Combinatorial ChemistrySeminar 2006
Carolin Ruß
Table of Contents
1. Introduction
2. Preparation of PSRs
Covalent Linkage between the Active Species and
Support
1. Solid-Phase Chemistry, 2. Copolymerisation
Immobilisation Using Intermolecular Interactions
3. Ion-exchange, 4. Microencapsulation
Table of Contents
3. Examples
• Amide Bond Formation, Wittig-Reagents
• Schiff Base Zinc Complexes
• Reduction, Oxidation, Halogenation
4. Scavengers
5. Simultaneous Multistep Synthesis
6. Literature
1. Introduction
The use The use of polymerof polymer--supported reagents supported reagents ((PSRsPSRs) ) can combine can combine
the benefits the benefits of solidof solid--phase chemistry with the advantages phase chemistry with the advantages
of of solutionsolution--phase synthesisphase synthesis..
reagent
(insoluble)
reaction conditions
A
starting material (dissolved)
B
product(dissolved)
B
product(dissolved)
reagent
(insoluble)
+filtration
1.1 Definitions
•• PolymerPolymer--supported Reagentsupported Reagent (PSR):(PSR):Reagents that are either covalently or ionically Reagents that are either covalently or ionically
boundbound to to the supportthe support
••SupportSupport
InorganicInorganicmaterialsmaterials e.g. Oxides, e.g. Oxides, glassesglasses
Organic Organic polymerspolymers e.g. linear, e.g. linear, crosscross--linkedlinked
1.2 Advantages
•Simplification of Product Work-up,Separation, and Isolation
•Automation•Excess of Reagents
•Potential of Recovery of Reagents
•Higher Stability•Reduction of Toxicity•One-pot Reactions
1.2 Disadvantages
•Change in Reactivity•Additional Time and Cost in Synthesis•Slow Reaction and Low Yields•Limited Chemical and Mechanical Stability
of the Support
2. Preparation of PSRs
1. Solid-Phase Chemistry
X + reactive moietyY
solid phase organic chemistry
X reactive moietyY
2. Preparation of PSRs
2. Copolymerisation
reactive moiety polymerization
+ reactive moietycovalent
bond
2. Preparation of PSRs
3. Ion-exchange
NMe3+X-
M reagent
ion exchangechromatography
NMe3+X- reagent
ionicinteraction
2. Preparation of PSRs
4. Microencapsulation
3. Examples1. Covalent Linkage- Amide Bond Formation
Cl O
ClNO2
NO2OH
O+
NO2O
O O
Et1) AlCl3, Ph-NO2, 60 °C, 5h Et
O
pyridine2) BnMe3N+OH-, H2O, dioxane, 90 °C, 8h A
OCO2Me
NH2 O
MeO2CNH
O
ACHCl3, Et3N, 15 min,quant. yield
3. Examples1. Covalent Linkage- Wittig Reagents
Ph H
O
PhPh+
P PhPh
O
1) NaOMe, MeOH, THF, rt, 3h
2) MeOH, THF, rt (16 h), 70 °C (2 h) 89 %
Polystyrene
Br2, Tl(OAc)3,CCl4
Br1) n-BuLi, toluene2) ClPPh2, THF or LiPPh2, THF
PPh2 P PhPh
PhBr
DMF, 70 °C, 48 h, 93 %
PhBr
3. Examples
2. Copolymerisation- Schiff Base Zinc Complexes
O
Ph
PhOH
H2N
+AIBN, benzene,THF, 75 °C
O OO
cross-linkingagent
O
Ph
PhOH
H2N
n
n n
Crosslinkage
A
3. Examples2. Copolymerisation- Schiff Base Zinc Complexes
CHO
Cl Cl
HOA, Et2Zn,toluene, hexane, 0 °C, 6h, 92%, 94% ee
N
OHPh
Ph
Cl Cl
O
HN Ph
Ph
Intermediates
3. Examples3. Ion-Exchange- Reduction
NMe3 +ClH2O
NMe3NaBH4 BH4
R1 R2 (H)
O NMe3 BH4
R1 R2 (H)
OH
MeOH
O OH
NMe3 BH4
MeOH
90 %
3. Examples3. Ion-Exchange- Oxidation
OHCHO
NMe3
2
Cr2O72-
75 %
3. Examples
3. Ion-Exchange- Halogenation
O
NMe3 Br3
O
Br
OHNH Br3
OH
Br
4. Scavengers
A + B A-B + side products A-B
XY A-B+
filter
Some Solid-Supported Scavenger Reagents
4. Scavengers
Urea Library Using Scavenger Reagents
5. SimultaneousMultistep Synthesis
OH O O
Br
O
O
NH+ HCr2O7
cyclohexane, 65 °C,12 h, 55 %
NMe3+ Br3
NMe3+
N N
HOCl
CF3
N N
Cl
CF3
cyclohexane, 65 °C,12 h, 78 %
cyclohexane, 65 °C,12 h, 98 %
a b
c
a, b, ccyclohexane, 65 °C, 16 h, 48 %
"one-pot reaction"
6. Literature
• A. Akelah, D.C. Sherrington, Application of Functionalized Polymers in Organic
Synthesis, Chem. Rev. 1981, 81, 557-587.
• Bannwarth W. and Felder E. (eds.): Combinatorial chemistry, A Practical Approach,
Wiley-VCH, Weinheim, 2000 (86/VK 5500 B219).
• Hodge P. and Sherrington D. C. (eds.): Polymer-supported Reaction in Organic
Synthesis, John Wiley & Sons, New York, 1980 (86/VK 5500 H688).
• D. H. Drewry, D. M. Coe, S. Poon, Solid Supported Reagents in Organic Synthesis,
Medicinal Research Reviews, Volume 19, Issue 2, Pages 97-148.
• Kobayashi, New methods for high-throughput synthesis, Pure Appl. Chem., Vol. 73,
No. 7, pp. 1103–1111, 2001.
That´s
It!
Many Thanks!