Highly efficient chemoselective construction of 2,2-dimethyl-6-substituted 4-piperidones via multi-component tandem Mannich reaction in ionic liquids

Article abstract of DOI:10.1039/b926498a

The room temperature ionic liquid [bmim][PF₆] has been demonstrated to be an efficient and recyclable medium for highly chemoselective synthesis of 2,2-dimethyl-6-substituted 4-piperidones via a l-proline catalyzed tandem Mannich reaction of ammonia, aldehydes and acetone, and good yields were achieved for aryl and alkyl aldehydes.

Full text of DOI:10.1039/b926498a

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Highly efficient chemoselective construction of 2,2-dimethyl-6-substituted
4-piperidones via multi-component tandem Mannich reaction in ionic
liquids†
Li-Chun Feng,a Ya-Wei Sun,a Wei-Jun Tang,a Li-Jin Xu,*a Kim-Lung Lam,b Zhongyuan Zhoub and
Albert S. C. Chanb
Received 17th December 2009, Accepted 24th March 2010
First published as an Advance Article on the web 13th April 2010
DOI: 10.1039/b926498a
The room temperature ionic liquid [bmim][PF6] has been
demonstrated to be an efficient and recyclable medium
for highly chemoselective synthesis of 2,2-dimethyl-6-
substituted 4-piperidones via a L-proline catalyzed tandem
Mannich reaction of ammonia, aldehydes and acetone, and
good yields were achieved for aryl and alkyl aldehydes.
the recyclability, but also enhances the stability and selectivity
of the catalyst.3e
Functionalized 4-piperidones are versatile building blocks for
the preparation of a range of piperidine derivatives, which are
important frameworks in a large number of bioactive natural
products and pharmaceuticals.4 Moreover, many piperidones
themselves are an integral part of many biologically active
compounds.5 Consequently, much effort has been devoted to
the efficient construction of these useful compounds, and many
successful examples can now be found in the literature.6 How-
ever, most attention has focused on the synthesis of 2-substituted
and 2,6-disubstituted 4-piperidones, and there are few methods
available for the synthesis of 2,2,6-trisubstituted 4-piperidones.7
During our recent research on using versatile and cheap ammo-
nia to activate direct aldol reaction of aldehydes and ketones,
we unexpectedly found that 2,2-dimethyl-6-aryl-4-piperidones
could be readily prepared through a tandem Mannich reaction in
room temperature ammonia solution.8 However, this chemistry
is limited to hydroxybenzaldehydes, pyrrole-2-carboxyaldehyde
and indole-3-carboxyaldehyde. Therefore, a more efficient and
practical method for the preparation of 2,2,6-trisubstituted 4-
piperidones is still highly desirable. Herein we wish to report
that the use of RTIL [bmim][PF6] in a tandem Mannich reaction
of aldehydes, acetone and ammonia in the presence of L-proline
additive enhances the chemoselectivity dramatically, providing
the desired 2,2-dimethyl-6-substituted 4-piperidones in high
yields. Moreover, the ionic liquid phase containing L-proline
catalyst could be easily recycled for several times without loss of
reactivity and chemoselectivity.
To establish suitable experimental conditions for this tandem
Mannich reaction we first tried the reaction of benzaldehyde
1a with acetone and ammonia in ethanol. Ammonia gas was
bubbled into 1 mL ethanol for 5 min, followed by the addition
of 1a (1 mmol, 102 mL) and acetone (10 mmol, 0.75 mL) at
room temperature. The mixture was stirred at room temperature,
and the reaction went to completion in 20 h. The crude
1H NMR spectrum indicated the formation of four products
2a–5a in a ratio of 4 : 1 : 23 : 1. The major one corresponded
to the aldol product 4a (79%), and the chemoselectivity of the
desired 2,2-dimethyl-6-phenyl-4-pyrilidinone 2a was only 13%
(Table 1, entry 1). Replacing ethanol with ethylene glycol led to
the production of 3a–5a in a ratio of 1 : 11 : 2, and no 2a was
observed (Table 1, entry 2). Recent reports disclosed that Man-
nich reaction could be promoted in RTILs.9 Subsequently, we
examined the reaction in a series of RTILs. To our delight, the use
Room-temperature ionic liquids (RTILs) have recently been
highlighted as effective replacements of traditional organic
solvents.1–2 The attractiveness of RTILs as reaction media is
attributed to their favorable physicochemical properties, such as
negligible vapor pressure, low volatility, tunable polarity and
miscibility with organic or inorganic compounds. The ionic
nature of RTILs ensures that catalysts that are ionic or possess
polar or ionic groups can be readily immobilized, separated
and recycled through a biphasic operation without laborious
catalyst modification or work up, thereby providing a convenient
solution to both the solvent emission and catalytic recycling
problem. Numerous catalytic reactions have proven feasible
in a variety of ionic liquids with facile catalyst recovery and
reuse.1–2 Of particular note is that many reactions in RTILs
displayed enhanced reactivities and selectivities, some of which
were not readily accomplished in common organic solvents.3
For example, Xiao and coworkers found that RTILs could
significantly improve the regioselectivity of Pd-catalyzed Heck
arylation of electron-rich olefins.3a–b Lee et al. observed dramatic
enhancement of catalytic activity in RTILs in their study of
Friedel–Crafts alkenylation of arenes with alkynes.3c Alper and
coworkers reported that Pd-catalyzed cyclocarbonylation of
enynols with thiols could be successfully conducted in ionic
liquids, which was not possible in normal organic solvents.3d
More recently, we disclosed that Ru-TsDPEN catalyst displayed
unprecedented reactivity and high enantioselectvity in the
asymmetric hydrogenation of quinolines in neat RTIL, and
employing RTIL as the reaction medium not only facilitates
aDepartment of Chemistry, Renmin University of China, Beijing, 100872,
China. E-mail: xulj@chem.ruc.edu.cn
bOpen Laboratory of Chirotechnology of the Institute of Molecular
Technology for Drug Discovery and Synthesis and Department of
Applied Biology and Chemical Technology, The Hong Kong Polytechnic
University, Hong Kong, China
† Electronic supplementary information (ESI) available: Experimental
and NMR spectra. CCDC reference numbers 259948. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/b926498a
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Table 1 Reaction condition optimization using different solvents and
Table 2 L-Proline catalyzed tandem Mannich reaction of aldehydes
catalystsa
with acetone and ammonia in [bmim][PF6]a
Entry
1
Aldehydes
Products
Yields (%)b
85
Entry
Solvent
Catalyst
2a : 3a : 4a : 5ab
2
3
4
5
6
84
79
81
75
65
1
2
3
4
5
6
7
8
Ethanol
none
none
none
none
none
none
none
14 : 3 : 80 : 3
0 : 7 : 79 : 14
55 : 30 : 10 : 5
74 : 16 : 5 : 5
41 : 0 : 56 : 3
67 : 0 : 30 : 3
78 : 9 : 9 : 4
78 : 9 : 11 : 2
79 : 4 : 15 : 2
84 : 9 : 5 : 2
93 : 1 : 0 : 6
84 : 8 : 0 : 8
Ethylene glycol
[dmpim][NTf2]
[emim][NTf2]
[bmim][Cl]
[bmim][BF4]
[bmim][PF6]
[bmim][PF6]
[bmim][PF6]
[bmim][PF6]
[bmim][PF6]
[bmim][PF6]
PhCOOH (20 mol%)
PhOH (20 mol%)
InCl3 (20 mol%)
L-proline (20 mol%)
L-proline (20 mol%)
9
10
11
12c
a Reaction conditions: 1.0 mL solvent (bubbled with ammonia gas for
5 min), 1a (1.0 mmol), acetone (10.0 mmol, 0.75 mL), room temperature,
20 h. b Determined by 1H NMR based on the integration of the relevant
peaks of the crude products. c 5 equiv. acetone was used.
of [dmpim][NTf2] led to 55% chemoselectivity favoring the for-
mation of 2a (Table 1, entry 3). A slightly better chemoselectivity
was observed in [emim][NTf2], but using [bmim][Cl] gave rise to
a lower chemoselectivity (Table 1, entries 4–5). Much better
results were achieved in both [bmim][BF4] and [bmim][PF6], and
[bmim][PF6] proved to be the most suitable solvent, affording
the best chemoselectivity of 78% (Table 1, entries 6–7). We
speculate that RTILs may favor the formation of imine and
consequently result in the preferential occurrence of Mannich
reaction over aldol reaction. The different chemoselectivities
obtained may be attributed to the different viscosity of RTILs or
NH3-solubility.
In an attempt to further improve the chemoselectivity of the
reaction, it seems that the use of catalyst is necessary. Then
several acid catalysts were tested. While benzoic acid, phenol or
InCl3 failed to provide significant improvement (Table 1, entries
8–10), we found that with L-proline (20 mol%) as catalyst the
tandem Mannich reaction in IL proceeded effectively to give
the desired product 2a in 85% isolated yield with very good
chemoselectivity (93%) (Table 1, entry 11). This result is in
good agreement with the previous reports that L-proline could
efficiently catalyze Mannich reactions.9a,10 However decreasing
the amount of acetone led to a poor chemoselectivity (Table 1,
entry 12).
With these encouraging results in hand, we turned to ex-
plore the scope of the reaction using different aldehydes as
substrates under the optimized reaction conditions. The results
are summarized in Table 2. Aryl aldehydes underwent effective
tandem Mannich reaction in [bmim][PF6] regardless of the
nature of the substituents on the aryl ring, affording the desired
products in moderate to good yields (Table 2, entries 1–7). The
heteroaromatic aldehydes also proved to be viable substrates
(Table 2, entries 8–9). Interestingly, ferrocenecarboxyaldehyde
could be subjected to the tandem Mannich reaction as well,
giving the product in 65% yield (Table 2, entry 10). The
7
69
8
71
68
65
9
10
11
12
66
61
13
14
80
78
a Reaction conditions: [bmim][PF6] (1.0 mL) (bubbled with ammonia
gas for 5 min), aldehydes (1.0 mmol), acetone (10 mmol, 0.75 mL) and
L-proline (23 mg, 0.20 mmol), room temperature, 20 h. b Isolated yield.
950 | Green Chem., 2010, 12, 949–952
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Table 3 Recycling of [bmim][PF6]/L-proline system for tandem Man-
reactions of aliphatic aldehydes gave rise to 2,2-dimethyl-6-
substituted 4-piperidones in 61–66% yields (Table 3, entries
11–12). In addition, aryl aldehydes with a hydroxy group at
ortho or para position also exhibited high reactivity, and the
corresponding piperidones were formed in 80%, 78% yields,
respectively (Table 2, entries 13–14). The structure of 2m was
determined by X-ray crystallography, confirming the product
nich reactiona
Run
1
2
3
4
5
Yield (%)b
85
84
80
77
75
a Reaction conditions: [bmim][PF6] (1.0 mL) (bubbled with ammonia gas
for 5 min), 1a (1.0 mmol), acetone (10.0 mmol, 0.75 mL) and L-proline
(23 mg, 0.20 mmol), room temperature, 20 h. b Isolated yield.
formed (Fig. 1).11 The space group is P1 with 4 molecules
¯
in a cell. There are two independent molecules of 2m in an
asymmetric unit, and only one is shown in Fig. 1.
methodology are: (1) easily available and low-cost starting
materials, (2) easy operation, (3) recyclability of catalyst, and (4)
mild reaction conditions. These advantages make this process
potentially useful for industrial applications.
Acknowledgements
Financial supports from National Natural Science Foundation
of China (20873179), Renmin University of China, the Hong
Kong Research Grants Council (PolyU 5001/07P), the Hong
Kong UGC AoE Scheme (AoE P/10-01) and the Hong Kong
Polytechnic University Areas of Strategic Development Fund
are gratefully acknowledged.
Notes and references
Fig. 1 X-Ray structure of 2m (30%).
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Scheme 1 Diastereoselective tandem Mannich reaction in [bmim][PF6].
Having established the viability of this reaction, attention was
then switched to the recyclability of the ionic liquid and catalyst.
The insolubility of [bmim][PF6] and L-proline in Et2O offered a
possibility of recycling both. We carried out the study by using
1a as the model substrate. When the reaction finished in 20 h, the
volatiles were removed in vacuo and the mixture was extracted
with Et2O. The residue was then subjected to the next batch
of catalytic reaction to give the desired product. The catalyst
system could be used consecutively for five times, but the yield
decreased gradually (Table 3).
In summary, we have developed an efficient route for the
construction of 2,2-dimethyl-6-substituted 4-piperidones via a
four-component tandem Mannich reaction using the RTIL
[bmim][PF6] as the solvent at room temperature. The ionic
liquid not only serves as a reaction medium, but also signi-
ficantly enhances the chemoselectivity. The advantages of this
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The Royal Society of Chemistry 2010
Green Chem., 2010, 12, 949–952 | 951
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Tetrahedron Lett., 2005, 46, 8685.
11 X-Ray crystallographic study of 2m: Compound 2m: (C13H17NO2,
¯
˚
Mr = 219.28) triclinic system space group P1 (No. 2), a = 5.7313(7) A,
◦
˚
˚
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2003, 5, 657; (d) G. Zhao, T. Jiang, H. Gao, B. Han, J. Huang and
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K. Fuchibe, Synlett, 2005, 1024; (f) S. Sahoo, T. Joseph and S. B.
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b = 11.8701(14) A, c = 18.407(2) A, a = 72.324 (2) , b =
◦ ◦
3
˚
85.809 (2) , g = 79.963 (2) , V = 1174.6(2) A , Z = 4, rcalc
=
1.240 mg m-3, T = 294(2) K, m = 0.083 mm-1, F(000) = 472,
˚
Mo-Ka radiation (l = 0.71073 A), colorless plate 0.30 ¥ 0.26 ¥
0.24 mm. 11 208 reflections were collected on a Bruker-AXS SMART
CCD diffractometer with 5412 reflections > 2s(I), parameters 293,
goodness of fit on F2 1.016, R1 = 0.0528, wR2 = 0.1274. Further
crystallographic data for 2m have been deposited with the Cambridge
Crystallographic Data Centre. CCDC number 259948. For crystal-
lographic data in CIF or other electronic format see DOI: 10.1039/
b926498a.
952 | Green Chem., 2010, 12, 949–952
This journal is
The Royal Society of Chemistry 2010
©