trade-off: all carbon electrophiles for nucleophiles in ni ...organic seminar by badru-deen barry...

Organic seminar

By

Badru-Deen Barry

02/08/17

TRADE-OFF: All Carbon Electrophiles for

Nucleophiles in Ni-Catalyzed Cross

Electrophile Coupling (XEC)

Classical Cross-Coupling Reactions

Conventional

Coupling

Nu + E

Oxidative

Coupling

Nu + Nu

Reductive

Coupling

E + E

Cross Coupling Reagents/Precursors

A. Conventional Cross Coupling Reactions

General Conventional Cross-Coupling Reaction

Mechanism:

Christmann , U.; Vilar, R. Angew. Chem. Int. Ed. 2005, 44, 366

Conventional Method

Advantages High yielding synthetic route for the cross-selective product.

Broad substrate scope.

High functional group tolerance

Mild reaction conditions

Limitations Non-commercial availability of many organometallics and their sensitivity to air and water

Instability of reagents and short shelf-life (e.g. organoboronic acid dimerization).

Sensitivity to air and water.

Toxicity of some metals(e.g. Sn)

Toxicity of organohalides/Formation of PCBs and dioxins.

Additives required to accelerate the transmetallation step (for organoboron and

organosilicon)

General Cross-Coupling Reactions

B. Oxidative Cross-Coupling-Two Nucleophiles

Challenges:

Suitable oxidizing agent to convert the Pd(0) species into a Pd(II) species capable of doing

the double transmetallation

System that will favor the formation of a heterosubstituted intermediate R1-Pd(II)- R2

Pd-Catalyzed Oxidative Nu-Nu Cross-Coupling

Liu, C.; Zhang, H.; Shi, W.; Lei, A. Chem. Rev. 2011, 111, 1780

Palladium-Catalyzed Cross-Coupling of Alkylzinc and

Alkynylstannanes

Zhao, Y.; Wang, H.; Hou, X.; Hu, Y.; Lei, A.; Zhang, H.; Zhu, L. J. Am. Chem. Soc. 2006, 128, 15048

Optimization

Csp-M to Csp-M, Csp-M to Csp2 –M, Csp-M to Csp3 –M, Csp2 -M to Csp2 –M, Csp2 -M to Csp3 –M, Csp3 -M to Csp3 –M

as nucleophiles have been reported.

Palladium-Catalyzed Cross-Coupling of Alkylzinc

and Alkynylstannanes


Scope

Double Transmetallation




Mechanism:



Advantages

Oxidative addition step common to conventional cross-coupling skipped.

High selectivity with good yields for the Csp-Csp3 cross-coupled products

Substrates with β-hydrogens tolerated

Limitations

Use of unstable organometallic reagents as precursors

Toxicity of metal byproduct in the transmetallation step

Need for an oxidant

C. Cross Electrophile Coupling (XEC)

Cross Electrophile Coupling (XEC) – A Field in its

Infancy

Wurtz, A. Ann. Chim. Phys. 1855, 44, 275

Drawbacks:

limited to the efficient synthesis of symmetric alkanes

production of alkenes from side reactions

Suzuki Arylation of an Unactivated Tertiary Alkyl

Bromide

Zultanski, S. L.; Fu, G. C. J. Am. Chem. Soc. 2013, 135, 624

limitations with respect to the nucleophile (ortho- and para-substituted aryl-(9- BBN)

reagents generally do not couple in useful yields

Mechanism for the Ni-catalyzed Suzuki Cross-Coupling

Zultanski, S. L.; Fu, G. C. J. Am. Chem. Soc. 2013, 135, 624

Need for More Innovative Reaction Development

1. Use of reagents that exclude use of R – [M]

2. A catalyst system that undergoes facile oxidative addition

Easy accessibility to variable oxidation states: -1, 0, +1, +2, +3, +4

Facile oxidative addition

Radical pathway more readily accessed

Some key features of Ni as a potential candidate

Strategies for Achieving Good Yields of Cross-

Coupling Products in XEC

III. Employ an Excess of One Reagent

I. Electronic Differentiation of Starting Materials - Sequential Oxidative Addition

II. Catalyst-Substrate Steric Matching

Gosmini, C.; Lasry, S.; Nédélec, J.-Y.; Périchon, J. Tetrahedron 1998, 54, 1289.

bipyridine was the only ligand investigated

limited substrate scope.

I. Electronic Differentiation of Starting Materials

The Ni-catalyzed electrochemical and chemical coupling of aryl with pyridyl/pyrazinyl

I. Electronic Differentiation of Starting Materials:

Sequential Oxidative Addition

Qian, Q.; Zang, Z.; Wang, S.; Chen, Y.; Lin, K.; Gong, H. Synlett 2013, 24, 619

Reductive Cross-Coupling of Aryl Halides for Csp2-Csp

2 Bond Formation

Electronic Differentiation of Starting Materials

[Csp2-Csp

2] Bond Formation


without Bu4NI 53%

2b instead of 2a, without Bu4NI 48%

3b instead of 2a, without Bu4NI 36%

DMF instead of DMA, without Bu4NI 39%

NiBr2 and 2b instead of NiI2 and 2a, without Bu4NI 35%

2b instead of 2a, 100 mol% MgCl2, without pyridine, without Bu4NI n.d

i-Pr-Pybox 3b instead of 2a, without Bu4NI trace

Model Reaction:

Electronic Differentiation of Starting Materials


Synthesis of Unsymmetrical Biaryl Compounds [Csp2-Csp

2]


Heteroaromatic Halides as Substrates


2]

Elimination of an in-situ Negishi Process

1. King, A. O.; Okukado, N.; Negishi, E. J. Chem. Soc., Chem. Commun. 1977, 683.

2. Qian, Q.; Zang, Z.; Wang, S.; Chen, Y.; Lin, K.; Gong, H. Synlett 2013, 24, 619


2]

How about a Kumada!!!

Proposed Ni(I) /Ni(III) and Ni(0)/Ni(II) Catalytic Cycle



2]

Synthesis of Unsymmetrical Biaryl Compounds

[Csp2-Csp

2]

Formation of unsymmetrical biarlys from electronenriched aryl halides and aryl halides

No organometallic reagents involved.

Differences in electron properties between the coupling partners impacted the high coupling

efficiency

Summary

Limitations

Limited to OMe as the phenyl electron enriching group


Selectivity in XEC

III. Equal Substrate Reactivity: Employ an Excess of One Reagent

I. Electronic Differentiation of Starting Materials - Sequential Oxidative Addition

II. Catalyst-Substrate Steric Matching

II. Catalyst/substrate Matching – [Csp2 – Csp

3] Bond Formation

Shrestha, R.; Dorn, S. C. M.; Weix, D. J. J. Am. Chem. Soc. 2013, 135, 751

Three approaches to conjugate addition

Catalyst/substrate Steric Matching [Csp2 – Csp

3]


Ni-Catalyzed Reductive Conjugate Addition to Enones

Optimization

Ni-Catalyzed Reductive Conjugate Addition to

Enones [Csp2 – Csp

3]


Aryl Halide Electronic Effects

Ni-Catalyzed Reductive Conjugate Addition to Enones


Ligand/Catalyst Sterics

Catalyst-Substrate Steric Matching: Ni-Catalyzed

Reductive Conjugate Addition to Enones [Csp2 – Csp

3]


Mechanism

Catalyst-Substrate Steric Matching: Ni-Catalyzed Reductive

Conjugate Addition to Enones [Csp2 – Csp

3]

Three electrophilic reagents

Substrate and ligand sterics complement each other

Summary


Catalyst-Substrate Matching -Csp3-Csp3 Bond

Formation

Nickel-catalyzed Cross-Coupling of Unactivated Alkyl Halides using

Bis(pinacolato)diboron as Reductant -

Xu, H.; Zhao, C.; Qian, Q.; Deng, W.; Gong, H. Chem. Sci., 2013, 4, 4022

Nickel-catalyzed Cross-Coupling of Unactivated Alkyl Halides

using Bis(pinacolato)diboron as Reductant


Coupling of Unactivated Alkyl Halides using Bis(pinacolato)diboron as Reductant

Coupling of secondary with primary alkyl bromides


Proposed Catalytic Intermediates for Conjugate

Addition

Nickel-catalyzed Cross-Coupling of Unactivated Alkyl Halides using Bis(pinaco-

lato)diboron as Reductant - Csp3-Csp3 Bond Formation


Radical Process


alkyl radical intermediate generated during the course of coupling

Nickel-catalyzed Cross-Coupling of Unactivated Alkyl Halides using bis(pinac-

olato)diboron as Reductant - Csp3-Csp3 Bond Formation

Coupling of Unactivated Alkyl Halides using bis(pinacolato)diboron as Reductant - Csp3-Csp3 Bond Formation


Mechanism

Coupling of Unactivated Alkyl Halides using bis(pinac-

olato)diboron as Reductant - Csp3-Csp3 Bond Formation

Safer and easier synthetic route with bench-stable and readily available substrates

Need for organometallics is eliminated

Conclusions


Selectivity

3. Employ an Excess of One Reagent

1. Electronic Differentiation of Starting Materials - Sequential Oxidative Addition

2. Catalyst-Substrate Steric Matching

III. Excess of one Reagent - (Csp3-Csp

3) Bond

Formation

Yu, X.; Yang, T.; Wang, S.; Xu, H.; Gong, H. Org. Lett., 2011, 13, 8

Nickel-Catalyzed Reductive Cross-Coupling of Unactivated Alkyl Halides

Challenges– Cross-Coupling vs Homocoupling



Substrate Scope and Selectivity Determining Factor



Coupling of cyclic 2o alkyl bromides with 1o alkyl halides



Nickel-Catalyzed Reductive Cross-Coupling of

Unactivated Alkyl Halides

Selectivity induced by using an excess of one organohalide coupling partner.

Summary


Summary

Csp2 – Csp

2 bond formation via electronic differentiation

Csp2 – Csp

3 bond formation by matching catalyst/ligand and substrates

Csp3 – Csp

3 bond formation by using an excess of one reagent

Utility of readily available, easy-to-handle and stable starting materials

Acknowledgement

Dr. Robert E Maleczka

Dr. Xuefei Huang

Faculty of the Chemistry Department

The Maleczka Group: Susanne Miller,Chathurika Jayasundara, Jonathan Dannatt, Fangyi

Shen, Damith Perera, Jose Montero

Zheng Li, Shuang, Aliakbar, Saeedeh

Thank You

trade-off: all carbon electrophiles for nucleophiles in ni ...organic seminar by badru-deen barry...

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