C-H Directed AlkynylationKIERAN JONES

BOSS: DR SCOT T STEWART

What Is C-H Activation

DG: Directing Groups, diverse and inventiveM: Broad range of metal catalyst including; Pd, Cu, Au, Rh, Ru, Ni, Co

• Functionalization of sp2/sp3 H bonds through direct catalytic cleavage

What Is C-H Activation

DG: Directing Groups, diverse and inventiveM: Broad range of metal catalyst including; Pd, Cu, Au, Rh, Ru, Ni, Co

• Functionalization of sp2/sp3 H bonds through direct catalytic cleavage

What Is C-H ActivationAdvantages:• Eliminates the need of functional intermediates• Reduced synthetic steps• Increased library of simple starting materials• New Perspective on retrosynthesis

One of the first reported C-H activation reactions from the 1950’s. S. Murhashi, J. Am. Chem. Soc. 1956, 78, 4816.

What Is C-H ActivationDisadvantages:• Complexity of starting directing group: bulky, removable, steps to install• Reactions conditions diverse/convoluted/EXPENSIVE!!• Yields sometimes not comparable to alternative• Its really hard…..

One of the first reported C-H activation reactions from the 1950’s. S. Murhashi, J. Am. Chem. Soc. 1956, 78, 4816.

Example of Directing Groups

Examples of Monodentate Directing groups:

Example of Directing Groups

Uniquie/highly successful Directing groups

Bidentate DG:

Traceless DG:

C-H Directed Alkynylation

R = TIPS, Ph

R = Aromatics, Alkyl, heteroatoms, alkenes

Extremely Popular in Lit.Limited R group: Silicon groups and t-butyl only

$$$$$$$

Triisopropylsilyl (TIPS), Trimethyl silyl (TMS), Phenyl (Ph), t-butyl di-methyl silyl (TBDMS), Ethynylbenziodoxolones (EBX)

Chatani Bidentate DG Alkynylation

X = OH (0%) OMe (0%) NH2 (2%) NHPh (4%)

Y. Ano, M. Tobisu, N. Chatani. 2012. Org. Lett. 14. 354-357

Chatani Bidentate DG Alkynylation

Y. Ano, M. Tobisu, N. Chatani. 2012. Org. Lett. 14. 354-357

Marketing Chatani’s DG

Y. Ano, M. Tobisu, N. Chatani. 2012. Org. Lett. 14. 354-357

Selectiveaddition over

Halogenated site

Selective removal of DG

Methyl Ester allows Further manipulations

Selective removal of TIPS

Allows further Functionalisation

Of alkyne

C-H Directed Alkynylation

R = TIPS, Ph

R = Aromatics, Alkyl, heteroatoms, alkenes

Extremely Popular in Lit.Limited R group: Silicon groups and t-butyl only

$$$$$$$

Triisopropylsilyl (TIPS), Trimethyl silyl (TMS), Phenyl (Ph), t-butyl di-methyl silyl (TBDMS), Ethynylbenziodoxolones (EBX)

In Situ Copper Acetylide C-H Alkynylation

• High temperatures (100 °C) cause cyclisation of products

• Homocoupling occurs, 3 eq of alkyne used to allow primary reaction to occur

• Absence of copper resulted in no reaction

• Air over O2 as molecular oxygen results in alkyne homocoupling and ortho hydroxylation.

• Reaction works well on a gram scale

M. Shang, H. Wang, S. Sun, H. Dai, J. Yu. 2014. J. Am. Chem. Soc. 136. 11590-11593

In Situ Copper Acetylide C-H Alkynylation

M. Shang, H. Wang, S. Sun, H. Dai, J. Yu. 2014. J. Am. Chem. Soc. 136. 11590-11593

In Situ Copper Acetylide C-H Alkynylation

M. Shang, H. Wang, S. Sun, H. Dai, J. Yu. 2014. J. Am. Chem. Soc. 136. 11590-11593

Removal of DG

M. Shang, H. Wang, S. Sun, H. Dai, J. Yu. 2014. J. Am. Chem. Soc. 136. 11590-11593

Usefulness of o-Alkynylbenzoic Acids

M. Shang, H. Wang, S. Sun, H. Dai, J. Yu. 2014. J. Am. Chem. Soc. 136. 11590-11593

C-H Directed Alkynylation

R = TIPS, Ph

R = Aromatics, Alkyl, heteroatoms, alkenes

Extremely Popular in Lit.Limited R group: Silicon groups and t-butyl only

$$$$$$$

Triisopropylsilyl (TIPS), Trimethyl silyl (TMS), Phenyl (Ph), t-butyl di-methyl silyl (TBDMS), Ethynylbenziodoxolones (EBX)

Site Selective Alkynylation: Quinolones

D. Kang, S. Hong. 2015. Org. Lett. 17. 1938-1941

C5 Selective Alkynylation

• 17 examples yields range 46 to 84%• N-substituents of quinolone

were flexible (R1):Benzyl, methyl, ethyl, cyclopropyl, MOM

MOM: Methoxymethyl acetal

D. Kang, S. Hong. 2015. Org. Lett. 17. 1938-1941

C2 Selective Alkynylation

• 12 examples yields range 47 to 93%• Both Rhodium and Ruthenium cat.

worked with comparable yieldshowever Rh crazy expensive

• No C5 alkynylation was observed

D. Kang, S. Hong. 2015. Org. Lett. 17. 1938-1941

Rh Bis-Alkynylation

D. Kang, S. Hong. 2015. Org. Lett. 17. 1938-1941

Summary