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

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, …)

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

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

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

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

Transition-metal (other than Ni) catalyzed C(sp2)-N bond activation Kakiuchi - 2007 Loh - 2011 Loh & Xu - 2015 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

Ni catalyzed C(sp2)-N bond activation McMillan - 2003 Chatani & Tobisu - 2014 Kurahashi & Matsubara - 2009 Matsubara & Kurahashi - 2008 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

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

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

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

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

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

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

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

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

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

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

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

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