Weinreb Amides Research Articles

Remote Selective Cross‐Dehydrogenative Coupling Reactions of Aryl C−H Bonds with Carboxylic Acids at Room Temperature

AbstractAn efficient Pd(II)‐catalyzed remote selective cross‐dehydrogenative coupling of broadly useful synthetic building blocks biphenyl Weinreb amides with carboxylic acids is developed. This acetoxylation protocol is performed under room temperature using N‐fluorobenzene‐sulfonimide (NFSI) as the oxidant, exhibiting a wide range of functional group tolerance and affording δ‐position‐ selective products up to 85 % yield. Notably, a diverse set of carboxylic acid‐containing drugs is also found to be compatible under the current reaction conditions. Preliminary mechanistic studies indicate that this reaction presumably proceeds through a seven‐membered palladacycle intermediate.

Rhodium-Catalyzed Pyridylation of Alkynamides with Pyridylboronic Acids: A Route to Functionalized Enamides.

The catalytic direct hydroarylation of alkynamides is a highly efficient approach for accessing functionalized trisubstituted arylalkenes with amide groups. Herein, we report a rhodium-catalyzed pyridylation of alkynamides with pyridylboronic acids, producing a variety of primary, secondary, and tertiary enamides with high yields (up to 94 %). This reaction demonstrates broad tolerance towards various alkyl and aryl functional groups, providing convenient access to a diverse array of alkenylpyridine derivatives. To demonstrate potential applications in late-stage hydropyridylation, we synthesized α,β-unsaturated ketones, aldehydes, and esters with high yields from the pyridylation product of Weinreb amides. This indirect expansion of the substrate scope enhances the practicality of this strategy. Additionally, the α,β-unsaturated ketone obtained can be further reduced to yield a chiral alcohol with a 99 % ee, further demonstrating the versatility and potential utility of this approach.

Azirine Weinreb amides: Preparation and use in the synthesis of 2-acylated aziridines and azirines

Azirine Weinreb amides (N-methoxy-N-methyl-2H-azirine-2-carboxamides) were synthesized in yields of 35–94 % by the reaction of N,O-dimethylhydroxylamine with 2H-azirine-2-carbonyl chlorides, formed by the catalytic isomerization of 5-chloroisoxazoles. Red-Al reduction of azirine Weinreb amides affects only the azirine CN bond and leaves the C(O)NMeOMe group unaffected, forming stereoselectively 1-unprotected 3-substituted cis-N-methoxy-N-methylaziridine-2-carboxamides. The developed approach is a stereo-complementary addition to the previously proposed method for preparing unprotected trans-N-methoxy-N-methyl-3-phenylaziridine-2-carboxamide. The Weinreb amide group in the synthesized cis-N-methoxy-N-methylaziridine-2-carboxamides was used to prepare cis-2-acyl-3-arylaziridines by reaction with organometallic compounds. The reaction of organomagnesium compounds with azirine Weinreb amides allow the stereoselective preparation of 3-aryl-3-aryl/hetary/alkyl-N-methoxy-N-methylaziridine-2-carboxamides; which, in turn, were used to obtain the corresponding aziridinyl ketones. The reaction of azirine Weinreb amides with bulky substituents in the 3-position of azirine with organometallic compounds occurs only at the C(O)NMeOMe group with retention of the azirine CN bond with the formation of 2-acyl-2H-azirines.

The Application of Flow Chemistry for the Synthesis of Alkyl Sodium Compounds and Their Transformations with Weinreb Amides and Carboxylic Acids.

Herein, we describe the application of a flow system for the generation of a soluble organo sodium compound and the transformation of this primary nucleophile with various Weinreb amides for the synthesis of alkyl-aryl ketones. Thereafter, the generation of secondary sodium intermediates, such as benzylic sodium nucleophiles or ortho-metalated sodium nucleophiles from various carbon pre-nucleophiles, is described. These transformations generated more complex ketones, and in this investigation the key aspect was to identify factors for the chemoselective and regioselective C-H deprotonation of concurring sites within the starting material. Finally, the direct synthesis of ketones from carboxylic acids and the organo sodium compound is described, revealing interesting aspects regarding the nucleophilicity and basicity of the alkyl sodium reagent.

Isomerization of E-Cinnamamides into Z-Cinnamamides Using a Recycling Photoreactor.

The photocatalytic synthesis of thermodynamically less-stable Z-alkenes has received considerable research attention in recent years. In this study, a recycling photoreactor was applied to the photoisomerization of E-alkenes (cinnamamide and Weinreb amide derivatives) to produce Z-alkenes. The closed-loop recycling system comprises an immobilized photosensitizer to achieve rapid photoisomerization and a high-performance liquid chromatography instrument for separation of the Z/E diastereomers. After 4-10 cycles, the desired pure Z-alkenes were obtained efficiently. In the photoreactor system, a photosensitizer (thioxanthone) was covalently immobilized on silica gel via amide bonding, which led to an enhanced photocatalytic activity compared to the parent thioxanthone. This recycling photoreactor shows promise as an alternative system for the production of Z-alkenes.

Ruppert‐Prakash Reagent (TMSCF3)‐Catalyzed Chemoselective Esterification of Weinreb Amides

AbstractA straightforward TMSCF3‐catalyzed conversion of Weinreb amides into esters through the treatment with sodium alkoxides is reported. The procedure documents a genuine selectivity for the esterification of primary alcohols with Weinreb amides featuring diverse substitution pattern. The constitutive N‐methoxy fragment of these acylating agents is responsible for the unique reactivity they display, thus enabling to explore alkoxides as competent nucleophilic elements. The protocol is compatible with the fully transfer of stereochemical information embodied in the starting material, as well as, guarantees the preparation of pharmaceuticals. Mechanistic investigations revealed that under the adopted reaction conditions (NaOR, R primary) TMSCF3 does not release the trifluoromethyl (CF3−) anion – as occurs with tertiary alkoxides – but rather it catalytically activates the amidic bond.

Synthesis of 18F-labelled aryl trifluoromethyl ketones with improved molar activity.

A method for the radiosynthesis of 18F-labelled aryl trifluoromethyl ketones starting from widely available Weinreb amides using [18F]fluoroform is presented. The method uses potassium hexamethyldisilazane as base and delivers products in high molar activity (up to 24 GBq μmol-1) and excellent radiochemical conversions. The applicability for PET tracer synthesis is demonstrated by the radiosynthesis of ten (hetero)aryl trifluoromethylketones, bearing electron-withdrawing and -donating substituents including a derivative of bioactive probenecid.

The synthesis of alk-2-ynl Weinreb amides via Pd/Cu-catalysed oxidative carbonylation of terminal alkynes.

Synthesis of alk-2-ynl-Weinreb amides via Pd-catalyzed oxidative carbonylation of terminal alkynes and N,O-dimethylhydroxylamine hydrochloride at room temperature under low CO/O2 pressure is reported for the first time. This protocol offers tolerance of various functional groups under mild reaction conditions. The protocol incorporates aromatic- and aliphatic-substituted alkynes through a one-step oxidative carbonylative route toward desired alkynyl Weinreb amides, which are of considerable importance as valuable synthetic building blocks.

Evans’ Chiral Auxiliary‐Based Asymmetric Synthetic Methodology and Its Modern Extensions

AbstractAlthough the asymmetric catalysis has made a spurt of progress, the use of chiral auxiliaries remains crucial in asymmetric synthesis due to both the reliability and versatility of the methods, and the predictability of stereochemistry of the reactions. Up to date, Evans’ chiral non‐racemic oxazolidinone‐based asymmetric synthetic methodology is still widely used in asymmetric synthesis. More importantly, the Evans asymmetric synthetic methodology turned out to be a fruitful source of inspiration for the development of related asymmetric synthetic methodologies. However, although reviews on the application of Evans’ asymmetric synthetic methodology in both organic synthesis and medicinal chemistry continually to appear in the literature, a comprehensive review dedicating to the extensions of Evans’ chiral non‐racemic oxazolidinone‐based asymmetric methodology remains elusive. In this review, we summarize the extensions of the Evans asymmetric methodology, which cover: (1) the modification of the chiral oxazolidinone auxiliaries; (2) the extension of the Evans’ asymmetric aldol reaction from Evans’ syn‐aldol to other diastereomeric aldol adducts; (3) the extension of the asymmetric reaction types; (4) the extension of chiral imide‐type substrates to N‐alkenyl, N‐allenenyl and N‐alkynyl oxazolidinones; (5) the achiral oxazolidinone‐based asymmetric catalysis; (6) the catalytic transformation of Evans’ products; and (7) the straightforward transformations of Evans’ chiral products to other classes of compounds than the chiral carboxylic acids, esters, alcohols, and Weinreb amides.

The Chemical Synthesis of the 1-C-Alkyl Substituted Pyrrolidine and Piperidine Iminosugar Natural Products and their Analogues

Abstract: A review of the chemical synthesis of the 1-C-alkyl substituted pyrrolidine and piperidine iminosugar natural products and their analogues (where the alkyl chain comprises two or more carbons) is provided. These syntheses can be grouped into nine different synthetic strategies that share a common approach toward installing the alkyl substituent. These include nucleophilic addition to aldimines; Grignard additions to glycosylamines, cyclic imides, and carbohydrates; Weinreb ketone synthesis; nucleophilic addition to cyclic nitrones; the Overmann rearrangement; the allylation of hemiaminals; and the Petasis borono-Mannich reaction. The broussonetine alkaloids have proven popular synthetic targets to develop new synthetic methods and verify these target molecules' structures and stereochemistry.

Synthesis of Highly Substituted Pyrrolo[1,2‐a]quinoline‐3,5‐diones through Ag(I) Catalyzed Cyclization of 4‐Hydroxyquinolinyl‐2‐ynones

AbstractAn efficient synthetic route to access highly substituted pyrrolo[1,2‐a]quinoline‐3,5‐diones in which the core is formed by fusion of quinolone and pyrrolone moieties is discussed. The method involves Ag(I) catalyzed cyclization of 4‐Hydroxyquinolinyl‐2‐ynones which in turn may be accessed from kynurenic acid derivatives through Weinreb amide intermediate, followed by alkyne addition. Studies involving substrates with different substitution pattern revealed that factors increasing the nucleophilicity of quinoline nitrogen or Lewis acid‐coordination of the ynone unit gives high yields in short reaction times. It was possible to execute tandem cyclization‐arylation sequence by using Pd(II) generated by oxidative addition of Pd(0) with aryl iodide as the electrophilic species to get substitution pattern as seen in Discoipyrrole A.

Selective C-H Iodination of Weinreb Amides and Benzamides through Iridium Catalysis in Solution and under Mechanochemical Conditions.

The acid mediated ortho-iodination of Weinreb amides using a readily available catalyst is described. The selective ortho-iodination of Weinreb amides, challenging substrates in directed C-H activations, and also of benzamides is achieved. The process works under mild conditions and tolerates air and moisture, having a great potential for industrial applications. The methodology can be applied under mechanochemical conditions maintaining the reaction outcome and selectivity.

Copper‐Catalyzed Photoinduced [3+3] Cycloaddition Reactions of α‐Acidic Isocyanides with Tetrazoles

AbstractHerein, a copper‐catalyzed photoinduced [3+3] cycloaddition reaction of α‐acidic isocyanides with 2,5‐diaryltetrazoles is described. The reaction proceeded smoothly with high regioselectivity, affording a range of important 1,2,4‐triazines under mild conditions. The obtained 1,2,4‐triazines were converted into triazine alcohol, Weinreb amide and triazinone easily, which further illustrate the utility of this [3+3] cycloaddition process.

Syntheses of 9‐Vinylated Benzotropolones by a Sequence of Acylation, Ring‐Closing Enyne Metathesis, and Oxidation

AbstractPrevious studies from our group revealed that 6,7‐benzannulated nona‐1,8‐diene‐5‐ones of a variety of substitution patterns undergo ring‐closing diene metatheses in the presence of the Grubbs‐II catalyst; the benzocycloheptadienones formed thereby gave benzotropolones in between one and four follow‐up steps. The present study discloses that exemplary 6,7‐benzannulated non‐1‐en‐8‐yn‐5‐ones undergo ring‐closing enyne metatheses in the presence of the Grubbs‐II catalyst; the vinylated benzocycloheptadienones formed thereby gave 9‐vinylbenzotropolones in four steps: silyl enol ether formation, Rubottom‐type oxidation, desilylation, and Dess‐Martin oxidation. The metathesis substrates were synthesized either from (ortho‐bromoaryl)ethynes with an unsubstituted sp‐carbon by a Br→Li exchange and an acylation with an H2C=CH‐containing Weinreb amide; or, they were synthesized from (ortho‐bromoaryl)ethynes with a trimethylsilylated sp‐carbon by a Br→Li→ZnHal exchange, an acylation with an H2C=CH‐containing thioester, and a desilylation.

Synthesis and Photophysical Properties of Charge-Transfer-Based Pyrimidine-Derived α-Amino Acids.

The four-step synthesis of fluorescent pyrimidine-derived α-amino acids from an l-aspartic acid derivative is described. The key synthetic steps involved preparation of ynone intermediates via the reaction of alkynyl lithium salts with a Weinreb amide, followed by an ytterbium-catalyzed heterocyclization reaction with amidines. Variation of substituents at the C2- and C4-position of the pyrimidine ring allowed tuning of the photoluminescent properties of the α-amino acids. This revealed that a combination of highly conjugated or electron-rich aryl substituents with the π-deficient pyrimidine motif resulted in fluorophores with the highest quantum yields and overall brightness. Further analysis of the most fluorogenic α-amino acid demonstrated solvatochromism and sensitivity to pH.

A Photochemical Protocol for the Synthesis of Weinreb and Morpholine Amides from Carboxylic Acids Cover Feature: (Eur. J. Org. Chem. 24/2023)

The Cover Feature illustrates the photochemical conversion of carboxylic acids to Weinreb and morpholine amides. Sunlight or LED 370 nm irradiation mediates the direct coupling of carboxylic acids to N,O-dimethylhydroxylamine or morpholine in the presence of 4-dimethylaminopyridine and bromotrichloromethane, providing the corresponding amides in satisfactory to high yields. More information can be found in the Research Article by C. G. Kokotos, G. Kokotos et al.

Oxidative Coupling Approach to Sarpagine Alkaloids: Total Synthesis of (-)-Trinervine, Vellosimine, (+)-Normacusine B, and (-)-Alstomutinine C.

Sarpagine alkaloids are bioactive indole natural products that contain a highly rigid indole-fused 1-azabicyclo[2.2.2]octane, more than 100 members of which have been identified. Herein, a detailed examination of the intramolecular oxidative coupling between a ketone and a Weinreb amide for assembling the complex 1-azabicyclo[2.2.2]octane core structure of sarpagine family alkaloids is described. Precise late-stage manipulations of the ketone and Weinreb amide enable the divergent syntheses of (-)-trinervine, (+)-vellosimine, (+)-normacusine B, and (-)-alstomutinine C. Other notable transformations of the synthesis featured an aza-Achmatowicz/indole cyclization cascade to generate the azabicyclo[3.3.1]nonane structure, a regioselective elimination reaction to form the ethylidene motif embedded in the (+)-vellosimine and (+)-normacusine B structures, and a diastereoselective indole oxidative rearrangement to form the spirooxindole structure in (-)-alstomutinine C.

Oxidative Coupling Approach to Sarpagine Alkaloids: Total Synthesis of (−)‐Trinervine, Vellosimine, (+)‐Normacusine B, and (−)‐Alstomutinine C

AbstractSarpagine alkaloids are bioactive indole natural products that contain a highly rigid indole‐fused 1‐azabicyclo[2.2.2]octane, more than 100 members of which have been identified. Herein, a detailed examination of the intramolecular oxidative coupling between a ketone and a Weinreb amide for assembling the complex 1‐azabicyclo[2.2.2]octane core structure of sarpagine family alkaloids is described. Precise late‐stage manipulations of the ketone and Weinreb amide enable the divergent syntheses of (−)‐trinervine, (+)‐vellosimine, (+)‐normacusine B, and (−)‐alstomutinine C. Other notable transformations of the synthesis featured an aza‐Achmatowicz/indole cyclization cascade to generate the azabicyclo[3.3.1]nonane structure, a regioselective elimination reaction to form the ethylidene motif embedded in the (+)‐vellosimine and (+)‐normacusine B structures, and a diastereoselective indole oxidative rearrangement to form the spirooxindole structure in (−)‐alstomutinine C.

Metal-Organic Bichromophore Lowers the Upconversion Excitation Power Threshold and Promotes UV Photoreactions.

Sensitized triplet-triplet annihilation upconversion is a promising strategy to use visible light for chemical reactions requiring the energy input of UV photons. This strategy avoids unsafe ultraviolet light sources and can mitigate photo-damage and provide access to reactions, for which filter effects hamper direct UV excitation. Here, we report a new approach to make blue-to-UV upconversion more amenable to photochemical applications. The tethering of a naphthalene unit to a cyclometalated iridium(III) complex yields a bichromophore with a high triplet energy (2.68 eV) and a naphthalene-based triplet reservoir featuring a lifetime of 72.1 μs, roughly a factor of 20 longer than the photoactive excited state of the parent iridium(III) complex. In combination with three different annihilators, consistently lower thresholds for the blue-to-UV upconversion to crossover from a quadratic into a linear excitation power dependence regime were observed with the bichromophore compared to the parent iridium(III) complex. The upconversion system composed of the bichromophore and the 2,5-diphenyloxazole annihilator is sufficiently robust under long-term blue irradiation to continuously provide a high-energy singlet-excited state that can drive chemical reactions normally requiring UV light. Both photoredox and energy transfer catalyses were feasible using this concept, including the reductive N-O bond cleavage of Weinreb amides, a C-C coupling reaction based on reductive aryl debromination, and two Paternò-Büchi [2 + 2] cycloaddition reactions. Our work seems relevant in the context of developing new strategies for driving energetically demanding photochemistry with low-energy input light.

Palladium-Catalyzed Enantioselective Isodesmic C-H Iodination of Phenylacetic Weinreb Amides.

Isodesmic reactions represent mild alternatives to other chemical transformations that require harsh oxidizing agents or highly reactive intermediates. However, enantioselective isodesmic C-H functionalization is unknown and enantioselective direct iodination of inert C-H bond is very rare. Rapid synthesis of chiral aromatic iodides is of significant importance for synthetic chemistry. Herein, we report an unprecedented highly enantioselective isodesmic C-H functionalization to access chiral iodinated phenylacetic Weinreb amides via desymmetrization and kinetic resolution with PdII catalysis. Importantly, further transformations of the enantioenriched products are readily available at the iodinated or the Weinreb amide position, paving the way of related studies for synthetic and medicinal chemists.