Industrial Applications of

Flow Chemistry:

Novel Heterocycle Synthesis

and Making Dangerous

Chemistry Safer!

Richard Jones, CEOThalesNano Confidential

Organic Synthesis – Growing Complexity

• 1980’s – 2-3 Steps

• 1990’s – 3-4 Steps

• Today – 4-8 Steps

• Future – 8-50 Steps

R&D Spend

0.0

10.0

20.0

30.0

40.0

50.0

60.0

1980 1985 1990 1995 2000 2004 2005 2006

2.0 4.08.4

15.2

26.0

37.0 39.943.0

47.6

51.855.2

Investment in R&D 1980-2005(Expenditures Billions in Dollars)

PhRMA member companies Biopharmaceutical

• Source:Pharmaceutical research and manufacturers of America, 2007. • The „Biopharmaceutical R&D” figures include PhRMA research associates and nonmembers, these are not included in „PhRMA members companies’ R&D expenditures”. • 2006: estimated

Industry TrendsNCE Locations

97

90

68

4852

66

77

6663 61

29

15

5 6 4

15

0

20

40

60

80

100

120

1988-1992 1993-1997 1998-2002 2003-2007

New Molecular Entities 1988-2007

Europe

USA

Japan

Others

Source: SCRIP - FPIA calculations (according to nationality of mother company)

What is the issue with chemical space?

Region covered in a

conventional

laboratory

At ThalesNano

pressure / bar

Te

mp

era

ture

/ °C

100 200 300

Unexploited

chemistry space

-100

0

100

200

300

400

500

Accessing Novel Reaction Space

“prepare what you designed and

really want rather than what you

can readily synthesize”

Nature Reviews Drug Discovery 11,

355-365 (May 2012)

To achieve the above goal you

need a chemical technology

toolbox aiming at acceleration of

synthetic problem solving!

This is where flow chemistry can

Help.

What is flow chemistry?

Performing a reaction continuously, typically on small scale,

through either a coil or fixed bed reactor.

OR

PumpReactor Collection

Heating Control

Batch Flow

- Lower reaction volume. - Closer and uniform temperature control

Outcome:

- Safer chemistry.- Lower possibility of exotherm.

- Larger solvent volume. - Lower temperature control.

Outcome:

-More difficult reaction control. - Possibility of exotherm.

Heat Out

Lithium Bromide Exchange

Batch

Flow

• Batch experiment shows temperature increase of 40°C.

• Flow shows little increase in temperature.

Ref: Thomas Schwalbe and Gregor Wille, CPC Systems

Reactants

Products

By-products

Traditional Batch Method

Gas inlet

Reactants

Products

By-products

Batch vs. Flow

Better surface interaction

Controlled residence time

Elimination of the products

Flow Method

H-Cube Pro™

Survey Conducted

Discovery scale:

Making processes safer

Accessing new chemistry

Speed in synthesis and analysis

Automation

Process scale:

Making processes safer

Reproducibility-less batch to batch variation

Selectivity

Why move to flow?

Where is flow chemistry applied best?

Exothermic Reactions

• Very good temperature control

• Accurate residence time control

• Efficient mixing

• Less chance for thermal run-away

• Higher productivity per volume

• High selectivity

Endothermic Reactions

•Control over T, p and residence time

•High selectivity

•Accessing new chemistry

•Higher productivity per volume

•High atom efficiency

Reactions with gases

• Accurate gas flow regulation

• Increased safety

• Easy catalyst recycling

• High selectivity

• Higher productivity per volume

Scale up

• Increased safety

• Higher productivity per volume

• Selectivity

• Reproducibility

ThalesNano

Who are we?

• ThalesNano is a chemistry technology company that gives chemists tools to perform novel, previously inaccessible chemistry safer, faster, and simpler.

• Market leader: 800 customer install base on 6 continents.

• 33 employees with own chemistry team.

• 12 years old-most established flow reactor company.

• R&D Top 100 Award Winner.

• We only use flow chemistry where it’s advantageous.

ThalesNano Markets

Agrochemical Food, Cosmetics

PetrochemicalPharmaceutical

Biotech

Catalysis

Discovery Development Production

Safe High Energy

Reactions

Lithiation

Ozonolysis

Nitration

-70 – + 80°C

Inert Conditions

2 Reaction Zones

Fast Optimization

Reactions with

Gases Made

Simple

Hydrogenation

Oxidation

Carbonylation

150°C,100 bar

mg - Half a Kilo

13 Gases

No Catalyst Handling

Synthesize Novel

Compounds

Heterocycles

C-H activation

Catalyst screening

450°C, 100 bar

Microwave Scale Up

Homogeneous and

Heterogeneous

Untapped

Chemical Space

Cyclization

Molecule cleavage

Free radicals

Vacuum to 400 bar

RT to 1000°C

New Synthesis Routes

Clean

Number of publications about ThalesNano’s products

0

10

20

30

40

50

60

2005 2006 2007 2008 2009 2010 2011 2012 2013 2014Aug

Number of publications

0

50

100

150

200

250

300

350

2006 2007 2008 2009 2010 2011 2012 2013 YTD

Cumulative

287

H-Cube Pro and

Gas Module:

Dealing with Reagent

Gases

H-Cube Family

H-Cube®

H-Cube

Pro™

H-Cube Mini™ H-Cube Midi™

Industry Hydrogenations and

General Flow Platform

Catalysis reactor: Modular: H-Cube Pro

H-Cube Pro

H2 Generation

150°C, 100 bar

Hydrogenation

Selective C-C coupling

Gas Module

12 Extra gases

100 bar

Phoenix Module

450°C

Novel heterocycles

Automated injection

& collection.

Optimization

H-Cube Pro Overview

• HPLC pumps continuous stream of solvent

• Hydrogen generated from water electrolysis

• Sample heated and passed through catalyst

• Up to 150°C and 100 bar. (1 bar=14.5 psi)

NH

O2N

NH

NH2

Hydrogenation reactions:

•Benefits

• Safety

• No filtration necessary

• Enhanced phase mixing

Catalyst System-CatCart®

•Over 100 heterogeneous and

Immobilized homogeneous catalysts

10% Pd/C, PtO2, Rh, Ru on C, Al2O3

Raney Ni, Raney Co

Pearlmans, Lindlars Catalyst

Wilkinson's RhCl(TPP)3

Tetrakis(TPP)palladium

Pd(II)EnCat BINAP 30

Simple Validation Reactions (out of 5,000)

O O

10% Pd/C, RT, 1 bar

Yield: 86 - 89%

Raney Ni, 70°C, 50 bar,

2M NH3 in MeOH, Yield:

>85%MeO

N

MeO

NH2

Simple Validation Reactions (out of 5,000)

10% Pd/C, 60˚C, 1 bar

Yield: >90%

Batch reaction of {3-[(2-carbazol-9-yl-acetylamino)-

methyl]-benzyl}-carbamic acid benzyl ester Reagent:

H2, catalyst: 10% Pd/C, EtOH, 1 atm, Yield: 76 %

Conn, M. Morgan; Deslongchamps, Ghislain;

Mendoza, Javier de; Rebek, Julius; JACSAT; J. Am.

Chem. Soc.; EN; 115; 9; 1993; 3548-3557. NH

NH

O

O

NH

NH2

NOH

NH2

Raney Ni, 80˚C, 80 bar

Yield: 90%

Batch reference:

Reagent: HCOONH4, catalyst: 10% Pd/C, solvent: MeOH,

Reaction time: 30 min, 1 atm. Yield: 78 %

Kaczmarek, Lukasz; Balicki, Roman; JPCCEM; J. Prakt.

Chem/Chem-Ztg.; EN; 336; 8; 1994; 695-697

Lower temperature capability-more selective

T (oC) p (bar) Flow rate (ml/min)Conversion

(%)B Selectivity (%)

20 1, controlled 1 37 99

20 1, controlled 2 65 93

20 1, controlled 3 87 77

Solvent Conc. Temp. (°C)Pressure

(bar)

Flow Rate

(mL/min)

Product Distribution (%, GC-MS)

A B C

EtOH 0.1 M 10 10 1 0 100 0

H-Cube

H-Cube Pro

Synthesis of Pashminol using the H-Cube

Brunner, B.; Elmer, S.; Schröder, F.; Transition-Metal-Catalyzed Cyclopropanation of Nonactivated Alkenes in Dibromomethane with

Triisobutylaluminium; Eur. J. Org. Chem.; 2011; 4623–4633 and presentation by Schröder

Entry CatCart T (°C)/p

(bar)

Substrate

(%)

Cyclopropane

cleavage (%)

Pashminol

1 10% Pd/C 25 / 1 3 5 73

2 5% Pd/Al2O3 25 / 1 17 15 53

3 5% Pt/C 25 / 1 1 0 84

4 Raney Ni 80 / 1 2 1 87

5 5%

Pd/CaCO3

25 / 1 1 1 83

Givaudan

Selective hydrogenation in the presence of

cyclopropylcarbonyls or allyl alcohols

Pd/CaCO3 showed best result

Raney Ni showed best result

Pt/C showed best result

Cis-Javanol

+

Brunner, B.; Elmer, S.; Schröder, F; Eur. J. Org. Chem.; 2011; 4623–4633 and presentation by Schröder

ComInnex Applies ThalesNano Technologies for High fsp3

Compound Synthesis

Flat structures

Low sp3/sp2 ratio

3D structures

High sp3/sp2 ratio

Multifactorial parameter screening

Reaction database

Catalyst testing

Chemoinformatics

Optimization

ProductionNovel compounds

Uncharted chemical space

Higher sp3/sp2 ratio

Improved properties

Compound Collection Enhancement

Poorly soluble screening compounds transferred to well-behaved novel

samples that may make an immediate impact in screening campaigns.

• Often novel compounds obtained from proprietary compounds but

also from commercial samples: access to uncharted chemical space

• Higher sp3/sp2 ratio

• Fragments or lead-like compounds

Historical HT-Enhancement Results from Collaborations

>70% success rate

>95% of the samples produced in high cis-selectivity (much

higher than in pressure reactors in batch)

Average yield: 35% (in 20-50 mg range)

Average purity: 97% (after preparative HPLC)

Chiral separation possible for follow-up

A highly selective and efficient production system delivers

novel fragments and lead-like compounds with high success rates

Optimized for

preparative

separation

Original

conditions

H-Cube Autosampler™

Gilson 271 Liquid Handler

402 single Syringe pump (10 mL)

Direct GX injector (Valco)

Low-mount fraction collection (Bio-Chem)

Septum-piercing needle

Static drain wash station

Tubes, connectors, fittings

Open vial collection

Collection through probe (into closed vial)

Selected Examples of Possible Templates

Automation applications

• Reaction conditions optimization

• Library production

• Catalyst optimization

• Customers

C-C Coupling and other

reagent gas reactions

Selective Suzuki coupling (Cl, Cl)

The conditions were:

1 equivalent of 2,6-dichloroquinoxaline with 1.2 equivalent of o-Tolylboronic acid

Concentration set to 0.02M

Solvent: Methanol

Base: NaOH

Analytics: GC-MS

N

N Cl

Cl

B

HO OH

N

N ClFlow rate (ml/min)

Pressure TemperatureCatalyst Base

Result(bar) (

oC) LC-MS, 220nm

0.8 20 100Fibrecat 1007

(70mm)3 ekv

Conversion: 82%

Selectivity: 48%

0.3 20 100Fibrecat 1007

(70mm)3 ekv

Conversion: 99%

Selectivity: 48%

0.8 20 100Fibrecat 1035

2.5 ekvConversion: 16%

(30mm) Selectivity: 100%

0.8 20 100Fibrecat 1029

(30mm)2.5 ekv

Conversion: 18%

Selectivity: 100%

0.8 20 100Fibrecat 1048

(30mm)2.5 ekv

Conversion: 40%

Selectivity: 100%

0.8 20 10010% Pd/C

2.5 ekvConversion: 89%

(30mm) Selectivity: 14%

0.5 20 50Fibrecat 1048

2.5 ekvConversion:17%

(30mm) Selectivity: ~100%

0.5 20 100Fibrecat 1048

2.5 ekvConversion: 35%

(30mm) Selectivity: ~100%

0.2 20 100Fibrecat 1007

2.5 ekvConversion: 93%

(70mm) Selectivity: 73%

0.2 20 100Fibrecat 1007

2.5 ekvConversion: 93%

(70mm) Selectivity: 80%

0.2 20 100Fibrecat 1029

2.5 ekvConversion: 12%

(30mm) Selectivity: 100%

Synthesis of triazole derivatives with Cu

H-Cube in No H2

mode

900 mg Copper

powder in 70 mm

CatCart

0.21 mmol

0.32 mmol

Ötvös, S. B.; Georgiádes, Á.; Mándity, I. M.; Kiss, L.; Fülöp, F.; Beilstein J. Org. Chem.; 2013; 9; 1508–1516

Library synthesis of 1,4 substituted triazole derivatives

Condition A: 100 °C, 100 bar, 0.5 mL/min

Condition B: RT, 100 bar, 0.5 mL/min, 0.04 equ. DIEA and AcOH

100 mg crude product

Entry Azide (0.085

M)

Acetylene (1.5

equ.)

Product Yield –

Cond.

A. (%)

Yield –

Cond. B.

(%)

1 61 96

2 3376 – RT

98 – 100 °C

3 5389 – RT

98 – 100 °C

4 97 98

Gas Module

• Versatile:Compressed Air, O2, CO, C2H4, SynGas, CH4, C2H6, He, N2, N2O, NO, Ar.

• Fast: Reactions with other gases complete in less than 10 minutes

• Powerful: Up to 100 bar capability.

• Robust: All high quality stainless steel parts.

• Simple: 3 button stand-alone control or via simple touch screen control on H-Cube Pro™.

Alcohol oxidation: Investigation of different reactants

Reactant Solvent Desired Product Conversion Selectivitya

acetone

~100% 89% b,c

acetone

~100% 84% b,c

acetone

not clear

from

GC-MS

not clear

from

GC-MS

acetone

~100% 88% b,c

acetone

~100% 95%b,c

acetone

not clear

from

GC-MS

not clear

from

GC-MS

cyclopentyl-

methylether

58% ~100%

cyclopentyl-

methylether

59% ~100%

cyclopentyl-

methylether

~100% ~100%

cyclopentyl-

methylether

76% 96%

t-butanol

~100% ~100%

General conditions: H-Cube Pro with Gas

Modul, 100 bar, 140 ºC, 50 mL/min oxygen

gas, 1 mL/min liquid flow rate (0.05M, 10

mL sample volume), CatCart: Au/TiO2,

70mm.

Void volume: 0.575 mL

Catalyst loading: 0.0295 mmol/CatCart

Estimated residence time: 0.575 mL / 1

mL/min= 0.575 min

a 100 • Area% of desired product in GC-MS /

(100 – Area% of reactant in GC-MS)b Main side-products are originated from the

solvent itselfc Separation difficultd Peroxide strip shows no presence of

peroxides in reaction mixture

Carbonylation leading to esters

O

I

CO, DBUFibercat 1001

EtOH

O

OO Fibrecat 1001:

Pd content [mmol/g]: 0.47,

Load: mmol/catcart: 0.114.

Void volume: 0.62 ml

Ethanolic solution: DBU: 1.1 eq., 4-

iodo-anisole: 1.0 ekv,

concentration: 0.1 M - 1.0 M

Concentration Liquid

flow rate

(mL/min)

Temperature

(oC)

Gas flow

rate

(ml/min)

Pressure

(bar)

Pressure

drop

(bar)

Conversion

(%)

Selectivity

(%)

0.1 M 0.5 150 10 10 2 >99 >99

0.1 M 0.5 150 10 30 3 >99 >99

0.1 M 0.5 150 50 10 3 >99 >99

1 M 0.5 150 100 30 2 >99 >99

1 M 1 150 100 30 2 98.3 >99

Microwave reference from Nicholas Leadbeater’s lab (Org.Biomol.Chem. 2007, 65):

Concentration: 0.1M, Pressure: 10 bar, Temperature: 125oC, Reaction time: 30 min

Conversion: 90%

Flow reference from Nicholas Leadbeater’s lab (Org.Biomol.Chem. 2011, 6575):

Concentration: 1M, Pressure: 17 bar, Temperature: 120oC Residence time: 120 min

Conversion: 98%

Paal-Knorr pyrole synthesis

T /oC Conversion (%)

40 100

110 100

Phoenix with 4 ml loop

60bar, 0.5 ml/min 0.1M hexanedione, 0.5

ml/min NH3 (4 min residence time)

Batch reference (Chem.Ber. 1885, 367):

Temperature: 150oC, Reaction time: 120 min

Flow reference from Steve Ley’s lab (Org.Biomol.Chem. 2012, 5774):

Pressure: 0.1M solution, Pressure: 3.5 bar, Temperature: 0oC for dissolving

ammonia, than 110oC

Residence time: 10 min on 0oC than 110 min on 110oC

Conversion: 100%

O

ONH

NH3

MeOH

40-110oC

Accessing New

Molecules or

Chemical Space

Heterocyclic rings of the future, J. Med. Chem., 2009, 52 (9), pp 2952–2963.

• 3000 potential bicyclic systems unmade

• Many potential drug like scaffolds

Why?

• Chemists lack the tools to expand into new chemistry space

to access these new compounds.

• Time

• Knowledge

The quest for novel heterocycles

Phoenix Flow Reactor: High temperature synthesis

Temperature: RT-450°C

Versatile: Heterogeneous and

homogeneous capabilities.

Fast: Reactions in seconds or minutes.

Innovative: Validated procedure to

generate novel bicyclic compounds

Simple: 3 button stand-alone control or via

simple touch screen control on H-Cube

Pro™.

Phoenix loop-reactor possibilities

Coil Reactor-Homogeneous• Coil (1/16” 4-16 ml)

• Short coil (1/16” 1-4ml)

• Static mixer (3/8”, 32ml)

Easy to recoil

Versatile

Cartridge-Heterogeneous• H-Cube: 200°C.

• Midi: 150°C.

• HTC: 450°C.

User-packable

Heat in

Q amount of heat transferred

t time taken

k conductivity of the material

S surface area

d distance between the two ends

T1 higher temperature end

T2 lower temperature end

Flow reactor

Microwave

Oil Bath

Heat transfer of Microwave, Flow reactor, Oil Bath (Flask)

0 100 200 300 400 500 600 700

0

50

100

150

200

250

300

350

400

T / °

C

t / sec

Heat transfer works two ways

allowing rapid and safe control of reactions

Rapid Optimization

Simplex

optimalization

point

TemperatureFlow Rate

mL/minEquivalent Yield

1 180 0.5 1 40

2 200 0.5 2 60

3 200 1 2 35

4 220 1 2 50

5 250 1 2 80

6 250 1 4 80

7 250 0.7 2 88

8 270 0.5 2 99

9 250 0.5 2 98

Loop: 4 mL, concentration: 0.2M,

residence time: 8 min

Simplex

optimalization

point

TemperatureFlow Rate

mL/minEquivalent Yield

1 200 1 8 25

2 250 1 12 40

3 250 0.7 12 56

4 280 0.7 12 60

5 320 0.6 16 80

6 350 0.5 16 86

7 350 0.5 19 99

Loop:16 mL,concentration:0.05M,

residence time: 32 min

CN

F F

NH

NMP + 6 % MeOH

CN

F N

2 eq.

CN

N N

NH

8-19eq.

NMP

Diels Alder 1

• 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 (180 bar).

Me

Me

CN Me

Me

CN

+toluene (2.0M)

250°C, 60 bar

1 2 3(>99%)

Newmann-Kwart Rearrangement –

MW vs. Flow Experiments

“Difficult” Case

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

Product, DME

HPLC, 215 nm

Kinetic Analysis (HPLC)

sc. DME

critical point:

263 °C; 39 bar

Fischer-Indole Synthesis: Scale Out

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

Claisen Rearrangement

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 OHtoluene (0.1 M)

240°C, 100 bar1.0 mL/min

(95%)

Alcohol

Catalyst

c (M) T (°C)Vflow

(ml/min)

NMRb

yield (%)Zeolite

F160 (g)

Silica

(g)

n-butanol 8.0 3.4

1 350 1 77

1 370 1 93

1 390 1 98

1 390 1.25 97

n-pentanol 8.0 3.4

1 350 1 62

1 370 1 85

1 390 1 98

1 390 1.25 96

n-octanol 8.0 3.4

1 370 1 84

1 370 1.25 77

1 390 1.25 91

1 390 1 93

N

HN

N

N

RR-OH

acid ic zeolite

300-390 °C/ 90 bar

Phoenix Flow ReactorTM

Alcohol screen: primary alcohols

Selectivity: >97%

Over di-alkylated

Gould-Jacobs Cyclization

• Standard benzannulation reaction

• Good source of:

• Quinolines

• Pyridopyrimidones

• Naphthyridines

• Important structural drug motifs

Disadvantages:

• Harsh conditions

• High b.p. solvents

• Selectivity

• Solubility

Condensation

Cyclization

Saponification Decarboxylation

methylenemalonic ester

W. A. Jacobs, J. Am. Chem. Soc.; 1939; 61(10); 2890-2895

Gould-Jacobs Cyclization

• Standard benzannulation reaction

• Good source of:

• Quinolines

• Pyridopyrimidones

• Naphthyridines

• Important structural drug motifs

Disadvantages:

• Harsh conditions

• High b.p. solvents

• Selectivity

• Solubility

Condensation

Cyclization

Saponification Decarboxylation

methylenemalonic ester

W. A. Jacobs, J. Am. Chem. Soc.; 1939; 61(10); 2890-2895

The nature of the substituents is critical because they increase or decrease the nucleophilicity of the ring:

Electron donating groups increase yields, Electron withdrawing groups decrease yields.

56

Process exploration

Meldrum’s acidic route to pyridopyrimidones and to

hydroxyquinolines

Meldrum-sav

CH(OEt)3

3a-e

Batch Flow

1a-e 2a-e

a: R=H, R'=H, X=N

b: R=H, R'=H, X=N,

c: R=F, R'=H, X=C(CH3)

d: R=H, R'=CN, X=CH

e: R=H, R'=OCH3, X=CH

in THF

3d (43%) 3e (60%)3a (89%) 3b (60%) 3c (62%)

Cyclization conditions:

a: 300 °C, 160 bar, 0.6 min

b: 300 °C, 100 bar, 0.6 min

c: 360 °C, 100 bar, 1 min

d: 350 °C, 130 bar, 4 min

e: 300 °C, 100 bar, 1.5 min

Lengyel L., Nagy T. Zs., Sipos G., Jones R., Dormán Gy., Ürge L., Darvas F., Tetrahedron Lett., 2012; 53; 738-743

57

Validation: Simple Chemistry 1

ms = 180 mg, Tf = 450 °C, tp = 5 min,

p = 100 bar, mp = 107 mg (72%)

NMR purity >99%, white crystals

(33x2 cm tube)

S

N

NH

CO2Et

CO2EtS

N

N

OCO2Et

Formula Weight = 270.30486Formula Weight = 224.23642

FVP

72%

12

Thiazolopyrimidone

Available technique (3 in 1)

59

Apparatus for Reactions in the Vapour Phase (FVP)

Reactor Unit

geometry of the reactor surface

filling materials

temperature (gradient)

contact time (c.t.)

surface catalysis

(heterogenous

catalysis)

Evaporation Unit

carrier gas inlet (inert flow gas)

rate of evaporation

(vapor pressure)

flow rate

Condensor Unit

cooling medium

selective condensation

Cf., e.g.: R. F. C. Brown, ‘Pyrolytic Methods in Organic Chemistry’, Academic Press Inc., New York, 1980.

Vacuum Unit

reduced pressure

boiling point

high dilution

effect

Optimization Conclusions, VFP Ring Closures

• Green, solvent free FVP protocol is superior to batch and flow reactors for

Gould-Jacobs type ring closures.

• Simple protocol: loading of reactant and collection of product crystals

• A single FVP protocol furnishes various heterocyclic ring systems in good

yield and purity

450 °C, 2.5×10-1 mbar

Thiadiazolopyrimidinone

Oxazolopyrimidinone

Pyrimidotriazinone Pyrimidopyridazinone

Triazatricyclo-trideca-pentaenonePyrazolopyridinol

61

High Temperature Gas Phase Isomerization Reactions

M. Karpf, ‘Unterwegs von 12- zu 15-gliedrigen Ringen’, Dissertation Universität Zürich 1978.

M. Karpf, A. S. Dreiding, Helv. chim. Acta 1977, 60, 3045.

a-Alkinon-Cyclization

HO

550°C•

OO

O

H2/Pd

Exalton®

(36%)

Tandem-Reaction: [1,5]-H + [3.3]-Cope

12 1315 15

H

O

H

OH

H

OH

H HO

620°C

Vinyliden-Carben

+

(89 : 11)

H

H

[1,2]-H

M. Karpf, A. S. Dreiding Helv. chim. Acta 1979, 62, 852.

M. Karpf, ‘Organische Synthese bei hohen Temperaturen’, Angew. Chem. 1986, 98, 413 – 429.

Preparative Dynamic Gasphase Thermo-Isomerization (DGPTI):

Anellation C1-Ring Enlargement Reaction

W. S.Trahanovsky, S. L. Emeis, A. S. Lee, J. Org. Chem. 1976, 41, 4044.

M. Nagel, ‘Von Phenolen zu Heptalenen’, Diplomarbeit Universität Zürich 1998.

M. Nagel, H. J. Hansen, Helv. Chim. Acta 2000, 83, 1022 - 1048 and Synlett 2002, 692 - 696.

R. F. C. Brown, ‘Pyrolytic Methods in Organic Chemistry’, Academic Press Inc., New York, 1980.

O

RR

R = H, Me

O

O

RR

O

H

H

O

RR

O

H

O

O

R

R

DGPTI

650°C

R

R

R''

Polyalkylazulene

R, R, R'' = Alkyl, H

R'''

[8+2]-CA

– CO2

''R

R'''

X

X = OR: EnoletherX = NR2:Enamin

R

R

X

X

R'''R

R

X

X

R'''

Molecular Switch

off-stateon-state

based on heptalene core

no reaction320°C

Alkenes(dehydration)

420°C

stationary conditions

(glass ampoules)12

O

DGPTI

(ca. 650°C)

(80 - 90%)

(75 - 90%)

MgBr

Dimitrov cond.

12

HO

14

O

DGPTI

(65 - 75%)

(ca. 650°C)

14

HO

(75 - 90%)

MgBr

Dimitrovcond.

16

O

DGPTI

(70 - 80%)

(ca. 650°C)

10

HO

A New, Short and Repeatable Two-Carbon Ring Enlargement

Dimitrov conditions: 1. Precomplexation of the ketone with anhyd. CeCl3 in THF at r.t., 2. Vinyl MgBr (THF sol.).

M. Nagel, H.-J. Hansen, G. Fráter, Synlett 2002, 275 - 279.

R. W. Thies, J. E. Billigmeier,

J. Am. Chem. Soc. 1974, 96, 200 -

203.

V. Dimitrov, S. Bratovanov, S. Simova, K. Kostova, Tetrahedron Letters 1994, 35, 6713.

New

Repeatable

Ice Cube:

High Energy

Reactions In a Safe

Controlled Manner

? Halogenation

NitrationAzides

-70°C Modular

Lithiation

Ozonolysis

Exothermic Reactions

Set-up of the Ice Cube Modular System

Ozone Module:

generates O3 from O2 100 mL/min, 14 % O3.

Pump Module – 2 Rotary Piston Pumps.

Excellent chemical compatibility.

Automation in progress.

Reactor Module:

2 Stage reactor. -70°C-+80°C.

Teflon tubing.

A

B

C

D

-70-+80ºC -30-+80ºC

Potential Apps: Azide, Lithiation, ozonolysis, nitration, swern oxidation

Teflon tubing for cheap and easy blockage removal.

Temp: -25°C

Reactant conc.: 0.05 M (in EtOAc)

Quench conc.: 0.1 M (triphenylphosphine in EtOAc)

Reagent flow rate: 0.7 ml/min

Quench flow rate: 0.7 ml/min

Ozone: 50% excess

Yield: 67% (98% pure NMR)

Residence time: 15mins

Batch: -78°C With DMS, 72 hours, 78% yield.

With NEt3, 20 hours, 48% yield

O3

OO

Ozone concentration critical!

Reaction parameters:

Flow rate = 0,7 ml/min

Quench flow rate = 1,4 ml/min

O3 flow rate = 17,5 ml/min (~2 eq.)

T = -5 oC

cEugenol = 0,05 M

cNaBH4 = 0,05 M

Solvent = EtOH

Results:

Conversion = 100 %

misolated = 326,2 mg

mmax. yield = 504 mg

Isolated yield = 65 %

Purity of isolated product = 98 % *

IceCube™ – H-Cube® - ReactIR™

ozonolysis of decene

Ozonolysis Quenching with

H-Cube®T = -30 ºC

CSM = 0.02 M (in EtOAc)

O3 excess = 30 %

T = -30 ºC to r.t.

p = 1 bar

Cat: 10 % Pd/C

Mettler

Flow IR™

O-Cube and ReactIR are trademarks of ThalesNano Inc. and Mettler Toledo International

Inc., respectively, H-Cube is registered trademark of ThalesNano Inc.

ThalesNano lab based

chemistry-unpublishedOzonide eluted into cool vial under N2

Vflow (ml/min)

A - B - C

T (°C) τ (1. loop, min) τ (2. loop, min) Isolated

Yield (%)

FM81-1 0.6 0 1.42 2.22 77

FM81-2 1.5 0 0.56 0.88 99

FM81-3 1.5 15 0.56 0.88 99

NH2N N+ Cl-NaNO2

HCl NaOH

N N

O-

OH

Advantages of diazotization in flow:

• safe handling of the diazonium salt• only small amount of diazonium is present at one time, determined by the size of thefirst loop (1.7 ml in our case)• Cooling is very effective, no danger of overheating and explosion• Diazotization can be driven safely > 5°C, if the residence time in the first loop is shortenough• pH can be kept constant during the coupling• Residence time can be as low as 0.5-1 min, with concentrations similar to batchconditions (0.66M solutions)

Diazotization and azo-coupling

Nitration

Nitration is a general class of chemical process for the introduction of a nitro

group into an organic chemical compound.

Industrial use of nitro compounds:

• Drugs

• Explosives

• Solvents

• Plastics

• Rocket propellants

Hazards of nitrations:

• Highly exothermic

• Tends to be runaway

• Sideproducts are highly poisoning

• The products are explosives

Novel scaffold synthesis from explosive intermediates

Nitration of Aromatic Alcohols

Pump A Pump B Temperature(oC)

Loop size (ml)

Conversion (%)

Selectivity (%)

SolutionFlow rate (ml/min) Solution

Flow rate (ml/min)

ccHNO3 0.41g PG/15ml

ccH2SO4 0.4 5 - 10 7 1000 (different products)

1.48g NH4NO3/15ml ccH2SO4 0.7

1g PG/15ml ccH2SO4 0.5 5 - 10 13 100 100

1.48g NH4NO3/15ml ccH2SO4 0.5

1g PG/15ml ccH2SO4 0.5 5 - 10 13 50 80 (20% dinitro)

70% ccH2SO4 30% ccHNO3 0.6

1g PG/15ml ccH2SO4 0.5 5 - 10 13 (3 bar) 100 100

70% ccH2SO4 30% ccHNO3 0.6

1g PG/15ml ccH2SO4 0.5 5 - 10 13 (1 bar) 80

70 (30% dinitro and nitro)

Conversion of liquid rocket fuel oxidizers to fertilizer

Melanj: Eastern

European Liquid

Rocket Fuel

Component

+

Liquid ammonia

(neat)

Ammonium Nitrate

(Fertilizer)

1 kilo/hour

Swern Oxidation

MethodResidence

time (tR1) [s]T [oC]

Selectivity of cyclohexanone [%]

Microreactor2.4 -20 88

0.01 0 890.01 20 88

Flask-20 19-70 83

If the temperature is not kept near -78°C, mixed thioacetals may result:

Chemistry-A European Journal 2008, 7450

Cryogenic operating conditions

(< - 60°C), limit its utility for scale up

operations in batch.

Temperature (°C) OAC Solution (ml/min) Alcohol and DMSO Solution (ml/min) Conversion (%) Selectivity (%)

-30 0.96 1.9 100% 100%

-20 0.96 1.9 100% 100%

-10 0.96 1.9 100% 100%

0 0.96 1.9 100% 60%

Using TFAA as a DMSO activator seems to afford even higher temperatures.

No chloromethyl-methyl-sulfide production at higher Temps.

Swern Oxidation

OH O

DMSO, Oxalyl-ChlorideQuench: TEA

Ice-Cube Flow Reactor

Larger scale

capabilities

H-Cube Maxi™

• Maximum Temperature: 250°C (± 0.5°C)

• Maximum Pressure: 130 bar (± 0.8 bar)

• Flow Rate (liquid): 0.1 - 50 mL/min

• Flow Rate (gases):10 - 1000 mL/min

• Column Diameter: ID 30 mm

• Column Length: 900 mm

• Duty + Standby Column

• Users can pack their own column

• Heated reaction line for viscous liquids

• 5 kg/day

Pilot scale possibilities through partners

Ionic liquid Production Capability

5-10 liters/year

Who are our customers? (>800 worldwide)

20 out of 20 Top Pharmaceutical

5 out of 10 agrochemical companies

4 out of Top 5 Fragrance companies

Petrochemical emerging

International R&D Top 100 Award Winner!

Over 250 publications.

Flow Chemistry Society

• Impact factor: 4.091

• Fundamentals of flow chem

• Available now

• Applications: September.

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