C-H Functionalization: Recent Applications
Jean-Francois Vincent-Rocan
Department of Chemistry
University of Ottawa
Organic and Biological Chemistry Graduate seminar
April 12, 2012
1
Books and Reviews
2
C-H Functionalization in SciFinder
500
450
400
Publication per year
350
300
250
200
150
100
50
0
1981
1987
1992
1997
2002
2007
-Constant growth in the past 30 years
-Explosion in the last 5 years
-Focus on recent applications (not a comprehensive review)
3
Activation vs Functionalization
• C-H bond activation: Cleavage of C-H bond that leads to the
formation of a metal-C bond either through oxidative addition
to a low valent metal center or electrophilic substitution
• C-H bond functionalization: Cleavage of C-H bond that is
followed by new bond formation at the carbon center
Shilov, A. E.; Shul'pin, G. B. Chem. Rev. 1997, 57, 2879-2932
Kaikuchi, F.; Chatani, N. Adv. Synth. Catal. 2003, 345, 1077-1101
4
Outline
• Part 1: Factors of selectivity
– Inductive effects
– Hyperconjugation
– Steric factors
– Strain release
– Directed oxidations
•
Part 2: Recent applications
– Mimicking nature
– Increasing molecular complexity
– Cross-Coupling
– Divergent functionalization in drug discovery
5
Part 1
Factors of selectivity
6
C-H Oxidation Mechanism using Dioxiranes
7
Curci Acc. Chem. Res. 2006, 39, 1
Bond Strengths
-Stronger bonds are formed
-Most electron rich C-H is the easiest to break
8
Inductive Effects
-The most electron rich position is oxidized for non-metal insertions
-Typical reactivity trend is tertiary> secondary> primary
-Secondary positions are less sterically hindered
Selectivity can be tuned by reagent selection (polyoxometalates)
Asensio, G.; Castellano, G.; Mello, R.; Gonzalez-Nunez, M. E. J. Org. Chem. 1996, 61, 5564−5566
Kamata, K.; Yonehara , K.; Nakagawa, Y.; Uehara, K.; Mizuno, N. Nat. Chem. 2010, 2, 478 – 483
Hyperconjugation Effects
-Cyclopropane act as activating group (oxidation on the vicinal carbon)
-Orbital overlap is required
Daccolti, L.; Dinoi, A.; Fusco, C.; Russo, A.; Curci, R. J. Org. Chem. 2003, 68,7806 – 7810
Banwell, M. G.; Haddad, N.; Huglin, J. A.; MacKay, M. F.; Reum, M. E.; Ryan, J. H.; Turner, K. A. J. Chem. Soc. Chem. Commun.1993, 954 – 957
Brinker, U.H.; Lin, G.; Xu, L.; Smith, W. B.; Mieusset, J.-L. J. Org. Chem. 2007, 72, 8434 – 8451.
10
Hyperconjugation Enabled by Heteroatoms
-Non-bonding electrons of a heteroatom available for hyperconjugation
- Non-bonding electron MUST be available (Delocalization in the aromatic
ring in this case)
Davies, H. M. L.; Beckwith, R. E. J.; Antoulinakis, E. G.; Jin, Q. J. Org. Chem. 2003, 68, 6126 – 6132.
Barton, D. H. R.; Boivin, J.; Gaudin, D.; Jankowski, K. Tetrahedron Lett. 1989, 30, 1381 – 1382.
Liang, C.; Fabien, C.; Fruit, C.; Mller, P.; Dodd, R. H.; Dauban, P. Angew. Chem Int. Ed. 2006, 45, 4641 – 4644.
11
Steric Factors
-Rate reduction for hindered C-H bonds
-Hyperconjugation + steric factors
R=
TMS
TES
TBS
TIPS
TBDPS
Rel. Rate
102
39
14
1,7
1
Tenaglia, A.; Terranova, E.; Waegell, B. Tetrahedron Lett. 1989, 30, 5271 – 5274
Davies, H. M. L.; Venkataramani, C. Angew. Chem. Int. Ed. 2002, 41, 2197 – 2199
Gomez, L.; Garcia-Bosch, I.; Company, A.; Benet-Buchholz, J.; Polo, A.; Sala, X.; Ribas, X.; Costas, M. Angew. Chem. Int. Ed. 2009, 48,
5720 – 5723.
Davies, H. M. L.; Beckwith, R. E. J.; E. Antoulinakis, G.; Jin, Q. J. Org. Chem. 2003, 68, 6126 – 6132.
12
Strain Release
- Elimination of 1,3 syn diaxial interaction in the transition state promotes a faster
oxidation and an increased site-selectivity (in the example below)
- Schreiber and Eschenmoser proposed this idea for the oxidation of axial alcohols
(1955)
.
Chen, K.; Eschenmoser, A.; Baran, P.S. Angew. Chem. Int. Ed. 2009, 48, 9705 – 9708
Schreiber, J.; Eschenmoser, A. Helv. Chim. Acta 1955, 38, 1529 –1536
13
Energy diagram
14
Directed Oxidations
-Excellent in the presence of opposing steric and electronic influences
-Directing group is overriding the substrate’s preferences
Breslow, R.; Corcoran, R. J.; Snider, B. B.; Doll, R. J.; Khanna, P. L.; Kaleya, R. J. Am. Chem. Soc. 1977, 99, 905 – 915
Kasuya, S.; Kamijo, S. ; Inoue, M. Org. Lett. 2009, 11, 3630 – 3632.
15
How is it Selective ?
16
Directing Groups Override Substrate Preferences
-Directing groups can be employed to reverse the inherent selectivity
-Intramolecular delivery is more important than the steric effects of the substrate
Chen, K.; Richter, J. M.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 7247 – 7249
Hofmann, A. W. Ber. Dtsch Chem. Ges. 1879, 12 (1): 984–990
Löffler, K.; Freytag, C. Ber. Dtsch Chem. Ges. 1909, 42 (3): 3427–3431
17
Radical[1,6]-Hydrogen Shift
HLF reaction
18
Metal Promoted Directed Oxidation
Espino, C. G.; When, P. M.; Chow, J.; Du Bois, J. J. Am. Chem. Soc. 2001, 123, 6935 – 6936
Yu, J.-Q.; Giri, R.; Chen, X. Org. Biomol. Chem. 2006, 4, 4041 – 4047
19
Directed Pd C-H activation
• Insertion via CIPE, to form the new C-Pd bond
20
Chen, X.; Engle, K. M.; Yu, J.-Q. Angew. Chem. Int. Ed., 2009, 48, 5094-5115
Hydrogen Bonding
-Competitive ketone formation on the second substrate
-H-bonding with TFDO is impossible for the second example
21
Asensio, G.; Gonzlez-Nfflez, M. L.; Bernardini, C. B.; Mello, R.; Adam, W. J. Am. Chem. Soc. 1993, 115, 7250 – 7253
First Part: Conclusion
• Inductive effects, hyperconjugation, steric
factors and strain release will modulate C-H
selectivity
• Directed oxidation can be use for selective
oxidation of complicated system or to invert
the selectivity
22
Part 2:
Recent Applications
23
Late Stage Hydroxylation
• C-H activation can be used to avoid PGchemistry using late-stage hydroxylation
Wender, P. A.; Hilinski, M. K.; Mayweg, A. V. W. Org. Lett. 2005, 7, 79– 82
Seto, H.; Fujioka, S.; Koshino, H.; Yoshida, S. ; Tsubuki, M.; Honda, T. Tetrahedron 1999, 55, 8341 – 8352
Curci, R.; Detomaso, A.; Prencipe, T.; Carpenter, G. B. J. Am. Chem. Soc. 1994, 116, 8112−8115
24
Mimicking Nature
• Nature usually oxidizes the targeted
compound at the end of its biosynthesis
• An abundant number of natural products are
synthesised in 2 phases : Cyclase phase and
Oxidation phase
25
Chen, K.; Baran, P. S. Nature 2009, 459, 824–828
Baran’s Retrosynthetic Analysis for the
Eudesmane Terpenes Family
26
Chen, K.; Baran, P. S. Nature 2009, 459, 824–828
Eudesmanes Synthesis: Cyclase Phase
27
Chen, K.; Baran, P. S. Nature 2009, 459, 824–828
Eudesmanes synthesis: Oxidation phase
28
Chen, K.; Baran, P. S. Nature 2009, 459, 824–828
Eudesmanes synthesis: Oxidation phase
29
Chen, K.; Baran, P. S. Nature 2009, 459, 824–828
C-H functionalization
• Aliphatic C-H (inherent preference, Directed
oxidation)
30
The White Group
•
•
•
Major player in the allylic C-H functionalization field
Known for her Palladium(II) \ sulfoxide catalyst system for allylic oxidation
π-allyl complex followed by functionaliztion
Chen, M.S.; White, M.C. J. Am. Chem. Soc 2004, 126, 1346-1347
Fraunhoffer, K.J.; White, M.C. J. Am. Chem. Soc 2007, 129, 7274-7276
Reed, S. A.; Mazzotti, A. R.; White, M. C. J. Am. Chem.Soc. 2009, 131, 11701-11706
Young, A. J.; White, M. C. Angew. Chem., Int. Ed. 2011, 50, 6824-6827
31
Increasing Molecular Complexity
-Stang and White developed that method to take fairly simple S.M and
converted it to reactive intermediate
32
Stang, E. M.; White, M. C. J. Am. Chem. Soc. 2011, 133, 14892-14895
Optimization
Entry
1
Catalyst
Solvent
Pd(OAc)2 dioxane
Additive
Dienophile Yield diene %
Yield cycloadduct %
-
-
1
-
2
1
dioxane
-
-
6
-
3
2
dioxane
-
-
28
-
4
2
dioxane
-
NPM
1
33
5
2
DCE
-
NPM
1
52
6
2
DCE
p-NO2BzOH
NPM
1
74
7
2
DCE
p-NO2BzOH
-
35
33
Stang, E. M.; White, M. C. J. Am. Chem. Soc. 2011, 133, 14892-14895
Reaction Scope
34
Stang, E. M.; White, M. C. J. Am. Chem. Soc. 2011, 133, 14892-14895
Application in synthesis
35
Stang, E. M.; White, M. C. J. Am. Chem. Soc. 2011, 133, 14892-14895
C-H functionalization
• Aliphatic C-H (inherent preference, Directed
oxidation)
• Allylic C-H (Directed, allyl activation)
36
Cross-Coupling reactions
• Reaction using organohalides and pseudohalides and other
functional groups
• The reactive intermediate is the corresponding aryl and alkyl
palladium(II) species.
• The quickest and easiest sequences to prepare such
intermediates would certainly improve these reactions
• Unlimited opportunities for the use of unactivated carbon–
hydrogen (C-H) bond
37
Chen, X.; Engle, K. M.; Yu, J.-Q. Angew. Chem. Int. Ed., 2009, 48, 5094-5115
Cross-Coupling Featuring C-H
Functionalization
Lafrance, M.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 16496-16497
Giry, R.; Maugel, N.; Li, J. J.; Wang, D. H.; Breazzano, S. P.; Saunders, L. B.; Yu, J. Q. J. Am. Chem. Soc. 2007, 129, 3510– 3511
Satoh, T.; Kawamura, Y.; Miura, M.; Nomura , M. Angew. Chem. Int. Ed. Engl. 1997, 36, 1740
Kamer, P. C. J.; de Vries, J. G.;Van Leeuwen , P.W. N. M .J. Am. Chem. Soc. 2002, 124, 1586
38
Concerted Metalation Deprotonation
39
Lafrance, M.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 16496-16497
Oxidative Heck Cross-Coupling
Beck, E. M.; Grimster, N. P.; Hatley, R. ; Gaunt, M. J. J. Am. Chem. Soc. 2006, 128, 2528
40
Application in Total Synthesis
41
Beck, E. M.; Hatley, R.; Gaunt, M. J. Angew. Chem., Int. Ed. 2008, 47, 3004-3007
Late-Stage Functionalization
- 9 membered ring
- Late stage functionalization
- Functional group ‘’tolerance’’
42
Bowie, A. L.; Hughes, C. C.; Trauner, D. Org. Lett. 2005, 7, 5207-5209
Cross-coupling featuring C-H
functionalization
Lafrance, M.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 16496-16497
Giry, R.; Maugel, N.; Li, J. J.; Wang, D. H.; Breazzano, S. P.; Saunders, L. B.; Yu, J. Q. J. Am. Chem. Soc. 2007, 129, 3510– 3511
Satoh, T.; Kawamura, Y.; Miura, M.; Nomura , M. Angew. Chem. Int. Ed. Engl. 1997, 36, 1740
Kamer, P. C. J.; de Vries, J. G.;Van Leeuwen , P.W. N. M .J. Am. Chem. Soc. 2002, 124, 1586
43
Directing group
44
For a good review :Chen, X.; Engle, K. M.; Yu, J.-Q. Angew. Chem. Int. Ed., 2009, 48, 5094-5115
Drug Discovery
• Sulfonamide is an organic moiety present in
many drugs
• Has been found to direct C-H functionalization
45
Dai, H.-X.; Stepan, A. F.; Plummer, M. S.; Zhang, Y.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 7222-7228
Divergent Functionalization
46
Dai, H.-X.; Stepan, A. F.; Plummer, M. S.; Zhang, Y.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 7222-7228
Drug Analogues
47
Dai, H.-X.; Stepan, A. F.; Plummer, M. S.; Zhang, Y.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 7222-7228
C-H functionalization
• Aromatic C-H (inherent preference, protecting
group orientation, directing group)
48
Conclusion
– 4 factors have been identified to modulate C-H
functionalization selectivity (inductive effects,
hyperconjugation, steric factors, strain release)
– Directed oxidations can overcome the substrate’s
preferences
– C-H functionalization can be used easily in total
synthesis of complex and drug-like molecules
49
What Is Next ?
50
Mendoza, A.; Ishihara, Y.; Baran, P.S. Nature Chem. 2012, 4, 21-25.
Acknowledgements
Dr. André Beauchemin
Francis Loiseau
Melissa Macdonald
Christian Clavette
Amanda Bongers
Nicolas Guimond
Tom Markiewicz
Keira Garland
Bashir Hussain
Colin Hesp
Valérie Lemieux
Pierre Mouawad
Patrick Moon
Nicolas Das Neves
Wei Gan
Shu-Bin Zhao
51
Question
52