Cobalt-catalyzed alkyne-dihalomethane-amine coupling: An efficient route for propargylamines

Article abstract of DOI:org/10.1016/j.tetlet.2012.08.136

A cobalt-catalyzed three-component coupling of terminal alkynes, dihalomethanes, and amines was developed. This method offers an efficient way for propargylamines via the dual activation of C-H and C-halogen bond. The reaction uses cheap CoBr₂

Full text of DOI:org/10.1016/j.tetlet.2012.08.136

Tetrahedron Letters 53 (2012) 6199–6201
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Tetrahedron Letters
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Cobalt-catalyzed alkyne–dihalomethane–amine coupling: an efficient route for
propargylamines
Yanchi Tang a, Tiebo Xiao a, Lei Zhou a,b,
⇑
a School of Chemistry and Chemical Engineering, Sun Yat-Sen University, 135 Xingang West Road, Guangzhou 510275, China
b Beijing National Laboratory for Molecular Sciences, Beijing 100871, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A cobalt-catalyzed three-component coupling of terminal alkynes, dihalomethanes, and amines was
developed. This method offers an efficient way for propargylamines via the dual activation of C–H and
C–halogen bond. The reaction uses cheap CoBr2 as catalyst and is phosphine ligand-free. A wide range
of functional groups were found to tolerate the reaction conditions.
Received 15 June 2012
Revised 24 August 2012
Accepted 30 August 2012
Available online 12 September 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Cobalt
Propargylamines
Alkynes
Amines
Dihalomethane
Transition-metal-catalyzed methods for the direct activation of
C–H bonds have emerged as powerful alternatives to more tradi-
tional reactions that rely heavily on stoichiometric substrate preac-
tivation.1 In this context, the three-component coupling of an
aldehyde, an alkyne, and an amine (A3 coupling) reaction has re-
ceived considerable attention in which the terminal alkyne is used
as a carbon nucleophilic source via C–H activation.2 This excellent
reaction also provided an attractive and atom-efficient approach
for the synthesis of propargylamines, which are useful building
blocks as well as important skeletons of biologically active com-
pounds and synthetic intermediates.3 Recently, Contel and Urriola-
beitia reported an efficient gold-catalyzed three-component
coupling of alkynes, dihaloalkanes, and amines (AHA coupling),
which offered an alternative way for propargylamines via the acti-
vation of C–H and C–halogen bond.4 In addition, significant pro-
gress has been documented for AHA coupling catalyzed by
copper,5 nano-In2O3,6 and FeCl3.7 However, comparing to various
transition-metal-catalyzed A3 coupling, the catalyst employed for
AHA coupling is still limited.
with cobalt, the example for the cobalt-catalyzed reaction of termi-
nal alkynyl C–H bond is rare.12 As a catalytic Grignard type reaction
for the transformation of alkynyl C–H bond, herein we disclose an
alkyne-dihalomethane–amine coupling with simple CoBr2 as the
catalyst, which affords a series of propargylamines in good yields
under mild conditions.
At the outset of this investigation, we employed phenylacety-
lene, dichloromethane, and diethylamine as substrates by using
10 mol % of CoCl2 as catalyst in MeCN at 40 °C for 24 h, and the de-
sired propargylamine 4a was generated in 16% yield (Table 1, entry
1). Increasing the reaction temperature increased the yield, giving
55% and 74% yields when the reaction was carried out at 60 °C and
80 °C, respectively (Table 1, entries 2 and 3). Among the various co-
balt salts examined, CoBr2 gave the best results (Table 1, entries 3–
6). However decreased yields were observed when CoBr2(PPh3)2,
CoBr2(dppe), CoBr2(dppm), CoBr2(dppb), and CoCl2(PPh3)2 com-
plexes were employed as the catalysts (Table 1, entries 7–11). Fur-
ther inspection of the reaction conditions revealed that this
reaction proceeded more efficiently in the presence of organic
bases such as DBACO and TEA (Table 1, entries 12 and 13), whereas
inorganic bases K2CO3, NaOAc, and K3PO4 were found to be unfa-
vorable (Table 1, entries 14–16). MeCN appeared to be the best
choice among the common solvents such as CH2Cl2, THF, toluene,
DMF, and DMSO (Table 1, entries 17–21).
Cobalt-based systems as catalysts for the reactions involving al-
kynes such as Pauson–Khand reaction,8 Vollhardt [2+2+2] cycliza-
tion,9 and Nicholas reaction10 have been well studied. Cobalt
complexes were also proved to be efficient catalysts for the C–C
bond formation via C–H activation.11 However, all these reactions
are based on the
g
2 interaction between the triple bond of alkynes
With the optimized condition in hand, we then tested the scope
and limitation of this cobalt-catalyzed three-component coupling
of alkynes, dihalomethanes, and amines reaction. As shown in
Table 2, dichloromethane, dibromomethane, and diiodomethane
⇑
Corresponding author.
E-mail address: zhoul39@mail.sysu.edu.cn (L. Zhou).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.136

6200
Y. Tang et al. / Tetrahedron Letters 53 (2012) 6199–6201
Table 1
Optimization of reaction conditionsa
DBU (1 equiv)
MeCN, 80 o
N
Ph
+
Ph
C
Cl
N
H
Co(II) 10 mol%
solvent, base, ToC
NEt2
+
HNEt2
+
CH2Cl2
Ph
5
4g
, 91%
Ph
1a
2a
3a
4a
Scheme 1. The reaction of 3-chloro-1-phenyl-1-propyne 5 with piperdine.
Entry
Catalyst
Base
Solvent
T/°C
Yieldb
%
1
2
3
4
5
6
7
8
CoCl2
CoCl2
CoCl2
CoBr2
CoI2
DBUc
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
CH2Cl2
THF
40
60
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
16
55
74
90
68
36
51
44
61
52
40
82
75
47
40
25
88
45
48
60
74
4-methoxyphenylacetylene, and 4-fluorophenylacetylene under-
went coupling with dichloromethane and diethylamine smoothly
to afford propargylamines 4b–d in good yields (Table 2, entries
4–6). It is worth mentioning that the alkyl terminal alkynes 4-phe-
nyl-1-butyne and 1-hexyne were also suitable substrates for the
reaction, generated the propargylamines 4e and 4f in the yields
of 74% and 61%, respectively (Table 2, entries 7 and 8). For the
three-component coupling of aromatic alkynes, dichloromethane,
and piperdine, various functional groups including halogens, ester,
methyl, and methoxyl groups present in alkynes were well toler-
ated during the course of the reaction (Table 2, entries 9–14). Be-
sides, 1-ethynyl naphthalene was also suitable for the reaction,
yielding the desired product 4m in 88% (Table 2, entry 15). We
were pleased to find that both cyclic and acyclic secondary amines
such as 4-methyl piperdine, pyrrolidine, morpholine, and diisopro-
pylamine were efficiently converted into the corresponding AHA
coupling products in moderate to good yields (Table 2, entries
16–19). However, in the cases of primary amines and diphenyl-
amine, no coupling product was identified.
Co(OAc)2
CoBr2(PPh3)2
CoBr2(dppe)
CoBr2(dppm)
CoBr2(dppb)
CoCl2(PPh3)2
CoBr2
CoBr2
CoBr2
CoBr2
CoBr2
9
10
11
12
13
14
15
16
17
18
19
20
21
DABCOd
TEAe
K2CO3
NaOAc
K3PO4
DBU
DBU
DBU
CoBr2
CoBr2
CoBr2
CoBr2
toluene
DMF
DMSO
DBU
DBU
CoBr2
a
All the reactions were conducted by using phenylacetylene 1a (0.3 mmol),
dichloromethane 2a (0.9 mmol), diethylamine 3a (0.9 mmol), base (2 equiv) in 2 mL
To understand the mechanism of the reaction, 3-chloro-1-phe-
nyl-1-propyne 5 was prepared and reacted with piperdine in the
presence of DBU in MeCN at 80 °C, the reaction gave propargylam-
ines 4g in 91% isolated yield (Scheme 1).
of solvent.
b
Yields were determined by 1H NMR by using MeNO2 as the internal standard.
c
DBU: 1,8-Diazabicyclo[5.4.0]undec-7-ene.
DABCO: 1,4-Diazabicyclo[2.2.2]octane.
d
e
TAE: Triethylamine.
Based on this observation and the literature reports,4–7,12,13
a
plausible mechanism involving Co(I)–Co(III)–Co(I) catalytic cycle
was proposed as shown in Scheme 2. Initially, Co(I) catalyst was
generated in situ from Co(II), which might be reduced by alkynes
or bases. The insertion of the C–H bond of the terminal alkyne by
Co(I) species gave alkynyl-cobalt complex A. Oxidative addition
are all good coupling partners for the reaction with phenylacety-
lene and diethylamine under the present cobalt-catalyzed system
(Table 2, entries 1–3). Aromatic alkynes such as 4-ethynyl toluene,
Table 2
a,14
Cobalt-catalyzed three-component coupling of alkynes, dihaloalkanes, and amines.
CoBr2 (10 mol%)
N
HN
+
+
CH2X2
R
DBU (2 equiv)
R
MeCN, 80oC
4
1
2
3
Entry
Alkyne R
Dihalo methane
Amine
Product
Yieldb
%
1
2
3
4
5
6
Ph
Ph
Ph
CH2Cl2
CH2Br2
CH2I2
Et2NH
Et2NH
Et2NH
Et2NH
Et2NH
Et2NH
Et2NH
Et2NH
Piperdine
Piperdine
Piperdine
Piperdine
Piperdine
Piperdine
Piperdine
4-Methyl piperdine
Pyrrolidine
Morpholine
iPr2NH
4a
4a
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
85
87
88
88
80
75
74
61
92
87
71
80
77
89
88
94
60
68
42
p-MeC6H4
p-MeOC6H4
p-FC6H4
PhCH2CH2
C4H9
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
7c
8d
9
Ph
10
11
12
13
14
15
16
17
18
19
p-MeOC6H4
p-FC6H4
p-ClC6H4
p-MeO2CC6H4
m-MeC6H4
1-Naphthyl
Ph
Ph
Ph
Ph
4m
4n
4o
4p
4q
a
All the reactions were carried out by using 0.5 mmol of terminal alkynes, 3 equiv of dihalomethanes, 3 equiv of amines, and 2 equiv of DBU in the presence of 10 mol % of
CoBr2 in MeCN at 80 °C for 24 h.
b
Isolated yield.
Reaction time: 30 h.
The reaction was performed at 60 °C for 40 h.
c
d

Y. Tang et al. / Tetrahedron Letters 53 (2012) 6199–6201
6201
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4
NR'2
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[CoII]
[CoI]
R
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Scheme 2. Mechanistic Rationale.
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In conclusion, we have developed a method for the synthesis of
propargylamines via cobalt-catalyzed three-component coupling
of alkynes, dihalomethanes, and amines. A wide range of functional
groups were found to tolerate the reaction conditions. Moreover,
this reaction uses cheap CoBr2 as catalyst and is phosphine li-
gand-free, thus having significant economic advantages and poten-
tial application for large scale synthesis.
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Acknowledgments
Financial support from the NSFC (J1103305), the Sun Yat-sen
University and the Beijing National Laboratory of Molecular Sci-
ences (BNLMS) is gratefully acknowledged.
Supplementary data
14. Representative experimental procedure for cobalt-catalyzed three-component
coupling of alkynes, dihaloalkanes, and amines. Synthesis of 4a: CoBr2 (10.9 mg,
10 mol %) and DBU (152 mg, 1 mmol) were suspended in CH3CN (2 mL) in a
5 mL schlenk tube under nitrogen. And then phenylacetylene (51 mg,
0.5 mmol), dichloromethane (126 mg, 1.5 mmol), and diethylamine
(109.5 mg, 1.5 mmol) were added via syringe. The resulting solution was
stirred at 80 °C for 24 h. After cooling to room temperature, the resulting
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.08.
136.
References and notes
mixture was filtered through
a short path of silica gel, eluting with
dichloromethane. The volatile compounds were removed in vacuo and the
residue was purified by column chromatography (SiO2, hexane/ethyl
acetate = 10:1) to give 4a as
(300 MHz, CDCl3) d 7.43–7.40 (m, 2H), 7.30–7.25 (m, 3H), 3.68 (s, 2H), 2.68
(q, J = 7.2 Hz, 4H), 1.16 (t, J = 7.2 Hz, 6H); 13C NMR (75 MHz, CDCl3): d = 131.8,
128.3, 128.0, 123.5, 85.3, 84.5, 47.6, 41.8, 12.9 ppm.
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a
colourless oil (79.5 mg, 85%).1H NMR