Sunlight- or UVA-Light-Mediated Synthesis of Hydroxamic Acids from Carboxylic Acids

The development of light-mediated methods for synthetic applications is increasingly attracting high interest. We present herein a new photochemical protocol for the synthesis of hydroxamic acids, which constitute an important class of medicinal agents, mainly due to their anticancer properties. The method is mediated by UVA-light or sunlight and its key point is the generation of a charge transfer complex by the interaction of 4-dimethylaminopyridine with a halomethane. Various carboxylic acids were directly coupled with O-protected hydroxylamines, upon irradiation with either LED 370 nm or solar light. A detailed study of the mechanism was carried out by the employment of direct infusion–high resolution mass spectrometry (DI-HRMS), providing experimental evidence for the formation of various activated species, which may lead to the desired product. The light-mediated protocol was applied in the synthesis of the drugs Vorinostat and Bufexamac.     

One-pot synthesis of Weinreb amides employing 3,3-dichloro-1,2-diphenylcyclopropene (CPI-Cl) as a chlorinating agent

The synthesis of N^α-protected amino alkyl Weinreb amides starting from the corresponding α-amino acids as well as carboxylic acids has been delineated through the in situ generation of acid chlorides using CPI-Cl as a chlorinating agent. The protocol is simple; the reaction conditions employed were mild, and compatible with all the three commonly used urethane protecting groups namely, Boc, Cbz and Fmoc groups. The resulting Weinreb amides are obtained in good yields as optically pure products.     

Carbamoylimidazolium salts as diversification reagents: an application to the synthesis of tertiary amides from carboxylic acids

An efficient method for the preparation of tertiary amides from carbamoylimidazolium salts and carboxylic acids is described. The transformation occurs at room temperature and under relatively mild conditions. The carbamoylimidazolium salts are obtained from the reaction of secondary amines with N,N′-carbonyldiimidazole, followed by methylation with methyl iodide. The utility of this reaction was demonstrated in the formation of Weinreb amides and in a short synthesis of fused bicyclic amides. The introduction of this reaction now permits carbamoylimidazolium salts to be utilized in the formation of tertiary amides, ureas, carbamates and thiocarbamates under a single set of conditions.     

Preparation of Weinreb amides using 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM)

Weinreb amides were successfully prepared from the corresponding carboxylic acids using 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM) in the solvents, methanol, isopropyl alcohol, and acetonitrile, which can solubilize DMT-MM. A variety of carboxylic acids were converted to the corresponding Weinreb amides in excellent yields by simply mixing with DMT-MM and N,O-dimethylhydroxylamine hydrochloride.     

Synthesis of medicinally interesting polyfluoro ketones via perfluoroalkyl lithium reagents

The addition of (pentafluoroethyl)- and (heptafluoropropyl)lithium to various acyl derivatives was studied. Weinreb and morpholine amides led to polyfluoro ketones in high to quantitative yields in short reaction times. Derivatives of 2-fluorocarboxylic acids may produce 1,1,1,2,2,4-hexafluoro ketones and 1,1,1,2,2,3,3,5-octafluoro ketones. The methodology can provide inhibitors for various lipolytic enzymes, including phospholipase A2.     

An efficient entry to pyrrolo[1,2-b]isoquinolines and related systems through Parham cyclisation

Aryllithiums generated by lithium-iodine exchange undergo intramolecular cyclisation to give pyrrolo[1,2-b]isoquinolines, in high yields. The best results were obtained when Weinreb or morpholine amides were used as internal electrophiles. The procedure has been extended to the preparation of seven and eight membered rings, opening a route to benzazepine and benzazocine skeletons.     

A one-flask synthesis of Weinreb amides from chiral and achiral carboxylic acids using the deoxo-fluor fluorinating reagent

[structure] The reagent [bis(2-methoxyethyl)amino]sulfur trifluoride (Deoxo-Fluor reagent) converts carboxylic acids to the corresponding acid fluorides, which then react with N,N-dimethylhydroxylamine to give the corresponding Weinreb amides in high yields. The reaction proceeds without racemization when optically active acids are used as the starting material. This method is operationally simple and provides the products in high purity.     

Synthesis of various acylating agents directly from carboxylic acids

Abstract

A straightforward synthesis of acylating reagents such as Weinreb and MAP amides from aromatic, aliphatic carboxylic acids, and amino acids using PPh₃/NBS combination is described. A chemo-selective modification of the carboxylic acid group into Weinreb amide in the presence of more reactive aldehydes and ketones is presented. All reactions were performed at ambient temperature under air using undried commercial grade solvent. Furthermore, the present methodology could be performed at a gram scale under inert-free reaction conditions. In addition, 7-azaindoline amide auxiliary (used for catalytic asymmetric aldol- and Mannich-type reactions), which behaves like Weinreb amide is also synthesized under similar reaction conditions.     

Ortho lithiation-in situ borylation of substituted morpholine benzamides

Morpholine amides are cheap and safe alternative to Weinreb amides as acylating agents of organometallic species. Herein, the in-situ lithiation/borylation of 18 ortho- meta- and para-substituted morpholine benzamides has been investigated. 10 of the 18 substrates provided the desired boronic esters as the major isomer (>90% regioselectivity) in crude isolated yields ranging from 68 to 93%. The synthetic usability of such building blocks was subsequently illustrated via the synthesis of a kinase inhibitor.     

New approaches to β-trifluoromethylated enone derivatives

β-Trifluoromethylated enaminones 1 were prepared stereospecifically or high stercoselectively in 31-92% yields from the reaction of Weinreb amides with trifluoropropynyl lithium, followed by quenching with H₂O in the presence of amine derivatives. β-Trifluoromethylated enaminone 1a was reacted with aryl or alkynyl Grignard reagents to give Michael addition products 5 at 0 °C, whereas addition-elimination adducts, β-aryl (or alkynyl)-β-trifluoromethylated enones 6, were obtained stereospecifically in 50-92% yields after stirring at room temperature for several hours.     

Copper-catalyzed oxidative coupling of carboxylic acids with formamides for the synthesis of α,β-unsaturated amides

A novel and efficient protocol for the synthesis of α,β-unsaturated amides has been developed using catalytic amount of Cu(OAc)₂ and TBHP as an available oxidant. Oxidative coupling of various unsaturated carboxylic acids with N,N-disubstituted formamides was examined to furnish the desired products in good yields.     

Microwave‐Assisted Synthesis of Amide under Solvent‐free Conditions

An efficient and environmentally friendly synthetic method for the synthesis of primary amides under microwave irradiation was described, in which the primary amine was directly reacted with acid without any catalytic agents. The reaction took place in 8–12 min, which was much shorter than the traditional synthetic methods, with almost quantitative yields. The influential factor of the reaction was discussed. The tautomerization between the carboxylic acid group and the H atom in α‐carbon of L‐amino acid was observed, presumably a dehydrated intermediate forming from this tautomerized isomer.     

Palladium-catalyzed arylation of α,β-unsaturated Weinreb amides

Palladium-catalyzed arylation of α,β-unsaturated Weinreb amides has been examined to obtain β-aryl-α,β-unsaturated Weinreb amides. The chelation between the palladium center of an alkylpalladium intermediate and Weinreb amide moiety facilitated both coordination and insertion steps.     

Direct hydrogenation of nitroaromatics and one-pot amidation with carboxylic acids over platinum nanowires

A novel ultrathin platinum nanowire with uniform length and a diameter of 1.5 nm was synthesized by acidic etching of FePt nanowire in methanol. This nanowire was characterized by high‐resolution transmission electron microscopy (HRTEM). X‐ray diffraction (XRD) data indicated that the main plane is (111). The ability of this nanowire to catalyze the heterogeneous hydrogenation of nitroaromatics to give the corresponding amines has been investigated. The catalyst showed satisfactory activity in various solvents under mild conditions and showed excellent stability. The catalytic performance was also evaluated in the one‐pot reduction of nitroaromatics and amidation with carboxylic acids under a hydrogen atmosphere at 100 °C. These methods for the hydrogenation of nitroaromatics and the direct amidation of nitroaromatics with carboxylic acids are simple, economical, and environmentally benign, and have practical advantages for the synthesis of amines and amides without the production of toxic byproducts.     

Microwave-assisted synthesis of amides from various amines and benzoyl chloride under solvent-free conditions: A rapid and efficient method for selective protection of diverse amines

A number of structurally diverse amides were synthesized by reaction of the corresponding amines with benzoyl chloride under microwave irradiation. The proposed procedure ensures short reaction time, high yields, and excellent selectivity and considerably broadens the series of amines as compared to the microwave-assisted synthesis of amides directly from carboxylic acids. It can also be used for selective protection of various amines, including aromatic, aliphatic, and heterocyclic. Published in Russian in Zhurnal Organicheskoi Khimii, 2008, Vol. 44, No. 3, pp. 365–368. The text was submitted by the authors in English.     

Rapid and Mild Lactamization Using Highly Electrophilic Triphosgene in a Microflow Reactor

Lactams are cyclic amides that are indispensable as drugs and as drug candidates. Conventional lactamization includes acid-mediated and coupling-agent-mediated approaches that suffer from narrow substrate scope, much waste, and/or high cost. Inexpensive, less-wasteful approaches mediated by highly electrophilic reagents are attractive, but there is an imminent risk of side reactions. Herein, a methods using highly electrophilic triphosgene in a microflow reactor that accomplishes rapid (0.5–10 s), mild, inexpensive, and less-wasteful lactamization are described. Methods A and B, which use N-methylmorpholine and N-methylimidazole, respectively, were developed. Various lactams and a cyclic peptide containing acid- and/or heat-labile functional groups were synthesized in good to high yields without the need for tedious purification. Undesired reactions were successfully suppressed, and the risk of handling triphosgene was minimized by the use of microflow technology.     

One-pot synthesis of aldehydes or ketones from carboxylic acids via in situ generation of Weinreb amides using the Deoxo-Fluor reagent

A one-pot, high yield conversion of carboxylic acids to the corresponding aldehydes and ketones is described. The highlight of this methodology is the in situ generation of Weinreb amides with the Deoxo-Fluor reagent, which undergo nucleophilic reaction with DIBAL-H and Grignard reagents.     

One-Pot synthesis of (2E)- and (2E, 4E)- unsaturated carboxylic acid amides via organotellurium reagents

Di-n-butyl telluride, 2-bromoacetylisobutylamide (or 2-bromoacetylpiperidide) react directly with saturated or α,β-unsaturated aldehydes at room temperature in the presence of potassium carbonate(s) to afford (2E)-, or (2E, 4E)-unsaturated carboxylic acid amides, respectively, in excellent yields with high E stereoselectivity.     

Reaction of cis-2,3-dioctylaziridine with carboxylic acids

A series of aliphatic and aromatic carboxylic acids reacted with 2,3-dioctylaziridine to yield β-hydroxyalkyl amides in 69–89% yields and 2-substituted 4,5-di-n-octyl-δ²-oxazolines in amounts ranging from traces to 12% of the theoretical. No correlation could be found between carboxylic acid strength and either hydroxyamide or δ²-oxazoline yields. Solvents affected the product distribution.     

The Broad Aryl Acid Specificity of the Amide Bond Synthetase McbA Suggests Potential for the Biocatalytic Synthesis of Amides

Amide bond formation is one of the most important reactions in pharmaceutical synthetic chemistry. The development of sustainable methods for amide bond formation, including those that are catalyzed by enzymes, is therefore of significant interest. The ATP‐dependent amide bond synthetase (ABS) enzyme McbA, from Marinactinospora thermotolerans, catalyzes the formation of amides as part of the biosynthetic pathway towards the marinacarboline secondary metabolites. The reaction proceeds via an adenylate intermediate, with both adenylation and amidation steps catalyzed within one active site. In this study, McbA was applied to the synthesis of pharmaceutical‐type amides from a range of aryl carboxylic acids with partner amines provided at 1–5 molar equivalents. The structure of McbA revealed the structural determinants of aryl acid substrate tolerance and differences in conformation associated with the two half reactions catalyzed. The catalytic performance of McbA, coupled with the structure, suggest that this and other ABS enzymes may be engineered for applications in the sustainable synthesis of pharmaceutically relevant (chiral) amides.