over cyclic amines,
addition of the silver catalyst is essential; in the absence of the such as piperidine-derived tertiary amine (2g, 2h) and morpho-
silver catalyst, only a trace amount of 3a is detected under line-derived tertiary amine 2i (Table 2, entries 7–9). Under similar
similar reaction conditions (Table 1, entry 15).
reaction conditions, secondary amines are also good substrates,
The method can be successfully applied to other terminal and higher yields (95–96%) of the corresponding products via
alkynes and tertiary amines, indicating that the reaction is selective N–H cleavage are obtained in comparison to those of the
generally applicable to production of propargylamines previously reported catalytic systems (Table 2, entries 10–12).6
(Tables 2 and 3). Under the optimized conditions described
Besides the tertiary amines, a variety of alkynes can be
above, we find that a variety of tertiary amines 2a–2i, both sym- smoothly converted to the corresponding propargylamines
metrical and unsymmetrical, react readily with phenylacetylene under the optimized conditions. As compiled in Table 3, the
and dichloromethane to give the corresponding propargyl- silver-catalyzed system is effective for both aromatic and ali-
amines via C–N bond cleavage (Table 2). For a symmetrical ter- phatic alkynes. It is worth noting that the reaction shows wide
tiary amine, only one of the three C–N bonds is cleaved to give functional-group tolerance; functional groups such as ether
the product (Table 2, entries 1–5). The three-component coupling (Table 3, entry 5), Br (Table 3, entry 6), Cl (Table 3, entry 7),
reaction seems to be strongly affected by the alkyl chain length of F (Table 3, entry 8), CF3 (Table 3, entry 9), NO2 (Table 3,
amines. It is found that the increase of alkyl chain length has a entry 10), CN (Table 3, entry 11), and ester (Table 3, entry 16)
negative effect on the yield of products; namely, the longer the are all compatible, and the corresponding propargylamines are
Table 2 Substrate scope of aminesa
Entry
Amine
Time (h)
Product
Yieldb (%)
1
2
R3N
R = Et
R = n-Pr
2a
2b
12
36
3a
3b
93
88
3
4
5
2c
2d
2e
R = allyl
R = n-Bu
R = n-Oct
40
60
96
3c
3d
3e
86
85
70
6
2f
8
3f
89
7
2g
10
3g
85
8
9
2h
2i
12
10
3g
3h
87
88
10c
11d
2j
2k
(n-C2H7)2N–H
Cy2N–H
7
12
3b
3i
96
95
12e
2l
7
3h
96
a Reaction conditions: phenylacetylene (1.0 mmol), CH2Cl2 (15 mmol), amines (3 mmol), dioxane (1 mL), N2, 120 °C, a sealed tube. b Isolated
yield. c Di-n-propylamine. d Dicyclo hexylamine. e Morpholine.
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Table 3 Substrate scope of terminal alkynesa
Table 4 Scope of alkynes and tertiary aminesa
Yieldb (%)
Entry
Terminal alkyne
Product
Yieldb (%)
Entry
Alkyne
Amine
Product
1
1a
1b
1c
1d
1e
1f
3a
3j
93
88
89
89
90
92
90
89
91
92
90
88
87
89
1
2
2f
3z3
3z4
92%
91%
2
2a
3
3k
3l
4
3
2b
3z5
90%
5
3m
3n
3o
3p
3q
3r
6
a Reaction conditions: alkyne (1.0 mmol), CH2Cl2 (15 mmol), tertiary
amine (3 mmol), dioxane (1 mL), N2, 120 °C, a sealed tube. b Isolated
yield.
7
1g
1h
1i
8
9
10
11
12c
13
14
1g
1k
1q
1l
products (Table 4). Methyl phenyl acetylene 1b reacts with N,N-
dimethyl cyclohexylamine 2f to give the corresponding propar-
gylamine 3z3 in 92% yield (Table 4, entry 1). The carbonyl
group is found compatible in this reaction system, e.g. 1-(4-
ethynylphenyl)ethanone 1v reacts with 2a and 2b to give the
corresponding products 3z4–3z5 in 90% and 91% yield respect-
ively (Table 4, entries 2–3).
3s
3t
3u
3v
1m
15
1n
3w
80
The reaction mechanism was also investigated. Under the
adopted reaction conditions, it is found that CH2Cl2 reacts
with Et3N to form 1-chloro-N,N,N-triethylmethaniminium chlor-
ide (4a) in 85% yield as colorless crystals at 80 °C in DMF
(eqn (2)). By heating 4a with an equal amount of phenyl-
acetylene under the conditions of 5 mol% AgOAc in dioxane at
120 °C for 6 h, the corresponding propargylamine 3a is
obtained quantitatively (eqn (3)). An experiment using CD2Cl2
instead of CH2Cl2 as the substrate confirms that the two
protons of the methylene group of dichloromethane are not
affected during the reaction, indicating that the proton for the
formation of amine hydrochloride comes from alkyne (eqn (4)).
16
17
1o
1p
—
—
3x
91
18
19
1r
1s
3y
3z
82
83
20
1t
3z1
88
21
1u
3z2
87
a Reaction conditions: terminal alkynes (1.0 mmol), CH2Cl2
(15 mmol), Et3N (3 mmol), dioxane (1 mL), N2, 120 °C, 12 h, a sealed
tube. b Isolated yield. c 1,4-Diethynylbenzene (1.0 mmol), AgOAC
(10 mol%), CH2Cl2 (30 mmol), Et3N (6 mmol), dioxane (1 mL), 20 h.
ð2Þ
ð3Þ
produced in high to excellent yields. In addition, two amino
groups can be easily introduced into diyne as exemplified by
the alkylation of aromatic diyne 1q (Table 3, entry 12). Further-
more, aliphatic alkynes are good substrates, giving the corres-
ponding propargylamines in good yields (Table 3, entries
13–15, 16–19). Especially the yields are still good when ali-
phatic alkynes bearing active hydroxyl groups are used as sub-
ð4Þ
According to the reported studies7–9 and our experimental
strates (Table 3, entries 13–15). Unfortunately, ethynylphenol results, the catalytic reaction pathways for the three-com-
fails to give the propargylamine product perhaps due to the ponent coupling reaction are proposed as shown in Scheme 1.
acidity (Table 3, entry 15). The heteroaryl alkynes such as 2- First, methaniminium chloride 4 is formed by the reaction of
ethynylpyridine and 2-ethynylpyridine are also good sub- R1R2R3N with CH2Cl2,7 and then decomposes via R1Cl dis-
strates, and products 3z1 and 3z2 are obtained in good yields sociation to produce methyleneammonium chloride 5.8 It is
(Table 3, entries 20–21).
known that 5 is a Mannich reaction intermediate,5 which
Under the optimized conditions, substituted alkynes react reacts with silver acetylide9 to give the corresponding
with different tertiary amines smoothly to furnish the desired propargylamine, with the Ag(I) catalyst being regenerated.5c
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Scheme 1
propargylamines.
A
plausible
mechanism
for
the
formation
of
In conclusion, for the first time, an efficient method for the
preparation of propargylamines via a silver-catalyzed three-
component coupling reaction using tertiary amines as the
source of the nitrogen group is demonstrated. The reaction
shows high functional-group tolerance and can be conducted
without the use of an exotic base, a co-catalyst or an additive.
The success of the present studies not only provides a new
strategy for the preparation of propargylamines but also
suggests a powerful method for C–N bond cleavage.
This work was supported by the NSFC (U1162109,
21172062, and 21003040), the Program for NCET in Univer-
sities (NCET-10-0371), and the PCSIRT (IRT1238). C.T. Au
thanks HNU for an adjunct professorship.
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