Formation of C(sp²)–C(sp³) Bonds Instead of Amide C–N Bonds from Carboxylic Acid and Amine Substrate Pools by Decarbonylative Cross-Electrophile Coupling

Abstract

Carbon–heteroatom bonds, most often amide and ester bonds, are the standard method to link together two complex fragments because carboxylic acids, amines, and alcohols are ubiquitous and the reactions are reliable. However, C–N and C–O linkages are often a metabolic liability because they are prone to hydrolysis. While C(sp2)–C(sp3) linkages are preferable in many cases, methods to make them require different starting materials or are less functional-group-compatible. We show here a new, decarbonylative reaction that forms C(sp2)–C(sp3) bonds from the reaction of activated carboxylic acids (via 2-pyridyl esters) with activated alkyl groups derived from amines (via N-alkyl pyridinium salts) and alcohols (via alkyl halides). Key to this process is a remarkably fast, reversible oxidative addition/decarbonylation sequence enabled by pyridone and bipyridine ligands that, under reaction conditions that purge CO (g) , lead to a selective reaction. The conditions are mild enough to allow coupling of more complex fragments, such as those used in drug development, and this is demonstrated in the coupling of a typical Proteolysis Targeting Chimera (PROTAC) anchor with common linkers via C–C linkages.

Formal Cross-Coupling of Amines and Carboxylic Acids to Form sp3–sp2 Carbon–Carbon Bonds

“…In conclusion, we have developed a formal cross-coupling of amines and carboxylic acids to form new C(sp 3 )–C(sp 2 ) bonds . HTE enabled identification of the key additives phthalimide 4 to improve yield and RuCl 3 to improve selectivity for the C–C product.…”

Anhydrous and Stereoretentive Fluoride-Enhanced Suzuki–Miyaura Coupling of Immunomodulatory Imide Drug Derivatives

“…Screening of four different commercially available Pd(P( t Bu) 3 ) precursors led us to the conditions in entry 12, which gave 2a in 93% yield. We found that the effect of fluoride in the reaction was independent of catalyst precursor and necessary for a high yield, as no matter the precatalyst, fluoride provided a notable increase in reactivity versus the same conditions as sans fluoride (entries [8][9][10]12). As an alternative route, we attempted Niwa's zinc-mediated SMC, which gave 2a in 85% yield (entry 11), but when we attempted to extend the coupling to other important IMiD derivatives (2b−f), the conditions failed to fully convert starting material to product, which we concluded was at least partially due to the high degree of insolubility of 2b−e in the ethereal solvents required for the reaction to proceed.…”

“…While a variety of methods have been used to generate IMiD derivatives, − the glutarimide moiety presents synthetic challenges, stemming from poor solubility and propensity to open under a variety of basic or aqueous conditions (Figure ). − An additional complication is that the stereocenter adjacent to the imide is susceptible to epimerization under basic and acidic conditions. − As a result, newly reported synthetic methods often highlight glutarimide compatibility. , In our efforts to generate vinyl IMiD derivatives, we found a dearth of conditions in the academic literature for this particular kind of coupling in the presence of a glutarimide, despite the fact that vinylation of aryl halides is a well-studied reaction class . This can be explained, at least in part, by aforementioned sensitivity of the glutarimide to the traditional aqueous alkali conditions employed for Suzuki–Miyaura couplings (SMCs) .…”

Nickel and Chiral Phosphoric Acid Cocatalysis Enables Synthesis of C-Acyl Glycosides

“…Furthermore, mechanistically, the key to the success of the proposed reaction lies in the rapid formation of acyl metal species and smooth generation of glycosyl radicals. However, the challenges for such a process include (i) the fast reversible decarbonylation of acyl metal species, , (ii) the β-elimination of glycosyl radicals, and (iii) the functional group compatibility of the reactions and stability of the products. Herein, we disclosed a nickel and chiral phosphoric acid (CPA) cocatalyzed protocol to access diverse C -acyl glycosides under mild conditions with broad functional group compatibility through the coupling of readily available glycosyl halides and activated carboxylic acid esters (Scheme C).…”