« In chemistry the new wave is micro »

Thierry Besson

Laboratoire Biotechnologies et Chimie Bio-organique, FRE CNRS 2766, UFR Sciences Fondamentales et Sciences pour l'Ingénieur,

Université de la Rochelle, Bâtiment Marie-Curie, F-17042 La Rochelle Cedex 1, France

Chimie assistée par micro-ondes, de la stratégie expérimentale au résultat: Application à la préparation d'hétérocycles aromatiques.

FUNDAMENTAL RESEARCHFUNDAMENTAL RESEARCH

APPLIED RESEARCHAPPLIED RESEARCH

TECHNOLOGICAL TRANSFERTECHNOLOGICAL TRANSFER

- Created in 1993- About 40 Persons in 2004 (25 academic staff)- More than 150 publications since 1994- 1 exploited international patent

Different fields covered:- ORGANIC CHEMISTRY- BIOTECHNOLOGY, BIOCHEMISTRY- MICROBIOLOGY

LBCB : Laboratoire de Biotechnologie et Chimie Bioorganique (FRE CNRS 2766)

Biocatalysis in non conventional media:

EnzymesOrganic solvents,

Microwaves

High pressureHeterogeneous catalysis (solid/gas system)

Organic and Bioorganic synthesis

Pharmaceutical active heterocyclic compounds

Microwave assisted chemistryHeterogeneous (solid supports) media

Homogeneous (solvents) media

Biogenesis from proteins and bacteria

Pharmaceutical active heterocyclic compounds : topoisomerases inhibitors ?

N

N

NH

N

NH

O

N

HN

S

N

N

N

N

N

S

N

N

N

O

N

Kuanoniamines

Dercitines

NH

OWakayinemakaluvamines

Hinckdentine

NH

N

O

O

HN

N

S

pyrrololthiazolobenzoquinolinones

NH

N

RHN

O

N

N

OH

Hpyrroloiminoquinones

N

S

N

N

S

N

N

NS

R3

R3

R2

R2

R1

R1

R1

R2

R3

(Ellipticine)

Thiazolocabazoles

Br

Br

Br

N

NR

N

NindoloquinazolinesN O

R

(N)

(S)

Pharmaceutical active heterocyclic compounds : CDK and GSK3 inhibitors ?

N

N N

N

HN

HN

OH

RR

Roscovitine

NH

SN

NH

O

R

Oxoindole 91

N

NN

N

R1

R2

R3

pyrazolopyrimidines

N

N

R1

R2

R3

Quinazolines

N

N

SN

OR1

R2

Thiazoloquinazolines

N

N

R1

R2N

NR3

pyrimidopyrimidines

N

NN

NH

O

pyrazinoquinazolines

R2R1

Appel, R.; Janssen, H.; Siray, M.; Knoch, F. Chem. Ber. 1985, 118, 1632.Wannagat, U.; Schindler, G. Angew. Chem. 1957, 69, 784.

Besson, T.; Rees, C. W. J. Chem. Soc., Perkin Trans. 1, 1995, 1659.Besson, T.; Emayan, K.; Rees, C. W. J. Chem. Soc., Perkin Trans 1, 1995, 2097.Rees, C.W.; Roe, D.G.; Thiéry, V. J. Chem. Soc., Chem. Commun. 1996, 24, 2775.Besson, T.; Guillaumet, G.; Lamazzi, C.; Rees, C. W. Synlett, 1997, 704.Besson, T.; Guillaumet, G.; Lamazzi, C.; Rees, C. W. Thi éry, V. J. Chem. Soc., Perkin Trans 1, 1998, 4057.Besson, T.; Rees, C.W.; Thiéry, V. Synthesis, 1999, 1345.Besson, T.; Rees, C.W.; Roe, D.G.; Thiéry, V. J. Chem. Soc., Perkin Trans 1, 2000, 555.

Appel’s salt chemistry

4,5-Dichloro-1,2,3-dithiazolium chloride

S

NR

N

N

XO

N CN

XS

N CN

N

SCNN

N

CN

S

OR

CNR

R

R

RR

CN

Benzothiazoles Quinazolines

Benzoxazines

Benzothiazines

Indolines

Imidazoquinolines

X = CH2,C=O

SS

N

ClNAr

2Nu1

SS

N

ClCl

ClAr-NH2

pyridine

CH2Cl2

r.t.

1S

SN

ClCl

ClS2Cl2ClCH2CN

CH2Cl2

r.t.(85%)

Microwave assisted organic synthesis: MAOS

Interaction of MW with polar molecules

Interests of MW for organic chemistry

DIRECT APPLICATIONS :

- Organic Reactions requiring “Long Heating”

or Slow Reactions where high activation energies are required

Reaction times reduced from days to minutes

- Temperature Sensitive Reagents/Reactions

Limitation of the degradation products

- MW / Sealed Vessel:

High temperatures are more rapidly obtained

No limitation by the boiling point of the solvent

“equilibrium” or presence of volatile molecules

Applications in organic chemistry

WIDE RANGE OF REACTIONS

- Protection/Deprotection/Hydrolysis

- Oxidation

- Condensation

- Alkylation

- Ring Formation

- C-C bond forming reactions… and many others !

APPLICATIONS

- Heterocyclic Chemistry

- Organometallic Chemistry

- Peptides Synthesis

- Carbohydrates

- Steroids

- Enzymatic Synthesis

- Preparation of Radiolabelled Compounds

Ø Use of Supported Reagents / Use of Supported Catalysts :

Minerals reagents (inorganic oxides) supported on

Alumine or Silica derivatives, Alumino-silicates, Montmorillonite…

Ø Use of Ionic Liquids (“Supersolvents” under MW)

Microwaves in a “green chemistry” context

To reduce superheating observed with polar solvents under MW irradiation

To reduce the absorption of MW by polar solvents (limitation of MW effects)

To increase the potential of MW for further development (SCALE-UP)

Ø Homogeneous/Heterogeneous MW synthesis

Ø Coupling MW/ Phase Transfer Catalysis

Different Ways to perform Solvent Free Conditions under MW irradiation :

SOLVENT FREE CONDITIONS

(a) Microwave enhanced chemistry, Kingston, H. M.; Haswell, S. J., Eds.; American Chemical Society: Washington DC, 1997.

(b) Microwaves in organic synthesis, Loupy, A., Ed.; Whiley-VCH Verlag Gmbh & Co. KGaA, Weinhein, 2002.

(c) Hayes, B. L. Microwave synthesis : chemistry at the speed of light, CEM Publishing, Matthews (USA), 2002.

(d) Microwave-Assisted Organic Synthesis ; Lidström, P. ; Tierney, J., P., Eds. ; Blackwell Publishing: Oxford, 2005.

Main books on MAOS

a) For a recent review in the area see: Kappe, C. O. Angew. Chem. Int. Ed. 2004, 43, 6250-6284.

b) Lidström, P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron 2001, 57, 9225-9283. c) Varma, R. S. Green Chem. 1999, 43-55.

d) Loupy, A.; Petit, A.; Hamelin, J.; Texier-Boullet, F.; Jacquault, P.; Mathe, D.

Synthesis 1998, 1213-1233. e) Caddick, S. Tetrahedron 1995, 51, 10403-10432.

The most cited reviews in Microwave-Assisted Chemistry:

Instrumentation

Currently :

THREE MAIN SUPPLIERS OF DEDICATED MICROWAVE REACTORS

- Efficient application of MW irradiation

- Reliable monitoring temperature, pressure and/or power feedback control

Detailed descriptions of single-mode microwave reactors with integrated robotics were recently published:

(a) For CEM corp.: Ferguson, J. D. Mol. Diversity 2003, 7, 281-286; (b) For Milestone srl: Favretto, L. Mol. Diversity 2003, 7, 287-291; (c) For Biotage (Personal Chemistry AB): Schanche, J. -S. Mol. Diversity 2003, 7, 293-300.

Multi-mode vs single-mode microwave systems

* Non-uniform heat distribution

* Lack of temperature-pressure control

* lack of reproducibility and safety

* open systems ?

Muti-mode domestic ovens

* Uniform heat distribution

* Temperature-pressure control and regulation

* Reproducibility and safety

* open or closed systems (pressure, No to 20 bars)

Single-mode microwave reactors

CEM Discover Systems (up to 5 g)

SINGLE MODE REACTORSEnergy is focused with a “wave-guide”

CEM Voyager

BATCH OR CONTINUOUS FLOW REACTOR

(RELEASED ON THE MARKET in 2002)

Transposition

REACTORS from www.cemsynthesis.com

Volume inside the cavity from 0.1 mL to 40 mL

Ethos NP MicroSYNTH Labstation

MULTI-MODE REACTORS from MILESTONE :

Transposition

(from 100 mL to 1 L, opened system)

ETHOS PILOT 4000

CONTINUOUS FLOW REACTOR

ETHOS MRS BATCH REACTORS

(up to 14 bars (10 bars) / 400 mL (600 mL) pressurized system)

www. milestonesrl.com

Emrys Synthesizer

Prototype Specifications (MBR) : BATCH REACTOR• 350ml (300ml)

• 260 °C• 100 Bar

• 100-1200W• Overshoot < 2 °C• Stability <0.5 °C

• Safety valves, Safety Interlock

www.biotage.com

Emrys OptimizerEmrys Creator

Kilo-lab reactor

Capacity :Liq. : 800 mLSol. : 1.5 Kg

Power max :800W

Working in the presence of solvent

What kind of solvent may I use?

ABSORBANCE LEVEL OF VARIOUS SOLVENTS

High : DMSO, EtOH, MEOH, ethylene glycol, nitrobenzene, formic acid

Medium : water, DMF, NMP, Butanol, Acetonitrile, ketones, o-dichloroethane

Low : Chloroform, dichloromethane, carbon tetrachloride, THF, ethers, ethyl acetate, pyridine

Very low : hydrocarbons

Solvent free experiments

Reactions on graphite

Good adsorbent properties towards organic moleculesHigh rate of heating under microwaves

Used as a « sensitizer » (energy converter)

Multi-step synthesis

Laporterie, A.; Marquié, J.; Dubac , J. Microwave-assisted reactions on graphiteMicrowaves in organic synthesis, Loupy, A., Ed.; Whiley-VCH Verlag Gmbh & Co. KGaA, Weinhein, 2002.

Benzothiazoles and derivatives

Traditional thermolysis procedure :

Neat imines under argon at 200-250°C for 1 or 2 minutes

Scale limited to 0.2 g

Complicated mixtures of carbonaceous compounds and impuritiesDifficult to purify

Synthesis of benzothiazoles from imino-1,2,3-dithiazoles

Besson, T.; Rees, C. W. J. Chem. Soc., Perkin Trans. 1, 1995, 1659.English, R.F.; Rakitin, O.A.; Rees, C.W.; Vlasova, O.G., J. Chem. Soc., Perkin Trans. 1, 1997, 201.

S

NR R

N

S SN

Cl

RN CN

Cl

NH2CNR

1

∆S

SN

ClCl

Cl

pyridine, rt a or b

cyanoimidoyle chloridebenzothiazole

Alternative methodologies (conventional conditions or microwave (mw) irradiation)

- at 200°C in biphenyl ether- at 140°C, 2 or 3 days, sealed tube , toluene,

- neat imines (in a glass vial with a screw-cap lid)

Microwave procedures are more rapid than the purely thermal processes

Yields in the desired benzothiazoles were constant

- Scaling up (up to 0.2 g) the quantity of starting material led to lowest yields of product

Average yield : 60-85%Average time : ∆ = 1H; µw = 10 minScale : 0.2g - 1g

> 30 examples

Bénéteau, V.; Besson, T.; Rees, C. W. Synth. Commun. 1997, 27, 2275.

An other route

S

NR

N

S SN

Cl

CNR

∆

benzothiazole

Br

CuI, pyridine

_______________________________________________________________________Method A: 3 (1g), N-methylpyrrolidin-2-one, µw (150 °C, 90 W)a_______________________________________________________________________

Starting imine 2 (R) Time (min) b Product (R) Yield of product (%)_______________________________________________________________________

a (H) 1 (H) 49b (4-CH3) 2 (6-CH3) 55c (4-OCH3) 1 (6-OCH3) 48d (2,5-diCH3) 1 (4,7-diCH3) 58e (2,5-diOCH3) 3 (4,7-diOCH3) 64

_______________________________________________________________________

a) In these experiments the amount of cyanoimidoyle chlorides was very low ;b) Reaction time;

Re-investigation of the microwave synthesis of benzothiazoles

Solvent : NMP

Scale : 1g - 5g

Method B: 3 (5g), graphite (0.5g, 10% by wt.), µw (150 °C, 150 W)_______________________________________________________________________

Starting imine 2 (R) Time (min) Product (R) Yield of product(%)_______________________________________________________________________

a (H) 3 (H) 42b (4-CH3) 5 (6-CH3) 50c (4-OCH3) 5 (6-OCH3) 50a,b

d (2,5-diCH3) 2 (4,7-diCH3) 49e (2,5-diOCH3) 5 (4,7-diOCH3) -

_______________________________________________________________________

a) The yield decreased (35%) in the presence of an excess of graphite (3 equiv. by wt.), in 5 min with 1g of starting material;b) No modification of the yield (50-54%) with longer reaction times (20 or 30 min).

Re-investigation of the microwave synthesis of benzothiazoles

Solvent free(graphite 10% by wt.)

Scale 1g - 10g

S

NR

N

S SN

Cl

CNR∆

benzothiazole

Synthesis of thiazolocarbazole analogs of ellipticine

NH

N

Ellipticine

H. Chabane, C. Lamazzi, V. Thiéry, G. Guillaumet, T. BessonTetrahedron Lett. 2002, 43, 2483.

NH

R O

ONH

R

R = H, Br, OCH3Br = 50%

NH

Br

NO2

NH

NH2

NH

NS S

NCl

NH

N CN

NH

N NH

N

PTSA, ETOH, 75°C

µW (40W), 2h (50-75%)

Pd/C, ETOH, HCO 2NH4, 75°C

µW (30W), 15 min, (95%)

NMP, 200°C

µW (60W), 15 min, (75%)

NH2CH2CH2NH2

EtOH,

µW (30W), 15 min, (95%)

Appel salt

pyridine

r.t., (73%)

r.t., (80%)

AcOH, HNO3

Lamazzi, C.; Chabane, H.; Thi éry, V.; Pierré, A.; Léonce, S.; Pfeiffer, B.; Renard, P.; Guillaumet, G.; Besson,T. J. Enz. Inh. Med. Chem. 2002, 17, 397.Chabane, H.; Lamazzi, C.; Thi éry, V.; Guillaumet, G.; Besson,T. Tetrahedron Lett. 2002, 43, 248.Besson, T.; Guillard, J. Tetrahedron 1999, 55, 5139.Bénéteau, V.; Besson, T.; Guillard, J.; Leonce, S.; Pfeiffer, B. Eur. J. Med. Chem. 1999, 34, 1053.

S

NS

N

N

N

S

N

OO N

S

N

NS

N

R2

R1

R2

R1 R1

R2

R1R1

R3R2 VIV

I II III

S

N

O

R1

VIO

R2

Thiazoloquinazolines Benzothiazoles

Dioxinobenzothiazoles Thiazolocarbazoles

Thiazolocoumarins

Quinazolines and derivatives

NN

NH

O

Br

Br

BrN

N

HN

N

11H-Indolo[3,2-c]quinolineIndolo[1,2-c]quinazolineHinckdentine

NN

NY

R

µwN

N

Indolo[1,2-c]quinazoline

NN

N Oµw

R

Indoloquinazolines, indoloquinolines and benzimidazoquinazolines

Frère, S.; Thiéry, V.; Bailly, C.; Besson, T. Tetrahedron 2003, 59, 773.Domon, L.; Le Coeur,C.; Grelard, A.; Thiéry,V.; Besson, T. Tetrahedron Lett. 2001, 42, 6671.Soukri, M.; Guillaumet, G.; Besson, T.; Aziane, D.; Aadil, M.; Essassi,El M.; Akssira, M. Tetrahedron Lett. 2000, 41, 5857.

________________________________________________________________________________________________________Starting material (R) product (I) time (min) yield (%) product (II) time(min) yield (%)

________________________________________________________________________________________________________3a (H) a 135 64 a 90 703b (6-F) b 240 53 b 150 563c (6-CH3) c 150 60 c 60 713d (6-OCH3) d 30 68 d 10 733e (4,7-diCH3) e 90 61 e 65 653f (4,7-diOCH3) f 115 54 f 80 58

________________________________________________________________________________________________________

Synthesis of indolo[1,2-c]quinazolines (I) and benzimidazo[1,2-c]quinazolines (II)

Indolo[1,2-c]quinazoline (I) Benzimidazo[1,2-c]quinazoline (II)

Average time thermal heating : 4-5 hGraphite : not as support but 10% by weight (fusion accelerator)

Microwave irradiation : 150W, 150 °C

Frère, S.; Thi éry, V.; Bailly, C.; Besson, T. Tetrahedron 2003, 59, 773.

HN X

H2NY

NCNR

NN

NY

RY = S,O

X = CH, N

N

N

NN

Y

R

graphite

µw

graphite

µw

8 examples of each

Synthesis of indolo[1,2-c]quinazolines and benzimidazo[1,2-c]quinazolines

Autre voie envisagée

NH NH2 N

NH

NC

sel d'Appel

N

NNC

NH

N

NH2

N

N

N

NC

sel d'Appel

Nu:

Nu:

Nu:

Nu:

and/or ?

Nu:

Nu:

?

Lamazzi, C.; Léonce, S.; Pfeiffer, B.; Renard, P., Guillaumet, G.; Rees, C. W.; Besson, T. Bioorg. Med. Chem. Lett. 2000, 10, 2183-2185.

N

N

NH

O

N

O

N

N N

O

N

O

N

N

N X

O

N

N N

O

N

O

NN

N

O

Rutaecarpine I Luotonine A II Tryptanthrine III

IV (X = CH2)V (X = NH)

VI VII

Synthesis of 2,3-fused quinazolines and natural products derivatives

X = CH : 5a,14b,15-triazabenzo[a]indeno[1,2-c]anthracen-5-one X = N : 5a,10,14b,15-tetraaza-benzo[a]indeno[1,2-c] anthracen-5-one

2,3-Fused quinazolin-4-ones from imino-1,2,3-dithiazoles

N

NHN

O

R

N

NN

NN

NHN

O

R

N

N

O

R

HN

R

O

N

N X

O

R

N

RN

S SN

Cl

CO2Me

R

N

NH2 X

R

NMeS

CO2Me

X = CH ou N

pyrazinoquinazoline

Besson, T.; Emayan, K.; Rees, C. W. J. Chem. Soc., Perkin Trans 1, 1995, 2097Besson, T.; Rees, C.W. J. chem. Soc., Perkin Trans 1, 1996, 2857Besson, T.; Dozias, M. J.; Guillard, J.; Jacquault, P.; Legoy, M. D.; Rees, C. W. Tetrahedron, 1998, 54, 6475

Synthesis of 2-cyanoquinazolin-4-ones and thiocarbamates from imino-1,2,3-dithiazoles

Concentration (g/100ml) : 3-5%Average time : 40h (∆) è 2h (µw),

Scale 0.2g - 50gAverage yield: 60-80%

Concentration (g/100ml) : 1-20%Average time: 2h (∆) è 3 min (µw),

Scale 0.2g - 100gAverage yield: 85-95%

Heterogeneous mixture (>5%)

Homogeneous mixture

N

N

OR

CNR1R1

N

S SN

Cl

NH

N

O

R1∆, H+ROH

µw µwCN

R1

HN

SCN

PPh3CH2Cl2

r.t. ROH ∆

R1

NCS

X

X = CN or Hisothiocyanates

CN

ROHµw

R1

N

X

OR

S

Quinazolines

cyanothioformamides

thiocarbamates

NaH, THF reflux

imino-1,2,3-dithiazole

Domon, L.; Le Coeur,C.; Grelard, A.; Thiéry,V.; Besson, T. Tetrahedron Lett. 2001, 42, 6671.Soukri, M.; Guillaumet, G.; Besson, T.; Aziane, D.; Aadil, M.; Essassi,El M.; Akssira, M. Tetrahedron Lett. 2000, 41, 5857.

X = CH : indoleX = N : benzimidazole

Microwave-assisted Niementowski reaction :Preparation of fused polyheterocycles

Z = O : Quinazolin-4 oneZ = S : Quinazoline-4-thione

N

NH

ZR1

R2

N

NR1

R2

N

O

R3R4

Z = O or S

NH

X

H2N

N X

N

N

O

R N

X

NHZ

X = CH or N Z = O or S

von Niementowski, S. J. Prakt. Chem. 1895, 51, 564-572

Conventional conditions :130-150°C,

Average time : 6 hScale: 0.2-1g

Microwave-assisted Niementowski reaction – Back to the roots

CO2H

NH2

R1

R2R3

N

N

OR1

R2R3

HNR5

X

R4

NR5

Cl

R4

NR5

MeS

R4

X = O,S

chloroimine

thioether

amide or thioamide

R5

R4

quinazolin-4-ones

_________________________________________________________ SMa R1 R2 R3 Reaction time (min) yield product (%)

_________________________________________________________

a H H H 20 90a

b Me ” " 15 75

c Br ” " 20 75

d NO2 ” " 20 87

e OMe OMe " 40 70

f Br H Br 15 78

g OH ” H 15 86

h OMe OMe OMe 40 77

i -C2H4- H 15 77

j Pyridine 20 80

_________________________________________________________a Starting material

Alexandre, F.R.; Berecibar, A.; Besson, T. Tetrahedron Lett. 2002, 43, 3911.

Microwave experiments150°C (60W)

Average time: 20 minScale

0.2g - 5g

Microwave-assisted Niementowski reaction – Back to the roots

CO2H

NH2

R1

R2R3

N

NH

OR1

R2R3

NH2-CHO

a or b

Domon, L.; Le Coeur,C.; Grelard, A.; Thiéry,V.; Besson, T. Tetrahedron Lett. 2001, 42, 6671.Soukri, M.; Guillaumet, G.; Besson, T.; Aziane, D.; Aadil, M.; Essassi,El M.; Akssira, M. Tetrahedron Lett. 2000, 41, 5857.

5a,14b,15-Triazabenzo[a]indeno[1,2-c]anthracen-5-ones and5a,10,14b,15-tetraaza-benzo[a]indeno[1,2-c] anthracen-5-ones

X = CH : 5a,14b,15-triazabenzo[a]indeno[1,2-c]anthracen-5-one X = N : 5a,10,14b,15-tetraaza-benzo[a]indeno[1,2-c] anthracen-5-one

X = CH : indoleX = N : benzimidazole

(a) : CS2, KOH, CH3OH, reflux, µw : 55 min, 95;( ∆ : 12h, 92%) (b) 20 min, 95-98%.

a

b

NH

X

H2N

N

X

N

N X

N

MeS

N

O

NH2

CO2HR

RN

X

NHS

ICH3, NaH

NH2

CO2HR

DMF, r.t.

Graphite (large excess)140°C (P 120W)

Time: 30 minScale: 0.2 - 1 g

5a,14b,15-Triazabenzo[a]indeno[1,2-c]anthracen-5-ones from indolo[1,2-c]quinazoline

indolo[1,2-c]quinazoline

Domon, L.; Le Coeur,C.; Grelard, A.; Thiéry,V.; Besson, T. Tetrahedron Lett. 2001, 42, 6671.

NN

MeS

NN

N O

CH3

NN

N O

NN

N O

Cl

NN

N O

90%

90%

45%14%

NH2

CO2HR

5a,10,14b,15-Tetraaza-benzo[a]indeno[1,2-c] anthracen-5-ones from benzimidazo[1,2-c]quinazoline

benzimidazo[1,2-c]quinazoline

Graphite (large excess)170°C (P 105W)Time: 90 min

Scale: 0.2 - 1 g

Soukri, M.; Guillaumet, G.; Besson, T.; Aziane, D.; Aadil, M.; Essassi,El M.; Akssira, M. Tetrahedron Lett. 2000, 41, 5857.

N

N

NMeS

N

N

NN O

N

N

NN O

CH3

95%

75%

NH2

CO2HR

Method A

Method B

Alexandre, F.R.; Berecibar, A.; Wrigglesworth, R.; Besson, T. Tetrahedron 2003, 59, 1413.

Novel 8H-quinazolino[4,3-b]quinazolin-8-ones

Average time : 20 minAverage yield: 75-95 %

Average time : 10 minAverage yield: 75-90 %

N

NH

OR1

R2

N

NH

SR1

R2 N

NR1

R2

SMe

N

NR1

R2

Cl

N

NR1

R2

N

O

R3R4

NH2

CO2H

R3

R4

graphite, µw

ICH3, NaOH

MeOH, r.t.

POCl3µw, 100°C

Lawesson,pyridineµw, 115°C

a or b

a) CH3CO2H, atmospheric pressure, µW (P 100W) 105°C, 20 min b) sealed tube, µW (P 100W) 130°C, 10 min.

__________________________________________________________________________________

Compound R1 R2 R3 R4 Method A Method B (a or b)Yield (%) Yield (%)

__________________________________________________________________________________a H H H H 79 82b Me H H H 58 70c Br H H H 21 54d MeO MeO H H 34 62e H H Me H 53 85f H H Br H 50 76g H H MeO MeO 29 41h MeO MeO MeO MeO / 65

__________________________________________________________________________________

Alexandre, F.R.; Berecibar, A.; Wrigglesworth, R.; Besson, T. Tetrahedron 2003, 59, 1413.

Novel 8H-quinazolino[4,3-b]quinazolin-8-ones

Last step: Reagents and conditions:

Method A: S-methyl derivative, anthranilic acid (6 equiv.), graphite, µW (P 60W) 150 °C, 30min;Method B: a) chloroquinazolinone, anthranilic acid (2 equiv.), CH3CO2H, atmospheric pressure, µW (P 100W) 105°C, 20 min

or

b) sealed tube, µW (P 100W) 130°C, 10 min.

Novel 8H-quinazolino[4,3-b]quinazolin-8-ones

Alexandre, F.R.; Berecibar, A.; Wrigglesworth, R.; Besson, T. Tetrahedron 2003, 59, 1413.

path B

path A

Comparison with usual thermal conditions___________________________________________

Path A Path BSteps 4 3___________________________________________Overall yield (%) better under µw similar

For R1=R2=H: 34 (∆), 66 (µw)

Last step solvent free solventOverall time 24 h (∆), 2h (µw) 11h (∆), 1h (µw)Scale 0.2g - 1g 0.2g - 1g

N

NH

OR1

R2

N

NH

SR1

R2 N

NR1

R2

SMe

N

NR1

R2

N

O

R3

R4

N

NR1

R2

Cl

NH2

CO2H

R1

R2

N

O

SS N

Cl

OMeR

NH2 NH2

N

NNH

NH

O

R

N

NN

NH2

O

R

NH2

OH

O

N

NN

N

O

OR

THF, r.t.

1 a-d

2 a-d

15

+graphite, 220°C, 5 min

µM (100W), sealed vial

2 a-d

3 a-d

_______________________________________________________________Starting imine (R) Yield of 2 (%) Yield of 3 (%)

_______________________________________________________________1a H 56 521b 4-Cl 61 681c 5-Br 74 651d 4,5-diOMe 68 36

_______________________________________________________________

Efficient synthesis of novel pentacyclic 6,7-dihydro-5a,7a,13,14-tetraaza-pentaphene-5,8-diones

Pereira, M.F.; Picot, L.; Guillon, J.; Léger, J.-M.; Jarry,C.; Thiéry, V.; Besson, T. Tetrahedron Lett,. 2005, in press.

Multi-step synthesis

Pharmaceutical active heterocyclic compounds : CDK and GSK3 inhibitors ?

N

N N

N

HN

HN

OH

RR

Roscovitine

NH

SN

NH

O

R

Oxoindole 91

N

NN

N

R1

R2

R3

pyrazolopyrimidines

N

N

R1

R2

R3

Quinazolines

N

N

SN

OR1

R2

Thiazoloquinazolines

N

N

R1

R2N

NR3

pyrimidopyrimidines

N

NN

NH

O

pyrazinoquinazolines

R2R1

Besson, T.; Guillard, J.; Rees, C. W. Tetrahedron Lett., 2000, 1027

a) 1, pyridine, r.t., 10h, 78%; b) NaH, ROH, reflux; c) SnCl2, EtOH, 70°C; d) Br2, CH3COOH, r.t., 4H, 74%;e) 1, pyridine, r.t., 4H, 66%; f) CuI, pyridine, reflux; g) HCl, reflux

b 640 37 80 61c 60 72 10 94f 90 50 20 53g 60 49 10 50

Step time (min) yield (%) time (min) yield (%)

∆ µw

Synthesis of thiazolo[5,4-f]quinazolin-9-one

o

(∆) (µw)Overall yield (%): 6 15 Overall time: 14h 2h

Scale: 0.2g - 1g

NO2NC

H2N

aNO2NC

N

SSN

Cl

b N

N

NO2

OR

NC

c N

N

NH2

OR

NC

d N

N

NH2

OR

NC

Br

N

N

NOR

NC

Br

S SN

Cl

e

N

N

ORN

SCN

NC

f HN

N

ON

Sg

Thiazolo[5,4-f]quinazolin-9-ones (I) and thiazolo[4,5-h]quinazolin-6-ones (II)

I

II

O2NCO2H

NH2

a,bO2N

N

N

O

H2NN

N

O

c

N

N

O

N

N

O

H2N

H2N

dBn Bn

Bn

Bn

d

Br

Br

HN

N

ON

S

HN

N

O

SN

N

N

O

N

N

O

N

N

NS S

SSN

Cl

Cl

Br

Br

N

N

O

N

N

O

Bn

Bn

Bn

Bn

SN

NC

NS

NC

e

e

f

f

g

g

Thiazolo[5,4-f]quinazolin-9-ones (I) and thiazolo[4,5-h]quinazolin-6-ones (II)

Microwave assisted reactions for step 1,2 and 3_____________________________________________________________________________________________

Starting anthranilic acid derivative 5-NO2 4-NO2_____________________________________________________________________________________________

(a) formamide (5 equiv.), µW 150°C (P 60W), 40 min; 87% 86%(b) BnBr, NaH, DMF, µW 70°C (P 60W), 15 min, 95% 80% (c) Ammonium formate / Pd/C, EtOH, µW 65°C (P 60W), 10 min; 92% 75% (d) Br2, acetic acid, room temp., 2 h 90% 76%

O2NCO2H

NH2

a,bO2N

N

N

O

H2NN

N

O

c

N

N

O

N

N

O

H2N

H2N

dBn Bn

Bn

Bn

d

Br

Br

Thiazolo[5,4-f]quinazolin-9-ones (I) and thiazolo[4,5-h]quinazolin-6-ones (II)

I

II

Microwave assisted reactions for step 6 and 7__________________________________________________________________________

Starting anthranilic acid derivative 5-NO2 4-NO2

_____________________________________________________________

(e) Appel’s salt, pyridine, CH2Cl2, room temp.,3h 90% 46%

(f) CuI, pyridine, µW 115°C (P 90W), 15 min 83% 75%

(g) conc.H2SO4, µW 130°C (P 80W), 15 min 40% 38%

Comparison ∆ /µwOverall yield: x 2 Overall time: /8 Scale: 0.2g - 1g

Alexandre, F.R.; Berecibar, A.; Wrigglesworth, R.; Besson, T. Tetrahedron Lett. 2003, 44, 4455-4458.

HN

N

ON

S

HN

N

O

SN

N

N

O

N

N

O

N

N

NS S

SSN

Cl

Cl

Br

Br

N

N

O

N

N

O

Bn

Bn

Bn

Bn

SN

NC

NS

NC

e

e

f

f

g

g

CDK and GSK3 inhibitors

N

N N

N

HN

HN

OH

RR

Roscovitine

NH

SN

NH

O

R

Oxoindole 91

N

N

SN

OR2

R1

N

N

OR2

NS

R1

R1

H

CN

R

RHN

N

R

O

N

R

RHN

O

R2

alkyle

aryle

H

R3

R3

R3 = H

Testard,A.; Picot, L.; Lozach, O.;, Blairvac, M.; , Meijer, L.; Murillo, L.; Piot, J.M.;Thiéry, V.; Besson, T. J. Enz. Inh. Med. Chem. 2005, sous presse..

NH2

COOHO2NO2N

N

N

O

R NH2

N

N

O

R

NH2

N

N

O

R

BrN

N

N

O

RSS

NCl

N

N

O

R

SN

NC

a, b c d

e f

Réactions

Temps ∆ Rdt CEM Temps Miles. Temps

PC (P)

(heure) °C % (min.) (W) Rdt % (min.) (W) Rdt % (min.) °C Rdt %

a) HCHO excès 5 150 80 40 (80 W) 83 40 - 90 10 200 95 b) NaH, RX, DMF 5 80 54 15 (40 W) 98 15 - 98 5 140 90 c) HCOONH4, Pd-C, 1 80 84 15 (40 W) 97 15 - 95 - - - d) Br2, AcOH 2 rt 93 - - - - - - 4 80 97 e) Sel d’Appel 2 rt 75 - - - - - - - - - f) CuI, pyridine 0.5 115 94 15 (60 W) 95 15 - 93 1 160 95 15.5 h 20 5.5h 52 5.5h 56 2.5h 57

Alexandra Testard, Thèse de l’Université de La Rochelle, 2005.

On the interest to work at atmospheric pressure or in sealed vials

________________________________________________________________________________Method Starting material DMSO p-TSA Microwave irradiation

(mL) (equiv.) reaction time (min) yield (%)________________________________________________________________________________

A X = S, R = 5-Cl 35 - 360 62B X = S, R = 5-Cl 35 1.5 20 65C X = S, R = 5-Cl 7 1.5 10 69C X = O, R = 5-Cl 7 1.5 10 40C X = NH, R = 5-OMe 7 1.5 10 65

________________________________________________________________________________

Pictet-Spengler heterocyclizations via microwave-assisted degradation of DMSO

Laboratoire de Chimie Thérapeutique, EA1043, Faculté des Sciences Pharmaceutiques et Biologiques, BP 83, 59006 Lille

X

NHCOCH3

R RNCOCH3

X

X = NH, O, SR = Cl, OMe

DMSO, p-TSA

mw (140W), reflux,10 min

Mésangeau,C.; Yous, S.; Pérès, B.; Lesieur, D.; Besson, T. Tetrahedron Lett. 2005,46, 2465-2468.

NH

N

NO

R1

R2 R 3

R4 N

N

O O

CH3

RS

RO

NHCOC6H5

N

N

S N

R1

R 2O

CO2Et

NN

NR1

R2

NN

NN R

Me

Ph

OO

S

NRO

O S

NR

Ar

C6H5

CNN

N NH

OR

XCH3

10 examples, 53-98% 9 examples, 70-75% 6 examples, 81-83%

5 examples, 92-95% 6 examples, 78-97% 2 examples, 94-95%

1 example, 42% 1 example, 42%

Fused ring heterocycles

Mont, N.; Teixido, J.; Borell, J., I.; Kappe, C.,O., Tetrahedron lett. 2003 , 44, 5385-5387.Quiroga, J.; Cisnero, C.; Insuasty, B.; Abonia, R.; Nogueras, M.; Sanchez, A., Tetrahedron lett. 2001 , 42, 5625-5627.Dave, C.,G.; Shah, R.,D., Heterocycles 1999, 51, 1819-1826.Kidwai, M.; Venkataramanan, R.; Garg, R.,K.; Bhushan, K.,R., J. Chem. Res. (S) 2000 , 586-587.Paul, S.; Gupta, M.; Gupta, R.; Loupy, A., Tetrahedron lett. 2001 , 42, 3827-3829.Guillard, J.; Besson, T., Tetrahedron 1999, 55, 5139-5144.

NN

R

NN

N

RN

N N

OR

N

N N N

OR

NN

S

CN

N

NN

COREtO2C

R1

R2

Ar

N

N

S N

R1

R2

R3

N

N

O

n(CH2)

4 examples, 14-90%

2 examples, 75-95%

8 examples, 53-69% 8 examples, 58-77%

1 example 52% 6 examples, >95%

7 examples, 80-90%5 examples, 85-92%

Fused heterocycles sharing at least one heteroatom

Soukri, M.; Guillaumet, G.; Besson, T.; Aziane, D.; Aadil, M.; Essassi, El M.; Akssira, M., Tetrahedron Lett. 2000, 41, 5857-5860.Besson, T.; Rees, C. W.; Roe, D. G.; Thiéry, V., J. Chem. Soc., Perkin Trans. 1 2000, 555-561.Vanden Eynde, J.,J.; Hecq, N.; Kataeva, O.; Kappe, C.,O.,Tetrahedron 2001, 57, 1785-1791.Yadav, J.,S.; Reddy, B.,S.,V., Tetrahedron Lett. 2002, 43, 1005-1907.Prasad, M.,R.; Rao, A.,R.,R.; Rao, P.,S.; Rajan, K.,S., Synthesis 2001, 2119-2123.

-Microwaves enhance synthetic processes-

* limited to small quantities ?* Scaling-up in progress

- Benefits include :

* Reduced reaction times* Better yields and easier purification * Time saving

CONCLUSION

Working under focused microwave irradiation need a special attention:

a) The ratio between the quantity of the material and the support ?

b) Use of solid supports = green chemistry ?

c) Association of liquid/solid reactants ?

d) Scale-up and multi-step synthesis ?

Dr Valérie Thiéry (Staff)Dr Lisianne Domon (Staff)

Alexandra Testard (PhD)Maria de Fatima Pereira (PhD)

Anne Beauchard (PhD)Gaëlle Gosset (PhD) (CNRS/CEA)

Dr François-René Alexandre (post-Doc)Dr Laurence Perreux (post-Doc)

Dr Natalia Gospodinava (post-Doc)

Dr Stéphane FrèreDr Hadjila ChabaneDr Valérie BénéteauDr Jérome Guillard

Dr Christelle Lamazzi

Acknowledgements

PartnersAcademics

Pr C.W. Rees (IC, London)Orléans, Nantes, Lyon,

Clermont-Ferrand

Pr Finaru (Bacau) RomaniaPr Carpov (Iasi) Romania

CEA, Le Ripault

Saclay

Dr L.Meijer (Roscoff, CNRS)Ligue contre le cancer

(comités 16 et17)Cancéropôle Grand Ouest

Industry

ORGANON PFIZERSERVIER

LBCB