Synthesis of Aliphatic Carboxamides Mediated by Nickel NN₂‐Pincer Complexes and Adaptation to Carbon‐Isotope Labeling

Abstract

The development of a nickel-mediated aminocarbonylation utilizing NN -pincer Ni-complexes, alkylzinc reagents, stoichiometric carbon monoxide and amines is described for the first time, which can be adapted to late-stage carbon-isotope labeling. This work expands the scope of the highly established palladium-promoted version of the reaction, by allowing carbon-sp fragments to take part in the three-component reaction. Finally, the results obtained show a remarkable effect of the pincer ligand for the reductive elimination step with the amine, which is followed by C NMR spectroscopy studies.

A Nickel(II)‐Mediated Thiocarbonylation Strategy for Carbon Isotope Labeling of Aliphatic Carboxamides

“…With these resultsi nh and, we speculated whether these series of intermediate reactions for thiocarbonylation and amidation could be convertedi nto ao ne-pot protocol in order to improvet he overall scope for accessing aw ide variety of aliphatic carboxamides compared to our previous work. [16] Furthermore, if successful, such ap rotocol would obviate the need for inert and dry reaction conditions after the thioester has been prepared, in contrasttothe use of Ni II -acyl complexes as the direct acylationr eagent. This may prove advantageous for the acylation of amine compounds that require water as a (co)solvent for solubility,f or example, biomolecules including peptides and proteins.T hioesters are well known to be stable under aqueous conditions in contrastt oo thera ctivee sters such as acid chlorides, despite their similar reactivity.…”

“…[21] The optimization of the one-pot reaction with dibenzylamine to yield N,N-dibenzyl-4-phenyl-butanamide (1)w as initiated (Table 1), a transformation with secondary amines, which was unsuccessful in our previous carboxamide synthesis efforts. [16] THF was initially used as the solventt of orm the Ni II -acyl complex from CO and 3-phenylpropyl zinc bromide in at wochamber reactorw ith stirring for 2h.T he 2-pyridyl thioester was thereafter preparedf rom the direct addition of 2,2'-dipyridyl disulfide, and after 10 min, dibenzylamine was added. Amideb ond formation was complete after 30 min, leading to a7 8% yield of the carboxamide 1 based on 1 HNMR analysiso f the reaction mixture (entry 1).…”

“…However,y ields wereu nder 30 %f or the former,a nd whereas the two thiols tested provided ay ield of 66 and 74 %o ft he thioesters, considerable reaction times (2.5 h) were necessary for competition. [16] With adesire to identify amore efficient N-acylation technology applying our Ni-chemistry and am ethod, which could also be adaptable to the carbon isotope labeling of structurally more sophisticatedc arboxamides, we turned to some of our previous results obtained for the Ni II -catalyzed carbonylative coupling of alkyl zinc reagents with reactivea lkyl halides. [18][19][20] In this work, we observed that simple (NN 2 )Ni II acyl complexes were able to react rapidly with benzylb romides and a-bromonitriles to generate benzyl ketonesa nd b-ketonitriles, respectively.F urther investigationss uggested the presence of single electron transfer steps in the mechanism, and an ickel(II/III/I) catalytic cycle involving bimetallic oxidative addition (Scheme 4).…”

“…[27] On the other hand, our method provedi deal for accessing pharmaceutical derivatives with longer alkyl chains, as ituation which would be problematic with Pd-mediated aminocarbonylations due to b-hydride elimination. [9] This included the synthesis of six variants of commercial pharmaceuticals, linezolide (14), agomelatine (15), prozac (16), lacosamide (17), melatonine( 18)a nd gefitinib (19) along with their corresponding 13 C-isotope analogs (sectionD ). Interestingly,i nt he case of 19,apiperazine derivative of gefitinib, this compound was shown to possess significant activity towardsh uman cancer cell lines.…”

Direct Access to Isotopically Labeled Aliphatic Ketones Mediated by Nickel(I) Activation

“…Having illustrated that the alkyl iodide could react with the preformed Ni II ‐acyl complex through a Ni I ‐mediated activation, the scope of this transformation was undertaken as illustrated in Scheme . A broad range of primary and secondary alkyl iodides with various functionalities was employed as electrophiles in the coupling with pregenerated Ni II ‐acyl complexes formed from different Negishi reagents and subsequent CO insertion . For most entries, both 12 CO and 13 CO were employed, showing the applicability of the method for carbon isotope labeling.…”