PPT Chapter 9 Synthetic Applications - Seoul National University

Polymer Supported Reagents &

Polymer Supported Reagents &

Catalysts Catalysts

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

Polymeric Supports ⁱⁿ

Organic Chemistry

Rapid Development of Combinatorial Chemistry Rapid Development of Combinatorial Chemistry

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

(Peptides, DNA, ...) Supported Reagents &

Catalysts during Synthesis Supported Reagents &

Catalysts during Synthesis

Basic Concept of Solid Phase

Organic Synthesis

Basic Concept of Solid Phase

Organic Synthesis

Catalyst or

 Reagents

Polymer Supported Reagents Polymer Supported Reagents

Reagent

substrate ^filtration product

• Oxidation

• Reduction

• Nucleophilic reaction

• C-C bond formation

• Amide bond formation

O

N O.

NMe₃ RuO₄

+ -

- Example of polymer supported oxidant

NMe₃ Cr₂O₇

+ 2-

OsO₄

L [ ]

• Oxidation of alcohol C-OH C=O

• Dihydroxylation of alkene

• Epoxidation & oxidation of amine

O O

Polymeric Reagents

Polymeric Reagents for amide bond formationfor amide bond formation

O

NH N

N O H

NO₂

or R-CO₂H, DIC, DMAP, DMF, RT,

O

NH N

N O

NO₂ R

O

R'-NH₂

R 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 Scavenger Polymeric Scavenger

 Acidic

OH O

S OH

O

 Basic ^N

CH₃ CH₃

N

 Nuclophilic ^{NH2 N}

NH₂

NH₂

 Electrophilic N C O

H 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 N H

O O

R I

O O

AcO OAcOAc I

O O

O OH

Polymeric

Polymeric Oxidant : IBX reagentOxidant : IBX reagent

Polymer supported IBX Polymer supported IBX

I O O

O OH

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 IBX

Thottumkaraa et al.

T. L. (2002)

IBX amide

Zhdankin et al.

Angew. Chem. (2003) β-cyclodextrin

Solubility Problem of IBX Solubility 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 Catalyst Rxn 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 active substrate 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

N H

O

O O

R O

O

acetone, RT

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

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

IBX-ester resin

IBX-amide resin

OH ^I

O O H

O

O I

O

O I O

O

NH₂ ^I

O O H

NH

O I

NH

O I O

O

DIC,DMAP/DMF

TBAO,MeSO₃H / MC

BOP,DIEA,HOBt

TBAO,MeSO₃H / MC or DMDO

or DMDO

Coupling

Coupling Activation_Activation

OH ^I

O O H

O

O I

O

O I O

O

NH₂ ^I

O O H

NH

O I

NH

O I O

O

DIC,DMAP/DMF

TBAO,MeSO₃H / MC

BOP,DIEA,HOBt

TBAO,MeSO₃H / MC or DMDO

or DMDO

Coupling

Coupling Activation_Activation

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

Preparation of IBX Reagent Resin Preparation 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

O I

1724 cm^-1

NH₂ N

H O

I

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

 Coupling of 2-Iodobenzoic acid to BTCore^TM-OH

Bu₄N-Oxone, MeSO₃H (5eq. each) / DCM, 30℃, 20 h

NH O

I

O O

O O

I

O O

O O

I

NH O

I

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 O

I

activation

- 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

excess

RT, 18hr

Determination of Loading Level Determination of Loading Level

0 10 20 30 40 50 60 70 80 90 100

0 1 2 3 4 5 6 7 8 9 10 11 12

Time (h)

Conversion (%)

0 10 20 30 40 50 60 70 80 90 100

0 1 2 3 4 5 6 7 8 9 10 11 12

Time (h)

Conversion (%) ^{ 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 exhibited fast oxidation of benzyl alcohol

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

Bromination using IBX Amide resin Bromination using IBX Amide resin

NH O

I

O O

TEAB ( Tetraethylammonium Bromide )

Et₄NBr₃ * : Mild brominating agent IBX 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=NH_2, OH R=Cl,NO₂

TEAB, / DCM , r.t.

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

Results of Bromination Results of Bromination

entry

entry IBXIBX^aa:TEAB:TEAB Time (h)Time (h) SubstrateSubstrate ProductProduct YieldYield^bb (%)(%)

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 NH₂

Br

NH₂

Br NH₂

NO₂

NH₂

NO₂ Br

OH

NO₂

OH

NO₂ Br Br

OH

Cl Cl

OH

Cl Cl

Br

entry

entry oxidantoxidant

(eq)(eq) t (h)t (h) substratesubstrate productproduct conversionconversion^aa (%) (%)

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 & Phosphites Oxidation of Sulfides & PhosphitesOxidation of Sulfides & Phosphites Oxidation of Sulfides & Phosphites

S CH₃ S

CH₃ O

S CH₃ O₂N

S CH₃ O

O₂N S CH₃

O H

S CH₃ O

O

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7

1 2 3 4 5 6 7 8 9 10

Regeneration of IBX Amide Regeneration of IBX Amide

Resin Resin

reuse (#)

Initial 1 2 3 4 5 6

Loading capacity (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 9times oxidation & regeneration

NH O

I

O O

7 8 9

Macroporous PS-supported IBX amide Macroporous PS-supported IBX amide

 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 amide Solvent-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

MPS-IBX amide

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

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

Cl + N N

1) CHCl₃ 50℃

5hr 1.3 eq

N + N PF₆-

[MVBIM][PF₆^-] 2) NaPF₆

Acetone 25℃

2 days

 immiscible with styrene and water.

N + NPF₆-

 Suspension polymerization

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

N N

+

N N

+

N N

+

N

+ N

N

+N

N

+N N

N

+

N

N

+

N N+

N

N +

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. Lee Tetrahedron Lett. 2004, 45, 5827-5831, J. H. Kim, Y. S. Lee

IB-Core Resin IB-Core Resin

water

oil

20 ㎛

20 ㎛

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

IB-Core Resin IB-Core Resin

N

+ N^PF6

-

Pd(OAc)₂

1, 2, 4 eq

Cs₂CO₃ H₂O/DMF 50 ℃, 2 h IB-1 (0.23 mmol/g)

N N

N N

Pd PF₆ F₆P

 Immobilization of Pd for Suzuki C-C coupling

IB-NHC-Pd complex

IB-Core Resin IB-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 Base Time

(h)

Isolated Yield

(%)

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 Resin IB-Core Resin

 Reusability of IB-NHC-Pd complex

0 20 40 60 80 100

1 2 3 4 5 6 7 8 9 10

The number of recycling

Isolation yield(%)

I IB-NHC-Pd complex (1 mol %) Ph-B(OH)₂ 1.2 eq

Na₂CO₃ 5 eq for 1 h at 50℃

IB-Core Resin IB-Core Resin