1. Charette Group Literature Meeting
“Conversion of amides to esters by the nickel-catalyzed activation of amide C-N bonds” Hie L. & Al., Nature, 2015, 524, 79
Nicolas Diercxsens
Charette Group Literature Meeting
April 20th, 2016

2. Introduction
Amides : key building blocks of proteins - very stable linkage Amides are known to be almost unreactive towards most nucleophiles (poor electrophiles) Reason : delocalization of electrons – less nucleophilic carbon center Need to be activated (alkylation, halogenation, acylation, …)

3. Known transformations
Amides may be converted to : Nitriles, Acids, Aldehydes, Ketones, Amines, … But most of those amide transformations require harsh reaction conditions, excess of reagents and are often incompatible with other functional groups - this is due to their chemical stability.
Nahm S., Tetrahedron Lett., 1981, 22 (39), 3815 ; Spletstoser J. T., J. Am. Chem. Soc., 2007, 129, 3408

4. Activation strategies - conversion to esters
Amides have to be activated in order to react in an chemical reaction Keck’s : Methylation/Hydrolysis strategy Charette’s : Triflic anhydride activation Garg’s : Ni(0) catalyzed C-N bond cleavage
Keck G. E., Tetrahedron, 2000, 56, 9875 ; Charrette A. B., Can. J. Chem., 2001, 79, 1694 ; Hie L., Nature, 2015, 524, 79

5. Nickel : generalities Group 10 metal (Pd, Pt)
Extracted from sulfides like
Bravoïte (Fe,Ni)S2 or
Pentlandite (Fe,Ni)9S8
Annual production of 1,3
million tons
Leading country : Russia
(Canada 3rd !)
Elemental form 2000 times
cheaper than Pd and 10,000
times cheaper than Pt
Tasker S. Z., Nature, 2014, 509, 299

6. Nickel : chemical behavior
Elementary organometallic reaction steps highlighting changes in oxidation state at Nickel :
No Nickel insertion into simple amide C-N bonds in a review from 2014 !
Tasker S. Z., Nature, 2014, 509, 299

7. Transition-metal (other than Ni) catalyzed C(sp2)-N bond activation
Kakiuchi Loh Loh & Xu
Aromatic amine
Directing group
Aromatic hydrazine
Phenantroline ligand
Heck-type cross-coupling
N-vinylacetamide
Intramolecular Heck-type cross-coupling
Wang Q., Chem. Soc. Rev., 2016, 45, 1257 ; Ueno S., J. Am. Chem. Soc., 2007, 129, 6098 ; Zhu M.-K., Org. Lett., 2011, 13, 6308 ; Wang M., J. Am. Chem. Soc., 2015, 137, 1341

8. Ni catalyzed C(sp2)-N bond activation
McMillan Chatani & Tobisu Kurahashi & Matsubara Matsubara & Kurahashi
Arylammonium salt
Ni catalyzed Suzuki- type cross coupling
N-aryl amide
No directing group
Complete chirality retention
Isatoic anhydride
Decarboxylative
TMS alkynes give complete selectivity
Imide activation
Electron-poor substrates
Terminal alkynes excluded
Wang Q., Chem. Soc. Rev., 2016, 45, 1257 ; Blakey S. B., J. Am. Chem. Soc., 2003, 125, 6046 ; Tobisu M., J. Am. Chem. Soc., 2014, 136, 5587 ; Yoshino S., J. Am. Chem. Soc., 2009, 131, 7494 ; Kajita Y., J. Am. Chem. Soc., 2008, 130, 6058

9. Garg’s Ni catalyzed C-N bond activation
All the aforementioned reactions do not activate simple amide C-N bonds. Moreover, most of them require directing groups or quite harsh reaction conditions - high temperatures, and long reaction times - and are very substrate dependent.
Influence of the N-substituents ?
Nature of the amide ?
Nature of the alcohol nucleophile ?
DFT driven mechanistic investigations ?
Selective and mild amide-bond cleavage ?
Hie L., Nature 2015, 524, 79

10. Influence of the N-substituents ?
Preliminary DFT study : N-Substituents
Hie L., Nature 2015, 524, 79

11. Nature of the amide ? Limited to aromatic substrates
Substituted phenyl rings (EWG and EDG)
Regiochemistry
Naphtyl derivatives
Heterocyclic derivatives
Alkyl amides fail to undergo the C-N bond activation
Other N-substituents
Longer alkyl chains
Cyclic amide
N-protected amides
Hie L., Nature 2015, 524, 79

12. Nature of the alcohol nucleophile ?
Works with a lot of different alcohols
Bulky ones
Cyclopropyl carbinols
Oxetane-derived alcohol
Hindered secondary alcohol
Protected prolinol
Indole containing alcohol
Sugar derived alcohol
Steroidal alcohol
Hie L., Nature 2015, 524, 79

13. DFT driven mechanistic investigations ?
Rappel sur la DFT ?
Hie L., Nature 2015, 524, 79

14. Simplified mechanism
Hie L., Nature 2015, 524, 79 ; Wang Q., Chem. Soc. Rev., 2016, 45, 1257

15. Selective and mild amide-bond cleavage - Examples
Tertiary amide preferred over secondary amide Aryl amide preferred over alkyl amide Amide preferred over ester
Hie L., Nature 2015, 524, 79

16. Recent and related work : “Nickel-Catalyzed Activation of Acyl C-O Bonds of Methyl Esters”
Extended aromatics work better than simple phenyl rings : distortion
Decarbonylation is 15,4 kcal/mol less favorable than the reductive elimination - DFT
Hie L., Angew. Chem. Int. Ed., 2016, 55, 2810

17. Recent and related work : “Nickel-Catalyzed Suzuki-Miyaura Coupling of Amides”
Limited to arylamides
EDG, EWG, Esters and Ketones are tolerated on the arylamide
Heteroarylamides and heteroaryl boronic acids and esters are also tolerated
Water plays an important role : seems to form a stable 6 membered Nickel intermediate
Weires N. A., Nature Chem. 2016, 8, 75 ; Quasdorf K. W., J. Am. Chem. Soc., 2011, 133, 6352

18. Recent and related work : “Nickel-Catalyzed Alkylation of Amide Derivatives”
Mild reaction conditions : room temperature
Arylamides : EDG, EWG, Phenyl & Naphtalenes derivatives
Organozinc reagent : hindered, α-branched, secondary (cyclopentyl & cyclohexyl)
Simmons B. J., ACS Catal. 2016, Just Accepted

19. Conclusions
Unlike Pd and Ru, Ni catalysis doesn’t allow decarbonylation
Garg’s group developed a very mild Ni-catalyzed amide C-N bond activation process
Supported by Houk’s DFT calculations
Chemo- and stereo-selective transformations
Broad substrate and reagent scope

20. Aknowledgements Centre en chimie verte et catalyse
Centre in Green Chemistry and Catalysis