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.     

Microwave acceleration in DABAL-Me3-mediated amide formation

Facile direct coupling of esters and secondary amines to afford tertiary amides proceeds under microwave irradiation using the air-stable trimethylaluminium source DABAL-Me₃ [(DABCO)(AlMe₃)₂]. Excellent yields (88-98%) are attained for cyclic secondary amines in reactions that are complete in 5-16 min. The process can be extended to the formation of Weinreb amides (upto 76% from commercial MeNHOMe·HCl) in a one-pot procedure using NaH to liberate the free methoxyamine.     

Asymmetric synthesis and applications of beta-amino Weinreb amides: asymmetric synthesis of (S)-coniine

Conjugate addition of lithium (S)-N-benzyl-N-alpha-methylbenzylamide to a range of alpha, beta-unsaturated Weinreb amides proceeds with high levels of diastereoselectivity (>95% de). The beta-amino Weinreb amide products may be transformed into beta-amino ketones via reactions with Grignard reagents, while treatment with DIBAL-H furnishes beta-amino aldehydes. Trapping of the aldehyde via Wadsworth-Emmons reaction and subsequent manipulation offers an efficient route to homochiral delta-amino acid derivatives and 2-substituted piperidines. The application of this methodology for the synthesis of (S)-coniine is demonstrated.     

Asymmetric synthesis of anti-α-substituted β-amino ketones from sulfinimines

Previously unknown, enantiopure, β-amino ketones were prepared in modest yield by addition of lithium reagents to N-sulfinyl anti-α-substituted β-amino Weinreb amides. Grignard reagents failed to add to these Weinreb amides in contrast to the syn-α-substituted isomers which did. The anti-α-substituted β-amino Weinreb amides were prepared by addition of LiN(OMe)Me to the corresponding N-sulfinyl anti-α-substituted β-amino esters because α-alkylation of N-sulfinyl β-amino Weinreb amide enolates resulted in poor diastereoselectivities.     

Rhodium/diene-catalyzed asymmetric 1,4-addition of arylboronic acids to alpha,beta-unsaturated Weinreb amides

Rhodium/chiral diene (S,S)- complex has been found to effectively catalyze the 1,4-addition of arylboronic acids to alpha,beta-unsaturated Weinreb amides, furnishing useful beta-chiral Weinreb amides in high enantioselectivity.     

In Situ Quench Reactions of Enantioenriched Secondary Alkyllithium Reagents in Batch and Continuous Flow Using an I/Li-Exchange

We report a practical in situ quench (ISQ) procedure involving the generation of chiral secondary alkyllithiums from secondary alkyl iodides (including functionalized iodides bearing an ester or a nitrile) in the presence of various electrophiles such as aldehydes, ketones, Weinreb amides, isocyanates, sulfides, or boronates. This ISQ-reaction allowed the preparation of a broad range of optically enriched ketones, alcohols, amides, sulfides and boronic acid esters in typically 90–98 % ee. Remarkably, these reactions were performed at −78 °C or −40 °C in batch. A continuous flow set-up permitted reaction temperatures between −20 °C and 0 °C and allowed a scale-up up to a 40-fold without further optimization.     

Preparation of Esters and Amides from Carboxylic Acids by Activation with Dialkyl Phosphite-Carbon Tetrachloride Mixture

A simple one pot phase transfer catalytic method is described for the synthesis of carboxylic amides and esters from carboxylic acids and amines or alcohols, respectively. For the activation of the carboxylic acids “in situ” generated phosphoric acid diester chlorides were applied.     

Asymmetric synthesis of beta-amino carbonyl compounds with N-sulfinyl beta-amino Weinreb amides

[reaction: see text] Diverse organometallic reagents readily add to enantiopure N-sulfinyl beta-amino Weinreb amides providing the corresponding, stable, N-sulfinyl beta-amino carbonyl compounds in good to excellent yields. This new methodology represents a general solution to the problem of beta-amino carbonyl syntheses, which are important chiral building blocks and constituents of natural products. N-Sulfinyl beta-amino Weinreb amides are prepared by reaction of the potassium enolate of N-methoxy N-methylacetamide with sulfinimines (N-sulfinyl imines) or lithium N,O-dimethylhydroxylamine with N-sulfinyl beta-amino esters.     

Palladium-catalyzed carbonylation reactions of aryl bromides at atmospheric pressure: a general system based on Xantphos

A method for the Pd-catalyzed carbonylation of aryl bromides has been developed using Xantphos as the ligand. This method is effective for the direct synthesis of Weinreb amides, primary and secondary benzamides, and methyl esters from the corresponding aryl bromides at atmospheric pressure. In addition, a putative catalytic intermediate, (Xanphos)Pd(Br)benzoyl, was prepared and an X-ray crystal structure was obtained revealing an unusual cis-coordination mode of Xantphos in this palladium-acyl complex.     

Mild one-pot conversion of carboxylic acids to amides or esters with Ph3P/trichloroisocyanuric acid

The reaction of trichloroisocyanuric acid (TCICA) and triphenylphosphine in the presence of a carboxylic acid results in the in situ formation of the corresponding acid chloride under mild conditions. Subsequent addition of amines or alcohols, in the presence of a tertiary amine affords the corresponding amides, or esters, in good to excellent yields. The methodology was applied to the synthesis of a dipeptide.     

N-acyl-5,5-dimethyloxazolidin-2-ones as latent aldehyde equivalents

A study of the properties of N-hydrocinnamoyl- derivatives of 5,5-dimethyloxazolidin-2-one, 4,4-dimethyloxazolidin-2-one and oxazolidin-2-one upon hydride reduction with DIBAL-H demonstrates that the 5,5-dimethyl-group is essential for inhibition of endocyclic nucleophilic attack. For instance, treatment of N-hydrocinnamoyl-5,5-dimethyloxazolidin-2-one with DIBAL-H results in the selective formation of the stable N-1'-hydroxyalkyl derivative which may be regarded as a masked hydrocinnamaldehyde equivalent, as treatment under basic conditions affords the parent aldehyde in excellent yield. Treatment of N-hydrocinnamoyl-4,4-dimethyloxazolidin-2-one with DIBAL-H under identical conditions affords a complex mixture of products, including the formate ester product of endocyclic cleavage. As an alternate strategy, DIBAL-H reduction of straight chain and branched N-acyl-5,5-dimethyloxazolidin-2-one derivatives, followed by a Horner-Wadsworth-Emmons reaction affords alpha,beta-unsaturated esters in good yields. Branching alpha- to the exocyclic carbonyl in N-acyl-oxazolidinones inhibits DIBAL-H reduction, but this can be overcome by precomplexation with ZnCl2, with subsequent fragmentation generating either the corresponding aldehyde or alpha,beta-unsaturated esters. The addition of ZnCl2 has been shown to increase the diastereoselectivity observed in Wadsworth-Horner-Emmons reactions of lithiated phosphonates.     

Recyclable hypervalent iodine(III) reagent iodosodilactone as an efficient coupling reagent for direct esterification, amidation, and peptide coupling

A hypervalent iodine(III) reagent plays a novel role as an efficient coupling reagent to promote the direct condensation between carboxylic acids and alcohols or amines to provide esters, macrocyclic lactones, amides, as well as peptides without racemization. The regeneration of iodosodilactone (1) can also be readily achieved. The intermediate acyloxyphosphonium ion C from the activation of a carboxylic acid is thought to be involved in the present esterification reaction.     

Conversion of N-aromatic amides to O-aromatic esters

[reaction: see text] N-Aromatic secondary amides can be transformed into O-aromatic esters in high yield via N-nitrosamide intermediates. The amides can be generated in situ from the corresponding aromatic amines or nitro compounds, and phenols can easily be made from the esters. The reaction can be modified by addition of methyl methacrylate or toluene at 0 degrees C to give polymerization or deamination, respectively. The rearrangement mechanism may involve radical formation and recombination.     

Lewis Acid Promoted Ruthenium(II)‐Catalyzed Etherifications by Selective Hydrogenation of Carboxylic Acids/Esters

Ethers are of fundamental importance in organic chemistry and they are an integral part of valuable flavors, fragrances, and numerous bioactive compounds. In general, the reduction of esters constitutes the most straightforward preparation of ethers. Unfortunately, this transformation requires large amounts of metal hydrides. Presented herein is a bifunctional catalyst system, consisting of Ru/phosphine complex and aluminum triflate, which allows selective synthesis of ethers by hydrogenation of esters or carboxylic acids. Different lactones were reduced in good yields to the desired products. Even challenging aromatic and aliphatic esters were reduced to the desired products. Notably, the in situ formed catalyst can be reused several times without any significant loss of activity.     

有机锌试剂制备Weinreb酰胺的研究

探索了带Weinreb酰胺官能团的有机锌试剂的制备及其与酰氯的反应, 得到了另一类Weinreb酰胺, 提供了一种制备Weinreb酰胺的新方法.     

Synthesis of omega-hydroxy ketones from omega-benzyloxy Weinreb amides by using a chemoselective nucleophilic addition/Birch reduction process

[reaction: see text] A chemoselective nucleophilic addition/Birch reduction process applied to omega-benzyloxy Weinreb amides led to omega-hydroxy ketones in good yields.     

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.     

Facile amidation of esters with aromatic amines promoted by lanthanide tris (amide) complexes

The development of catalysts capable of catalyzing amidation of esters with amines to construct amides under mild conditions is of great importance. Compared to aliphatic amines, the direct catalytic amidation of esters with less nucleophilic aromatic amines is rather difficult. Employing simple lanthanide tris (amide) complexes Ln[N (SiMe₃)₂]₃(μ-Cl)Li (THF)₃ as the catalysts, it was found a broad range of aromatic amines and esters were efficiently converted into various amides in good yields under mild conditions. A plausible mechanism for this transformation was experimentally supported as starting from an amide exchange reaction between the lanthanide tris (amide) complex and the substrate amine.     

A new method for the preparation of functionalized unnatural α-H-α-amino acid derivatives

A new method for the preparation of α-H-α-amino acids is reported based on the α-alkylation of iminoacetic acid esters or amides. These imines are readily available by the reaction of glyoxylic acid esters with branched primary amines. The subsequent reaction with methanolic ammonia gave the corresponding iminoacetic acid amides. α-Alkylation of these imines with various electrophiles under basic conditions, followed by an acidic hydrolysis, gave α-amino acids, esters, or amides in up to 93% yield. α-Alkylation under chiral PTC conditions resulted in mono-alkylated amino acids with 90% ee.     

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.