Carbon-Carbon Bond Activation

Literature seminar#3
M2 Hiromu Fuse
2018/10/06(Sat)Introduction• Carbon-carbon bond and carbon-hydrogen bond activation

Dong, G. et al. Nature, 2016, 539, 546.

• Carbon-carbon bond activation Suzuki-Miyaura crosscoupling

Dong, G. et al. J. Am. Chem. Soc. 2018, 140, 5347.

Unstrained carbon-carbon bond can betransformed to carbon-carbon bond.

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Introduction
Dr. Guangbin Dong received his B.S. degree from Peking
University and completed his Ph.D. degree in Chemistryfrom Stanford University with Professor Barry M. Trost.
In 2009, He joined the group of Prof. Robert H. Grubbs at
California Institute of Technology, as a postdoctoral
researcher. His expertise is in the field of organic
synthesis, catalysis, organometallics and medicinalchemistry. His future research interests lie at thedevelopment of powerful chemical tools for addressing
questions of biological importance. His research program
will bring together the complimentary knowledge oforganic synthesis, medicinal chemistry andorganometallic chemistry in collaboration with scientists
in the field of cellular biology and animal pharmacology
to identify effective small-molecule agents that target
new molecular mechanisms for cancer treatment.
https://donggroup-sites.uchicago.edu/page/about-guangbin
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Introduction
Ph. D. studies

Trost, B. M.; Dong, G. Nature, 2008, 456, 485.
https://donggroup-sites.uchicago.edu/page/about-guangbin
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Introduction
postdoctoral studies

Dong, G.; Teo, P.; Wickens, Z. K.; Grubbs, R. H. Science, 2011, 333, 1609.

https://donggroup-sites.uchicago.edu/page/about-guangbin
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Today’s Content

1. Overview of C-C activation
2. C-H activation
3. SMC (Suzuki-Miyaura coupling)6

Today’s Content

1. Overview of C-C activation
2. C-H activation
3. SMC (Suzuki-Miyaura coupling)7

Utility of C-C cleavage• Late stage functionalization– C-C bond is usually inert.

early stage

late stage

C-X, C-O,
C=C

C-C

reactive bonds

unreactive bonds• Total synthesis– Quick construction of complex skeltones

Dong, G. et al. J. Am. Chem. Soc. 2018, 140, 9652.

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Methodologies of C-C bond activation

Murami, M.; Ito, Y. et al. J. Am. Chem. Soc. 1997, Nomura, M. J. Am. Chem. Soc. 2001, 123, 10407.
119, 9307.
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Methodologies of C-C bond activation

We mainly focus on it today.
(Prof. Dong’s strategy)

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Difficulty of C-C bond cleavage• Thermodynamic factor– Unstability of products– Weak carbon-metal bond11

Murakami, M.; Ishida, N. J. Am. Chem. Soc. 2016, 138, 13759.

Difficulty of C-C bond cleavage• Kinetic factor– Interaction between metal orbitals and C-C bondDistortion of C-C bond is needed.
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Murakami, M.; Ishida, N. J. Am. Chem. Soc. 2016, 138, 13759.

Driving force of C-C bond activation• Aromatization (Only stoichiometric reaction)

Crabtree, R. H. J. Am. Chem. Soc. 1986, 108, 7222.

• Strained molecules

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Murami, M.; Ito, Y. et al. J. Am. Chem. Soc. 1997, 119, 9307.

Driving force of C-C bond activation• Directing group

Suggs, J. W.; Jun, C. -H. et al. J. Am. Chem. Soc. 1984, 106, 3054.
Suggs, J. W.; Jun, C. -H. et al. J. Chem. Soc., Chem. Commun. 1985, 92.

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Driving force of C-C bond activation• Temporary directing group(15 eq.)2-amino-3-picoline15Jun, C. -H. et al. J. Am. Chem. Soc. 1999, 121, 880.

Short summary• Carbon –carbon activation is a promising reaction fororganic synthesis.
– Late-stage functionalization– Total synthesis• But, it has difficulty about both thermodynamics andkinetics factor.
– Unstability of products– Weak C-M bond– Interaction between metal orbitals and C-C bond.

• Therefore, some strategies for driving force weredeveloped.
– Aromatization– Strained molecules– Directing group– Temporary directing group16

Today’s Content1. Overview of C-C activation2. C-H activation
3. SMC (Suzuki-Miyaura coupling)17

C-H activation type reaction• Carbon-carbon bond and carbon-hydrogen bond activation

Dong, G. et al. Nature 2016, 539, 546.

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C-C bond cleavage of unstrained molecule

Murakami, M.; Amii, H.; Ito, Y. Nature 1994, 370, 540.

• Low efficiency (8 days)• C-C bond activation of unstrained molecule isusually difficult.

19Temporary directing groupJun, C.-H.; Lee, H.; Lim, S.-G. J. Am. Chem. Soc. 2001, 123, 751.

• For stable 5 or 6-membered ring, low reactivity wasobserved.

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Problematic point• Reversibility of oxidative addition step

stableunstable• Due to stability of cyclopentanones, thermodynamic
driving force is lacked.

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Reaction design• Overall thermodynamically favored transformation(ΔG ≃ -6 kcal/mol)Dong, G. et al. Nature 2016, 539, 546.

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Substrate scope

C1-C2

C1-C5Dong, G. et al. Nature 2016, 539, 546.

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Substrate scope

Dong, G. et al. Nature 2016, 539, 546.

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Scope of 6-membered ring

C1-C6

C1-C2Dong, G. et al. Nature 2016, 539, 546.

25Asymmetric synthesis of terpenoids

Dong, G. et al. Nature 2016, 539, 546.

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Selectivity of C-C activation

X=N(2-pyridine)

Why cleavage is occurred at hindered position?

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Calculation study

Dong, G. et al. Nature 2016, 539, 546.

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Calculation study

relatively low barrier = reversible

Dong, G. et al. Nature 2016, 539, 546.

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Calculation study

determine selectivity.

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Calculation study

Steric repulsion between ligand and C5 methylenegroup, due to six-membered rhodacycle.

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Where is TLS (turnover limiting step) ?
• According to calculation study, C-H metalation
requires large energy.
• Is C-H metalation step TLS?

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KIE experiment• According to calculation study, If C-H metalation is a soleturnover limiting step, KIE≃4.3.
• This result indicated slow and reversible C-H metalation step
(C5 scrambling).
• Both C-H metalation and reductive elimination are TLS?
Dong, G. et al. Nature 2016, 539, 546.

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Reversible C-H metalation step

Dong, G. et al. Nature 2016, 539, 546.

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Deuterium labeling experiments• C5 scrambling is consist with reversible C-H step.
• Unreacted reactants showed deuterium lost at phenyl group.
Dong, G. et al. Nature 2016, 539, 546.

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C-H activation type reaction• Carbon-carbon bond and carbon-hydrogen bond activation

reductive elimination& protonation• Due to reaction design, driving force is obtained.
Dong, G. et al. Nature 2016, 539, 546.

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Today’s Content

1. Overview of C-C activation
2. C-H activation
3. SMC (Suzuki-Miyaura coupling)37

Suzuki-Miyaura coupling type reaction• Carbon-carbon bond activation Suzuki-Miyaura crosscoupling

Dong, G. et al. J. Am. Chem. Soc. 2018, 140, 5347.
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SMC (Suzuki-Miyaura coupling)39

C-O or C-N bond activation• C-O bond activation

Houk, K. N.; Newman, S. G. et al. J. Am. Chem. Soc. 2017, 139, 1311.

• C-N bond activation

Sasaki, S.; Nakao, Y. et al. J. Am. Chem. Soc. 2017, 139, 9423.
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C-C bond activation• Strained molecules

Murakami, M. et al. Org. Lett. 2004, 6, 1257.

• Quinoline typeWang, J. et al. Angew. Chem., Int. Ed. 2012, 51, 12334.
C-C bond activation SMC is developed not so much.

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Catalytic cycle

Dong, G. et al. J. Am. Chem. Soc. 2018, 140, 5347.42

Optimization study

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Dong, G. et al. J. Am. Chem. Soc. 2018, 140, 5347.

Scope of Arylborates
Strain cyclobutane
ring is remained.
(Entry 6)
Various functionalgroups which areuseful in crosscoupling aretolerated(Entry 9, 13, 18, 20)

Ortho-substituted
substrates aredifficult.

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Dong, G. et al. J. Am. Chem. Soc. 2018, 140, 5347.

Scope of substituted cyclopentanones
The site-selectivity slightly favoredthe more sterically hindered side.

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Dong, G. et al. J. Am. Chem. Soc. 2018, 140, 5347.

Scope of 1-indanones
First example of C−C
activation of 1-indanone isachieved.

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Dong, G. et al. J. Am. Chem. Soc. 2018, 140, 5347.

Scope of acyclic ketones

Even acyclic bond can be activated.

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Dong, G. et al. J. Am. Chem. Soc. 2018, 140, 5347.

Synthetic utility• Deriatization of natural product• Scalability and chromane synthesis

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Mechanistic insightcf. Murakami, M. et al. Org. Lett. 2004, 6, 1257.

• β-carbon elimination pathway is denied.
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Dong, G. et al. J. Am. Chem. Soc. 2018, 140, 5347.

Suzuki-Miyaura coupling type reaction• Even 5 or 6-membered ring and acyclic bond can be activated.
Dong, G. et al. J. Am. Chem. Soc. 2018, 140, 5347.50

Summary• Achievement– Unstrained (5, 6-membered ring or acyclic) C-Cbond can be cleaved.
– C-H activation and SMC• Future perspective– Harsh conditions (Application to complex
molecules is difficult.)– Mainly for ketone substrates

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