chiral ionic liquids (cils) in asymmetric synthesis: the ... · chiral ionic liquids (cils) in...
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Chiral Ionic Liquids (CILs) in Asymmetric Synthesis:
The story so far….
Literature Presentation
Aman DesaiAman Desai
06.16.06
1. Angew. Chem. Int. Ed. 2006, 45, 3689
2. Angew. Chem. Int. Ed. 2006, 45, 3093
3. Tetrahedron: Asymmetry, 2006, 17, 1032
4. Tetrahedron: Asymmetry, 2005, 16, 3921
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Ionic liquids – what?
“….are salts that are liquid at low temperatures (< 100 °C) – they are liquids which consist only of ions.”
FEATURES:
• Form biphasic systems with organic product mixtures – easy isolation & recovery.
• Reusability.
• No vapor pressure – facilitates product separation by distillation.
• Tuneability - optimization for specific applications – referred to as “designer
& why?
2
• Tuneability - optimization for specific applications – referred to as “designer solvents”.
• Easy manipulation of melting points, thermal stability, density, viscosity & solubility characteristics.
• Green & clean.
• Chirality in either cation or anion.
• Commercial availability & costs pose a problem.
Angew. Chem. Int. Ed. 2000, 39, 3772
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Chiral Ionic Liquids (CILs)
“Pure imidazolium ionic liquid can be described as polymeric hydrogen-bonded
supramolecules and in some cases when mixed with other molecules, they should
better be regarded as nanostructured materials with polar and non polar regions
rather than homogeneous solvent”
– Dupont, J. J. Braz. Chem. Soc. 2004, 43, 4988
With chiral ILs, solvent structuration – basis for molecular recognition – can be used to
devise stereoselective reactions.∴
3
devise stereoselective reactions.
Applications of CILs:
• Chiral solvents for stereoselective polymerisation
• Chiral phases for gas chromatography
• Chiral shift reagents in NMR
• Chiral crystals
• Chiral solvents for asymmetric synthesis
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CILs in Asymmetric Synthesis up till 2006 – only upto 44% ee
First example of the use of a chiral solvent: Seebach, D. Angew. Chem. Int. Ed. 1975, 87, 629
O
Ph
O
O
N
N
(S,S)-( + )-1,4-Bis (dimethylamino)-2,3-dimethoxybutane
DDB
hv
DDB/pentane
(1/5 w/w)
OH
Ph
HO
Ph
23.5% ee
First significant asymmetric induction in use of a CIL as the sole source of chirality:
4
First significant asymmetric induction in use of a CIL as the sole source of chirality:
Vo-Thanh, Tetrahedron Letters, 2004, 45, 6425
O
Ph H+
O
OMe1 eq DABCO, 30 °C, 7 days
O
OMePh
OH
*
60% yield
44% ee3 eq CIL
Ph
HO
NC8H7
OTf
MW
(1) C8H7Br, 30 min, 110 °C
(2) KOTf, 35 min, 95 °C
1-pot, solvent-free
CIL
91% yields
viscous liquid at RT
Ph
HO
N
(1R,2S) N-methyl ephedrine
Workup: Simple extraction with ether -CIL (aq) recycled by dissolving in CH2Cl2 & washing with water & reused w/o loss of yield or ee
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CILs in Asymmetric Synthesis in 2006
the light at the end of the tunnel?
1. Malhotra, S. Tetrahedron: Asymmetry 2006, 17, 1032
→ α-pinene based CILs in Cu-catalyzed enantioselective conjugate addition of
diethyl zinc to α,β-unsaturated enones – upto 76% ee
2. Leitner, W. Angew. Chem. Int. Ed. 2006, 45, 3689
→ L-malic acid based CILs in enantioselective aza-Baylis-Hillman reaction – upto
5
→ L-malic acid based CILs in enantioselective aza-Baylis-Hillman reaction – upto
84% ee
• LuO, S. and Cheng, J. P. Angew. Chem. Int. Ed. 2006, 45, 3093
→ L-proline based CILs as organocatalysts in enantioselective Michael addition to
nitro-olefins – upto 99% ee
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Malhotra’s Chemistry
α-pinene CILs in 1,4 additions of Et2Zn to enones
ChirIL
6
OHNH2
HOOC O
N(1) C3H7Br
(2) anion exchange
NaBF4 or NaPF6
Malhotra, S. Tetrahedron: Asymmetry 2006, 17, 1032
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Malhotra’s Chemistry
Optimization of CIL concentration
7Malhotra, S. Tetrahedron: Asymmetry 2006, 17, 1032
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Malhotra’s Chemistry
Results
8
ChirIL
Malhotra, S. Tetrahedron: Asymmetry 2006, 17, 1032
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Leitner’s Chemistry
L-malic acid CILs in aza-Baylis Hillman (ABH) reactions
9Leitner, W. J.A.C.S. 2005, 127, 16762
Leitner, W. Angew. Chem. Int. Ed. 2006, 45, 3689
Possible bifunctional stabilization
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Leitner’s Chemistry
Synthesis of the CILs
10Leitner, W. Angew. Chem. Int. Ed. 2006, 45, 3689
Colorless viscous liquid MP -32 °C
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Leitner’s Chemistry
Results
No Imine Nucleophilic
catalyst
CIL product conversion
%
%ee
11Leitner, W. Angew. Chem. Int. Ed. 2006, 45, 3689
catalyst %
1-4 1a PPh3 9 4a 34-39 71-84
5 1a PPh3 10 4a 15 racemic
6 1a PPh3 11 4a 14 racemic
7 1a P(o-tolyl)3 9 4a 35 74
8 1a (C6F5)PPh2 9 4a 9 71
9 1b PPh3 9 4b 39 64
10 1c PPh3 9 4c - 10
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No Imine Nucleophilic
catalyst
CIL product conversion
%
%eeComparable with the best
Leitner’s Chemistry
Results
12Leitner, W. Angew. Chem. Int. Ed. 2006, 45, 3689
catalyst %
1-4 1a PPh3 9 4a 34-39 71-84
5 1a PPh3 10 4a 15 racemic
6 1a PPh3 11 4a 14 racemic
7 1a P(o-tolyl) 9 4a 35 74
8 1a (C6F5)PPh2 9 4a 9 71
9 1b PPh3 9 4b 39 64
10 1c PPh3 9 4c - 10
Comparable with the best catalysts in conventional solvents for ABH reactions
→ 94% ee
JACS, 2005, 127, 3680
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Luo & Cheng’s Chemistry
L-proline CILs in Michael Addition to Nitroolefins
The inspiration:
Design for functionalized CILs
Ionic liquid moiety
13
Ionic liquid moiety
Phase-tag & chiral-induction group
Chiral pyrrolidine unit
Catalytic Site
(1) Bulky & planar organic cation imparts space shielding to reaction intermediate
(2) Proximity of ionic-liquid unit to active site creates reaction friendly environment
LuO, S. and Cheng, J. P. Angew. Chem. Int. Ed. 2006, 45, 3093
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Luo & Cheng’s Chemistry
Synthesis of CILs
45% total yield
Straightforward synthesis
All CILs – viscous liquids at RT
Soluble in moderately polar solvents & insoluble in less polar solvents
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& insoluble in less polar solvents
Hence, suffice for practical applications!!
LuO, S. and Cheng, J. P. Angew. Chem. Int. Ed. 2006, 45, 3093
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Luo & Cheng’s Chemistry
Trying out the different toys…
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LuO, S. and Cheng, J. P. Angew. Chem. Int. Ed. 2006, 45, 3093
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Luo & Cheng’s Chemistry
Trying out the different toys…
16
LuO, S. and Cheng, J. P. Angew. Chem. Int. Ed. 2006, 45, 3093
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Luo & Cheng’s Chemistry
Trying out the different toys…
17
LuO, S. and Cheng, J. P. Angew. Chem. Int. Ed. 2006, 45, 3093
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Luo & Cheng’s Chemistry
Trying out the different toys…
18
LuO, S. and Cheng, J. P. Angew. Chem. Int. Ed. 2006, 45, 3093
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Luo & Cheng’s Chemistry
Trying out the different toys…
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But wait a minute!! Why ionic
liquids right?
Well, recoverability & reusability!!
LuO, S. and Cheng, J. P. Angew. Chem. Int. Ed. 2006, 45, 3093
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Luo & Cheng’s Chemistry
Trying out the different toys…
20
LuO, S. and Cheng, J. P. Angew. Chem. Int. Ed. 2006, 45, 3093
Experimental: Mix, stir, dilute
with ether, separate – product
to column and catalst used
directly for next run
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Luo & Cheng’s Chemistry
Trying out the different toys…
optimal
catalysts
21
LuO, S. and Cheng, J. P. Angew. Chem. Int. Ed. 2006, 45, 3093
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Luo & Cheng’s Chemistry
Trying out the different toys…
22
LuO, S. and Cheng, J. P. Angew. Chem. Int. Ed. 2006, 45, 3093
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Luo & Cheng’s
Chemistry
How general is this?
23LuO, S. and Cheng, J. P. Angew. Chem. Int. Ed. 2006, 45, 3093
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opp. facial
Luo & Cheng’s
Chemistry
How general is this?
24
LuO, S. and Cheng, J. P. Angew. Chem. Int. Ed. 2006, 45, 3093
opp. facial
induction???
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Acyclic synclinical model
Luo & Cheng’s Chemistry
Model for observed diastereo- & enantio-selectivity
25Betancourt, J. M. Synthesis, 2004, 9, 1509
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Conclusions
• A series of tables containing all the CILs described to date and their physical
properties.
Tetrahedron: Asymmetry, 2005, 16, 3921
• Owing to their unique features, CILs are lot better than conventional solvents from a
practical standpoint
• Recoverable & reusable repeatedly with almost equivalent results.
26
• Green & clean.
• Easy manipulation to suit needs.
• If developed, it might be a powerful lab as well as industrial scale tool.
• Recent applications have shown excellent results – comparable with results from
conventional systems – could be the start of an exciting field…
or with just a few good papers out there, does it really have a future?