1,4,7-Trimethyl-1,4,7-triazacyclononane as a low-loading catalyst: CuBr-tmtacn catalysed Glaser reaction of acetylenes

Article abstract of DOI:10.3184/174751914X681970

1,4,7-Trimethyl-1,4,7-triazacyclononane (tmtacn, a cyclic trident-ligand) has been developed as a facile and efficient catalyst for Cu-catalysed homocoupling of terminal alkynes at room temperature. A variety of 1,3-diynes have been synthesised in excelle

Full text of DOI:10.3184/174751914X681970

362 RESEARCH PAPER
VOL. 38 JUNE, 362–364
JOURNAL OF CHEMICAL RESEARCH 2014
1,4,7-Trimethyl-1,4,7-triazacyclononane as a low-loading catalyst:
CuBr–tmtacn catalysed Glaser reaction of acetylenes
Jian Sun, Hua-He Zhang, Jian-Qiang Wang and Jing-Hua Li*
College of Pharmaceutical Sciences, Zhejiang University of Technology, 310032, Hangzhou, P.R. China
1,4,7-Trimethyl-1,4,7-triazacyclononane (tmtacn, a cyclic trident-ligand) has been developed as a facile and efficient catalyst for
Cu-catalysed homocoupling of terminal alkynes at room temperature. A variety of 1,3-diynes have been synthesised in excellent
yields with a catalyst loading on a scale of 0.1–0.5 mol% CuBr–tmtacn.
Keywords: 1,3-diynes, tmtacn, low-loading catalyst, Glaser reaction
The 1,3-diyne moiety is a key structural motif in numerous
compounds that possess biological activity.1 In particular,
recent research has shown that it is a crucial intermediate
for the synthesis of certain heterocyclic compounds such as
3,5-disubstituted pyrazoles,2 2,5-disubstituted furans3 and
alkylidene lactones4 in favourable yields. Consequently,
oxidative homocoupling of terminal alkynes has attracted great
interest as it represents the most straightforward approach to
produce 1,3-diyne derivatives.
performed in 97% yield only using 0.03–0.04 mol% Mn(II)–
tmtacn as catalyst.22 Notably, this ligand has not yet been
applied in oxidative homocoupling reactions. Intrigued by the
development of diamine ligands in copper-catalysed reactions,23
we speculated that the combination of a copper salt and tmtacn
might lead to better results.
Initially, phenylacetylene 1a was chosen as a model
substrate with CuI–ligand as a catalyst in acetone (Table 1).
The corresponding 1,3-diyne was generated smoothly with
no sign of by-products (monitored by TLC). Moreover, the
experiment with tmtacn took much less time than the one with
tmeda (Table 1, entries 1 and 2) to achieve a similar result.
Interestingly, it revealed that excellent yields could still be
obtained in the presence of only 0.5 mol%tmtacn (Table 1, entry
4). The catalytic activity severely declined when the catalyst
loading was further decreased to 0.1 mol% (Table 1, entry 5).
Nevertheless, it revealed that the catalytic activity of tmtacn is
nearly 100 times higher than the one of tmeda (Table 1, entries
1 and 5). The plausible reason could be that combination of
copper salt and tmtacn lead to a more stable complex, compared
with Cu–linear ligand catalyst systems.
In order to reduce the reaction time, 0.5 mol% of catalyst
loading was chosen in the subsequent studies. In the case of the
homocoupling of phenylacetylene 1a under the same conditions
but in the absence of tmtacn (Table 1, entry 6), only a trace
of 1,3-diyne was detected. Thus, we demonstrated that tmtacn
is a highly efficient ligand for Cu-catalysed homocoupling of
phenylacetylene.
Since Glaser’s ground-breaking work on the oxidative
dimerisation of copper(I) acetylide in 1869, the homocoupling
of terminal alkynes has been much studied and improved as
researchers focus on maximising the general efficiency. Uses
of catalyst systems involving noble metals such as Pd5–7 and
Au8 are both innovative and feasible but often not industrially
practicable. Moreover, copper salts are commonly considered
as important co-catalysts in these protocols. Exploration of
an efficient copper-catalysed system is more straightforward.
Hay’s procedure,9 which requires only the combination of a
copper(I) salt and tertiary amines, has been known for a long
time. The influence of ligands, bases and other conditions
on the outcome of this type of coupling has been studied
systematically. In Adimurthy’s work,10 it is shown that the CuCl–
tmeda (tetramethylethylenediamine) complex is a favourable
catalyst with the aid of an equivalent amount of DBU as a base.
In 2011, Zhang 11reported that 10 mol%CuCl–tmeda complex
with Solkane®365mfc as solvent is an environmentally benign
route for synthesis of 1,3-diynes and this reaction could also be
achieved with CuI as the copper salt in common solvents.
A key limitation of previous copper-catalysed protocols is
the requirement for harsh conditions (stoichiometric amounts
of copper salts,12 particular solvents,13 high temperature,14,15
long reaction times,15,16 and unfavourable yields17). More
recently, Vilhelmsen’s group18 has reviewed improvements of
the Glaser–Hay reaction and screening of linear ligands. Up
to now, macrocyclic ligands have not yet been investigated.
Other catalyst systems such as Cu(OH)x/OMS-2,19 [(Lx)
(μ-Cl)2Ni2Cl2(CH3OH)2] 20 and copper catalysed homocoupling
in a ball mill21 have been developed providing viable routes
to obtain 1,3-diynes. These approaches usually suffer from
the disadvantage of complicated set-ups and moderate yields
when applied to the synthesis of aliphatic diynes. Hence,
the development of a facile and effective method to prepare
1,3-diyne derivatives under mild conditions with minimal
catalyst loading is desirable.
With this efficient protocol in mind, the scope of the
copper salts was explored. Results clearly indicated that CuBr
was superior to other copper compounds (Table 2, entry 2).
Therefore, the following experiments were all carried out with
CuBr (0.5 mol%). The influence of solvent was also evaluated.
Poor conversion in the reaction was observed in the presence of
Table 1 Investigation of catalyst loading for homocoupling of
phenylacetylenea
CuI-Ligand
Ph
Ph
Ph
Et3N / acetone / O2
r.t.
Entry
CuI/equiv.
Ligand/equiv.
Time/hb Yield/%c
1
2
3
4
5
6
5 mmol%
5 mmol%
1 mmol%
0.5 mmol%
0.1 mmol%
0.5 mmol%
tmeda/10 mmol%
tmtacn/5 mmol%
tmtacn/1 mmol%
tmtacn/0.5 mmol%
tmtacn/0.1 mmol%
0
20
<0.5
3
5
20
90
92
94
93
91
<1
Tmtacn has been proved to be a highly efficient catalyst.
For example, epoxidation of methyl acrylate was successfully
5
aReaction conditions: 1a (1 mmol), Et3N (3 mmol), acetone (2.5 mL) as
solvent, O2, room temperature.
bProgress of reaction was monitored by TLC.
cIsolated yield.
* Correspondent. E-mail: lijh@zjut.edu.cn
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JOURNAL OF CHEMICAL RESEARCH 2014 363
Table 2 Scope of copper salts, solvents and bases for optimisationa
ones while yields of the corresponding 1,3-diynes were still
satisfactory.
Entry Copper salts Base/equiv.
Solvent
Time/hb Yield/%c
In summary, we have successfully developed a mild and
highly efficient CuBr–tmtacn catalyst system for preparation
of 1,3-diynes, as the catalyst loading can be as low as 0.1%. A
wide variety of terminal alkynes were smoothly converted to
the corresponding 1,3-diynes in high to excellent yields.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
CuI
CuBr
CuCl
CuCl2`2H2O
Cu(OAc)2
CuSO4·5H2O
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
Et3N/3
Et3N/3
Et3N/3
Et3N/3
Et3N/3
Et3N/3
Et3N/3
Et3N/3
Et3N/3
Et3N/3
Et3N/3
Et3N/3
Et3N/2
Et3N/1.1
0
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
MeOH
MeCN
EtOAc
THF
5
4
9
10
5
2
2
2
2
2
2
2
2
2
2
2
2
98
98
99
99
99
Trace
99
76
65
70
98
Trace
90
85
0
Experimental
Commercially available reagents were used without further
purification unless mentioned. All reactions were monitored by
TLC. Visualisation of TLC plates was accomplished with an UV
lamp. The column chromatography was performed using silica gel
(200–300 mesh) with ethyl acetate/hexane as eluent. Melting points
were recorded on a X-4 micro melting point apparatus. 1H NMR
spectra were obtained in CDCl3 on a Bruker Spectrospin 500 MHz
spectrometer using TMS as an internal standard. All products are
known and their physical and spectroscopic data are compared with
those reported in the literature.
CH2Cl2
H2O
MeOH
MeOH
MeOH
MeOH
MeOH
K2CO3/3
Na2CO3/3
Trace
Trace
CuBr-tmtacn-catalysed oxidative homocoupling of terminal alkynes;
general procedure
aReaction conditions: 1a (1 mmol), copper salts (0.5 mmol%), tmtacn
(0.5 mmol%), base, solvent (2.5 mL), room temperature.
bProgress of reaction was monitored by TLC.
cIsolated yield.
Alkyne 1a–k (1 mmol), tmtacn (0.85 mg, 0.5% mmol), CuBr (0.71 mg,
0.5% mmol) and Et3N (303 mg, 3 mmol) and methanol (2.5 mL)
were added successively to a 10 mL tube. The resulting mixture was
then stirred under O2 atmosphere (balloon) at room temperature.
Progress of this reaction was monitored by TLC. After completion of
the reaction, water (10 mL) was added and the mixture was extracted
by ethyl acetate (5 mL×3). The combined organic layer was washed
by brine (10 mL), dried by anhydrous Na2SO4 overnight, and then
concentrated under reduced pressure. The residue was purified by
flash chromatography on silica gel to give the desired 1,3-diynes 2a–k.
H2O (Table 2, entry 12). Reactions with methanol or CH2Cl2 as
solvent gave excellent yields within a short time (Table 2, entries
7 and 11). Methanol was regarded as a more environmentally
benign solvent than the latter. Hence, the choice of methanol is
preferable. In addition, an organic base was shown to be better
than an inorganic base (Table 2, entries 7, 16 and 17), a slightly
decreased yield was observed when the base loading was
decreased from 3 to 1.1 equiv. (Table 2, entries 7, 13 and 14).
Therefore, 3 equiv. Et3N as base was chosen as the optimum.
Under these optimised reaction conditions, the CuBr–tmtacn
catalyst system was applied to the homocoupling reaction
of a series of alkynes. As shown in Table 3, this approach to
1,3-diynes was both efficient and versatile. Dimerisation of
the terminal alkyne, whether with electron-donating groups or
electron-withdrawing groups (1a–g), proceeded smoothly to
give high to excellent yields. For heterocyclic aromatic alkynes
(1h and 1i), the yields were also excellent. Alkynes bearing an
aliphatic group (1j and 1k) were less reactive than aromatic
1
1,4-Diphenylbuta-1,3-diyne (2a): M.p. 85–86°C (lit.6 86–87°C); H
NMR (500 MHz, CDCl3): δ 7.55(m, 4H), 7.34–7.39 (m, 6H).
1,4-Bis(p-methylphenyl)buta-1,3-diyne (2b): M.p. 181–182 °C (lit.24
182–184 °C); 1H NMR (500 MHz, CDCl3): δ 7.43 (d, 4H, J=8.1 Hz), 7.16
(d, 4H, J=8.1 Hz), 2.38 (s, 6H).
1,4-Bis(p-ethylphenyl)buta-1,3-diyne (2c): M.p. 95–96°C (lit.10
95–96°C); 1H NMR (500 MHz, CDCl3): δ 7.47 (d, 4H, J=8.2 Hz), 7.18
(d, 4H, J=8.2 Hz), 2.67 (q, 4H, J=7.6 Hz), 1.25 (t, 6H, J=7.6 Hz).
1,4-Bis(p-propylphenyl) buta-1,3-diyne (2d): M.p. 107–108°C (lit.25
1
107–108°C); H NMR (500 MHz, CDCl3): δ 7.45 (d, 4H, J=8.1 Hz),
7.16 (d, 4H, J=8.1 Hz), 2.61 (t, 4H, J=7.6 Hz), 1.65 (m, 4H), 0.95 (t, 6H,
J=7.3 Hz).
1,4-Bis(p-methoxyphenyl)buta-1,3-diyne (2e): M.p. 139–140°C (lit.6
1
141–142 °C); H NMR (500 MHz, CDCl3): δ 7.48 (d, 4H, J=8.9 Hz),
6.87 (d, 4H, J=8.9 Hz), 3.84 (s, 6H).
1,4-Bis(m-chlorophenyl)buta-1,3-diyne (2f): M.p. 86–87°C (lit.26
73°C); 1H NMR (500 MHz, CDCl3): δ 7.53 (d, 2H, J=1.7 Hz), 7.43 (dd,
2H, J=7.9 Hz, 1.7 Hz), 7.38 (m, 2H), 7.31 (d, 2H, J=7.9 Hz).
1,6-Diphenoxyhexa-2,4-diyne (2g): M.p. 79–80°C (lit.6 77–79°C);
1H NMR (500 MHz, CDCl3): δ 7.32 (m, 4H), 7.02 (dd, 2H,
J=10.6 Hz,4.1 Hz), 6.96 (dd, 4H, J=4.1 Hz, 1.7 Hz), 4.77 (s, 4H).
1,4-Bis(2-pyridine)buta-1,3-diyne (2h): M.p. 118–119 °C (lit.7
116–118 °C); 1H NMR (500 MHz, CDCl3): δ 8.65 (m, 2H), 7.71 (dd, 2H,
J=7.7 Hz, 1.7 Hz), 7.57 (m, 2H), 7.32 (m, 2H).
Table 3 CuBr–tmtacn catalysed homocoupling reaction of terminal
alkynesa
0.5% CuBr-tmtacn
R
R
R
Et3N / MeOH / O2
r.t.
Entry
Substrate,
1a, R=Ph
Product
Time/h
Yield/%b
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2i
2
3
4
4
3
3
5
5
6
7
7
95
98
90
94
99
96
88
94
95
82
80
1b, R=4-MeC6H4
1c, R=4-EtC6H4
1d,R=4-PrC6H4
1e, R=4-MeOC6H4
1f, R=3-ClC6H4
1g, R=PhOCH2
1h, R=Pyridin-2-yl
1i,R=Thiophen-3-yl
1j, R=n-Bu
1,4-Bis (thiophen-3-yl)buta-1,3-diyne (2i): M.p. 107–108°C (lit.27
1
111–113 °C); H NMR (500 MHz, CDCl3): δ 7.61 (dd, 2H, J=3.1 Hz,
1.1 Hz), 7.30 (dd, 2H, J=5.0 Hz, 3.1 Hz), 7.19 (dd, 2H, J=5.0 Hz, 1.1 Hz).
Dodeca-7,9-diyne (2j): 28 1H NMR (500 MHz, CDCl3): δ 2.26 (t, 4H,
J=7.1 Hz), 1.48–1.55 (m, 4H), 1.37–1.46 (m, 4H), 0.91 (t, 6H, J=7.1 Hz).
29
Hexadeca-7,9-diyne (2k): 1H NMR (500 MHz, CDCl3): δ 2.24 (t,
4H, J=7.0 Hz), 1.47–1.57 (m, 4H), 1.35–1.42 (m, 4H), 1.33 (m, 8H), 0.88
(t, 6H, J=7.0 Hz)
10
11
2j
2k
1k, R=n-Hex
Received 23 March 2014; accepted 22 April 2014
Paper 1402548 doi: 10.3184/174751914X681970
Published online: 10 June 2014
aSee ESI for experimental details.
bIsolated yield.
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364 JOURNAL OF CHEMICAL RESEARCH 2014
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