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EXAMPLES OF GREEN CHEMISTRY AT THE IBMM

Valrie Declerck, Patrice Ribire,

Evelina Colacino, Latifa Daich, Jean Martinezand Frdric Lamaty

UMR 5247 CNRS-UM1-UM2Montpellier, France

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APPLICATIONS

Aminoacids, Peptides, Peptidomimetics

Heterocycles

ANALYSIS

Mass spectrometry

-METHODOLOGY

Polymer-supported

chemistry

Catalysis

Multi Component reactions

Green Chemistry

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INTRODUCTION

Concept of

green chemistry

: pollution

prevention rather than pollution treatment. Use of alternative feed

stock, innocuous

reagents, natural processes, catalysis,

alternative solvents

or reaction

conditions,

minimization

of energy

consumption.

Organic

solvents

are very

often

toxic

and

volatile.

Need

to find

alternatives (ionic

liquids,

water, fluorous media, supercritical CO2 )

Principle 8 from the 12 Principles : Use safer solvents and reactionconditions.

1. PEGs as solvent

2. No solvent

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Alternative aux Liquides Ioniques

-plusieurs tailles disponibles

-point dbullition lev/solide-toxicit faible

-bon march

-fonctions alcools (rducteur)-modifications possibles

-chlation/stabilisation de catalyseursO

OO

OOK+

PEG = SOLVANT

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NSES CO2Me

NSES CO2Me

NSES CO2Me

O

O

NSES CO2Me

CO2Me

NSES CO2Me

F

NSES CO2Me

TMS

NSES CO2Me

MeO

NSES CO2Me

F

95% 98% 51% 82%

91% 37% 83% 76%

SYNTHESIS OF BENZAZEPINES

Declerck, V.; Ribire, P.; Martinez, J.; Lamaty, F. Eur. J. Org. Chem. 2007, 201

Precipitate

Filtrate

SES N CO2Me

Ar

Br

SESNH

CO2MeAr

K2CO3, CH3CN

reflux, 6h

62-90%

Br

RBr

RPEG3400OHMW 300W

100 C, 30min

Ar

NSES CO2Me

Pd(OAc)2K2CO3

37-95%

R

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PEG-METALS

+ Metal +

ArX

CO2-tBu

10% mol CuI

K2CO3PEG

Micro-ondes

ArCO2-tBu

R

ou ou

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MECHANOCHEMICAL ACTIVATION

Solvent-free reactions can be carried out by stirring or by grinding

reactants

in a mortar.

Ball-milling usually improves speed of reaction. Many advantages: reduced pollution, low costs,simplicity. Resulting yields are remarkably high starting from stoichiometric amount of reactants, especially in the case of solid-solid reactions.

1. Tanaka, K.; Toda, F. Chem. Rev, 2000, 100, 1025.

2. Tanaka, K.; Toda, F. Solvent-free Organic Synthesis, Wiley-VCH, 2003.

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MECHANOCHEMICAL ACTIVATION

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SYNTHESIS OF PEPTIDES FROM UNCAS

Entry UNCA Aminoacid DipeptideConversion

(%)Yield

(%)

1 Boc-Val-NCA HCl.H-Leu-OMe Boc-Val-Leu-OMe 100 87

2 HCl.H-Ala-OMe Boc-Val-Ala-OMe 100 100

3 Fmoc-Val-NCA HCl.H-Leu-OMe Fmoc-Val-Leu-OMe 90 -

4 HCl.H-Ala-OMe Fmoc-Val-Ala-OMe 100 76

5 Boc-Phe-NCA HCl.H-Leu-OMe Boc-Phe-Leu-OMe 85 -

6 HCl.H-Ala-O-tBu Boc-Phe-Ala-OtBu 100 73

N

O

PG

O

O

R1

+HCl.H2N

OR3

O

R2

NH

PGHN

O

OR3

OR1NaHCO3

Ball-millling

1h; 30 Hz

+ CO2

+ NaClR2

UNCA

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SYNTHESIS OF ASPARTAME

V. Declerck, J. Martinez, F. Lamaty, Patent Fr. Dem. 0753970 on 21.03.07

N

OO

O

Boc

CO2tBu

+

HCl.H2NOMe

OHN

OMe

O

BocHN

CO2tBu

HN

OMe

O

ClH3N

CO2H

HCl gas

no solvent

HN

OMe

O

H3N

CO2

precipitate

NaHCO3Ball-milling1h 30 Hz

no solvent

aq. Na2CO3

pH= 5.2

O

O O