WELCOME

AmidocarbonylationAn Efficient Route to Amino acid Derivatives

UNDER THE SUPERVISION OF- NASHRA SALEEMDr. S. MASHHOOD Ali 12-0CHM-17

GH1792

CONTENTS

INTRODUCTION

DISCOVERY OF AMIDOCARBONYLATION

WAKAMATSU REACTION

COBALT CATALYSED REACTION APPLICATIONS

PALLADIUM CATALYSED REACTION APPLICATIONS

CONCLUSION

REFERENCES

Amidocarbonylation is the transition metal catalysed multicomponent reaction that constructs the aminoacid framework directly from simple, inexpensive starting materials.

The structure of N-acyl-a-amino acids are found in many compounds. e.g - CAPTOPRIL , FLAMPROP-ISOPROPYL, ASPARTAME etc.

INTRODUCTION

STRUCTURES-

HISTORICAL BACKGROUND

WAKAMATSU et al. FIRST DISCOVERED

COBALT-CATALYZED

AMIDOCARBONYLATION IN 1970

WITTE AND SEELIGER DEVELOPED A

CORRESPONDING KOCH

CARBONYLATION IN SULPHURIC ACID

THE DISCOVERY OF AMIDOCARBONYLATION

THE WAKAMATSU REACTION

THE DEVELOPMENT OF THE OXO PROCESS FOR THE PREPARATION OF 3-CYANOPROPIONALDEHYDE FROM ACRYLONITRILE WAS ESSENTIAL STEP IN THE DISCOVERY OF TODAY’S WELL KNOWN AMIDOCARBONYLATION REACTION.

AS EARLY AS 1962 THE HYROFORMYLATION OF ACRYLONITRILE WITH METHANOL AS THE SOLVENT HAD BEEN USED SUCCESSFULLY ON THE COMMERCIAL SCALE.

REACTION

COBALT CATALYSED REACTIONS

REACTION CONDITIONS

70-160◦C

50-200 bar

Solvents-dioxane ,THF,DME,ethyl acetate acetone, or benzene.

Concentration of starting material in solutions is usually 0.1-3 M and amide may be used in excess.

MECHANISM

METHOD DEVELOPMENT IN COBALT CATALYSED REACTION

IN ADDITION TO ALDEHYDES , OLEFINS , ACETALS, EPOXIDE, ALLYL ALCOHOLS AND BENZYLCHLORIDE CAN ALSO BE USE AS STARTING MATERIAL.

ALDEHYDES

INTRAMOLECULAR AMIDOCARBONYLATION

ACETALS,EPOXIDE AND ALLYL ALCOHOLS

ACETALS AS SIMPLE PROTECTED ALDEHYDE EQUIVALENTS ARE EITHER HYDROLYED IN SITU UNDER THE REACTION CONDITIONS AND REACT IN AN ANALOGOUS MANNER TO THE ALDEHYDES,OR THEY LEADS TO THE CORRESPONDING N-ACYLAMINOACID ESTERS BY WATER REMOVAL.

ADVANTAGE

IF OTHER FUNCTIONAL GROUPS ARE PRESENT IN THE STARTING MATERIAL THEN IT ACTS AS PROTECTING GROUP AND HELPS TO GET DESIRED PRODUCT

EPOXIDE EPOXIDE SUCH AS STYRENE OXIDE OR PROPENE

OXIDE, MAY BE REARRANGED INTO ALDEHYDES BY LEWIS ACID CATALYSIS AND THEN AMINOCARBONYLATED.

TRANSITION METAL COMPLEXES SUCH AS [Fe2(CO)9],[PdCL2(PPh3)] etc. HAVE PROVED TO BE SUITABLE FOR THE IN SITU ISOMERIZATION OF ALLYL ALCOHOLS TO ENOLS,WHICH THEN TAUTOMERIZE TO ALDEHYDES.

ALCOHOLS AND BENZYLCHLORIDE

ALCOHOLS THAT FORMS STABLE CARBENIUM IONS MAY BE HYDROFORMYLATED TO CORRESPONDING ALDEHYDE.

1-CYCLOPROPYLMETHANOL WAS CONVERTED INTO N-ACETYL-3-CYCLOPROPYLALANINE BY CARONYLATION-AMIDOCARBONYLATION.

APPLICATIONS

N-ACETYL-D,L-PHENYLALANINE

IT IS A PRECURSOR OF L-PHENYLALANINE,THE KEY INTERMEDIATE IN THE SYNTHESIS OF ASPARTAME(THE METHYL ESTER OF L-ASPARTYL-L-PHENYLALANINE),AN ARTIFICIAL SWEETENER.

REACTION

SARCOSINATES

THE LONG–CHAIN N-ACYL DERIVATIVES OF SARCOSINE (N-METHYL-GLYCINE)BELONGS TO THE GROUP OF ANIONIC TENSIDES THAT ARE USED AS COMPONENTS OF SURFACTANTS, SOAPS AND EMULSIFIERS BECAUSE OF THEIR LOW HARDENING SENSITIVITY AND GOOD DERMATOLOGICAL COMPATIBILITY .

PALLADIUM CATALYSED AMIDOCARBONYLATION

MILDER CONDITIONS.

PRESENCE OF HALIDE IONS AS CO-CATALYST.

SYNERGISTIC EFFECT IS SEEN.

BOTH PALLADIUM(O) AND PALLADIUM(II) CAN BE USE.

PALLADIUM CATALYST HAVE AN ACTIVITY GREATER THAN THE COBALT SYSTEM BY A FACTOR OF 10 -100.

MECHANISM

DEVELOPMENT IN THE METHODOLOGY OF PALLADIUM CATALYSED AMIDOCARBONYLATION

DEPENDING ON THE NATURE OF THE STARTING MATERIAL, THE USE OF UREA DERIVATIVES AS AMIDE COMPONENTS HAS MADE IT POSSIBLE TO ISOLATE THE ACTUAL AMIDOCARBONYLATION PRODUCTS, THE N-UREIDOAMINO ACIDS. HOWEVER, THE SUBSTITUTED HYDANTOIN IS USUALLY OBTAINED WITH HIGH SELECTIVITY.

HYDANTOIN ARE VERY IMPORTANT IN BOTH PRODUCTION OF AMINO ACIDS AND IN RESEARCH OF PHARMACEUTICALLY ACTIVE ,LOW MW HETEROCYCLES.

AMIDOCARBONYLATION OF NITRILES

AMIDOCARBONYLATION OF NITRILES WAS DEVELOPED IN WHICH THE AMIDE IS GENERATED INSITU.

AMIDE IS USEFUL IN THE PRODUCTION OF N ACETYL-D,L-VALINE OR METHIONINE.

SYNTHETIC APPLICATIONS OF PALLADIUM-CATALYSED AMIDOCARBONYLATION

FUNCTIONALYSED ARYLGLYCINES THE PRODUCTS OF AMIDOCARBONYLATION OF

BENZALDEHYDES,N-ACYL-ARYLGLYSINE OCCURS AS SUBSTRUCTURES IN MANY DIFFERENT PHARMACOLOGICALLY ACTIVE COMPOUNDS.

N-SUBSTITUTED GLYCINES

THE AMIDOCARBONYLATION OF SECONDARY AMIDES ARE MORE DIFFICULT TO CARRY OUT THAN THE CORRESPONDING REACTIONS PRIMARY AMIDES.HOWEVER ,IT HAS BEEN POSSIBLE TO PREPARE A SERIES OF N-SUBSTITUTED N-GLYCINES BY REACTION WITH FORMALDEHYDE .

REACTION

CONCLUSION

WITH THE ESTABLISHMENT OF TRANSITION METAL CATALYSED AMIDOCARBONYLATION,CRITICAL ADVANCES HAVE BEEN MADE IN THE RECENT YEARS WITH THE ATTAINMENT OF HIGHER CATALYST ACTIVITIES UNDER MILDER CONDITION.

IT WILL LEADS TO THE FORMATION OF INTERESTING PRODUCTS FROM SIMPLE STARTING MATERIALS.

REFERENCES

Angewandte Chemie. International Ed.2000,39,1010-1027

K.Kuhlein, H.Geissler in Transition metals for Organic synthesis.1998 p.79

A.P.Mikhalin, Russ. Chem. Rev. 1995,64,259.