1,1-Organodimetallics in Organic Synthesis

Daniel Schmitt1/24/08

Introduction

1st reports of gem-dimetallic compounds

Introduction

1,1-Organodimetallic reagents create 2 new C-C bonds

Organometallic reagents create a new C-C bond

1,1-Organodimetallics allow rapid building of dense molecular complexity

Outline

• Generation of 1,1-Organodimetallics • Reactions of Bis(iodozincio)methane

• Carbenoid Reactivity of 1,1-Dimetallics

• Allylmetals as 1,1-Dimetallic Precursors

• Dimetallic Allylations

• 1,1-Dimetalloids: Silylboration and Diboration

Generation of 1,1-Organodimetallics:Deprotonation

Generation of 1,1-Organodimetallics:Carbometalation

Generation of 1,1-Organodimetallics: Metal – Halogen Exchange

Cyclopropanediols from 1,2-Diketones

Ukai, K.; Oshima, K.; Matsubara, S. J. Am. Chem. Soc. 2000, 122, 12047.

1 diastereomer

Cyclopropanediol TMS ether opens to 1,3 diketone

Cyclopropanation of α-Ketoimines

Nomura, K.; Oshima, K.; Matsubara, S. Tetrahedron Lett. 2004, 45, 5957.

Bis(iodozincio)methane and 1,2 Diimines

Deuterium Labeling Study

Proposed Initial Coordination

Cyclopropanation of α,β-Epoxy Ketones

Preservation of Enantiopurity

Chelation Control

Normal Chelation Control: Hydride Reduction

Proposal for Stereochemical Outcome

Conjugated Dienes From Alkynes

Conjugated Dienes From Alkynes

Proposed Mechanisms of Butadiene Formation

Kinetic Zinc Enolate from Bis(iodozincio)methane

Preparation of Silyl Enol Ethers from Thiol Esters and Bis(iodozincio)alkane

Regioselective Enolate Preparation

Bis(iodozincio)methane Mediated Pinacol Type Rearrangement

Possible Mechanism

Bis(iodozincio)methane

Outline

• Generation of 1,1-Organodimetallics • Reactions of Bis(iodozincio)methane

• Carbenoid Reactivity of 1,1-Dimetallics

• Allylmetals as 1,1-Dimetallic Precursors

• Dimetallic Allylations

• 1,1-Dimetalloids: Silylboration and Diboration

Carbenoid Reactivity – Carbonyl Olefination

Carbenoid Reactivity – Carbonyl Olefinaton

Takai’s Method Applied to Natural Product Synthesis

One-Pot Olefination and Ring-Closing Metathesis

Titanium-Mediated RCM

Iodocyclopropanation of Alkenes

• Diamine accelerates reaction; boosts yield and diastereoselectivity• Less reactivity with e- rich olefins - contrasting Simmons-Smith

Iodocyclopropanation of Alkenes

Possible Mechanism

Dizinc Carbenoid Cyclopropanation

Stereochemical Control

Further Study of Stereoselectivity

Four Possible Diastereomeric Products

Cyclopropanation of E-Alkenes

Allylic bulk influences selectivity

Comparison of Simmons-Smith to Dimetallic Carbenoid Cyclopropanation Methods

Simmons-Smith Monozinc Dichromium Dizinc

Dimetallic Carbenoid Cyclopropanation Methods:Opportunity for Further Functionalization

Outline

• Generation of 1,1-Organodimetallics • Reactions of Bis(iodozincio)methane

• Carbenoid Reactivity of 1,1-Dimetallics

• Allylmetals as 1,1-Dimetallic Precursors

• Dimetallic Allylations

• 1,1-Dimetalloids: Silylboration and Diboration

Allylmetals as Dimetallic Precursors

Stereocontrol in Reaction of Allylmetals with Metalated Homoallylic Ethers

Possible Explanation: Double Chelation-Controlled Carbometalation

Stereocontrol in Reaction of Allylmetals with Metalated Homoallylic Ethers

Possible Explanation: Double Chelation-Controlled Carbometalation

Allylzincation of Alkenylboronates

Chirality Induction

Hydrazone Carbometalation

Metalla-Aza-Claisen Versus Carbometalation

Four – Component Coupling with Zincated Hydrazone

Synthesis of Pyrroles from Zincated Hydrazone and Vinyl Stannane

Coupling of Hydrazone, Alkenylboronate, and Electrophile

•Chemoselective: carbometalates rather than attacking boron•Diastereoselective: 3 contiguous stereocenters

Zincated Hydrazones

Zincated hydrazone carbometalation allows rapid functionalization γ to carbonyl

Outline

• Generation of 1,1-Organodimetallics • Reactions of Bis(iodozincio)methane

• Carbenoid Reactivity of 1,1-Dimetallics

• Allylmetals as 1,1-Dimetallic Precursors

• Dimetallic Allylations

• 1,1-Dimetalloids: Silylboration and Diboration

Monometallic and Dimetallic Allylation

Allylation with a Dimetallic Zinc Reagent

E1: Acyl Chlorides, Aldehydes, Ketones, Phenyl Isocyanate, Methyl Chloroformate, Alkyl BromidesE2: Iodine, Aryl/Vinyl Iodide + Pd (0)

Nucleophilicity decreases after 1st addition• Vinylic position of 2nd metal• O/M chelation

Mechanism of Dizinc Allylation

Allylic Dimetallics – Indium

Coupling to C1 and C3

Dicoupling to C1

Diastereoselective Distannane Allylation

Chromophore Retrosynthesis

Diastereoselective Distannane Allylation

Outline

• Generation of 1,1-Organodimetallics • Reactions of Bis(iodozincio)methane

• Carbenoid Reactivity of 1,1-Dimetallics

• Allylmetals as 1,1-Dimetallic Precursors

• Dimetallic Allylations

• 1,1-Dimetalloids: Silylboration and Diboration

Rhodium Catalyzed Diboration

Selective gem-Silylboration

Silylboration onto an sp Carbon

Silylboration onto an sp Carbon

Preparation of Axially Enantioenriched gem-Silylborylallenes

Silylboration and Diboration onto an sp2 Carbon

Tamoxifen: One-Pot Synthesisvia Stereoselective Cross-Coupling

• Works for e- rich and poor aryl iodides• Complete diastereoselectivity in all cases

Silylboration onto an sp3 Carbon

Stereodivergent Allylation

Stereodivergent Allylation

Uncatalyzed Allylboration

Catalyzed Allylsilation

Synthetic Elaboration

B = B(OCMe2)2Si = SiMe2Ph

Synthons of 1,1-Organodimetallics

Dimetallic Synthon

1,1-Organodimetallics are valuable synthetic intermediates:

Conclusions

• Can be generated in a number of ways• Deprotonation• Carbometalation• Metal / halogen exchange

• Carbenoid Reactivity• Cyclopropanation• Carbonyl olefination

• Stereocontrol• Single or double chelation

• Perform multiple synthetic steps in one pot• Sequential electrophile addition to double nucleophile• Double cross coupling

Acknowledgements

Jeff JohnsonJohnson Group

Preparation of Bis(iodozincio)methane

Proposed Catalytic Cycle for Enolate Generation

Aerobic Oxidation of gem-Dimetallics