Iridium‐Catalyzed Reductive Alkylations of Secondary Amides

Reported herein is the first direct, metal‐catalyzed reductive functionalization of secondary amides to give functionalized amines and heterocycles. The method is shown to have exceptionally broad scope with respect to suitable nucleophiles, which cover both hard and soft C nucleophiles as well as a P nucleophile. The reaction exhibits good chemoselectivity and tolerates several sensitive functional groups.     

Copper Catalyzed C−H Activation

Activation of C?H bonds and their application in cross coupling chemistry has received a wider interest in recent years. The conventional strategy in cross coupling reaction involves the pre‐functionalization step of coupling reactants such as organic halides, pseudo‐halides and organometallic reagents. The C?H activation facilitates a simple and straight forward approach devoid of pre‐functionalization step. This approach also addresses the environmental and economical issues involved in several chemical reactions. In this account, we have reported C?H bond activation of small organic molecules, for example, formamide C?H bond can be activated and coupled with β‐dicarbonyl or 2‐carbonyl substituted phenols under oxidative conditions to yield carbamates using inexpensive copper catalysts. Phenyl carbamates were successfully synthesized in moderate to good yields by cross dehydrogenative coupling (CDC) of phenols with formamides using copper catalysts in presence of a ligand. We have also prepared unsymmetrical urea derivatives by oxidative cross coupling of formamides with amines using copper catalysts. Synthesis of N,N‐dimethyl substituted amides, 5‐substituted‐γ‐lactams and α‐acyloxy ethers was carried out from carboxylic acids using recyclable CuO nanoparticles. Copper nanoparticles afforded N‐aryl‐γ‐amino‐γ‐lactams by oxidative coupling of aromatic amines with 2‐pyrrolidinone. Reusable transition metal HT‐derived oxide catalyst was used for the synthesis of N,N‐dimethyl substituted amides by the oxidative cross‐coupling of carboxylic acids and substituted benzaldehydes. Overview of our work in this area is summarized.     

Direct Nucleophilic Addition to N‐Alkoxyamides

While the synthesis of amide bonds is now one of the most reliable organic reactions, functionalization of amide carbonyl groups has been a long‐standing issue due to their high stability. As an ongoing program aimed at practical transformation of amides, we developed a direct nucleophilic addition to N‐alkoxyamides to access multisubstituted amines. The reaction enabled installation of two different functional groups to amide carbonyl groups in one pot. The N‐alkoxy group played important roles in this reaction. First, it removed the requirement for an extra preactivation step prior to nucleophilic addition to activate inert amide carbonyl groups. Second, the N‐alkoxy group formed a five‐membered chelated complex after the first nucleophilic addition, resulting in suppression of an extra addition of the first nucleophile. While diisobutylaluminum hydride (DIBAL‐H) and organolithium reagents were suitable as the first nucleophile, allylation, cyanation, and vinylation were possible in the second addition including inter‐ and intramolecular reactions. The yields were generally high, even in the synthesis of sterically hindered α‐trisubstituted amines. The reaction exhibited wide substrate scope, including acyclic amides, five‐ and six‐membered lactams, and macrolactams.     

Cross‐Coupling of Alkyl Redox‐Active Esters with Benzophenone Imines: Tandem Photoredox and Copper Catalysis

Alkyl amines are an important class of organic compounds in medicinal and materials chemistry. Until now very have been very few methods for the synthesis of alkyl amines by metal‐catalyzed cross‐coupling of alkyl electrophiles with nitrogen nucleophiles. Described here is an approach to employ tandem photoredox and copper catalysis to enable the cross‐coupling of alkyl N‐hydroxyphthalimide esters, readily derived from alkyl carboxylic acids, with benzophenone‐derived imines. Hydrolysis of the coupling products furnish alkylated primary amines. Primary, secondary, and tertiary alkyl groups can be transferred, and the coupling tolerates a diverse set of functional groups. The method allows rapid functionalization of natural products and drugs, and can be used to expedite syntheses of pharmaceuticals from readily available chemical feedstocks.     

A metal-free approach to access ketones,amides, and nitriles employing TBAI/TBHP oxidative system in water

Hydrocarbons, benzylamines, and heteroaromatic-bearing amines have been efficiently employed as substrates in allylic and benzylic oxidations via C(sp3)–H bond activation by TBAI/TBHP in water. This operationally simple method allows access to ketones, nitriles, and amides in moderate to high yields and a regio- and chemoselective late-stage functionalization.     

Intermolecular C−H Amidation of (Hetero)arenes to Produce Amides through Rhodium‐Catalyzed Carbonylation of Nitrene Intermediates

Amide bond formation is one of the most important reactions in organic chemistry because of the widespread presence of amides in pharmaceuticals and biologically active compounds. Existing methods for amides synthesis are reaching their inherent limits. Described herein is a novel rhodium‐catalyzed three‐component reaction to synthesize amides from organic azides, carbon monoxide, and (hetero)arenes via nitrene‐intermediates and direct C?H functionalization. Notably, the reaction proceeds in an intermolecular fashion with N₂ as the only by‐product, and either directing groups nor additives are required. The computational and mechanistic studies show that the amides are formed via a key Rh‐nitrene intermediate.     

Iron‐Catalyzed Cα?H Oxidation of Tertiary,Aliphatic Amines to Amides under Mild Conditions

De novo syntheses of amides often generate stoichiometric amounts of waste. Thus, recent progress in the field has focused on precious metal catalyzed, oxidative protocols to generate such functionalities. However, simple tertiary alkyl amines cannot be used as starting materials in these protocols. The research described herein enables the oxidative synthesis of amides from simple, noncyclic tertiary alkyl amines under synthetically useful, mild conditions through a biologically inspired approach: Fe‐catalyzed C_α H functionalization. Mechanistic investigations provide insight into reaction intermediates and allow the development of a mild C_α H cyanation method using the same catalyst system. The protocol was further applied to oxidize the drug Lidocaine, demonstrating the potential utility of the developed chemistry for metabolite synthesis.     

Iron‐Catalyzed CαH Oxidation of Tertiary,Aliphatic Amines to Amides under Mild Conditions

De novo syntheses of amides often generate stoichiometric amounts of waste. Thus, recent progress in the field has focused on precious metal catalyzed, oxidative protocols to generate such functionalities. However, simple tertiary alkyl amines cannot be used as starting materials in these protocols. The research described herein enables the oxidative synthesis of amides from simple, noncyclic tertiary alkyl amines under synthetically useful, mild conditions through a biologically inspired approach: Fe‐catalyzed C_α? H functionalization. Mechanistic investigations provide insight into reaction intermediates and allow the development of a mild C_α? H cyanation method using the same catalyst system. The protocol was further applied to oxidize the drug Lidocaine, demonstrating the potential utility of the developed chemistry for metabolite synthesis.     

Microwave-assisted deacylation of unactivated amides using ammonium-salt-accelerated transamidation

The combination of an ammonium salt and ethylenediamine promotes deacylation of a variety of unactivated amides to give the corresponding amines in high yields without the use of strong acids or bases. The reactions proceed without special care regarding air and moisture, and tolerate a wide range of functional groups.     

Convenient metal-free direct oxidative amidation of aldehyde using dibromoisocyanuric acid under mild conditions

A facile method for the direct synthesis of amides from aldehydes is described. Amide bonds were synthesized by an oxidative amidation in the presence of dibromoisocyanuric acid (DBI). Treatment of aromatic and aliphatic aldehydes with dibromoisocyanuric acid generated acyl bromide intermediates, which were employed to react with a variety of secondary and primary amines to give amides. Through this reaction method, various amides were synthesized directly from aldehydes under mild conditions in high yields and short times. This facile and efficient procedure provides potential strategy for the direct synthesis of amides from aldehydes.     

Selective α‐Oxyamination and Hydroxylation of Aliphatic Amides

Compared to the α‐functionalization of aldehydes, ketones, even esters, the direct α‐modification of amides is still a challenge because of the low acidity of α‐CH groups. The α‐functionalization of N−H (primary and secondary) amides, containing both an unactived α‐C−H bond and a competitively active N−H bond, remains elusive. Shown herein is the general and efficient oxidative α‐oxyamination and hydroxylation of aliphatic amides including secondary N−H amides. This transition‐metal‐free chemistry with high chemoselectivity provides an efficient approach to α‐hydroxy amides. This oxidative protocol significantly enables the selective functionalization of inert α‐C−H bonds with the complete preservation of active N−H bond.     

Palladium-catalyzed carbonylation of aryl bromides using microwave heating and bis[CP-Fe(II)-(CO)2] as a carbon monoxide source

A palladium-catalyzed, microwave assisted carbonylative reaction is described for the synthesis of benzamides from aryl bromides and primary or secondary amines. The developed method uses bis(cyclopentadienyldicarbonyliron) as a solid source of carbon monoxide to produce a diverse set of secondary and tertiary amides in 42–82% yield.     

Supported Gold Nanoparticles for Efficient α‐Oxygenation of Secondary and Tertiary Amines into Amides

Although the α‐oxygenation of amines is a highly attractive method for the synthesis of amides, efficient catalysts suited to a wide range of secondary and tertiary alkyl amines using O₂ as the terminal oxidant have no precedent. This report describes a novel, green α‐oxygenation of a wide range of linear and cyclic secondary and tertiary amines mediated by gold nanoparticles supported on alumina (Au/Al₂O₃). The observed catalysis was truly heterogeneous, and the catalyst could be reused. The present α‐oxygenation utilizes O₂ as the terminal oxidant and water as the oxygen atom source of amides. The method generates water as the only theoretical by‐product, which highlights the environmentally benign nature of the present reaction. Additionally, the present α‐oxygenation provides a convenient method for the synthesis of ¹⁸O‐labeled amides using H₂¹⁸O as the oxygen source.     

The ruthenium-catalyzed reduction and reductive N-alkylation of secondary amides with hydrosilanes: practical synthesis of secondary and tertiary amines by judicious choice of hydrosilanes

A triruthenium cluster, (mu3,eta2,eta3,eta5-acenaphthylene)Ru3(CO)7 (1) catalyzes the reaction of secondary amides with hydrosilanes, yielding a mixture of secondary amines, tertiary amines, and silyl enamines. Production of secondary amines with complete selectivity is achieved by the use of higher concentration of the catalyst (3 mol %) and the use of bifunctional hydrosilanes such as 1,1,3,3-tetramethyldisiloxane. Acidic workup of the reaction mixture affords the corresponding ammonium salts, which can be treated with a base, providing a facile method for isolation of secondary amines with high purity. In contrast, tertiary amines are formed with high selectivity by using lower concentration of the catalyst (1 mol %) and polymeric hydrosiloxanes (PMHS) as reducing agent. Reduction with PMHS encapsulates the ruthenium catalyst and organic byproducts to the insoluble silicone resin. The two reaction manifolds are applicable to various secondary amides and are practical in that the procedures provide the desired secondary or tertiary amine as a single product. The product contaminated with only minimal amounts of ruthenium and silicon residues. On the basis of the products and observed side products as well as NMR studies a mechanistic scenario for the reaction is also described.     

Practical synthesis of amides from alkynyl bromides, amines, and water

A general and efficient method for the synthesis of a wide range of amides is described here. The reactions were conducted under convenient conditions and provided secondary and tertiary amides in moderate to excellent yields. A variety of amines and substituted alkynyl bromides were used to investigate the scope of the reactions.     

Versatile Functionalization of Carbohydrate Hydroxyl Groups through Their O-Cyanomethyl Ethers

O-Cyanomethyl ethers of carbohydrates are shown to be versatile intermediates for the preparation of sugar amines, carboxylic acids, amides, and amidine salts. This methodology for the functionalization of carbohydrates can thus provide a new array of analogs for the study of carbohydrate binding proteins. In addition, the resulting O-aminoethyl and O-carboxymethyl carbohydrates can be coupled to amino acids under standard conditions used in solid-phase peptide synthesis, providing a method for the construction of glycopeptides in which the carbohydrate moiety can be linked through any of its hydroxyl groups to the C- or the N-terminus of a given peptide.     

Microwave-assisted solution phase synthesis of dihydropyrimidine C5 amides and esters

Multifunctionalized dihydropyrimidine-5-carboxylic amides and esters are generated in a multistep sequence integrating a variety of enabling and high throughput technologies such as automated or parallel microwave synthesis, the use of polymer-supported reagents, fluorous synthesis and purification strategies, and a continuous flow hydrogenation system. The key dihydropyrimidine-5-carboxylic acid intermediates are obtained in two steps by Biginelli multicomponent condensation of benzyl or allyl β-ketoesters with aldehydes and urea/thioureas, followed by suitable benzyl or allyl deprotection strategies. Further functionalization of the acid cores with amines using polymer-supported coupling reagents or with alcohols utilizing Mitsunobu chemistry provides the desired amides or esters, respectively.     

Transition-Metal-Free Reductive Functionalization of Tertiary Carboxamides and Lactams for α-Branched Amine Synthesis

A new method for the synthesis of α-branched amines by reductive functionalization of tertiary carboxamides and lactams is described. The process relies on the efficient and controlled reduction of tertiary amides by a sodium hydride/sodium iodide composite, in situ treatment of the resulting anionic hemiaminal with trimethylsilyl chloride and subsequent coupling with nucleophilic reagents including Grignard reagents and tetrabutylammonium cyanide. The new method exhibits broad functional-group compatibility, operates under transition-metal-free reaction conditions, and is suitable for various synthetic applications on both sub-millimole and on multigram scales.     

Reductive hydroxyalkylation/alkylation of amines with lactones/esters

We have developed a one-pot method for the direct intermolecular reductive hydroxyalkylation or alkylation of amines using lactones or esters as the hydroxyalkylating/alkylating reagents. The method is based on the in situ amidation of lactones/esters with DIBAL-H-amine complex (for primary amines) or DIBAL-H-amine hydrochloride salt complex (for secondary amines), followed by reduction of the amides with an excess of DIBAL-H. Different from the reduction of Weinreb amides with DIBAL-H where aldehydes are formed, the reduction of the in situ formed Weinreb amides yielded amines. Moreover, this method is not limited to Weinreb amides, instead, it also works for other amides in general. A plausible mechanism is suggested to account for the outcome of the reactions.     

Zinc-catalyzed chemoselective reduction of tertiary and secondary amides to amines

General and convenient procedures for the catalytic hydrosilylation of secondary and tertiary amides under mild conditions have been developed. In the presence of inexpensive zinc catalysts, tertiary amides are easily reduced by applying monosilanes. Key to success for the reduction of the secondary amides is the use of zinc triflate and disilanes with dual Si-H moieties. The presented hydrosilylations proceed with excellent chemoselectivity in the presence of sensitive ester, nitro, azo, nitrile, olefins, and other functional groups, thus making the method attractive for organic synthesis.