De Novo Synthesis of α-Ketoamides via Pd/TBD Synergistic Catalysis

doi:10.21203/rs.3.rs-4272667/v1

Download PDF

Article

De Novo Synthesis of α-Ketoamides via Pd/TBD Synergistic Catalysis

https://doi.org/10.21203/rs.3.rs-4272667/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Precise control on the product selectivity of a reaction is an important objective in organic synthesis. α-ketoamides are vital intermediates in chemical transformation and privileged motifs in numerous drugs, natural products and biologically active molecules. The selective synthesis of α-ketoamides from feedstock chemicals in a safe and operationally simple manner under mild conditions is a long-standing challenge in catalysis. Herein we disclose an unprecedented TBD-switched Pd-catalyzed double isocyanide insertion reaction of (hetero)aryl halides or pseudohalides for the assembly α-ketoamides in aqueous DMSO under mild conditions. The effectiveness and utility of this protocol are demonstrated by diverse substrate scope (85 examples), late-stage modification of pharmaceuticals, scalability in large-scale synthesis, transformations of functional groups, as well as the synthesis of pharmaceutically active molecules. Mechanistic studies indicate that TBD is a key ligand to modulate the Pd-catalyzed double isocyanide insertion process, thus selectively providing the desired α-ketoamides in a unique manner. In addition, imidoylpalladium(II) complex and α-ketoimine amide are successfully isolated and determined by X-ray analysis, proving them the probable intermediates in the catalytic pathway.

Physical sciences/Chemistry/Organic chemistry/Synthetic chemistry methodology

Physical sciences/Chemistry/Catalysis/Homogeneous catalysis

α-Ketoamides and their derivatives are important organic moieties, prevalent in many pharmaceuticals,¹⁻³ biologically relevant molecules⁴⁻⁶ and natural products (Fig. 1).^7,8 They also serve as versatile building blocks in a variety of functional group transformations because of the structural specificity with multiple potential reaction sites.⁹⁻¹⁵ In this context, some general approaches, including decarboxylative acylation,¹⁶⁻²¹ oxidative amidation,²²⁻³³ direct oxidation³⁴⁻⁴² and others,⁴³⁻⁴⁸ have been rapidly developed for the synthesis of α-ketoamides (Fig. 2A). However, most of them focus on prefunctionalized substrates (e.g., 2-hydroxyamides, α-arylacetamides, aryl acetaldehydes, aryl methyl ketones, terminal alkynes, α-carbonyl aldehydes, α-ketoacids and terminal alkenes), the development of novel approaches for α-ketoamides from simple starting materials has thus inspired longstanding interests. Noteworthily, palladium-catalyzed double-carbonylative amination of halogenated hydrocarbon in the presence of amines under carbon monoxide (CO) atmosphere, represents a direct and efficient strategy in the synthesis of α-ketoamides (Fig. 2B), which was pioneered by Yamamoto et al. in 1982.⁴⁹⁻⁵¹ The scope of this elegant amino dicarbonylation was further explored by Yamamoto,^52,53 Kollár,⁵⁴⁻⁵⁹ Ryu,^60,61 Jensen,⁶² Buchwald,⁶² Skrydstrup,^63,64 Wu,⁶⁵⁻⁶⁷ Lei,^68,69 Zhu,⁷⁰ Luo,⁷⁰ Xiao,⁷¹ Liao,⁷² Chen^71,73 and others.⁷⁴⁻⁸³ In 2018, Lei and co-workers first reported the oxidative double radical carbonylation of alkanes promoted by carbon nanofibrous microspheres (CNMs) under 60 bar of CO atmosphere using stoichiometric di-tert-butyl peroxide (DTBP) as the oxidant to afford a series of α-ketoamides in 17−77% yields.⁶⁸ In order to improve this relatively low conversion efficiency, the same group in 2022 further developed a tunable oxidative mono- and double-carbonylation of alkanes with CO by choosing a Co and Cu catalyst, respectively (Fig. 2B i).⁶⁹ In the same year, Wu developed a copper-catalyzed highly selective double-carbonylative amination of alkyl bromides, and the mono- and double- carbonylation of alkyl iodides with amines were controlled precisely under different conditions.⁶⁷ Recently, Xiao and Chen illustrated a philicity-regulation strategy by photocatalytic processes for the switchable single and double carbonylation reactions of strained ring oxime ester in different pressure conditions of CO (Fig. 2B ii).⁷¹ Shortly after that, Liao and Wu further expanded the carbonylation to cyclic diaryliodonium salts, disclosing a high-valent Pd(II/IV)-catalyzed asymmetric single- and double carbonylation employing a chiral sulfoxide phosphine ligand under CO atmosphere, giving axially chiral biaryl compounds bearing amides or ketoamides in up to 93% yield with up to 99% enantioselectivity.⁷² Quite recently, Chen’s group further reported a visible light-driven radical relayed multi-component radical double aminocarbonylation reaction of alkenes under 80 atm of CO to valuable γ-trifluoromethyl α-ketoamides.⁷³ Despite the aforementioned state-of-the-art approaches, surprisingly, except for the rare examples relying on CO surrogate (9-methylfluorenecarbonyl chloride), there is not a safer and simpler protocol to α-ketoamides under CO gas-free conditions.

Isocyanides, a class of important reagents extensively utilized in multicomponent reactions and imidoylative reactions, are easily operated liquids or solids and can be utilized in stoichiometric quantities.⁸⁴⁻⁹⁵ In 2011, Jiang reported a palladium-catalyzed amidation of aryl halides with isocyanides access to amides.⁹⁶ Mechanistically, the reaction involves successive oxidative addition of aryl halide to Pd(0) species, single migratory insertion of isocyanides, nucleophilic substitution, reductive elimination and amide-iminol tautomerism process (Fig. 2C, catalytic cycle in gray and blue). While palladium-catalyzed double isocyanide insertion reaction for the synthesis of α-iminoimidates,⁹⁷ ketimine−amidine,⁹⁸ 1,2-diketones,^99,100 α-ketoester,¹⁰¹ α-diimines,¹⁰² α-iminonitriles,¹⁰³ 3-amino pyrroles,¹⁰⁴ 3-iminoindol-2-amines,¹⁰⁵ fused tetracyclic heterocycles,¹⁰⁶ aza-saddle-type framework,¹⁰⁷ et al, is well-precedented, expending this strategy to the construction of α-ketoamides with H₂O as the nucleophile is always a formidable challenge, supposedly due to imidoylpalladium(II) B favors nucleophilic substitution with H₂O to give intermediate C rather than the second isocyanide insertion reaction to form intermediate D. As our ongoing interests in palladium-catalyzed domino reactions^108−114 as well as our recent progress in palladium-enabled rearrangement process with isocyanides,¹¹⁵ we envisaged that if a bifunctional (NH, N)-ligand could stabilize the intermediate B by coordination of the nitrogen atom and Pd(II) center, and lower the activation barrier for the second isocyanide insertion to give intermediate D, followed by partial hydrolysis of imine moiety and nucleophilic substitution of α-imine palladium species with H₂O to provide β-carbonyl α-imino palladium species E, which further undergoes reductive elimination and amide-iminol tautomerism process to afford α-ketoamides along with regeneration of Pd(0) catalyst (Fig. 2C, catalytic cycle in gray and orange). To explore this possibility, various reaction parameters, including ligands, catalysts, bases and solvents, were subsequently examined. It was found that the ligand plays an utmost effect on the reaction pathway towards the selectivity of α-ketoamides and amides, herein, we reported a 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD)-enabled palladium-catalyzed double isocyanide insertion of (hetero)aryl halides or pseudohalides access to α-ketoamides (Fig. 2D). The protocol was distinguished by its operational simplicity, mild conditions as well as cheap and abundant feedstocks, thus representing a convenient platform for the construction of valuable α-ketoamides.

Search for the optimal reaction conditions

Based on our mechanistic assumption depicted in Fig. 2C, we initially evaluated an array of bifunctional (NH, N)-ligands on the palladium-catalyzed double isocyanide insertion reaction by subjecting bromobenzene (1) and tert-butyl isocyanide (2) to PdCl₂ (10 mol%), Cs₂CO₃ (1.0 equiv), H₂O (100 μL) in DMSO (1.0 mL) under an Ar atmosphere at 90 ºC for 12 hours (Table 1, entries 1−7).¹¹⁶ The desired α-ketoamide product 3 was smoothly generated in 36% yield in the presence of 1,1,3,3-tetramethylguanidine (L1, TMG) (Table 1, entry 1). Disappointingly, benzimidamide (L2), propionimidamide (L3), 1,3-diphenylguanidine (L4), 1,3,5-triazine-2,4,6-triamine (L5) and 2-methylpyrimidine-4,6(1H,5H)-dione (L6) were ineffective for this transformation (Table 1, entries 2−6). To our surprise, 1,5,7-triazabicyclo[4.4.0]dec-5-ene (L7, TBD) was proven to be the best cocatalyst, offering 3 in 49% yield together with trace amount of the single isocyanide insertion product amide 4 (Table 1, entry 7). Inspired by these fascinating results, other reaction parameters, including palladium catalysts, bases, solvents, et al, were further investigated in the presence of TBD (Table 1, entries 8−18). Replacement of PdCl₂ with Pd₂(dba)₃ resulted in raised 63% yield of 3 (Table 1, entry 12), while Pd(OAc)₂, Pd(TFA)₂, Pd(OPiv)₂ and Pd(PPh₃)₄ deliver the product in slightly lower yields (Table 1, entries 8−11). However, screening of inorganic bases failed to improve conversion (Table 1, entries 13−15). A survey of solvents revealed that DMSO was always the best choice (Table 1, entry 12 vs entries 16−18), even trace amount of product was yielded by harnessing MeCN or PhMe as the reaction medium (Table 1, entries 17 and 18). To our delight, the yield of 3 promptly increased to 81% from 63% when the reaction was performed with 2.5 equiv of 2 and 2.0 equiv of Cs₂CO₃ (Table 1, entry 19). As expected, the yield of 3 reduced as the loading of Pd₂(dba)₃ decreases (Table 1, entry 20). Of particularly noted was that the selectivity of products was quickly switched when the reaction was performed under classic palladium-catalytic conditions, giving amide 4 in 74% yield, while α-ketoamide 3 was not observed (Table 1, entry 21).⁹⁶

Scope of (hetero)aryl bromides

Having established the optimal reaction conditions for the formation of α-ketoamides, the generality of current protocol with regard to (hetero)aryl bromides was initially tested as outlined in Fig. 3. Whether the substituent group is an electron-donating or -withdrawing moieties at the ortho-, meta-, and para-position of bromoarenes, the reactions proceeded smoothly to deliver the desired α-ketoamides (5−20) in good yields (50−88%).¹¹⁷ In addition, this approach could be extended to disubstituted bromoarenes bearing electron-rich or electron-poor groups, affording the corresponding products 21−26 in good results. Given the importance of heteroarenes in pharmaceutical industry, the scope of this double insertion of isocyanides event toward heteroaryl bromides were further evaluated with the established methodology. Delightfully, α-ketoamides incorporating xanthone (27), quinoxaline (28), pyridine (29−32), quinoline (33) and isoquinoline (34) were smoothly accessed in up to 90% yield. Bromoarenes featuring a π-extended system also proved compatible to provide the corresponding α-ketoamides 35−37 in good results. Moreover, the sterically hindered 2-bromo-9,9'-spirobi[fluorene] and 4-bromo[2.2]paracyclophane were successfully applied to this TBD-switchable assembly platform, furnishing the desired products 38 in 80% yield and 39 in 83% yield, respectively.

Scope of (hetero)aryl sulfonates

In order to further explore the generality of current methodology, pseudohalides were investigated as depicted in Fig. 4.¹¹⁶ Notably, the double isocyanide insertion process appears to be laborious for (hetero)aryl sulfonates, in which a higher temperature (120 ºC) was required for the installation of desired α-ketoamides with low yields.

Scope of (hetero)aryl iodides

Subsequently, we explored the scope with respect to highly active iodoarenes for this TBD enabled Pd-catalyzed double insertion of isocyanides (Fig. 5).¹¹⁶ Incontrovertibly, aryl iodides with diversified functional groups reacted efficiently with isocyanides and H₂O, giving the desired products (3, 5−7, 11−14, 16, 17, 19−22, 24, 40 and 43−49) in good to excellent yields within 1 h. It is worth noting that some sensitive functional groups, including -NHAc, -CN and -CO₂Me, could also tolerate the current conditions, no observing further hydrolysates. The substrate scope was successfully extended to heteroaryl iodides, allowing for the corresponding α-ketoamides incorporated pyridine (29, 30 and 32), quinoline (33), indole (50), pyrazole (51), thiophene (52 and 53), benzo[b]thiophene (54), dibenzo[b,d]furan (55) and carbazole (56) in a highly efficient manner (in up to 98% yield). Although alkyl isocyanides, such as n-butyl isocyanide and 1-fluoro-2-(2-isocyanoethyl)benzene, were well compatible with the transformation to give 57 and 58 in good results, aryl isocyanides were found to be poor substrates under current catalytic conditions, and the corresponding products were not observed, supposedly due to the facile dimerization of aryl isocyanides.

Gram scale reactions

To exhibit the scalability of this protocol, three gram-scale reactions were performed as depicted in Table 2. The transformations of bromobenzene and iodobenzene under their individual reaction conditions were amenable to scale-up production of 3, albeit with loss of efficiency (Table 2, entries 1 and 2). Pleasingly, good result (1.50 g of 3 in 73% yield) was also gained with only 5 mol% of palladium catalyst (Table 2, entry 3).

Transformations of 3

After developing the novel strategy, we attempted to explore its utility for the synthesis of some valuable intermediates as depicted in Fig. 6. Compound 3 could be smoothly transformed by condensation with N₂H₄·H₂O, hydrogenation reduction with NaBH₄, reductive deoxygenation with N₂H₄·H₂O and nucleophilic addition with PhMgBr, leading to 59 in 98% yield, 60 in 92% yield, 61 in 83% yield, and 62 in 94% yield, respectively. In addition, deprotection of the N-tertbutyl group using trifluoroacetic acid gave 63 in 60% yield, which could be further converted into pyrrol-2-one 65 through Cu-catalyzed C-N cross-coupling and Mo-catalyzed deoxygenative cross-coupling reactions. Moreover, oximation of 3 and subsequent hydrogenation reduction performed well to furnish 67 in good result. Surprisingly, unnatural amino acid 69 could be smoothly attained with 78% overall yield in two steps from 3 via successive hydrolysis and reductive amination.

Late-stage modification of pharmaceuticals and their derivatives

Its application in the late-stage modification of pharmaceuticals and their derivatives further demonstrated the inherent value of this approach. As outlined in Fig. 7, drug-like haloarenes derived from sulfadimethoxine, clofibrate, celecoxib, loratadine, δ-vitamin E and trametinib underwent the current reaction smoothly and furnished corresponding α-ketoamides 70−75 in good to excellent yields, with only one exception of 74, in this case, a slightly lower yield was obtained.

Synthesis of pharmaceutically active molecules

Considering the frequency of α-ketoamide moieties in pharmaceuticals, this protocol thus provides an alternative method for the applications in drug discovery and development. The ligand-switchable assembly platform was successfully applied to three de novo synthesis of pharmaceutically active molecules. As depicted in Fig. 8, oxerin receptor agonist (76), epoxide hydrolase inhibitor (77) and RARγ agonist (78) were smoothly forged in 3−4 steps form the safe, cheap, and commercially available feedstock chemicals.

Mechanistic investigation on the TBD enabled Pd-catalyzed double insertion of isocyanides

Mechanistic experiments were next carried out to probe the proposed reaction pathway. First, we found that cross-product 58 was not detected when 2-(3-fluorophenyl)ethan-1-amine was added to the model reaction (Fig. 9A). This finding indicates that acylpalladium species was not involved in current catalytic system. Compound 3 was not detected in the absence of TBD (Fig. 9B), and the reaction without Cs₂CO₃ led to only 9% yield of desired product (Fig. 9C), indicating that TBD was not acted as a base, but it is likely to participate in the reaction as a ligand. In order to verify this conjecture, control experiment with MTBD by methylation of the N−H group of TBD led to decreases in activity (Fig. 9D), probably because the steric hindrance effect or the methyl group eliminates the hydrogen bond with the imine moiety of imidoylpalladium(II) intermediate. Surprisingly, α-ketoimine amide 79 was attained in 58% yield by recrystallization (Fig. 9E).¹¹⁷ In addition, ¹⁸O-labeled α-ketoimine amide 80 was generated in 64% yield, which rationalized that the oxygen atom in amide moiety derived from H₂O of the reaction system (Fig. 9F). To our delight, a linearly dicoordinated palladium complex 81 was isolated and its structure was determined by single crystal X-ray diffraction (Fig. 9G).¹¹⁷ Similarly, α-ketoimine amide 79 was obtained in 45% yield when imidoylpalladium complex 81 was subjected to the reaction (Fig. 9H). Treatment of α-ketoimine amide 79 by silica gel column chromatography utilizing a mixed solvent of ethyl acetate and petroleum ether (volume ratio 20:1) as eluant led to hydrolysis product 11 in 93% yield (Fig. 9I), suggesting that compounds 79 and 81 are possible intermediates for the formation of target product 11, and that the oxygen atom in ketone carbonyl group comes from the silica gel utilized in column chromatography. To probe the electronic effects on the TBD enabled Pd-catalyzed double insertion of isocyanides, seven reactions with bromoarenes bearing para-substituted groups (-OMe, -Me, -H, -F, -Cl, -CF₃, -CN) under the optimal conditions were conducted. As shown in Fig. 9J, a linear Hammett plot (R² = 0.961) with a positive ρ value of 1.235 was obtained, which indicated that the double insertion of isocyanides is clearly facilitated by electron withdrawing groups. Finally, the orders from the initial rates for five individual components [p-bromofluorobenzene, tert-butyl isocyanide, H₂O, Pd₂(dba)₃ and TBD] in the reaction was surveyed (Fig. 9K). The reaction is zero-order relationship with respect to p-bromofluorobenzene, tert-butyl isocyanide and TBD, suggesting that the oxidative addition of haloarenes to Pd(0) species, migratory insertion of isocyanides and coordination of imidoylpalladium(II) intermediate with TBD are not the rate-limiting step. Remarkably, the kinetic experiment of H₂O did not implicate a simple zero- or first-order reaction, but a saturation kinetics—a hydrolysis pre-equilibrium of Cs₂CO₃ was involved, which implied that the halogen exchange with OH^- might be the rate-limiting step. Similarly, a pre-equilibrium process between the ligand exchange of Pd₂(dba)₃ and [Pd(CN^tBu)₂] determined by a saturation dependence on Pd₂(dba)₃ was observed, which is consistent with the mechanistic study on palladium-catalyzed imidoylative couplings using isocyanides as both substrates and ligands.¹¹⁸

Proposed mechanism

Based on the above experiments and related literatures,^97−107,118 a revised mechanism toward the TBD enabled Pd-catalyzed double insertion of isocyanides was proposed (Fig. 10). Initially, [Pd(CNR)₂] complex formed by the ligand exchange of Pd₂(dba)₃ with isocyanides (CNR). Next, imidoylpalladium(II) B was smoothly yielded through oxidative addition of [Pd(CNR)₂] to haloarenes and migratory insertion of isocyanides. Subsequently, the coordination of intermediate B with TBD to form a chelating seven-membered ring transition state I (TS I), in which the N-H moiety is associated to the imine of B and the N(sp²) atom in TBD is coordinated with the Pd(II) center. And then, the second migratory insertion of isocyanides and followed by dissociation of TBD occurred to give α-ketoimine imidoylpalladium(II) D, which was trapped by OH^- in situ generated from Cs₂CO₃ and H₂O to deliver palladium(II) complex F. Lastly, α-ketoamides was formed through successive reductive elimination and amide-iminol tautomerization, followed by silica gel-assisted hydrolysis process, while Pd(0) species is regenerated into the next catalytic cycle.

In summary, we have developed a selective synthesis of α-ketoamides from commercially available haloarenes and isocyanides through the TBD/Pd cooperative catalysis under mild conditions. This ligand-switchable assembly platform’s efficiency and application were proved by assorted substrate scope, compatibility with late-stage modification of pharmaceuticals, gram-scale reactions, diverse transformations of functional groups, and the synthesis of pharmaceutically active molecules. Additionally, the reaction mechanism was investigated by crossover reaction, control experiments, ¹⁸O-labeled experiment, identifying key intermediates and kinetic studies. Given that the modulability and operational simplicity of current protocol for the forging of α-ketoamides that are of interest in organic synthesis and medicinal chemistry, we anticipate that this strategy will open up a new avenue for advancing precision chemistry in the assembly of molecules.

Representative procedure for the synthesis of 3

A 4-mL flame-dried vial with a magnetic stir bar was charged with bromobenzene (20.9 μL, 0.2 mmol), TBD (5.6 mg, 20 mol%), Pd₂(dba)₃ (18.3 mg, 10 mol%), Cs₂CO₃ (130.3 mg, 0.4 mmol), H₂O (100 μL) and extra dry DMSO (1.0 mL). The vial was evacuated and backfilled with argon for three times and then tert-butyl isocyanide (56.6 μL, 0.5 mmol) was added by syringe under argon. The vial was then sealed and was stirred at 90 ºC (oil bath) for 12 h. After the completion of the reaction monitored by TLC (thin layer chromatography), the reaction mixture was cooled to the room temperature and treated with water (15 mL), extracted with CH₂Cl₂ (3 × 15 mL), washed with brine (2 × 40 mL). Then the organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash column chromatography on silica gel and eluted with petroleum ether/ethyl acetate (30:1 − 10:1) to afford the product 3 (33.2 mg, 81% yield).

Data availability

The authors declare that all other data supporting the findings of this study are available within the article and Supplementary Information files, and also are available from the corresponding author upon reasonable request. CCDC 2338684, 2338685 and 2338686 contains the supplementary crystallographic data for 6, 79 and 81, respectively. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

Acknowledgements

We are grateful for financial support from the National Natural Science Foundation of China (22261057 and 21901265), Guizhou Provincial Natural Science Foundation (QKHJC-2020-1Z072), the Science and Technology Department of Guizhou Province (QKHPTRC-CXTD[2022]012 and QKHPTRC-GCC[2023]003), Zunyi Medical University (18ZY-002, ZYDC2022005 and 202210661193), Science and Technology Department of Zunyi (ZSKH-2018-3, ZSKRPT-2020-5 and ZSKRPT-2021-5), and Fifth Batch of Talent Base in Guizhou Province (S-030-1).

Author contributions

J.H.C. performed the experiments and prepared the supplementary information. L.R.Z. and Z.Y.W. prepared some starting materials. L.R.Z., Z.Y.W., L.J.L. and L.P.T. checked the date and supplementary information. Y.Z. and Y.Z.C. provided useful advice to this work. W.Y.H conceived and directed the project, analyzed the data and wrote the paper. All authors discussed the results, commented on the manuscript and agreed on the final version.

Competing interests

The authors declare no competing interests.

Malcolm, B. et al. SCH 503034, a mechanism-based inhibitor of hepatitis C virus NS3 protease, suppresses polyprotein maturation and enhances the antiviral activity of alpha interferon in replicon cells. Antimicrob. Agents Chemother. 50, 1013–1020 (2006).
Perni, R. B. et al. Preclinical profile of VX-950, a potent, selective, and orally bioavailable inhibitor of hepatitis C virus NS3−4A serine protease. Antimicrob. Agents Chemother. 50, 899–909 (2006).
Flick, A. C., Ding, H. X., Leverett, C. A., Fink, S. J. & O’Donnell, C. J. Synthetic approaches to new drugs approved during 2016. J. Med. Chem. 61, 7004–7031 (2018).
Smith, A. L. Cyclandelate (cyclospasmol) in the treatment of peripheral circulatory diseases. Angiology. 16, 1–7 (1965).
Klaholz, B. P., Mitschler, A., Belema, M., Zusi, C. & Moras, D. Enantiomer discrimination illustrated by high-resolution crystal structures of the human nuclear receptor hRARγ. Proc. Natl. Acad. Sci. USA. 97, 6322–6327 (2000).
Patel, D. V., Gless, R. D. Jr., Webb, H. H. K., Anandan, S. K. & Aavula, B. R. Soluble epoxide hydrolase inhibitors. PCT Int. Appl. WO 2008073623, (2008).
Aoyagi, T. et al. Poststatin, a new inhibitor of prolyl endopeptidase, produced by streptomyces viridochromogenes MH534−30F3. J. Antibiot. 44, 949–955 (1991).
Toda, S. et al. Eurystatins A and B, new prolyl endopeptidase inhibitors. J. Antibiot. 45, 1580–1586 (1992).
Lin, Y.-S. & Alper, H. A novel approach for the one-pot preparation of α-amino amides by Pd-catalyzed double carbohydroamination. Angew. Chem. Int. Ed. 40, 779–781 (2001).
Sai, K. K. S., Esteves, P. M., Penha, E. T. & Klumpp, D. A. Superacid-promoted reactions of α-ketoamides and related systems. J. Org. Chem. 73, 6506–6512 (2008).
Xu, Y., Lu, G., Matsunaga, S. & Shibasaki, M. Direct anti-selective catalytic asymmetric mannich-type reactions of α-ketoanilides for the synthesis of γ-amino amides and azetidine-2-amides. Angew. Chem. Int. Ed. 48, 3353–3356 (2009).
Jia, Y.-X., Katayev, D. & Kündig, E. P. Synthesis of 3-hydroxyoxindoles by Pd-catalysed intramolecular nucleophilic addition of aryl halides to α-ketoamides. Chem. Commun. 46, 130–132 (2010).
Hu, J.-X. et al. Nickel-catalyzed intramolecular nucleophilic addition of aryl or vinyl chlorides to α-ketoamides through C−Cl bond activation. Chem. Eur. J. 17, 5234–5237 (2011).
Rogness, D. C. & Larock, R. C. Synthesis of N-arylisatins by the reaction of arynes with methyl 2-oxo-2-(arylamino)acetates. J. Org. Chem. 76, 4980–4986 (2011).
Raimondi, W., Bonne, D. & Rodriguez, J. 1,2-Dicarbonyl compounds as pronucleophiles in organocatalytic asymmetric transformations. Angew. Chem. Int. Ed. 51, 40–42 (2012).
Li, D., Wang, M., Liu, J., Zhao, Q. & Wang, L. Cu(II)-catalyzed decarboxylative acylation of acyl C−H of formamides with α-oxocarboxylic acids leading to α-ketoamides. Chem. Commun. 49, 3640–3642 (2013).
Zhang, X., Yang, W. & Wang, L. Silver-catalyzed amidation of benzoylformic acids with tertiary aminesvia selective carbon-nitrogen bond cleavage. Org. Biomol. Chem. 11, 3649–3654 (2013).
Guin, S., Rout, S. K., Gogoi, A., Ali, W. & Patel, B. K. A palladium(II)-catalyzed synthesis of α-ketoamides via chemoselective aroyl addition to cyanamides. Adv. Synth. Catal. 356, 2559–2565 (2014).
Lv, Y., Bao, P., Yue, H., Li, J. & Wei, W. Visible-light-mediated metal-free decarboxylative acylations of isocyanides with α-oxocarboxylic acids and water leading to α-ketoamides. Green Chem. 21, 6051–6055 (2019).
Zhao, F. et al. Metal-free electrochemical synthesis of α-ketoamides via decarboxylative coupling of α-keto acids with isocyanides and water. Org. Chem. Front. 8, 6508–6514 (2021).
Zhao, Y., Meng, X., Cai, C., Wang, L. & Gong, H. Synthesis of α-ketoamides via electrochemical decarboxylative acylation of isocyanides using α-ketoacids as an acyl source. Asian J. Org. Chem. 11, e202100748 (2022).
Zhang, C. & Jiao, N. Dioxygen activation under ambient conditions: Cu-catalyzed oxidative amidation-diketonization of terminal alkynes leading to α-ketoamides. J. Am. Chem. Soc. 132, 28–29 (2010).
Zhang, C., Xu, Z., Zhang, L. & Jiao, N. Copper-catalyzed aerobic oxidative coupling of aryl acetaldehydes with anilines leading to α-ketoamides. Angew. Chem. Int. Ed. 50, 11088–11092 (2011).
Mupparapu, N. et al. Metal-free oxidative amidation of 2-oxoaldehydes: a facile access to α-ketoamides. Org. Lett. 16, 1152–1155 (2014).
Mupparapu, N. et al. Aminocatalytic cross-coupling approach via iminium ions to different C−C bonds. Chem. Eur. J. 21, 2954–2960 (2015).
Chen, J.-Y. et al. Electrochemical synthesis of α‑ketoamides under catalyst‑, oxidant‑, and electrolyte-free conditions. Org. Lett. 22, 2206–2209 (2020).
Wang, H. et al. Oxidative coupling of diazo and NH₄I: a route to primary oxamates and α-Ketoamides. J. Org. Chem. 85, 3050–3058 (2020).
Zhuang, S.-Y., Tang, Y.-X., Chen, X.-L., Wu, Y.-D. & Wu, A.-X. I₂-DMSO mediated oxidative amidation of methyl ketones with anthranils for the synthesis of α-ketoamides. Org. Biomol. Chem. 19, 4258–4262 (2021).
Chaubey, T. N., Borpatra, P. J., Sharma, A. & Pandey, S. K. Metal-free syntheses of α‑ketothioamide and α‑ketoamide derivatives from sulfoxonium ylides. Org. Lett. 24, 8062–8066 (2022).
Jadav, J. P., Vankar, J. K., Gupta, A. & Gururaja, G. N. Atmospheric oxygen facilitated oxidative amidation to α‑ketoamides and unusual one carbon degradative amidation to N‑alkyl amides. J. Org. Chem. 88, 15551–15561 (2023).
Das, S. et al. Base-promoted tandem pathway for keto-amides: visible light mediated room-temperature amidation using molecular oxygen as an oxidant. J. Org. Chem. 88, 14847–14859 (2023).
Lv, C. et al. Copper-catalyzed transamidation of unactivated secondary amides via C−H and C−N bond simultaneous activations. J. Org. Chem. 88, 2140–2157 (2023).
Kishor, K., Prabhakar, N. S. & Singh, K. N. Visible-light-mediated synthesis of α-ketoamides via oxidative amination of 2-bromoacetophenones using Eosin Y as a photoredox catalyst. Chem. Asian J. 18, e202300669 (2023).
South, M. S., Dice, T. A. & Parlow, J. J. Polymer-assisted solution-phase (pasp) library synthesis of α-ketoamides. biotechnol. bioeng. 71, 51–57 (2000).
Chiou, A., Markidis, T., Constantinou-Kokotou, V., Verger, R. & Kokotos, G. Synthesis and study of a lipophilic α-keto amide inhibitor of pancreatic lipase. Org. Lett. 2, 347–350 (2000).
Xu, P., Lin, W. & Zou, X. Synthesis of a peptidomimetic HCMV protease inhibitor library. Synthesis 8, 1017–1026 (2002).
Han, W., Jiang, X., Wasserman, Z. R., Decicco, C. P. & Hu, Z. Investigation of glycine α-ketoamide HCV NS3 protease inhibitors: effect of carboxylic acid isosteres. Bioorg. Med. Chem. Lett. 15, 3487–3490 (2005).
Weng, S.-S., Shen, M.-W., Kao, J.-Q., Munot, Y. S. & Chen, C.-T. Chiral N-salicylidene vanadyl carboxylate-catalyzed enantioselective aerobic oxidation of α-hydroxy esters and amides. Proc. Natl. Acad. Sci. USA. 103, 3522–3527 (2006).
Bhalerao, D. S. et al. Synthesis and process optimization of boceprevir: a protease inhibitor drug. Org. Process Res. Dev. 19, 1559–1567 (2015).
Wang, A.-J. et al. Copper/tempo-promoted denitrogenation/oxidation reaction for synthesis of primary α‑ketoamides using α‑azido ketones. J. Org. Chem. 87, 16099–16105 (2022).
Peng, Y.-Y. et al. Mg(O^tBu)₂-catalyzed C−H oxidation of α-azido arylethanones using tbhp as the oxidant and carbonyl oxygen source: facile access to primary α-ketoamides. Org. Chem. Front. 9, 5858–5863 (2022).
Jesus, D.-M.-P., Mateo, A., Alberto, M.-C. & Jose, B. Reactivity of glutaconamides within [2]rotaxanes: mechanical bond controlled chemoselective synthesis of highly reactive α-ketoamides and their light-triggered cyclization. Angew. Chem., Int. Edit. 62, e202302681 (2023).
Kumar, D., Vemula, S. R. & Cook, G. R. Recent advances in the catalytic synthesis of α-ketoamides. ACS Catal. 6, 4920–4945 (2016).
Risi, C. D., Pollini, G. P. & Zanirato, V. Recent developments in general methodologies for the synthesis of α-ketoamides. Chem. Rev. 116, 3241–3305 (2016).
Ma, J.-T. et al. One-pot synthesis of α‑ketoamides from α‑keto acids and amines using ynamides as coupling reagents. J. Org. Chem. 87, 3661–3667 (2022).
Wu, Z.-Z. et al. Synthesis of α‑ketoamides via gold(i) carbene intermediates. Org. Lett. 24, 4349–4353 (2022).
Sarkar, S. et al. Visible-light-promoted metal- and photocatalyst-free reactions between arylglyoxylic acids and tetraalkylthiuram disulfides: Synthesis of α‑ketoamides. J. Org. Chem. 89, 1473–1482 (2024).
Kumar, R., Grover, N. & Jain, N. ¹O₂ Mediated conversion of β‑enaminonitriles to α‑keto amides photosensitized by recyclable H₂TPP in visible light. J. Org. Chem. DOI: 10.1021/acs.joc.3c02965 (2024).
Ozawa, F. & Yamamoto, A. Double carbonylation reactions of methyl- and phenylpalladium(II) complexes in the presence of secondary amines affording α-keto amides. Chem. Lett. 11, 865–868 (1982).
Ozawa, F., Soyma, H., Yamamoto, T. & Yamamoto, A. Catalytic double carbonylation of organohalogen compounds promoted by palladium complexes. Tetrahedron Lett. 23, 3383–3386 (1982).
Kobayashi, T. & Tanaka, M. Palladium(II)-catalyzed double carbonylation of organic halides in the presence of amines: a-ketoamide synthesis. J. Organomet. Chem. 233, 64–66 (1982).
Son, T., Yanagihara, H., Ozawa, F. & Yamamoto, A. Palladium-catalyzed double-carbonylation of alkenyl halides with secondary amines to give α-keto amides. Bull. Chem. Soc. Jpn. 61, 1251–1258 (1988).
Yamamoto, A. Palladium-catalyzed double and single carbonylation of aryl halides and allylic compounds. Bull. Chem. Soc. Jpn. 68, 433–446 (1995).
Szarka, Z., Skoda-Földes, R. & Kollár, L. Facile synthesis of novel ferrocene α-ketoamides via homogeneous catalytic carbonylation. Tetrahedron Lett. 42, 739–741 (2001).
Szarka, Z., Skoda-Földes, R., Kuik, Á., Berente, Z. & Kollár, L. Synthesis of ferrocene amides and α-ketoamides via palladium-catalyzed homogeneous carbonylation reaction. Synthesis 4, 0545–0550 (2003).
Muller, E. et al. Homogeneous catalytic aminocarbonylation of iodoalkenes and iodobenzene with amino acid esters under conventional conditions and in ionic liquids. Tetrahedron 61, 797–802 (2005).
Takács, E., Varga, C., Skoda-Földes, R., & Kollár, L. Facile synthesis of primary amides and ketoamides via a palladium-catalysed carbonylation–deprotection reaction sequence. Tetrahedron Lett. 48, 2453–2456 (2007).
Takacs, A., Jakab, B., Petz, A. & Kollár, L. Homogeneous catalytic aminocarbonylation of nitrogen-containing iodo-heteroaromatics. Synthesis of N-substituted nicotinamide related compounds. Tetrahedron 63, 10372–10378 (2007).
Carrilho, R. M. B., Pereira, M. M., Takacs, A. & Kollár, L. Systematic study on the catalytic synthesis of unsaturated 2-ketocarboxamides: palladium-catalyzed double carbonylation of 1-iodocyclohexene. Tetrahedron 68, 204–207 (2012).
Rahman, M. T., Fukuyama, T., Kamata, N., Sato, M. & Ryu, I. Low pressure Pd-catalyzed carbonylation in an ionic liquid using a multiphase microflow system. Chem. Commun. 21, 2236–2238 (2006).
Fukuyama, T., Inouye, T. & Ryu, I. J. Atom transfer carbonylation using ionic liquids as reaction media. J. Organomet. Chem. 692, 685–690 (2007).
Murphy, E. R., Martinelli, J. R., Zaborenko, N., Buchwald, S. L. & Jensen, K. F. Accelerating reactions with microreactors at elevated temperatures and pressures: profiling aminocarbonylation reactions. Angew. Chem. Int. Edit. 46, 1734–1737 (2007).
Hermange, P. et al. Ex situ generation of stoichiometric and substoichiometric ¹²CO and ¹³CO and its efficient incorporation in palladium catalyzed aminocarbonylations. J. Am. Chem. Soc. 133, 6061–6071 (2011).
Nielsen, D. U. et al. Palladium-catalyzed double carbonylation using near stoichiometric carbon monoxide: expedient access to substituted ¹³C₂-labeled phenethylamines. J. Org. Chem. 77, 6155–6165 (2012).
Shen, C., Fink, C., Laurenczy, G., Dyson, J. D. & Wu, X.-F. Versatile palladium-catalyzed double carbonylation of aryl bromides. Chem. Commun. 53, 12422–12425 (2017).
Chen, B., Kuai, C.-S., Xu, J.-X. & Wu, X.-F. Manganese(III)-promoted double carbonylation of anilines toward α-Ketoamides synthesis. Adv. Synth. Catal. 364, 487–492 (2022).
Zhao, F.-Q., Ai, H.-J. & Wu, X.-F. Copper-catalyzed substrate-controlled carbonylative synthesis of α-keto amides and amides from alkyl halides. Angew. Chem. Int. Ed. 61, e202200062 (2022).
Lu, L. et al. Carbon nanofibrous microspheres promote the oxidative double carbonylation of alkanes with CO. Chem 4, 2861–2871 (2018).
Lu, L., Qiu, F., Alhumade, H., Zhang, H. & Lei, A. Tuning the oxidative mono- or double-carbonylation of alkanes with CO by choosing a Co or Cu catalyst. ACS Catal. 12, 9664–9669 (2022).
Hu, H. et al. Palladium-catalyzed tandem Heck/carbonylation/aminocarbonylation en route to chiral heterocyclic α-ketoamides. Org. Chem. Front. 9, 939–945 (2022).
Lu, B. et al. Switchable radical carbonylation by philicity regulation. J. Am. Chem. Soc. 144, 14923–14935 (2022).
Han, J. et al. Photoinduced five-component radical relay aminocarbonylation of alkenes. J. Am. Chem. Soc. 144, 21800–21807 (2022).
Lu, B. et al. Photoinduced five-component radical relay aminocarbonylation of alkenes. Angew. Chem. Int. Ed. 62, e202309460 (2023).
Urata, H., Ishii, Y. & Fuchikami, T. Palladium-catalyzed double carbonylation of alkyl iodides bearing perfluoroalkyl group. Tetrahedron Lett. 30, 4407–4410 (1989).
Mizushima, E., Hayashi, T. & Tanaka, M. Palladium-catalysed carbonylation of aryl halides in ionic liquid media: high catalyst stability and significant rate-enhancement in alkoxycarbonylation. Green Chem. 3, 76–79 (2001).
Uozumi, Y., Arii, T. & Watanabe, T. Double carbonylation of aryl iodides with primary amines under atmospheric pressure conditions using the Pd/PPh₃/DABCO/THF system. J. Org. Chem. 66, 5272–5274 (2001).
Tsukada, N., Ohba, Y. & Inoue, Y. Double carbonylation of aryl iodides with diethylamine catalyzed by dinuclear palladium complexes. J. Organomet. Chem. 687, 436–443 (2003).
Xing, Q., Shi, L., Lang, R., Xia, C. & Li, F. Palladium-catalyzed mono- and double-carbonylation of indoles with amines controllably leading to amides and α-Ketoamides. Chem. Commun. 48, 11023–11025 (2012).
Genelot, M. et al. Palladium complexes grafted onto mesoporous silica catalysed the double carbonylation of aryl iodides with amines to give α-ketoamides. Catal. Sci. Technol. 2, 1886–1893 (2012).
Papp, M. & Skoda-Földes, R. Phosphine-free double carbonylation of iodobenzene in the presence of reusable supported palladium catalysts. J. Mol. Catal. A: Chem. 378, 193–199 (2013).
Du, H., Ruan, Q., Qi, M. & Han, W. Ligand-free Pd-catalyzed double carbonylation of aryl iodides with amines to α-ketoamides under atmospheric pressure of carbon monoxide and at room temperature. J. Org. Chem. 80, 7816–7823 (2015).
Saito, N. et al. Double carbonylation of aryl iodides with amines under an atmospheric pressure of carbon monoxide using sulfur-modified Au-supported palladium. Green Chem. 17, 2358–2361 (2015).
Wang, Z., Liu, C., Huang, Y., Hu, Y. & Zhang, B. Covalent tiazine framework-supported palladium as a ligand-free catalyst for the selective double carbonylation of aryl iodides under ambient pressure of CO. Chem. Commun. 52, 2960–2963 (2016).
Zhu, J. Recent developments in the isonitrile-based multicomponent synthesis of heterocycles. Eur. J. Org. Chem. 1133–1144 (2003).
Gulevich, A. V., Zhdanko, A. G., Orru, R. V. A. & Nenajdenko. V. G. Isocyanoacetate derivatives: synthesis, reactivity, and application. Chem. Rev. 110, 5235–5331 (2010).
Isocyanide Chemistry. Applications in synthesis and material science. (Eds.: V. G. Nenajdenko), Wiley-VCH, Weinheim, (2012).
Qiu, G., Ding, Q. & Wu, J. Recent advances in isocyanide insertion chemistry. Chem. Soc. Rev. 42, 5257–5269 (2013).
Vlaar, T., Ruijter, E., Maes, B. U. W. & Orru, R. V. A. Palladium-catalyzed migratory insertion of isocyanides: an emerging platform in cross-coupling chemistry. Angew. Chem. Int. Ed. 52, 7084–7097 (2013).
Chakrabarty, S. et al. Catalytic isonitrile insertions and condensations initiated by RNC−X complexation. Adv. Synth. Catal. 356, 2135–2196 (2014).
Giustiniano, M. et al. To each his own: isonitriles for all flavors. Functionalized isocyanides as valuable tools in organic synthesis. Chem. Soc. Rev. 46, 1295–1357 (2017).
Song, B. & Xu, B. Metal-catalyzed C−H functionalization involving isocyanides. Chem. Soc. Rev. 46, 1103–1123 (2017).
Wang, Q., Wang, D.-X., Wang, M.-X. & Zhu, J. Still unconquered: enantioselective passerini and Ugi multicomponent reactions. Acc. Chem. Res. 51, 1290–1300 (2018).
Collet, J. W. et al. Recent advances in palladium-catalyzed isocyanide insertions. Molecules 25, 4906(2020).
Massarotti, A., Brunelli, F., Aprile, S. Giustiniano, M. & Tron, G. C. Medicinal chemistry of isocyanides. Chem. Rev. 121, 10742–10788 (2021).
Roose, T. R. et al. Transition metal-catalysed carbene- and nitrene transfer to carbon monoxide and isocyanides. Chem. Soc. Rev. 51, 5842–5877 (2022).
Jiang, H., Liu, B., Li, Y., Wang, A. & Huang, H. Synthesis of amides via palladium-catalyzed amidation of aryl halides. Org. Lett. 13, 1028–1031 (2011).
Whitby, R. J., Saluste, C. G. & Furber, M. Synthesis of α-iminoimidates by palladium catalysed double isonitrile insertion. Org. Biomol. Chem. 2, 1974–1976 (2004).
Pálinkás, N., Kollár, L. & Kégl, T. Palladium-catalyzed synthesis of amidines via tert-butyl isocyanide insertion. ACS Omega. 3, 16118–16126 (2018).
Dechert-Schmitt, A.-M. et al. Highly modular synthesis of 1,2-diketones via multicomponent coupling reactions of isocyanides as CO equivalents. ACS Catal. 9, 4508–4515 (2019).
Chen, B. & Wu, X.-F. Palladium-catalyzed synthesis of 1,2-diketones from aryl halides and organoaluminum reagents using tert-butyl isocyanide as the CO source. Org. Lett. 22, 636–641 (2020).
Hu, W., Li, M., Jiang, G., Wu, W. & Jiang, H. Synthesis of 2,3-difunctionalized benzofuran derivatives through palladium-catalyzed double isocyanide insertion reaction. Org. Lett. 20, 3500–3503 (2018).
Kobiki, Y., Kawaguchi, S. & Ogawa, A. Palladium-catalyzed synthesis of α-diimines from triarylbismuthines and isocyanides. Org. Lett. 17,3490–3493 (2015).
Chen, Z.-B. et al. Palladium-catalyzed synthesis of alpha-iminonitriles from aryl halides via isocyanide double insertion reaction. J. Org. Chem. 81, 1610–1616 (2016).
Peng, J. et al. Synthesis of polysubstituted 3-amino pyrroles via palladium-catalyzed multicomponent reaction (MVR). J. Org. Chem. 82, 3581–3588 (2017).
Pan, Y.-Y. et al. Synthesis of 3-iminoindol-2-amines and cyclic enaminones via palladium-catalyzed isocyanide insertion-cyclization. J. Org. Chem. 80, 5764–5770 (2015).
Li, M. et al. Divergent synthesis of fused tetracyclic heterocycles from diarylalkynes enabled by the selective insertion of isocyanide. Angew. Chem. Int. Edit. 61, e202208203 (2022).
Luo, Y. et al. A new saddle-shaped aza analog of tetraphenylene: Atroposelective synthesis and application as a chiral acylating reagent. CCS Chem. 4, 2897–2905 (2022).
Han, W.-Y. et al. Palladium-catalyzed nucleophilic substitution/C−H activation/aromatization cascade reaction: one approach to construct 6-unsubstituted phenanthridines. J. Org. Chem. 80, 11580–11587 (2015).
Yang, S.-Y. et al. 2, 2-Bifunctionalization of norbornene in palladium-catalyzed domino annulation. Org. Lett. 21, 8857–8860 (2019).
He, C., Han, W.-Y., Cui, B.-D., Wan, N.-W. & Chen, Y.-Z. Efficient assembly of molecular complexity enabled by palladium-catalyzed Heck coupling/C(sp²)−H activation/C(sp³)−H activation cascade. Adv. Synth. Catal. 362, 3655–3661 (2020).
Zhu, W.-Q. et al. Palladium-catalyzed [2 + 2 + 1] annulation: Access to chromone fused cyclopentanones with cyclopropenone as the CO source. Org. Chem. Front. 8, 3082–3090 (2021).
Zhu, W.-Q. et al. Aziridine used as a vinylidene unit in palladium-catalyzed [2 + 2 + 1] domino annulation. Org. Chem. Front. 8, 3413–3420 (2021).
Li, F. et al. Palladium-catalyzed domino reaction for the assembly of norbornane-containing chromones with dimethyl squarate as the solid C1 source. Org. Lett. 24, 9392–9397 (2022).
Fang, Y.-C. et al. Palladium-catalyzed decarboxylation [2 + 2 + 2] annulation approach to chromone-containing polycyclic compounds. Org. Chem. Front. 10, 3752–3759 (2023).
Tong, Q. et al. Toward the generation of 2-amino-3-formyl difunctionalized chromones via Pd-enabled rearrangement strategy. ACS Catal. 13, 12692–12699 (2023).
For details about the optimization of reaction conditions, see the Supporting Information.
For details about the crystallographic data, see the Supporting Information.
Perego, L. A., Fleurat-Lessard, P., KaÏm, L. E., Ciofini, I. & Grimaud, L. Multiple roles of isocyanides in palladium-catalyzed imidoylative couplings: a mechanistic study. Chem. Eur. J. 22, 15491–15500 (2016).

Tables 1 and 2 are available in the Supplementary Files section.

There is NO Competing Interest.

79checkcif.pdf
CheckCIF 79
81checkcif.pdf
CheckCIF 81
6checkcif.pdf
CheckCIF 6
6.cif
Single Crystal 6
79.cif
Single Crystal 79
81.cif
Single Crystal 81
SupportingInformation.pdf
Supporting Information
Tables1and2.docx

Download PDF

Version 1

posted

You are reading this latest preprint version

De Novo Synthesis of α-Ketoamides via Pd/TBD Synergistic Catalysis

Status:

Version 1

Abstract

Figures

Introduction

Results and discussion

Discussion

Methods

Declarations

References

Tables

Additional Declarations

Supplementary Files

Status:

Version 1