Snieckus Group Research Interests - Directed Ortho Metalation

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RESEARCH INTERESTS

DIRECTED ORTHO METALATION

INTRODUCTION

DIRECTED ORTHO METALATION, DISCOVERED INDEPENDENTLY BY WITTIG AND GILMAN IN THE LATE 1930S, PROVIDES AN

EFFICIENT AND REGIOSELECTIVE METHOD FOR THE TRANSFORMATION OF A CARBON-HYDROGEN BOND TO A CARBON-CARBON OR

CARBON-HETEROATOM BOND.

A MAJOR THRUST WITHIN THE SNIECKUS LAB IS CONCERNED WITH THE DEVELOPMENT AND APPLICATION OF NEW DIRECTED

METALATION REACTIONS AND RELATED PROCEDURES TO THE SYNTHESIS OF POLYSUBSTITUTED AROMATIC AND

HETEROAROMATIC SYSTEMS (SCHEME 1).

SCHEME 1. DIRECTED ORTHO METALATION

NEW LATENT DMGS

THE SEARCH FOR NEW LATENT DMGS IS AN ONGOING CHALLENGE WITHIN THE SNIECKUS LABORATORIES. RECENTLY WE HAVE

REPORTED SEVERAL NEW LATENT DMGS, INCLUDING THE ARYL SULFONAMIDES AND ARYL SULFAMATES. FOR EXAMPLE, WE HAVE

SHOWN THAT ARYL SULFAMATES PARTICIPATE EFFICIENTLY AS CROSS-COUPLING PARTNERS WITH GRIGNARD REAGENTS UNDER

NICKEL(0) CATALYSIS (SCHEME 2).

SCHEME 2. NI-CATALYZED CROSS-COUPLING OF ARYL SULFAMATES AND ARYL GRIGNARD REAGENTS

WE HAVE ALSO DEMONSTRATED THE NICKEL(0) CATALYZED REDUCTIVE CLEAVAGE OF THE ARYL SULFONAMIDE GROUP UNDER

MILD CONDITIONS, ALLOWING THE FORMATION OF AROMATIC SYSTEMS THAT OVERRIDE THE USUAL SUBSTITUTION PATTERN

OBTAINED VIA CLASSICAL ELECTROPHILIC SUBSTITUTION (SCHEME 3).

SCHEME 3. NI-CATALYZED REDUCTION OF ARYL SULFONAMIDES

LIKE THE ARYL SULFAMATES, CROSS-COUPLING OF ARYL SULFONAMIDES WITH GRIGNARD REAGENTS MAY BE ACCOMPLISHED IN

GOOD TO EXCELLENT YIELD (SCHEME 4). THIS REPRESENTS A NEW VARIANT OF THE CORRIU-KUMADA-TAMAO PROTOCOL THAT

TAKES ADVANTAGE OF THE POWERFUL DIRECTED ORTHO METALATION CONNECTION.

SCHEME 4. NI-CATALYZED CROSS-COUPLING OF ARYL SULFONAMIDES AND ARYL GRIGNARD REAGENTS

DOM-XCOUPL

THE ADVENT OF MODERN TRANSITION METAL-CATALYZED REACTIONS, IN PARTICULAR NEW SP2-SP2 COUPLING PROTOCOLS,

HAS REVOLUTIONALIZED HOW CHEMISTS CONCEPTUALIZE (HETERO)ARYL-(HETERO)ARYL BOND FORMING PROCESSES. THE DOM

STRATEGY, WHEN LINKED WITH NAMED CROSS-COUPLING REACTIONS BY TRANSMETALATION, PROVIDES CONSIDERABLE

TACTICAL ADVANTAGE IN THE CONSTRUCTION OF POLYSUBSTITUTED AROMATIC AND HETEROAROMATIC COMPOUNDS.

WE HAVE RECENTLY REPORTED A GENERAL ONE-POT METHOD FOR THE SYNTHESIS OF AZABIARYLS THAT AVOIDS THE

RECOGNIZED DIFFICULTY IN ISOLATION OF PYRIDYL BORONIC ACIDS AND THEIR PROPENSITY TOWARDS PROTODEBORYLATION

(SCHEME 5).

SCHEME 5. ONE-POT BORYLATION/SUZUKI CROSS-COUPLING SYNTHESIS OF AZABIARYLS

A FURTHER EXAMPLE INVOLVES THE SYNTHESIS OF SACCHARIN DERIVATIVES STARTING FROM N-CUMYLSULFONAMIDES

(SCHEME 6). FIRST, FORMATION OF THE REQUIRED BIARYLS WAS ACHIEVED IN GOOD TO EXCELLENT YIELD USING THE

DOM-XCOUPL PROTOCOL. INSTALLATION OF A BENZAMIDE MOIETY BY A SECOND DOM REACTION FOLLOWED BY REMOVAL OF

THE CUMYL GROUP AND CYCLIZATION DELIVERED THE DESIRED SACCHARINS.

SCHEME 6. SYNTHESIS OF SACCHARINS FROM N-CUMYLSULFONAMIDES

DIRECTED REMOTE

METALATION

AN EXTENSION TO THE WELL ESTABLISHED DOM METHODOLOGY MAY BE CLASSED AS DIRECTED REMOTE METALATION (DREM).

IN COMBINATION WITH OUR OTHER METHODS, A DIVERSE RANGE OF FUSED AROMATIC AND HETEROAROMATIC COMPOUNDS

MAY BE PREPARED RAPIDLY AND EFFICIENTLY FROM SIMPLE STARTING MATERIALS.

FOR EXAMPLE, WE HAVE DEMONSTRATED A RAPID ROUTE TO BENZO[A]CARBAZOLES (SCHEME 7). THIS STRATEGY WAS ALSO

SUCCESSFULLY APPLIED TO THE SNTHESIS OF A SIMPLE ANTITUMOR AND ANTIVIRAL ALKALOID ISOLATED FROM THE BLUE

GREEN ALGA NOSTOC SPHAERICUM.

SCHEME 7. SYNTHESIS OF BENZO[A]CARBAZOLES BY DREM-XCOUPL METHODOLOGY