expanding the boundaries of organic synthesis through flow chemistry ildiko kovacs, m. sc
TRANSCRIPT
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
