Polymer Supported Reagents & Polymer Supported Reagents & CatalystsCatalysts

Contents Polymer reagent : oxidation reagent, bromination,.. Polymer catalyst : C-C coupling catalyst

Advantages of Supported Reagents• Easy separation of polymer and its bound component• Recycling possible (especially for expensive catalysts)• Can use high concentrations of reagents • Easier chemistry than solution-phase synthesis

Polymeric Supports in Organic Chemistry

Rapid Development of Combinatorial Chemistry

Solid-Phase Synthesis(Peptides, DNA, ...)

Supported Reagents & Catalysts during Synthesis

Basic Concept of Solid Phase

Organic Synthesis

Catalyst or

Reagents

Polymer Supported ReagentsPolymer Supported Reagents

Reagent

substrate productfiltration

• Oxidation• Reduction• Nucleophilic reaction• C-C bond formation• Amide bond formation

O

NO.

NMe3 RuO4

+ -

- Example of polymer supported oxidant

NMe3 Cr2O7

+2-

OsO4L [ ]

• Oxidation of alcoholC=OC-OH

• Dihydroxylation of alkene

• Epoxidation & oxidation of amineO O

Polymeric ReagentsPolymeric Reagents for amide bond formationfor amide bond formation

ONH

NN

OH

NO2

or R-CO2H, DIC, DMAP, DMF, RT,

ONH

NN

O

NO2

RO

R'-NH2R CNH-R'

O

R-COCl, TEA, THF, RT, 2 h

24 h

reddish orange

dark brown 60-99% yield

• R-COCl, R-CO2H

• R’-NH2

Yoon-Sik Lee et al. Tetrahedron Lett., 44, 2003, 8063-8067

Scavenger

A(excess) + B

A-B + A

Scavenger

A-B

filtration

Polymeric ScavengerPolymeric Scavenger

AcidicOH

OS

OH

O

Basic NCH3

CH3

N

Nuclophilic NH2 N

NH2

NH2

Electrophilic N C OH

O

IBX (o-iodoxybenzoic acid)• Efficient, selective, mild and environmentally safe oxidizing agent

• Synthesis of carbonyl compounds from primary or secondary alcohols

• No oxidative cleavage (1,2-diols)

• Insoluble in organic solvent (except DMSO) thru inter H-bonding

(1994)Frigerio et al.

IBX

(1983)Dess & Martin

DMP IBX amide

(2003)Zhdankin & Tykwinski

I

O

NH

OO

R

IO

O

OAcAcOOAc I

O

O

OHO

PolymericPolymeric Oxidant : IBX reagentOxidant : IBX reagent

Polymer supported IBX

IO

O

OHO

Rxn at elevated temp. Rxn in ionic liquid/water

With catalyst

Surenda et al.J. Org. Chem. (2003)

More et al.Org. Lett. (2002)

Liu et al.Org. Lett. (2003)

Water-soluble derivative of IBXThottumkaraa et al.T. L. (2002)

IBX amideZhdankin et al.Angew. Chem. (2003)

β-cyclodextrin

Solubility Problem of IBXSolubility Problem of IBX

OH

R1 R2

O

R1 R2

IBX (1eq)

-cyclodextrin, water/acetone(86:14), 12 h, RT

85 - 98%β

OH

R1 R2

O

R1 R2

IBX (3eq)

solvent, 3-6 h, 55-80¡É 0 - 100%

Rxn at elevated temperature

With catalyst

• Solvent: EtOAc, CHCl3, DCE, toluene, THF • Decomposition problem

- Jesse D. More et al. Org. Lett. 2002, 4, 3001-3003

- K. Surendra et al. J. Org. Chem. 2003, 68, 2058-2059

• Supramolecular catalysis

Rxn at High Temp or with CatalystRxn at High Temp or with Catalyst

Water-soluble derivatives - A. P. Thottumkaraa et al. Tetrahedron Lett. 2002, 43, 569-572

• Solvent: Water/THF (3:2)• Temp.: 55-60 ℃• Oxidant: 1.5 eq.• Rxn time: 3–12 h

• Only electronically activesubstrate were oxidized

Soluble IBX Derivatives (I)Soluble IBX Derivatives (I)

IBX amide - V. V. Zhdankin et al. Angew. Chem., Int. Ed. 2003, 42, 2194–2196

• Pseudo cyclic structure (intramolecular secondary I•••O bonds): - partially replace the intermolecular I•••O secondary bonds that afforded the polymeric structure of other reported iodylarenes

soluble

• Reactivity similar to IBX

R-NH2: amino acid

Soluble IBX Derivatives (II)Soluble IBX Derivatives (II)

I

O

NH

R

I

NH

O

O O

R

OO

acetone, RT

Polymer support: BTCore™-OH *, BTCore™-NH2

IBX-ester resin

IBX-amide resin

OH I

O

OH

O

O I

O

O IO

O

NH2I

O

OH

NH

O I

NH

O IO

O

DIC,DMAP/DMF

TBAO,MeSO3H / MC

BOP,DIEA,HOBt

TBAO,MeSO3H / MC

or DMDO

or DMDO

CouplingCoupling ActivationActivation

OH I

O

OH

O

O I

O

O IO

O

NH2I

O

OH

NH

O I

NH

O IO

O

DIC,DMAP/DMF

TBAO,MeSO3H / MC

BOP,DIEA,HOBt

TBAO,MeSO3H / MC

or DMDO

or DMDO

CouplingCoupling ActivationActivation

* Yoon-Sik Lee et al. Tetrahedron Lett. 1997, 38, 591–594

Preparation of IBX Reagent ResinPreparation of IBX Reagent Resin

Bu4N-Oxone,

Bu4N-Oxone,

DCM

DCM

Oxone : potassium peroxymonosulfate, 2KHSO5 KHSO4 K2SO4

hydroxy

FT-IR Spectra (coupling)FT-IR Spectra (coupling)

OH

carbonyl O

OI

1724 cm-1

NH2NH

OI

Appearance of 1655 cm-1 (C=O stretch of amide)

Coupling of 2-Iodobenzoic acid to BTCoreTM-OH

Bu4N-Oxone, MeSO3H (5eq. each)

/ DCM, 30 , 20 h℃

NH

OI

O O

O

OI

O O

O

OI

NH

OI

IBX ester resin

IBX amide resin

Activation (step 2)Activation (step 2)

Bu4N-Oxone, MeSO3H (5eq. each)

/ DCM, 30 , 20 h℃

Activation of BTCore™-2-iodobenzoate

after 20hr

after 6hr

after 12hr

1728 cm-1

1674 cm-1

Activation of BTCore™- 2-Iodobenzamide

FT-IR Spectrum (activation)FT-IR Spectrum (activation)

O

OI

activ

atio

n

- peak shift (C=O of amide) : 1655 cm-1 1620 cm-1

• C=O: 1674 cm-1 • I=O: 730-800 cm-1

Characteristic peak

- Titration by benzyl alcohol

GC-Mass Analysis

100mg of resin / 1mL of DCM

BTCore™-IBX ester(from 2.1 mmol/g )

BTCore™-IBX ester(from 0.91 mmol/g )

BTCore™- IBX amide(from 2.1 mmol/g )

Loading Level of resin 1.1 mmol/g (HL) 0.65 mmol/g (SL) 0.98 mmol/g

OH H

O

oxidant resin

excessRT, 18hr

Determination of Loading LevelDetermination of Loading Level

0102030405060708090

100

0 1 2 3 4 5 6 7 8 9 101112Time (h)

Con

vers

ion

(%)

BTCore™- IBX ester 2eq. of resin (SL) (▲) 2eq. of resin (HL) (■) 4eq. of resin (HL) (□)

BTCore™- IBX amide 1.2eq. of resin (○) 2eq. of resin (●)

at 25℃ in DCM (100mg of resin / 1 mL)

BTCore™- IBX amide exhibitedfast oxidation of benzyl alcohol

Time Course (benzyl alcohol oxidation)Time Course (benzyl alcohol oxidation)

Bromination using IBX Amide Bromination using IBX Amide resin resin

NH

OI

O O

TEAB ( Tetraethylammonium Bromide )

Et4NBr3 * : Mild brominating agentIBX amide resin : Oxidizing agent

Et4NBr IBX amide resin Et4NBr3

* S. Kajigaeshi et al., J. Chem. Soc., Perkin Trans. 1 1990, 897.

X

R

X

Br

R

X=NH2, OHR=Cl,NO2

TEAB, / DCM , r.t.

* Yoon-Sik Lee et al. SYNLETT. 2005, 2, 279–282

Results of BrominationResults of Brominationentryentry IBXIBXaa:TEAB:TEAB Time (h)Time (h) SubstrateSubstrate ProductProduct YieldYieldbb (%)(%)

1 3:3 0.5 82.8

2 4:4 1 51.6

3 3:3 0.5 95

4 1:1 2.5 94.5

a IBX : IBX amide resin (0.99mmol/g) , b isolated yields

(1 : 6.4)

NH2 NH2Br

NH2

BrNH2

NO2

NH2

NO2

Br

OH

NO2

OH

NO2

BrBr

OHCl Cl

OHCl Cl

Br

entryentry oxidantoxidant(eq)(eq) t (h)t (h) substratesubstrate productproduct conversionconversionaa (%) (%)

1 2 3 99%

2 2 6 99%

3 2 15 99%

4 1.2 0.25 P(OEt)3 O=P(OEt)3 99%

5 1.2 4.5 P(OPh)3 O=P(OPh)3 99%

a GC-MS analysis; 100 mg of resin / 1.5 mL of DCM

Oxidation of Sulfides & PhosphitesOxidation of Sulfides & Phosphites

SCH3

SCH3

O

SCH3

O2N

SCH3

O

O2N

SCH3

OH

SCH3

O

O

00.10.20.30.40.50.60.7

1 2 3 4 5 6 7 8 9 10

Regeneration of IBX Amide Regeneration of IBX Amide ResinResin

reuse (#)Initial 1 2 3 4 5 6

Load

ing

capa

city

(a.u

.)

Oxidant resin

(0.59 mmol/g)

Regeneration: Bu4N-Oxone, MeSO3H (5eq. each) / DCM at RT for 20h

Benzyl alcohol (3 eq.) oxidation : RT, 18h

Oxidative activity was maintained during 9 times oxidation & regeneration

NH

OI

O O

7 8 9

Macroporous PS-supported IBX amideMacroporous PS-supported IBX amide

NH2HN

HNΙΙMPSMPSMPSMPSMPSMPS

Advantages of MPS (Macroporous Polystyrene)

Less solvent diffusion problem.Less solvent diffusion problem.

Large surface area. Large surface area.

Much broader solvent system.Much broader solvent system.

Less swellable.Less swellable.

Applicable to Pack-bed reactor flow-systemApplicable to Pack-bed reactor flow-system..

Synthetic Scheme

i) 2-iodobenzoic acid, DIC, HOBT, DIEA, DMF, rt, 6h; ii) NBu4SO5H, MeSO3H, DCM, rt, 10~12 h.

Solvent-friendly MPS-IBX amideSolvent-friendly MPS-IBX amide

Using 2 equiv of oxidant at rt and methoxybenzyl alcohol as the Using 2 equiv of oxidant at rt and methoxybenzyl alcohol as the substrate.substrate. DCM (□), ACN (♦), THF (■), acetone (▲) and diethyl ether (+).DCM (□), ACN (♦), THF (■), acetone (▲) and diethyl ether (+). Conversion (%) was determined by 300MHz 1H NMR spectroscopy. Conversion (%) was determined by 300MHz 1H NMR spectroscopy.

Comparison of several solvents

0

20

40

60

80

100

0 20 40 60Time (min)

Conv

ersio

n(%

)

0

20

40

60

80

100

0 20 40 60Time(min)

Conv

ersio

n(%

)

MPS-IBX amideMPS-IBX amide A gel type of PS-IBX amideA gel type of PS-IBX amide

Preparation of imidazolium-bound Core (IB-Core) bead

Cl NN+

1) CHCl3

50℃ 5hr

1.3 eq

NN +

PF6-

[MVBIM][PF6-]

2) NaPF6

Acetone 25℃ 2 days

immiscible with styrene and water.

NN +PF6

-

Suspension polymerization

- Polymerization Time : 20 hours- Polymerization Temperature : 70 º C- RPM : 200 ~ 300

N

N

+

N

N

+

N

N

+

NN+

N

N+

N

N+N

N

+

N

N+

N

N+

NN +

N

N +

N

N

+

PF6-

PF6-

PF6-

PF6-

PF6-

PF6-

PF6-

PF6-

PF6-

PF6-

PF6-

PF6-

Tetrahedron Lett. 2004, 45, 1837-1840, J. W. Byun, Y. S. LeeTetrahedron Lett. 2004, 45, 5827-5831, J. H. Kim, Y. S. Lee

IB-Core ResinIB-Core Resin

water

oil

20 ㎛

20 ㎛

FE-SEM & CLSM images of imidazolium-bound Core (IB-Core) bead

IB-Core ResinIB-Core Resin

N

N+PF6

-

Pd(OAc)21, 2, 4 eq

Cs2CO3

H2O/DMF

50 , 2 h℃IB-1 (0.23 mmol/g)

NN

N N

Pd PF6F6P

Immobilization of Pd for Suzuki C-C coupling

IB-NHC-Pd complex

IB-Core ResinIB-Core Resin

Suzuki C-C coupling reaction using IB-NHC-Pd complex

R

X

R

IB-NHC-Pd complex(1 mol%)

Ph-B(OH)2 , 50℃DMF/ H2O

=1/1

Entry R X BaseTime

(h)

IsolatedYield(%)

1 OH I Na2CO3 1 95

2 OCH3 I Na2CO3 1 94

3 CH3 I Na2CO3 1 94

4 CH3 Br Na2CO3 6 93

5 OH Br Na2CO3 6 92

6 CHO Br Na2CO3 6 94

7 COOH Br Na2CO3 6 94

8 OCH3 Br Na2CO3 6 95

IB-Core ResinIB-Core Resin

Reusability of IB-NHC-Pd complex

0

20

40

60

80

100

1 2 3 4 5 6 7 8 9 10The number of recycling

Isol

atio

n y i

eld(

%)

IIB-NHC-Pd complex

(1 mol %)

Ph-B(OH)2 1.2 eqNa2CO3 5 eq

for 1 h at 50℃

IB-Core ResinIB-Core Resin