Mannich Synthesis of Acetylenic Amino Alcohols in Aqueous Ionic Liquids

Article abstract of DOI:10.1016/j.mencom.2012.11.013

Terminal alkynols react with formaldehyde and secondary amines in aqueous ionic liquid [emim]HSO^-₄ in the presence of Cu(OAc) to afford the corresponding 1-(a-hydroxyalkyl)- or 1-(b-hydroxyalkyl)-2- (aminomethyl)acetylenes in better yields in comparison with the reaction in conventional organic solvents. The catalytic system can be easily recovered and recycled.

Full text of DOI:10.1016/j.mencom.2012.11.013

Mendeleev
Communications
Mendeleev Commun., 2012, 22, 317–319
Mannich synthesis of acetylenic amino alcohols in aqueous ionic liquids
Nina I. Simirskaya,a Nikolai V. Ignat’ev,b Michael Schulteb and Sergei G. Zlotin*a
a N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian
Federation. Fax: +7 499 135 5328; e-mail: zlotin@ioc.ac.ru
b Merck KGaA, PM-ABE, D-64293 Darmstadt, Germany
DOI: 10.1016/j.mencom.2012.11.013
Terminal alkynols react with formaldehyde and secondary amines in aqueous ionic liquid [emim]HSO4– in the presence of Cu(OAc)2
to afford the corresponding 1-(a-hydroxyalkyl)- or 1-(b-hydroxyalkyl)-2-(aminomethyl)acetylenes in better yields in comparison
with the reaction in conventional organic solvents. The catalytic system can be easily recovered and recycled.
Propargylamine derivatives exhibit valuable biological activities,
An–
Et
An–
Bu
An–
Bu
[bmpyrr]
in particular, antibacterial,1 anticancer,2–4 antihistamine,5–7 and
may act as enzyme inhibitors.8 Some of them are used in practical
medicine: pargyline (1) – for curing of hypertension and depres-
sion, tremorine (2, X = H) or oxotremorine (3, X+X = O) – as
cholinergic drugs.9 Acetylene-derived alcohols are another phar-
macologically important family of organic substances: methyl-
pentynol (4, Alk = Me) and repocal (5, Alk = Et) are used in the
medications of psychotropic diseases; ethynylcyclohexyl allo-
phanate (6) – as a soporific agent.10 It can be anticipated that
1-(hydroxyalkyl)-2-(aminomethyl)acetylenes containing both
amino and hydroxy groups, would possess valuable biological
properties.8,11
N
N
N
N
N
IL =
Me
Me
Me
[bmim]
[emim]
An– = OTf–, NTf2–, BF4–, HSO4–
H2C NH2R32
10
R2
R1
+
(CH2O)n
+
HNR32
HO
8a–i
7a–d
X
X
R2
R1
NR32
Me
Cu(OAc)2 (30 mol%)
IL (+ H2O)
N
N
N
HO
1
9a–t
2, 3
Scheme 1 For substituents R1–R3, see Table 1.
H
O
N
O
HO
Alk
various inorganic or organic anions.† The experiments were carried
out with molar ratio 7a: 8a:(CH2O)n :IL of 1.0:1.2:3.0:3.0;
Cu(OAc)2 loading was 30 mol%. In all cases 1-[3-(piperidin-1-yl)-
prop-1-ynyl]cyclohexanol 9a was obtained as the major product.
The yield of 9a reached 80% if the reaction was performed in
1-alkyl-3-methylimidazolium triflates and was somewhat lower
(65%) in [emim]HSO4 medium. Furthermore, a higher reaction
temperature (50°C) was required in the experiments where rather
viscous [emim]HSO4 was used.
Surprisingly, addition of water to [emim]HSO4 accelerated
the reaction and improved the yield of product 9a, the best yield
(80%) being achieved in the case of 3:1 [emim]HSO4–H2O
mixture. This reaction medium was less viscous than [emim]HSO4
itself and could be well stirred at 40°C. However, further raising
of water content (to 50%) negatively influenced the yield of the
product, presumably by causing a partial hydrolysis of 9a in
aqueous environment.
The [emim]HSO4–H2O (2:1) reaction medium was then
extended on a variety of functionalized hydroxyalkylacetylenes
(see Scheme 1, Table 1).‡ Linear and cyclic amines 8a–i, and
natural alkaloids anabasine 8f and cytisine 8g, served as amino-
component to afford corresponding products 9a–u. Typically,
yields of compounds 9a,f,l,q in [emim]HSO4–H2O as reaction
media were higher than those in organic solvents (Table 1) whereas
O
NH2
4, 5
6
These compounds have been prepared in moderate to high
yields by Cuii-catalyzed three-component condensation of terminal
(hydroxyalkyl)acetylenes with aldehydes and amines (the Mannich
reaction) in organic solvents12–20 and ionic liquids (ILs).21–28
However, the broad application of ILs in organic synthesis29,30 is
limited by their relatively high price. Recently, it was shown31
that in some cases the consumption of hydrophilic ILs as reaction
media can be reduced by dilution with water without negative
influence on the reaction outcome. Importantly, the system reagents
–
IL–water remains homogeneous over a wide range of components
ratio. Herein, we applied this approach to Cuii-catalyzed three-
component reaction of alkynols with formaldehyde and secondary
amines and developed a useful procedure for the synthesis of
1-(hydroxyalkyl)-2-(aminomethyl)acetylenes. Typically, Mannich
reaction in aqueous medium requires rather drastic conditions
or microwave activation,24,32–34 which can be attributed to poor
solubility of acetylenes in water.
At first, we studied Cu(OAc)2-catalyzed interaction between
1-ethynylcyclohexanol 7a, piperidine 8a and paraformaldehyde
(model reaction, Scheme 1) in molten salts medium composed
of 1,3-dialkylimidazolium or 1,1-dialkylpyrrolidinium cations and
†
For optimization data, see Table S1 in Online Supplementary Materials.
© 2012 Mendeleev Communications. All rights reserved.
– 317 –

Mendeleev Commun., 2012, 22, 317–319
Table 1 Synthesis of 1-(a-hydroxyalkyl)-2-(aminomethyl)acetylenes 9a–t in the [emim]HSO4–H2O (2:1) solvent system.
Entry Alkynol
R1, R2
Amine
R3, R3
T/°C [lit.]
t/h [lit.]
Product Yield (%) (recycle) [lit. data]
1
2
7a
7a
7a
7a
7a
7a
7a
7b
7b
7b
7b
7b
7b
7c
7c
7c
7c
7c
7d
7d
–(CH2)5–
–(CH2)5–
–(CH2)5–
–(CH2)5–
–(CH2)5–
–(CH2)5–
–(CH2)5–
Me, Me
8a
8b
8c
8d
8e
8f
–(CH2)5–
40 [10114(b)
]
2.5 [2414(b)
]
9a
9b
9c
9d
9e
9f
80 (1), 82 (2), 85 (3) [5014(b)
]
c-C6H11, c-C6H11
–(CH2)2N(CO2Et)(CH2)2–
–(CH2)2N(Me)(CH2)2–
i-C5H11, i-C5H11
HNR32 = anabasinea
HNR32 = cytisineb
–(CH2)2N(Me)(CH2)2–
–(CH2)2O(CH2)2–
Bn, Bn
50
50
50
30
3
80 (1), 81 (2), 85 (3), 82 (4), 85 (5)
77 (1), 80 (2), 81 (3), 81 (4), 80 (5)
80 (1), 84 (2), 83 (3)
80 (1), 82 (2)
83 (1), 83 (2), 87 (3) [8625]
83 (1), 86 (2), 85 (3)
83 (1), 83 (2), 83 (3)
82 (1), 84 (2)
3
3
4
2.5
5
3
6
50 (7025
)
3.5 (825
)
7
8g
8d
8h
8i
50
2.5
2
9g
9h
9i
8
50
9
Me, Me
30
2
10
11
12
13
14
15
16
17
18
19
20
Me, Me
30
2
9j
90 (1), 91 (2), 90 (3)
70 (1), 72 (2)
72 (1), 73 (2) [6725]
Me, Me
8e
8f
i-C5H11, i-C5H11
30
3
9k
9l
Me, Me
HNR32 = anabasinea
HNR32 = cytisineb
–(CH2)2N(Me)(CH2)2–
Bn, Bn
50 (7025
)
)
3(825
2.5
2
)
Me, Me
8g
8d
8i
30
9m
9n
9o
9p
9q
9r
9s
9t
77 (1), 80 (2)
Me, Et
40
87 (1), 90 (2), 90 (3)
73 (1)
Me, Et
30
3
Me, Et
8e
8f
i-C5H11, i-C5H11
40
50 (7025
3
86 (1), 87 (2), 87 (3)
78 (1), 80 (2) [7225]
83
Me, Et
HNR32 = anabasinea
HNR32 = cytisineb
–(CH2)2N(CO2Et)(CH2)2–
–(CH2)2N(Me)(CH2)2–
3 (825
)
Me, Et
8g
8c
8d
40
3
Me, 3-pyridyl
Me, 3-pyridyl
50
2.5
3
73 (1), 76 (2)
50
71 (1), 73 (2)
aAnabasine is 2-(3-pyridyl)piperidine. b Cytisine is (1R,5S)-1,2,3,4,5,6-hexahydro-1,5-methano-8H-pyrido[1,2-a][1,5]diazocin-8-one.
CO2Et
N
the required temperature (30–50°C) and reaction time (1.5–3.5 h)
OH
were lower than those under water-free conditions. Presumably,
Bn
the polar IL–water system efficiently promoted a reversible forma-
tion of active iminium intermediates 10 from formaldehyde and
amines 8 in the Mannich reaction35 and accelerated condensation
process. Moreover, the use of the IL–water system simplified the
isolation of the final product. Evaporation of the solvent, acidic
treatment and neutralization of the reaction mixture is no more
required. Condensation products 9f,g,l,m,q,r having anabasine
or cytisine fragments in the structure are optically active. Specific
optical rotation values ([a]D) of the compounds 9f (–198), 9l
(–172) and 9q (–217) prepared according to described protocol35
were in agreement with reported data.18(a) This indicated that
stereo-centres remained untouched. In the case of substrate 7e
with secondary amino group, this group remained intact in the
presence of piperazine substrate 8c (Scheme 2).
The catalytic system Cu(OAc)2–[emim]HSO4–H2O can be
easily recovered and reused. After extraction of the product with
diethyl ether from the reaction mixture, fresh portions of starting
compounds were added to the residue and the reaction was re-
performed. This procedure can be repeated up to 5 times without
any decrease in the reaction rate or in the yield of the products
(Table 1, entries 2, 3). Moreover, the yield is slightly improved in
the second and further runs in the recycled catalytic system prob-
ably due to the saturation of reaction media with the final product.
Summing up, we have developed a convenient synthesis of
1-(a-hydroxyalkyl)- and 1-(b-hydroxyalkyl)-2-(aminomethyl)-
acetylenes by three-component condensation of terminal hydroxy-
+
(CH2O)n
+
N
H
N
H
7e
8c
OH
CO2Et
Cu(OAc)2 (30 mol%)
N
Bn
[emim]HSO4–H2O
(2:1, w/w),
N
N
H
50°C, 1.5 h
9u
Scheme 2
alkylacetylenes with formaldehyde and secondary amines catalyzed
with the Cu(OAc)2 in the [emim]HSO4–water solvent system
which can be easily recovered and reused several times. Invented
method is based on the use of commercially available and
inexpensive ionic liquid [emim]HSO4. This procedure is remark-
able for mild reaction conditions and high yields of the products.
Proposed approach to minimize IL-consumption by its dilution
with water may be useful to reduce the costs by industrial applica-
tions of ionic liquids.
This work was supported by Merck KGaA.
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2012.11.013.
‡
Typical procedure. A mixture of hydroxyalkylacetylene 7 (1.0 mmol),
secondary amine 8 (1.2 mmol), paraformaldehyde (3.0 mmol), Cu(OAc)2
(0.3 mmol), IL (3.0 mmol) and corresponding amount of water was stirred
under the conditions specified in Tables 1 and S1. The reaction mixture
was extracted with Et2O (3×5 ml). The combined extracts were passed
through a silica gel or neutral (Brockman) Al2O3 pad, the solvent was
evaporated in vacuo (15 Torr) and the residue was crystallized or purified
by column chromatography on silica gel (Acros, 40–60 mm; eluent, light
petroleum–Et2O–EtOAc). Fresh starting compounds 7, 8 and (CH2O)n
were added to the recycled catalytic system which remained in the vessel
after extraction of the products. The reaction was performed again according
to the conditions specified in Table 1.
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