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