Copper-catalyzed Amidation Research Articles

Sequential Copper-Catalyzed Amidation and Hydroxylation for Acetaminophen Synthesis

AbstractA sequential Cu-catalyzed amidation and hydroxylation of p-dihalobenzenes is applied to synthesize acetaminophen. This method allows the direct introduction of acetamido and hydroxy groups under acid-free conditions without forming other regioisomers. By using a one-pot process, acetaminophen can be prepared with an overall yield of up to 74%.

A relay catalysis strategy for enantioselective nickel-catalyzed migratory hydroarylation forming chiral α-aryl alkylboronates

A relay catalysis strategy for enantioselective nickel-catalyzed migratory hydroarylation forming chiral α-aryl alkylboronates

Kilogram-Scale Preparation of an Aminopyrazole Building Block via Copper-Catalyzed Aryl Amidation

We describe a scalable method for preparing an aminopyrazole building block using copper-catalyzed amidation with acetamide as an ammonia surrogate. This procedure provides an alternative to the standard nitration/reduction sequence and avoids energetic intermediates, specialized hydrogenation equipment, and potentially genotoxic impurities that arise from nitro reduction. The chemistry has been successfully scaled to produce >50 kg of the target compound and demonstrate the viability of this alternative route.

Ligand-free copper-catalyzed direct amidation of diaryliodonium salts using nitriles as amidation reagents

An efficient and practicalmethodology for the synthesis of N-arylamides has been developed via copper-catalyzed amidation of diaryliodonium salts with nitriles. Various substituted aryl nitriles and aliphatic nitriles could be applied in the reaction, providing a series of N-arylated amides in moderate to good yields. This procedure provides an alternative route for the synthesis of various N-arylamides. A proposed mechanism based on control experiments is also presented.

A Next Generation Synthesis of BACE1 Inhibitor Verubecestat (MK-8931)

The development of a commercial manufacturing route to verubecestat (MK-8931) is described, highlights of which include the application of a continuous processing step to outcompete fast proton transfer in a Mannich-type ketimine addition, a copper-catalyzed amidation reaction, and an optimized guanidinylation procedure to form the key iminothiadiazine dioxide core.

Dithienopyrrole-based monomers as an acceptor unit building for synthesis of donor – acceptor conjugated polymers

A new monomer of N-benzoyl dithieno[2,3-b:2’,3’-d]pyrrole (BDP), has been successfully prepared via copper-catalyzed amidation. Then, this monomer was brominated to form 2,6-dibromo-n-benzoyl dithieno[2,3-b:2’,3’-d]pyrrole (DiBDP) monomer. The structures of monomers were confirmed via the nuclear magnetic resonance (1HNMR) and Fourier transform infrared (FT-IR). BDP and DiBDP monomers will be used as monomers for Suzuki polycondensation reaction to synthesize the donor-acceptor (D-A) conjugated polymers.

ChemInform Abstract: Copper‐Catalyzed Amidation of Arylboronic Acids with Nitriles.

A copper-catalyzed amidation of arylboronic acids with nitriles has been developed. This reaction provides an efficient and complementary methodology for the synthesis of various N-arylamides with a broad substrate scope.

Copper-catalyzed one-pot oxidative amidation of alcohol to amide via C–H activation

Copper-catalyzed one-pot oxidative amidation of both aliphatic and aromatic alcohols with N-chloramines, prepared in situ from many types of primary and secondary amines, to form amides under mild conditions.

Copper-Catalyzed Amidation of Arylboronic Acids with Nitriles

A copper-catalyzed amidation of arylboronic acids with nitriles has been developed. This reaction provides an efficient and complementary methodology for the synthesis of various <i>N</i>-arylamides with a broad substrate scope.

Copper-Catalyzed Ligand-Free Amidation of Benzylic Hydrocarbons and Inactive Aliphatic Alkanes.

An efficient copper-catalyzed amidation of benzylic hydrocarbons and inactive aliphatic alkanes with simple amides was developed. The protocol proceeded smoothly without any ligand, and a wide range of N-alkylated aromatic and aliphatic amides, sulfonamides, and imides were synthesized in good yields.

ChemInform Abstract: Copper‐Catalyzed Oxidative Dehydrogenative Carboxylation of Unactivated Alkanes to Allylic Esters via Alkenes.

We report copper-catalyzed oxidative dehydrogenative carboxylation (ODC) of unactivated alkanes with various substituted benzoic acids to produce the corresponding allylic esters. Spectroscopic studies (EPR, UV-vis) revealed that the resting state of the catalyst is [(BPI)Cu(O2CPh)] (1-O2CPh), formed from [(BPI)Cu(PPh3)2], oxidant, and benzoic acid. Catalytic and stoichiometric reactions of 1-O2CPh with alkyl radicals and radical probes imply that C-H bond cleavage occurs by a tert-butoxy radical. In addition, the deuterium kinetic isotope effect from reactions of cyclohexane and d12-cyclohexane in separate vessels showed that the turnover-limiting step for the ODC of cyclohexane is C-H bond cleavage. To understand the origin of the difference in products formed from copper-catalyzed amidation and copper-catalyzed ODC, reactions of an alkyl radical with a series of copper-carboxylate, copper-amidate, and copper-imidate complexes were performed. The results of competition experiments revealed that the relative rate of reaction of alkyl radicals with the copper complexes follows the trend Cu(II)-amidate > Cu(II)-imidate > Cu(II)-benzoate. Consistent with this trend, Cu(II)-amidates and Cu(II)-benzoates containing more electron-rich aryl groups on the benzamidate and benzoate react faster with the alkyl radical than do those with more electron-poor aryl groups on these ligands to produce the corresponding products. These data on the ODC of cyclohexane led to preliminary investigation of copper-catalyzed oxidative dehydrogenative amination of cyclohexane to generate a mixture of N-alkyl and N-allylic products.

Studies Towards the Leucetta-derived Alkaloids Spirocalcaridine A and B - Possible Biosynthetic Implications.

An exploration of an abiotic approach to spirocalcaridines A and B is described centered on electrophile-induced dearomatizing spirocyclization of aryl enyne derivatives. Elaboration of the α-iodoenone via an Ullmann-like, copper-catalyzed amidation provided a formamide which upon treatment with methylamine undergoes a dienol-arene rearrangement, providing the corresponding kealiinine-like framework. This observation suggests a possible biosynthetic links between the spirocalcaridines and the naphthimidazole group of Leucetta alkaloids.

Copper-Catalyzed Amidation of π-Excessive Heterocycles

Copper-Catalyzed Amidation of π-Excessive Heterocycles

Copper-catalyzed oxidative dehydrogenative carboxylation of unactivated alkanes to allylic esters via alkenes.

We report copper-catalyzed oxidative dehydrogenative carboxylation (ODC) of unactivated alkanes with various substituted benzoic acids to produce the corresponding allylic esters. Spectroscopic studies (EPR, UV–vis) revealed that the resting state of the catalyst is [(BPI)Cu(O2CPh)] (1-O2CPh), formed from [(BPI)Cu(PPh3)2], oxidant, and benzoic acid. Catalytic and stoichiometric reactions of 1-O2CPh with alkyl radicals and radical probes imply that C–H bond cleavage occurs by a tert-butoxy radical. In addition, the deuterium kinetic isotope effect from reactions of cyclohexane and d12-cyclohexane in separate vessels showed that the turnover-limiting step for the ODC of cyclohexane is C–H bond cleavage. To understand the origin of the difference in products formed from copper-catalyzed amidation and copper-catalyzed ODC, reactions of an alkyl radical with a series of copper–carboxylate, copper–amidate, and copper–imidate complexes were performed. The results of competition experiments revealed that the relative rate of reaction of alkyl radicals with the copper complexes follows the trend Cu(II)–amidate > Cu(II)–imidate > Cu(II)–benzoate. Consistent with this trend, Cu(II)–amidates and Cu(II)–benzoates containing more electron-rich aryl groups on the benzamidate and benzoate react faster with the alkyl radical than do those with more electron-poor aryl groups on these ligands to produce the corresponding products. These data on the ODC of cyclohexane led to preliminary investigation of copper-catalyzed oxidative dehydrogenative amination of cyclohexane to generate a mixture of N-alkyl and N-allylic products.

ChemInform Abstract: Copper‐ and Palladium‐Catalyzed Amidation Reactions for the Synthesis of Substituted Imidazo[4,5‐c]pyridines.

Imidazo[4,5-c]pyridines were synthesized in three steps utilizing a palladium-catalyzed amidation/cyclization strategy. N-Aryl substrates were synthesized using copper-catalyzed amidation of 3-amino-N-Boc-4-chloropyridine. Complementary protocols for the selective chlorination of imidazo[4,5-c]pyridines at the C2 and C7 positions were also developed.

ChemInform Abstract: Copper‐Catalyzed Intermolecular Amidation and Imidation of Unactivated Alkanes.

AbstractThe copper‐catalyzed amidation of unactivated alkanes by benzamides, sulfonamides, carbamates, and phthalimides is described.

Copper- and Palladium-Catalyzed Amidation Reactions for the Synthesis of Substituted Imidazo[4,5-c]pyridines

Imidazo[4,5-c]pyridines were synthesized in three steps utilizing a palladium-catalyzed amidation/cyclization strategy. N-Aryl substrates were synthesized using copper-catalyzed amidation of 3-amino-N-Boc-4-chloropyridine. Complementary protocols for the selective chlorination of imidazo[4,5-c]pyridines at the C2 and C7 positions were also developed.

ChemInform Abstract: Copper‐Catalyzed Amidation of Acids Using Formamides as the Amine Source.

Copper-catalyzed amidation of acids with formamides or acetamide for the selective synthesis of amides with the aid of 1,4-diazabicyclo[2.2.2]octane as the ligand and tert-butyl hydroperoxide as the oxidant is presented. This method is highly compatible with a wide range of acids, including alkyl acids, aryl acids, α,β-unsaturated acids, and amino acids.

Synthesis of high performance polyamides utilizing copper-catalyzed amidation of a dibromoarene with different diamides

A series of diphenylquinoxaline-containing polyamides were prepared from the condensation polymerization of 2,3-bis (4-bromophenyl) quinoxaline (DBQ) with various primary and secondary diamides via copper-catalyzed amidation reaction. The polyamides were characterized with FTIR, NMR, GPC, differential scanning calorimeter, and thermo gravimetric analysis, and their solubility and viscosity were measured. The polyamides synthesized here are amorphous and showed relatively good solubility in polar aprotic solvents and demonstrate the ability to form brownish hard films by solvent casting; their inherent viscosities ranged from 49 to 55 mL/g. The average molecular weights of polyamides were in the range of Mw = 11,950–5592 g/mol (MWD = 1.21–1.87). These polyamides had relatively high thermal stability with Tg values up to 276°C, 10% weight loss temperatures (T10%) in the range of 364–476°C, and char yields at 600°C in N2 up to 72%. They also exhibit emission in the solid state and in dilute (0.2 g/dL) DMAc solution at 425–484 nm with photoluminescence quantum (ϕf) yields in the range of 14–23%. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2012

Copper-Catalyzed Amidation of 2-Phenylpyridine with Oxygen as the Terminal Oxidant

The Cu(OAc)(2)-catalyzed, O(2)-mediated amidation of 2-phenylpyridine via C-H bond activation is reported. A variety of nitrogen reagents including sulfonamides, carboxamides, and anilines participate in the reaction in moderate to good yields.