Expanding the Boundaries of Organic Synthesis Through Flow Chemistry Ildiko Kovacs, M. Sc

Expanding the Boundaries of Organic Synthesis Through Flow Chemistry

Ildiko Kovacs, M. Sc

Corporate History

1990s High Throughput chemistry

Combinatorial chemistry Parallel chemistry

Microwave chemistry started

2000sMicro-reactors

Chemistry on chips

Lab on chips

Flow chemistry

• ComGenex – Largest biotech acquisition in Eastern Europe – Ever• ThalesNano, Inc. - Founded in 2002

33 countries

ThalesNano’s Technology in the World

The most comprehensive bench top continuous process technology and instrument portfolio

H-Cube Autosampler™

and CatCart Changer™

H-Cube®

X-Cube™ X-Cube Flash™

H-Cube Midi™

P-Cube™O-Cube ™ QuantiFlow™

H-Cube Maxi™H-Cube Pro™

H-Cube Tutor™ CatCart Packer™

What is flow chemistry?

• Performing a reaction by pumping one or more starting materials, typically on small scale, through either a coil or fixed bed reactor.

• Mixing of liquids is typically performed through a T-piece creating laminar flow.

Reactants

Products

By-products

Traditional Batch Method

Gas inlet

Reactants

Products

By-products

Batch vs. Flow

Better surface interactionControlled residence timeElimination of the products

Flow Method

H-Cube®

Heating Control

Lower reaction volume. Closer and uniform temperature control

Outcome:Safer chemistry. Lower possibility of exotherm.

Batch Flow

Larger solvent volume. Lower temperature control.

Outcome:More difficult reaction control. Possibility of exotherm.

Batch

Flow

Wider parameter range

Region covered in a conventional laboratory

At ThalesNano

pressure / bar

Tem

perature / °C

Goal

100 200 300

Regions requested normally by supercritical fluids

Flow chemistry Region 2008 (ThalesNano)

-100

0

100

200

300

400

500

0

200

400

600

800

1000

1200

t / m

in

Alkylation Suzuki-Miyaura

Azidesynthesis

Sonogashirareaction

Flow

Batch

Reduced reaction time

0

5

10

15

20

25

30

Aldoxime reduction Aldehyde

reduction

t / m

in

FlowBatch

Where do I start?

Flow Chemistry Database

www.flowreact.com

Number of reaction schemes: 3297 Number of experiments: 5826

The H-Cube® Hydrogenation Flow Reactor

Disadvantages with batch reactors

Current batch reactor technology has many disadvantages: Need hydrogen cylinder-tough safety regulations Separate laboratory needed! Time consuming and difficult to set up Catalyst addition and filtration is hazardous Parr has low temperature, low pressure capability Analytical sample obtained through invasive means. Mixing of 3 phases inefficient - poor reaction rates

H-Cube® Overview

• HPLC pumps continuous stream of solvent • Hydrogen generated insitu• Sample heated and passed through catalyst• Up to 100°C and 100 bar. (1 bar=14.5 psi)

NH

O2N

NH

NH2

Hydrogenation reactions:Nitro ReductionNitrile reductionHeterocycle SaturationDouble bond saturationProtecting Group hydrogenolysisReductive AlkylationHydrogenolysis of dehydropyrimidonesImine ReductionDesulfurization

Example for fast optimization

• Batch reactions gave results after 4 hours!

H2 / cat.+

diphenyl-acetylene

cis-stilbene

trans-stilbene

1,2-diphenylethane

H2 / cat.

H. H., Horváth; G, Papp; Cs., Csajági; F., Joó; Catalysis Communications; 8; 3; 2007; 442-446

30 40 50 60 70 800

20

40

60

80

diphenylethane cis-stilbene trans-stilbene conversion%

T (0C)

Catalyst: [RuCl2(mTPPMS)2]/Molselect DEAE

• p(H2) = 30 bar, [S] = 0.1 M

• Solvent: toluene/ethanol 1/1

• 24 experiments, total operation time is one day

H. H., Horváth; G, Papp; Cs., Csajági; F., Joó; Catalysis Communications; 8; 3; 2007; 442-446

30 40 50 60 70 800

20

40

60

80

diphenylethane cis-stilbene trans-stilbene conversion

%

p(H2) (bar)

• T = 50 oC, [S] = 0.1 M

• Solvent: toluene/ethanol 1/1

• 26 experiments, total operation time is one day

Optimization of diphenylacetylene reduction

How long can a CatCart® be reused?

H-Cube® conditions: 0.1M, [50:50] EtOAc:EtOH, ~1 bar, 30 oC, 1 mL/min;

Total material processed = 30x 1mmole fractions = 30 mmoles = 4.85 g with 140 mg Pd/C

STARTING MATERIAL

PRODUCT

Starting Material

Product

Optimization of O-CBz group removal

O

COOHBocHN

OH

COOHBocHN

10% Pd/CEtOH/EtOAc (1:1)

H-Cube®

K. Knudsen, J. Holden, S. Ley, M. Ladlow, Adv. Synth. Catal. 2007, 349, 535-538.

Large Scale Hydrogenation

O

COOHBocHN

OH

COOHBocHN

10% Pd/CEtOH/EtOAc (1:1)

60°C, H-Cube®

K. Knudsen, J. Holden, S. Ley, M. Ladlow, Adv. Synth. Catal. 2007, 349, 535-538.

Single injections 0.2 M

Continuous run 0.2 M

Catalyst screening

Parameter scanning: effect of residence time to the conversion and selectivity

0,4 0,6 0,8 1,0 1,2 1,4 1,6 1,8 2,0 2,2

85

90

95

100

105

110

Conversion Selectivity

%

Flow rate / mLmin-1

1% Pt/C (V) catalyst at 0,02 concentration of 4-bromo-nitrobenzene

Selective aromatic nitroreduction

Catalyst Flow rate / mL/min

Residence time / sec

Conc. / mol/dm3

Conv. / %

Sel. / %

IrO2 2 9 0.2 52 69

Re2O7 2 9 0.2 53 73

(10%Rh 1% Pd)/C

2 9 0.2 79 60

RuO2

(activated)2 9 0.2 100 100

1 18 0.2 100 99

0.5 36 0.2 100 98

Ru black 2 9 0.2 100 83

1% Pt/C doped with Vanadium

2 9 0.2 100 96

1 18 0.2 100 93

0.5 36 0.2 100 84

Conditions: 70 bar, EtOH, 25°C

Increase and decrease of residence time on the catalyst cannot be performed in batch

Deuteration in flow

Substrate Product Deuterium content(%)

Isolated yield / %

99 99

97 98

93 97

96 98

96 99

PhPh Ph

Ph

D

D

Ph OMe

O

Ph OMe

OD

D

PhPhPh

PhD D

D D

NH

O

HN

O

Me

Me

HN

O

HN

O

Me

Me

D

D

HN

O

HN

O

Me

Me

HN

O

HN

O

Me

Me

D

D

Mándity, I.M.; Martinek, T.A.; Darvas, F.; Fülöp, F.; Tetrahedron Letters; 2009, 50, 4372–4374

Double bond reduction in H-Cube®

O

OO

OBz

BzO

OBz

OBz

OBz

OBz

O

OBzO

O

O

HN

HN

O

O

O

OBzO

BzO

O

OBz

O

OBz

BzO

OOBz

OBzOBz

BzO

OBz

BzO

O

OO

OBz

BzO

OBz

OBz

OBz

OBz

O

OBzO

O

O

HN

HN

O

O

O

OBzO

BzO

O

OBz

O

OBz

BzO

OOBz

OBzOBz

BzO

OBz

BzOO

OO

OBz

BzO

OBz

OBz

OBz

OBz

O

OBzO

O

O

HN

HN

O

O

O

OBzO

BzO

O

OBz

O

OBz

BzO

OOBz

OBzOBz

BzO

OBz

BzO

32%265 mg

44%233 mg

1.) Grubbs-I; CH2Cl2; rt, 60 h, N2

2.) H-Cube® Pd-C, EtOAc; 70°C(3 cycles; 530 mg of starting material)

Grubbs-I catalyst

Leyden, R.; Velasco-Torrijos, T.; Andre, S.; Gouin, S.; Gabius, H.; Murphy, P.V.; J. Org. Chem.; 2009; 74, 9010-9026

MeO

MeO

(±)-oxomaritidine

NH

O

Br

HONMe3N3

N3

HO

MeCN:THF (1:1), 70 oC

O

MeO

OMe

(1)

(2)

catch, react, release

MeO

OMe

N

HO

rt to 55 oC

Ph(nBu)2P

H2OH2 (g)electrolysis

Flow hydrogenation

10% Pd/C, THF

MeO

OMe

NH

HO

O

F3C O

O

CF3

MeO

OMe

N

HO

CF3O

80 oC

NMe3RuO4OH

MeO

OMe

PhI(O2CX3)2rt

NMeO

MeO

CF3

O

OMeOH / H2O (4:1)

NMe3OH

35 oC

I.R. Baxendale, J. Deeley, C.M. Griffith-Jones, S.V. Ley, S. Saaby, G. Tranmer, J. Chem. Soc., Chem. Commun., 2006, 2566.

Flow Synthesis of Oxomaritidine

Scaling up Hydrogenation Using H-Cube Pro™ and H-Cube Midi™

H-Cube Midi™ reactor for scale-up

H-Cube Pro™ and H-Cube Midi™ reactors for scale-up

Parameters:- p= 1-100 bar- T=25-100°C- v=0.1-3 ml/min- c=0.01-0.1 MH2 Control: upon constant

bubble/liquid ratio (saturation)

H-Cube Midi™ Parameters:- p= 1-100 bar- T=25-150°C- v=5-25 ml/min- c=0.05-0.25 MH2Control: upon stoichiometry (production of H2)

H-Cube Pro™ Parameters:- p= 1-100 bar-T=10-150°C- v=0.1-3 mL/min-c=0.01-0.4 M-H2Control: upon stoichiometry

(production of H2)

ca. 3-6 times

ca. 10-25 times

Scale-up with H-Cube Pro™

Protocol conversion from Batch to H-Cube Midi™

150 min 20 min

0.03 mol (5.43 g) compound was reduced in

Batch reactor H-Cube Midi™

c= 0.2 M Vsolution=7 L

t= 10 h

Purity: 100 %Analysed by

LCMS

Reaction parameter

360 mg 5% Pd/C

catalyst 2.43 g 5% Pd/C

0.05 C (M) 0.15

30 (60 cm3) T (°C) 70

20 p (bar) 70

Flow rate (mL/min) 10

Conversion (%) 100

Selectivity (%) 100

85 Yield (%) 89

NO2

OCH3O

NH2

OCH3O

H2

Analysis by GC-MSAt the same substrate: catalyst ratio 0.125 mol substrate was reduced

After 120 min After 50 min

N

N

NH

HN

Optimization on H-Cube Midi™

Reaction parameters

Batch in house H-Cube Midi™

CatalystC (M)

Flow rate (mL/min)T (°C)

p (bar)Conversion(%)

Selectivity(%)

360 mg RaNi0.05 (60 cm3)

-3020

10095

After 120 min 0.003 mol compound was reduced

15.02 g RaNi0.2

12.53020

10095

After 1.2 min 0.003 mol compound was reduced

Co

nversio

n (%

)

Flow rate (mL/min)

C = 0.20 M c = 0.25 M c = 0.30 M c = 0.35 M c = 0.40 M

Quinoxaline reduction

Reduction of bromonitrobenzene to bromoaniline

H-Cube® H-Cube Midi™

Autoclave: 0%, selectivity: 100%, byproduct (1h, 25°C, 20 bar, 5% Rh/C)

Conditions

T= 30 °C

p=70 bar

Catalyst: 5% Rh/C

Conditions

T= 30 °C

p=70 bar

Catalyst: 5% Rh/C

NO2

Br

NH2

Br

+

NH2

5 10 15 20 25 30 350

20

40

60

80

100

Residence time / sec

Se

lec

tiv

ity

/ %

0.05 M 0.10 M

0 5 10 15 20 25 300

20

40

60

80

100

Se

lec

tiv

ity

/ %

Residence time / sec

0 1 2 3 4 5 6 7 80

20

40

60

80

100

Se

lec

tiv

ity

/ %

Flow rate / mL/min0 5 10 15 20 25

0

20

40

60

80

100 0.05 M 0.10 M

Se

lec

tiv

ity

/ %

Flow rate / mL/min

The X-CubeTM continuous-flow heterogeneous catalyst/reagent

reactor

Next generation reactor: X-Cube™

Features:•Continuous-flow reactions at high T and high pressure•Dual pump system•Temperature up to 200ºC•Pressures up to 150 bar•Use of multiple cartridges for different step•Introduction of gases from an external source

Advantages:•Easy operation•Small footprint •Wide reaction conditions•Fast optimization•Multistep reactions•Tri-phase reactions (CO, H2, CO/H2)•Scale up reactions•In-line purification

two heatable CatCartTM holder

bubble detector

gas from an external source

six way valve for manual injection

built in HPLC pumps

touch screen panel

system pressure valve

system pressure sensor

gas inlet valve

inlet pressure sensor

liquid mixer

X-CubeTM overview

gas/liquid mixer

secondary mixer

Ext

ern

al g

as s

ou

rce

Conversion: 90-95% (TLC)

Purity: 70% (LC-MS) without work-up

Batch parameters: K3PO4, TBA-Br, Pd(OAc)2, DMF, 2 hours, 130 °C

Reference:

(Zim, Danilo; Monteiro, Adriano L.; Dupont, Jairton; Tetrahedron Lett.; EN; 41; 43; 2000; 8199-8202)

Suzuki-Miyaura C-C cross coupling:

Sample reactions

Br

NO2

BOHOH

NO2

X-CubeTM

CatCartTM 70*4 mm Pd EnCatTM BINAP 30,2-propanol, TBAF, 80°C, 20 bar, 0.05M, 0.5 ml/min

+

Model reaction chosen:

I

OH

OCO

NH

OH

O

N

O++X-CUBE

Reactions involving gases: Direct aminocarbonylation

Rapid, and versatile optimization including the following parameters

-Catalyst-Solvent-Base-Temperature-Pressure (CO)-Flow rate

Very few literature precedents* for direct formation

*F. Karimi, B. Langström, Eur. J. Org. Chem. 2003, 2132-2137 in microautoclave (200 microL) introducing 11C as radioactive tracer for PET

Catalyst Conversion (%)

Pd(TPP)4 83

FiberCat® 1001 25

FiberCat® 1007 9

PdEnCat™ TPP 30 20

PdEnCat™ 30 2

Pd(TPP)4 Tetrakis(triphenylphosphine)palladium(0) (polymer supported) (loading: 0.5-0.9 mmol Pd/g, PS cr. w/ PVB)

FibreCat 1001: Pd(OAc)2/TPP on polymeric fiber (Pd content: 6 %)

FibreCat 1007: Pd(OAc)2/tri-cyclohexylphosphine on polymeric fiber (Pd content: 1-10 %)

Pd EnCat™ TPP 30: microencapsulated Pd(TPP)4

Pd EnCat™ 30: microencapsulated Pd(OAc)2 (loading: 0.4 mmol Pd/g, crosslinked polyurea matrix)

Rapid optimization: catalysts

FiberCat is registered trademark of Johnson Matthey, Inc.

EnCat is trademark of Reaxa, Ltd.

*Conversion to 4-(pyrrolidine-1-carbonyl) benzoic acid

Reaction conditions: 0.01 M of 4-iodobenzoic acid in 20 mL of THF, 1.5 eq. of pyrrolidine, 2.0 eq. TEA, 30 bar, 0.5 mL/min flow rate

Comparison of continuous process flow, batch and MW conditions (in house experiments)

I

OH

OCO

NH

OH

O

N

O++X-CUBE

Method Conversiona (%) Product ratiob (%)

Comment

Autoclave - CO;100°C, 30 bar

22 36 Sampling after 30 min.

60 20 Reaction time: 60 min.

Balloon - CO;68°C (THF bp.); atm.

35 54 Sampling after 30 min.

69 75 Reaction time: 60 min.

Microwave - Mo(CO)6;

100°C, overpressure

72 65 Reaction time: 60 min.

Flow - CO; 100°C, 30 bar

96 83 Reaction time (i.e. residence time) was

1 minC.

a Conversion to all new compounds. b % of desired product (4-(pyrrolidine-1-carbonyl)-benzoic acid).

c Details: 4-iodobenzoic acid (1 mmol, 0.248 g), pyrrolidine (1.5 mmol, 124 μL), and triethylamine (2 mmol, 278 μL) dissolved in 50 mL of THF. Product: 4-(pyrrolidine-1-carbonyl)benzoic acid (0.177 g). Flow rate: 0.5 mL/min, 0.4 g Pd(TPP)4 catalyst (CatCart®)

Csajági, Cs., Borcsek, B., Niesz, K., Kovács, I., Székelyhidi, Zs., Bajkó, Z., Ürge, L., Darvas, F., OL, 2008, 10(8), 1589-1592.

NH2

NH

53

71

80

60

69

63

81

Yield (%) Iodobenzoicacid

Amine

30

55

88

89

25

80

Yield (%)AmineIodobenzoicacid

53

71

80

60

69

63

81

Yield (%) Iodobenzoicacid

Amine

30

55

88

89

25

80

Yield (%)AmineIodobenzoicacid

NH2

Automated test library synthesis Carbonylation

I

OH

O

NH2

NH

NH2

NH2

IOH

ONH

I

OHO NH

NH

NH2

NH2

NH2

X-Cube Flash™

Dual Pump and Injection System

Changeable Heater Block

UMPC – Operation System

Back Pressure Regulator

Outlet Tube

X-Cube Flash™ Schematic

Schematic Diagram

Stainless steel coil(1000 m i.d.)

www.thalesnano.com

Razzaq, T.; Glasnov, T. N.; Kappe, C. O. Eur. J. Org. Chem. 2009, doi:10.1002/ejoc.200900077  

Microwave and X-Cube Flash Comparison Table

System X-Cube Flash Microwave

Solvents Any solvent apart from conc. halogenated acids

Only solvents with a dipole moment

Pressure 180 bar Typically 20 bar.

Temperature limit

350°C Typically 250°C

Scale Reaction can be left to produce desired amount.

Large scale batch not possible due to limited penetration depth.

Diels Alder reaction

Me

Me

CN Me

Me

CN+ toluene (2.0M)

250°C, 60 bar

1 2 3(>99%)

• Diels-Alder reactions usually require long reaction times.

•This reaction time could be reduced to 5 minutes at 250°C using toluene.

•.Product isolated in near quantitative yield.

•Reaction also possible using lower boiling solvents (MeCN, THF, DME) with same result using higher pressures (200 bar).

Newmann-Kwart Rearrangement – MW vs. Flow Experiments

“Easy” Case

O

NCBatch MW: NMP,MW, 220 °C, 20 min

Flow X-Flash: NMP, 0.15 M,200 °C, 60 bar, 1 mL/minorDME, 0.15 M, 210 °C, 60 bar, 1 mL/min

S

NS

NCO

N

> 99% Conversion

Moseley, J. D. et al. Tetrahedron, 2006, 62, 4685; Moseley, J. D.; Lenden, P. Tetrahedron, 2007, 63, 4120

Product, DMEHPLC, 215 nm

Kinetic Analysis (HPLC)

Newmann-Kwart Rearrangement – MW vs. Flow Experiments

“Difficult” Case

O

MeOS

N S

MeOO

N

Batch MW: NMP,MW, >300 °C, 40 min

Flow X-Flash: NMP, 0.15 M,280 °C, 60 bar, 1 mL/minorsc. DME, 0.15 M, 300 °C, 80 bar, 1.3 mL/min

>99% Conversion

Moseley, J. D. et al. Tetrahedron, 2006, 62, 4685; Moseley, J. D.; Lenden, P. Tetrahedron, 2007, 63, 4120

Product, DMEHPLC, 215 nm

Kinetic Analysis (HPLC)

sc. DMEcritical point:

263 °C; 39 bar

Fluoride-amine exchange

CN

F F

CN

F NH2

NH3/NMP

Reaction Conditions: 275°C, 200 bar, c=0.1M, 1 mL/min; 8 mL loop

100% Conversion (GC-MS)100% Purity (NMR) – containing 10% NMP95% Yield

Mol Divers. Accepted publication, Lengyel et al.

Fischer-Indole Synthesis: Scale Out

NHNH2

O

NH

+AcOH/2-propanol (3:1) (0.5 M)

200°C, 75 bar, 5.0 mL min-1

96 %

cf. MW reaction: Bagley, M. C.; et al. J. Org. Chem. 2005, 70 , 7003

In AcOH/2-propanol (3:1) (0.5M)150 °C, 60 bars,

1.0 mL min-1 (4 min res. time) 88% isolated yield

Continuous Flow Results (4 mL or 16 mL Coil)

Scale-up 200 °C, 75 bars,

5.0 mL min-1 (~3 min res. time) 96% isolated yield

25 g indole/hour

Supercritical state

Solvent Tcrit (°C, K) pcrit

Propane 97°C (369.9 K) 42.5 bar

Ammonia 132.4°C (425.1 K) 112.8 bar

Butane 152°C (647 K) 38.0 bar

Butane-2-ol 233°C (512.5 K) 39.7 bar

Propane-2-ol 235.5°C (514 K) 47.6 bar

Metanol 239.4°C (506.2 K) 80.8 bar

Etanol 240.9°C (508.6 K) 61.4 bar

Water 374°C (405.5 K) 220.6 bar

Property Gas SCF Liquid

Density

(g/cm3)

10-3 0,1-0,5 1

Viscosity (Pa s)

10-5 10-4 10-3

Diffusivity

(cm2/s)

10-1 10-3 10-5-6

Claisen Rearrangement

O OHtoluene (0.1 M)

240°C, 100 bar1.0 mL/min

(95%)

Results

•Difficult reaction. Requires 1-2 hours reaction times in microwave.• Reaction proceeded in high yield after only 4 minutes residence time.• High temperature control needed:

• <230°C gave incomplete conversion• >250°C gives numerous side products.

•Reaction optimized “on the fly” for quick results.

O-Cube:

Ozonolysis Reinvented

What is ozonolysis?

Ozonolysis is a technique that cleaves double and

triple C-C bonds to form a C-O bond.

“Typically” Three Main Products Desired

Carboxylic Acid(oxidative work-up)

Aldehyde/Ketone(simple quenching)

Alcohol(reductive work-up)

R3

R1 R2

R4

OR

OH

OR

H

OHR

How to work-up?

Ozone and ozonide detection• Indigo can detect both ozonide and ozone

Few drops of indigo solution turns colorless if ozone or ozonide is present

• Isolation – safety• Never dry completely the solution• Use low temperature during evaporation of solvents• Be careful with handling and shaking• Ozonide can be detected by MS

Why is ozonolysis neglected?

The reaction is highly exothermic.

Temperature is difficult to control, so is carried out at -78ºC.

Batchwise accumulation of ozonide dangerous.

Typical batch ozonolysis equipment a collection of parts. Not a purpose built system Parameters difficult to monitor and control

Ozonolysis Chemical Substitutes

This has lead chemists to find alternatives

Sodium Periodate – Osmium Tetroxide (NaIO4-OsO4)

However: OsO4 is highly poisonous

OsO4 is very expensive so is not ideal for scale up.

Regeneration is required Water is required as a solvent for the hydrolysis of the

intermediate osmate ester.

Flow Ozonolysis Setup

Ozonolysis examples

*Isolated yield with full conversion (comparable with batch reactions)Irfan, M.; Glasnov, N. T.; Kappe, O. C.; Organic Letters; 2011; 13(5); 984-987

R1Ar

O

R1Ar

R2

+O3 1. Solvent, T, 0.05 M,1 mL/min

2. quenching reagent, T,, 0.7 mL/min5%, 1.5 equ.

Ar R1 R2 Step 1 Step 2 Product (%)*

HMeOH25°C

NaBH4/MeOH25°C 90

CH3H

Me2CO0°C

5% H2O/Me2CO10°C 91

HH

Me2CO25°C

5% H2O/Me2CO25°C 84

HCH3

Me2CO10°C

5% H2O/Me2CO15°C 72

F

O2N

H3CO

100-215 mg of product within 40 min

Ozonolysis examplesH3C CH3

O

H3C CH3

+ O3

1.) Me2CO, 25°C, 1 mL/min2.) 5% H2O/Me2CO, 25°C, 0.7 mL/minYield: 70%

Ph

OH

Ph

CO2H

Ph

HO

Ph

O

Ph

Ph

1. Ozone

2. Quenching agent

1.) CHCl3, 25°C, 1 mL/min2.) 1.5 M H2O2/CHCl3, 25°C, 0.5 mL/minYield: 86%

n-C8H17NH2 + O3 n-C8H17NO2

1.) EtOAc, 25°C, 1 mL/min, 0.05 M, 10% ozone (3 equ.)2.) 1.5 M H2O2/CHCl3, 25°C, 0.5 mL/minYield: 73%

Work-up (all cases) evaporation → >95% purity

Irfan, M.; Glasnov, N. T.; Kappe, O. C.; Organic Letters; 2011; 13(5); 984-987

Optimization of ozonolysis of thioanisole

SCH3 S

CH3

O

+

S

CH3

O

O

1 2 - 84% isol.yield 3 - 87% isol. yield

O3 equ.

Solvent Step 1.flow rate(mL/min)

Step 1.temperature

(°C)

Quenching solution

Step 2. flow rate(mL/min)

Step 2.Temperature

(°C)

Conv. of 1. (%)

Conv. of 2. (%)

Conv. of 3. (%)

1 MeOH 1 250.1 M

NaBH4/MeOH 0.7 25 0 99 0

2 Me2CO 0.5 250.05 M

NaIO4/H2O1 25

082 18

2 Me2CO 0.5 10 1 M H2O2/H2O 1 15 0 57 43

2 Me2CO 1 5 3 M H2O2/H2O 1 10 0 22 78

2 Me2CO 1 5 5 M H2O2/H2O 1 10 0 12 88

2 MeOH 1 -105 M

H2O2/MeOH 1 0 32 0 68

2 MeOH 1 -205 M

H2O2/MeOH 1 -10 14 0 86

4 MeOH 0.5 -205 M

H2O2/MeOH 0.5 -10 0 0 99

Irfan, M.; Glasnov, N. T.; Kappe, O. C.; Organic Letters; 2011; 13(5); 984-987

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