Effects of a flexible alkyl chain on an imidazole ligand for copper-catalyzed mannich reactions of terminal alkynes

Article abstract of DOI:10.1055/s-0030-1259069

Copper-catalyzed Mannich reactions of terminal alkynes and secondary amines with aqueous formaldehyde can be accelerated by the use of a catalytic amount of an imidazole ligand carrying a long alkyl chain. The alkyl chain shows an efficient steric effect

Full text of DOI:10.1055/s-0030-1259069

LETTER
3053
Effects of a Flexible Alkyl Chain on an Imidazole Ligand for
Copper-Catalyzed Mannich Reactions of Terminal Alkynes
Effects of
a
Flex
a
ible
A
lkyl
k
C
hainonan
aImidazole
a
Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Kyoutodaigaku-katsura,
Nishikyo, Kyoto 615-8510, Japan
Fax +81(75)3832459; E-mail: matsubar@orgrxn.mbox.media.kyoto-u.ac.jp
Received 15 October 2010
acetylide species, sterically assisted ligands seem to be ef-
ficient.13 In addition, the capability of using an aqueous
formaldehyde solution would also contribute to the effi-
ciency due to the easiness of handing and the stability
Abstract: Copper-catalyzed Mannich reactions of terminal alkynes
and secondary amines with aqueous formaldehyde can be accelerat-
ed by the use of a catalytic amount of an imidazole ligand carrying
a long alkyl chain. The alkyl chain shows an efficient steric effect
and helps the reaction. This imidazole ligand is efficient for various even at room temperature.14,15
substrates, including even bulky alkynes.
Table 1 Mannich Reaction between Phenylacetylene (1a), Piperi-
Key words: alkyl chain, imidazole, steric effect, copper, Mannich
reaction
dine (2a), and Formaldehyde with Various Ligandsa
H
CuI (0.5 mol%)
N
ligand (1.0 mol%)
+
+
Ph
HCHO (aq)
25 °C, 1.5 h
Ph
An alkyl chain is an important group included in many
amphiphiles or other organic materials; it helps to deter-
mine their properties.1 We recently reported that the imi-
dazole ligand with a long alkyl chain accelerates the
N
1a
2a
3aa
Entry
1
Ligand
none
Yield (%)b
copper(I)-catalyzed
azide–alkyne
cycloaddition
(CuAAC) reaction.2 The ligand with a flexible alkyl chain
shows an efficient steric effect, allowing a creation of a fa-
vorable environment around a Cu center, which can ac-
commodate even bulky substrates.3 Additionally, this
ligand is also useful in aqueous media. On the basis of this
work, we sought to expand the utility of the ligand to an-
other copper-catalyzed transformation of terminal
alkynes. Herein we describe the efficiency of an imida-
zole carrying a long alkyl chain2,4–6 as a ligand to enhance
the Mannich reactions of terminal alkynes mediated by a
copper catalyst.7
30
44
10
29
26
11
19
12
31
40
99
57
52
97
2
pyridine
2,6-lutidine
DMAPc
Et3N
3
4
5
6
n-Bu3N
EtNi-Pr2
4a R = Me
5
7
8
Propargylamines are important compounds because of
their biological activity or their utility as synthetic inter-
mediates.8,9 Although the classical Mannich reaction be-
tween terminal alkynes and secondary amines with
formaldehyde is a useful method to provide propargyl-
amines, it is applicable only to aryl acetylenes.7a The de-
velopment of copper-catalyzed processes removed many
limitations,7,10,11 but the processes still suffer from harsh
conditions, moderate yields, or complex procedures. The
harsh conditions employed in many procedures may be
necessary not only for the formation but also for the acti-
vation of copper-acetylide intermediates; otherwise they
are known to aggregate readily to become an inactive
polymeric form.12 If a certain ligand realizes the activation
of copper-acetylides under mild conditions, this copper-
catalyzed reaction will be more practical. To promote the
generation of active monomeric or oligomeric copper-
9
10
11
12
13
14
6
4b R = 1-add
4c R = n-Bu
4d R = n-C10H21
4e R = n-C16H33
a Reactions were run using 1a (1.0 mmol), 2a (1.0 mmol), formalde-
hyde (37% aq solution, 1.2 mmol), CuI (0.005 mmol), and a ligand
(0.01 mmol).
b Determined by 1H NMR using bromoform as an internal standard.
c DMAP = N,N-dimethyl-4-aminopyridine.
d ad = adamantyl.
We initially examined the reaction between phenylacety-
lene (1a, 1.0 mmol), piperidine (2a, 1.0 mmol), and aque-
ous formaldehyde (37% solution, 1.2 mmol) with 0.5
mol% of CuI and 1.0 mol% of various amine ligands with-
SYNLETT 2010, No. 20, pp 3053–3056
x
x
.x
x
.2
0
1
0
Advanced online publication: 24.11.2010
DOI: 10.1055/s-0030-1259069; Art ID: U09310ST
© Georg Thieme Verlag Stuttgart · New York

3054
T. Okamura et al.
LETTER
out any organic solvent at 25 °C (Table 1). The reaction deprotonate from a terminal alkyne in forming a copper-
without any ligand gave the product 3aa in only 30% yield acetylide intermediate. Thus, the steric effect of the long
(Table 1, entry 1), and the effects of pyridine derivatives, alkyl chain on 4e might also play a role in repulsing the
tertiary amines, or imidazole derivatives substituted by multiple coordination of 4e on a Cu center and releasing
methyl groups (4a, 5, 6; Figure 1)4d as a ligand were also free 4e working as a base.2,17
not satisfactory (Table 1, entries 2–10). On the other hand,
1-(1-adamantyl)imidazole (4b) was shown to be excellent
Table 3 Effects of the Amounts of Imidazole Ligandsa
as a ligand probably because its steric effect was sufficient
(Table 1, entry 11). We then investigated the efficiency of
CuI (0.5 mol%)
N
H
N
N
imidazoles substituted by a normal alkyl group in hopes of
finding a steric effect. As we expected, imidazole deriva-
tives with normal alkyl groups (4c–e) were efficient, and
especially 1-hexadecylimidazole (4e), with the longest
alkyl chain among them, showed as good a result as 4b
(Table 1, entries 12–14). With 4e, we also investigated
some other copper sources, and CuI was shown to be the
best among them (Table 2).
(4, x mol%)
R
+
+
Ph
HCHO (aq)
25 °C, 1.5 h
Ph
N
1a
2a
3aa
Entry
x (mol%) Yield with 4a R =
Yield with 4e
R = n-C16H33 (%)
Me (%)
1
2
3
4
0.5
1.0
1.5
2.0
21
12
14
13
32
97
89
82
R
Me
Me
N
N
N
Me
Me
N
N
N
4a (R = Me)
5
6
4b
4c
4d
4e
(R = 1-ad)
a Reactions were run using 1a (1.0 mmol), 2a (1.0 mmol), formal-
dehyde (37% aq solution, 1.2 mmol), CuI (0.005 mmol) and 4e.
(R = n-C4H9)
(R = n-C10H21
(R = n-C16H33
)
)
Figure 1 Imidazole ligands
We also applied the conditions using 4e as a ligand to
some other secondary amines (Table 4).18 Some cyclic
and acyclic secondary amines were also available, and the
ligand effect of 4e could be observed.19 Especially in the
case of pyrrolidine (2b), the product 3ab was obtained
quantitatively, and a large ligand effect was observed
(Table 4, entry 1).
Table 2 Optimization of Copper Sourcea
H
CuX (0.5 mol%)
N
4e (1.0 mol%)
+
+
Ph
HCHO (aq)
25 °C, 1.5 h
N
1a
2a
Ph
3aa
Table 4 Mannich Reaction of Various Secondary Amines 2 with
Entry
CuX
CuI
Yield (%)b
4ea
1
2
3
4
5
6
97
26
32
47
23
46
CuI (0.5 mol%)
4e (1.0 mol%)
NR2
R NH
+
+
HCHO (aq)
Ph
2
CuBr
CuCl
CuCN
Ph
25 °C, 1.5 h
1a
2
3
Entry 2 R2NH
3
Yield with 4e Yield without 4e
(%)c
(%)c
42
7
(CuOTf)2·benzene
Cu(MeCN)4PF6
1b
2
2b pyrrolidine
2c morpholine
2d Et2NH
3ab
3ac
3ad
3ae
99
34
a Reactions were run using 1a (1.0 mmol), 2a (1.0 mmol), formalde-
hyde (37% aq solution, 1.2 mmol), CuX (0.005 mmol), and 4e (0.01
mmol).
3
70
58
32
4
2e i-Pr2NH
43
b Determined by 1H NMR using bromoform as an internal standard.
a Reactions were run using 1a (1.0 mmol), 2 (1.0 mmol), formalde-
hyde (37% aq solution, 1.2 mmol), CuI (0.005 mmol), and 4e (0.01
mmol).
We then examined the effect of the amount of imidazole
ligands (Table 3). When the amount of 4e was decreased
to 0.5 mol%, the yield considerably dropped, while the re-
actions with larger amounts of 4e gave high yields. In con-
trast, such a drastic change in the yield was not observed
by using 4a as a ligand in any case.16 The acceleration ob-
tained by the use of an excess amount of 4e to a Cu cata-
lyst can be attributed to the effect of free 4e, which does
not coordinate to a Cu catalyst and works as a base to
b CuI and 4e were added after stirring the mixture of the other compo-
nents for 1 h.
c Determined by 1H NMR using bromoform as an internal standard.
We then investigated the reactions with some other
alkynes (Table 5).18 The reactions of various alkynes
could be performed, and 4e accelerated those reactions. 4-
Trifluoromethylphenylacetylene (1b) showed a rapid
Synlett 2010, No. 20, 3053–3056 © Thieme Stuttgart · New York

LETTER
Effects of a Flexible Alkyl Chain on an Imidazole Ligand
3055
reaction due to the use of 4e (Table 5, entry 1). In the In summary, we have shown the efficiency of an imida-
slower reactions with 4-methoxylphenylacetylene (1c) zole carrying a long alkyl chain as a ligand to enhance the
and 2-methylphenylacetylene (1d), 4e improved the rates copper-catalyzed Mannich reactions of terminal alkynes,
to an acceptable degree (Table 5, entries 2 and 3). Al- secondary amines, and aqueous formaldehyde. The alkyl
though the reactions of the acetylenes with aliphatic chain gave an efficient steric effect, and the imidazole
groups (1e–g) required higher temperatures, the effect of benefited the reaction not only as a ligand but also as a
4e was observed in these cases also (Table 5, entries 4–6).
base catalyst. Furthermore, the flexible alkyl chain could
provide a favorable environment around a copper center
for a variety of substrates. These results suggest a new
concept for an efficient ligand of transition-metal cataly-
sis. Further studies on the detailed clarification of the role
of the alkyl chain and on the application of this methodol-
ogy to other catalytic processes are currently under way in
our laboratory.
Table 5 Mannich Reaction of Various Alkynes 1 with 4ea
H
CuI (0.5 mol%)
N
4e (1.0 mol%)
+
+
R
HCHO (aq)
T °C, 1.5 h
N
1a
2a
R
3
Entry R
3
Temp Yield with Yieldwithout
(°C)
4e (%)b
4e (%)b
Acknowledgment
This work was supported financially by the Japanese Ministry of
Education, Culture, Sports, Science and Technology. The authors
acknowledge the support by the Global COE Program ‘Integrated
Materials Science’ (#B-09). K.A. also acknowledges the Japan
Society for the Promotion of Science for Young Scientists for the
fellowship support.
1
2
3
4
5
6
1b 4-F3CC6H4
1c 4-MeOC6H4
1d 2-MeC6H4
1e n-C8H17
3ba
3ca
3da
3ea
3fa
25
92
61
25
47
27
25
74
22
80
97
44
1f n-Bu
80
84
55
References and Notes
1g HO(CH2)4
3ga
50
65
42
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HCHO (aq)
CuI (0.5 mol%)
N
H
N
N
(4, 1.0 mol%)
R
+
R
80 °C, 1.5 h
N
R
1h (R = t-Bu)
1i (R = c-Hex)
2a
3ha (R = t-Bu)
3ia (R = c-Hex)
Entry
1
Yield with 4e (%) Yield with 4b Yield without 4
R = n-C16H33
1h 77
1i 97
(%) R = 1-ad
(%)
1
2
43
85
46
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LETTER
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(18) General Procedure for Mannich Reactions of Terminal
Alkynes and Secondary Amines with Formaldehyde
To a 5 mL vial were added sequentially terminal alkyne 1
(1.0 mmol), secondary amine 2 (1.0 mmol), formaldehyde
(37% aq solution, 1.2 mmol), 1-hexadecylimidazole (4e,
0.01 mmol), and CuI (0.005 mmol, 1.0 mg). The mixture
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C
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