Chemoselective Synthesis of N‐Substituted α‐Amino‐α′‐chloro Ketones via Chloromethylation of Glycine‐Derived Weinreb Amides

Functionalized α‐arylamino‐α′‐chloro ketones are obtained in high yield via a straightforward homologation reaction of Weinreb amides derived from N‐arylglycines using in situ generated chloromethyllithium. The use of the Weinreb amides is essential and allows the chemoselective homologation of N‐aryl‐N‐substituted glycine analogues, a transformation which is not possible using similar glycine esters. The procedure is promising for the large‐scale preparation of α‐amino‐α′‐chloropropanones, which are valuable precursors for a variety of bioactive compounds.     

N-methoxy-N-methylamides (Weinreb amides) in modern organic synthesis

N-Methoxy-N-methylamides (Weinreb amides) have facililated access to functionalized aldehydes and ketones in organic synthesis, including the total synthesis of complex natural products.     

Synthesis of N‐Arylamides by Copper‐Catalyzed Amination of Aryl Halides with Nitriles

A copper‐catalyzed amination of aryl halides with nitriles has been developed. The use of nitriles as nitrogen nucleophiles can make the synthesis of N‐arylamides more simple than that using amides through in‐situ hydrolysis. A variety of N‐arylamides and benzoxazole derivatives can be synthesized according to this approach.     

Increasing the Reactivity of Amides towards Organometallic Reagents: An Overview

The nucleophilic addition of carbon nucleophiles to amides has traditionally been a difficult task, both due to reactivity and selectivity problems. When successful, these processes would represent straightforward routes towards carbonyl‐type or amine compounds, depending on the fate of the generated tetrahedral intermediate. The direct addition of nucleophiles to amides for the preparation of ketones has been studied and applied to the syntheses of several natural products. On the other hand, the addition of nucleophiles to amides to obtain substituted amines represented a major challenge, and only scattered applications on particular substrates have appeared. Initial improvements were based on the activation of amides by introduction of particular substituents, such as in N‐methoxy amides (Weinreb amides) or electron‐withdrawing groups able to increase the carbon nucleophilicity. Although these strategies facilitate the introduction of nucleophiles, chemoselectivity issues arise when additional electrophilic moieties (i.e., carbonyls) are present, thus decreasing the versatility of the methods. In recent years, important advancements towards fully chemoselective methods have been realized. The capture of tetrahedral intermediates with acids generates highly electrophilic iminium species able to undergo chemoselective additions of various nucleophiles, thus accessing substituted amines. Alternatively, the in situ generation of an iminium triflate ion allows highly chemoselective additions of nucleophiles, yielding amines, ketones or ketimines. Also thioamides can be used as precursors of ketones or α‐substituted amines. The success of the above methodologies is further showcased by the application in various syntheses of natural products or biologically active molecules.

     

Water Solvent Method for Esterification and Amide Formation between Acid Chlorides and Alcohols Promoted by Combined Catalytic Amines: Synergy between N‐Methylimidazole and N,N,N′,N′‐Tetramethylethylenediamine (TMEDA)

An efficient method for esterification between acid chlorides and alcohols in water as solvent has been developed by combining the catalytic amines, N‐methylimidazole and N,N,N′,N′‐tetramethylethylenediamine (TMEDA). The present Schotten–Baumann‐type reaction was performed by maintaining the pH at around 11.5 using a pH controller to prevent the decomposition of acid chlorides and/or esters and to facilitate the condensation. The choice of catalysts (0.1 equiv.) was crucial: the combined use of N‐methylimidazole and TMEDA exhibited a dramatic synergistic effect. The catalytic amines have two different roles: (i) N‐methylimidazole forms highly reactive ammonium intermediates with acid chlorides and (ii) TMEDA acts as an effective HCl binder. The production of these intermediates was rationally supported by a careful ¹H NMR monitoring study. Related amide formation was also achieved between acid chlorides and primary or secondary amines, including less nucleophilic or water‐soluble amines such as 2‐(or 4‐)chloroaniline, the Weinreb N‐methoxyamine, and 2,2‐dimethoxyethanamine.     

An Efficient Domino Synthesis of Quinoxalin‐2(1H)‐ones via an SNAr/Coupling/Demesylation Reaction Catalyzed by Copper(I) as Key Step

An efficient copper‐catalyzed method for the synthesis of quinoxalin‐2(1 H)‐ones derivatives via domino S_NAr/coupling/demesylation reaction of N‐(2‐halophenyl)methylsulfonamides with 2‐halo amides has been developed. Various quinoxalinones with diversity at three positions on their scaffold have been obained, and the method is valuable for the construction of this kind of molecules with biological and pharmaceutical activities.     

(−)‐Sparteine‐Mediated Directed ortho‐Metalation of N‐Cumyl‐N‐ethylferrocenecarboxamide. Versatile Routes to Functionalized Planar Chiral Ferrocenecarboxamides,Amines, Esters and Phosphines

N‐Cumyl‐N‐ethylferrocenecarboxamide 5 provides planar chiral carboxamides 6 in high yield and % ee via (−)‐sparteine‐mediated directed ortho‐metalation. Mild decumylation affords secondary amides 7 , which serve as intermediates for a convenient and general route to the venerable Ugi planar chiral ferrocenylamines 13 and as versatile precursors for the preparation of novel chiral ferrocenes 15 and 20 . The chiral TMS‐ferrocenyl derivative 7c is used to prepare the enantiomeric (S)‐ 7f , circumventing the lack of availability of (+)‐sparteine.     

DNA‐Binding Properties of New Fluorescent AzaHx Amides: Methoxypyridylazabenzimidazolepyrroleimidazole/pyrrole

DNA minor groove binding polyamides have been extensively developed to control abnormal gene expression. The establishment of novel, inherently fluorescent 2‐(p‐anisyl)benzimidazole (Hx) amides has provided an alternative path for studying DNA binding in cells by direct observation of cell localization. Because of the 2:1 antiparallel stacking homodimer binding mode of these molecules to DNA, modification of Hx amides to 2‐(p‐anisyl)‐4‐azabenzimidazole (AzaHx) amides has successfully extended the DNA‐recognition repertoire from central CG [recognized by Hx‐I (I=N‐methylimidazole)] to central GC [recognized by AzaHx‐P (P=N‐methylpyrrole)] recognition. For potential targeting of two consecutive GG bases, modification of the AzaHx moiety to 2‐ and 3‐pyridyl‐aza‐benzimidazole (Pyr‐AzaHx) moieties was explored. The newly designed molecules are also small‐sized, fluorescent amides with the Pyr‐AzaHx moiety connected to two conventional five‐membered heterocycles. Complementary biophysical methods were performed to investigate the DNA‐binding properties of these molecules. The results showed that neither 3‐Pyr‐AzaHx nor 2‐Pyr‐AzaHx was able to mimic I‐I=N‐methylimidazole–N‐methylimidazole to target GG dinucleotides specifically. Rather, 3‐Pyr‐AzaHx was found to function like AzaHx, f‐I (f=formamide), or P‐I as an antiparallel stacked dimer. 3‐Pyr‐AzaHx‐PI ( 2 ) binds 5′‐ACGCGT′‐3′ with improved binding affinity and high sequence specificity in comparison to its parent molecule AzaHx‐PI ( 1 ). However, 2‐Pyr‐AzaHx is detrimental to DNA binding because of an unfavorable steric clash upon stacking in the minor groove.     

Synthesis of β‐Lactams by 4‐exo‐tet Cyclization Process Induced by Electrogenerated Cyanomethyl Anion,Part 2:[1] Stereochemical Implications

An efficient electrochemically induced synthesis of chiral cis β‐lactams has been described, via deprotonation of chiral amides containing an acidic methylene group and a bromine atom as leaving group and bearing a chiral auxiliary or amine function. The electrogenerated base – cyanomethyl anion – is easily obtained by galvanostatic reduction of acetonitrile‐tetraethylammonium hexafluorophosphate solutions under very mild conditions. The yields are high and the cis‐diastereoselection complete. The use of starting chiral amides has allowed in many cases the preparation of the most abundant isomer in a pure form.     

SOLVENT EXTRACTION OF URANIUM( VI) AND THORIUM( IV) FROM NITRATE MEDIA BY CARBOXYLIC ACID AMIDES

ABSTRACT

A series of nineteen N-alkyl carboxylic acid amides (R.CO.NHR') has been prepared, in which the alkyl groups R and R' have been varied in order to introduce different degrees of steric complexity into the compounds. A smaller number of N,N-dialkyl amides (R.CO.NR₂) and non-substituted amides (R.CO.NH₂) has also been prepared for comparison purposes. These amides were characterized by measurement of their boiling points, melting points, refractive indices and densities.|The solvent extraction of uranium(VI) and thorium(IV) from sodium nitrate media by solutions of the amides in toluene was studied. Increasing steric bulk of the alkyl groups R and R' was found to cause a marked decrease in the extraction of thorium, with a much smaller effect on the extraction of uranium, thus considerably enhancing the separation between these metals. Vapour pressure osmometry studies indicate that the N,N-alkyl amides are self-associated in toluene solution, with aggregation numbers up to about 2.5 for 0.6 M solutions at 35°C. In contrast, the N,N-dialkylamides behave as monomers under these conditions. The distribution ratios for the extraction of uranium and thorium show second- and third-order dependences, respectively, on the extractant concentration for both the N-alkyl and N,N-dialkyl amides.     

Iron‐Catalyzed Amidation of Aldehydes with N‐Chloroamines

A new direct conversion of aldehydes to amides has been realized, in the presence of iron(III) chloride as a catalyst and using tert‐butyl hydroperoxide (TBHP) as an oxidant. Both aliphatic and aromatic aldehydes were successfully reacted with variously mono‐ and di‐substituted N‐chloroamines. The methodology has a wide substrate scope, uses cheap and easily available reagents and is characterized by short reaction times.     

An Inexpensive and Efficient Copper Catalyst for N‐Arylation of Amines,Amides and Nitrogen‐Containing Heterocycles

An inexpensive and efficient catalyst system has been developed for the N‐arylation of nitrogen‐containing compounds including a variety of amines, amides, indole and imidazole. This simple protocol uses CuI as the catalyst, commercial available pipecolinic acid as the new ligand, K₂CO₃ as the base and DMF as the solvent.     

Rhodium‐Catalyzed Homogeneous Reductive Amidation of Aldehydes

The catalytic reductive amidation of an aldehyde (hexanal) with an amide (acetamide) is reported. Apart from the desired N‐hexylacetamide, the two isomeric unsaturated intermediates as well as hexanol are produced together with higher mass products that arise from aldol condensation and diamide coupling of the aldehyde. Screening of different catalyst precursor salts, ligands and reaction conditions led to the finding that the catalytic system based on the (cyclooctadiene)rhodium chloride dimer, [Rh(cod)Cl]₂, in combination with the ligand xantphos and an acid co‐catalyst results in high selectivity for the desired product. Under optimized conditions nearly full conversion is reached with high selectivity to the desired N‐alkylamide and with a very high N ‐ alkylamide/alcohol ratio, while producing only small amounts of by‐products. The scope of the reaction has been investigated using different amides as well as aldehydes; the results show the general applicability of this novel reaction, but with electron‐withdrawing amides the selectivity to N‐alkylamide is lower. NMR studies showed that the nucleophilic addition of acetamide to hexanal is acid catalyzed, forming N‐(1‐hydroxyhexyl)acetamide in equilibrium with both hexanal and the dehydrated unsaturated imides. A catalytic mechanism is proposed in which a strong acid such as HOTs acts as a co‐catalyst by establishing a rapid chemical equilibrium between the aldehyde, acetamide and the intermediates. Furthermore, it is proposed that the presence of acid causes a change in catalytic species, enabling a cationic Rh/xantphos hydrogenation catalyst to selectively hydrogenate the intermediates to N‐hexylacetamide in the presence of hexanal.     

Synthese potentieller Pflanzenschutzwirkstoffe auf 2, 3‐Dihydrothiazol‐2‐thion‐Basis. I. Strukturvariationen am N3 und C4

A considerable number of potential plant protecting compounds with the core structure of 2,3‐dihydrothiazol‐2‐thione has been prepared by the reaction of dithiocarbamates with halomethylcarbonyl compounds forming N‐substituted 4‐substituted 4‐hydroxythiazolidin‐2‐thiones 2—4 , which can split off water to yield 5 . The structural variability at N₃ is given either by the amine used for dithiocarbamate synthesis or by acylation of N‐unsubstituted 2,3‐dihydrothiazol‐2‐thiones like 4i . The variability at C₄ is either achieved by the kind of the halomethylcarbonyl compound or by reactions of 4‐chloromethyl derivatives 5 , which can be transformed by a number of nucleophilic reagents to derivatives like thioethers 8 , ethers 9 , amines 10 , nitriles 11 , azides 12a , thiocyanates 12b , the primary amine 14 and derived from that the amides 15 or the ureas 16 .     

Potassium Phosphate‐Catalyzed Chemoselective Reduction of α‐Keto Amides: Route to Synthesize Passerini Adducts and 3‐Phenyloxindoles

A chemoselective reduction of α‐keto amides to biologically important α‐hydroxy amides (mandelamides) by polymethylhydrosiloxane (PMHS) using 5 mol% potassium phosphate (K₃PO₄) as catalyst has been developed. This transition metal‐free protocol discloses excellent chemoselectivity for the ketone reduction of α‐keto amides in the presence of other reducible functionalities like ketone, nitro, halides, nitrile and amide. Also, the chemoselectively reduced α‐hydroxy amide has been derivatized to isocyanide‐free Passerini adducts. The N‐alkyl‐α‐hydroxy amides have been successfully converted to 3‐phenyloxindole derivatives by treatment with methanesulfonyl cholride and triethylamine.

     

Catalytic Dicyanative 5‐exo‐ and 6‐endo‐Cyclization Triggered by Cyanopalladation of Alkynes

A stereoselective dicyanative 5‐exo‐ and 6‐endo‐cyclization using various enynes has been investigated. The mode of cyclization is critically controlled by the structure of the substrates. For example, N‐allyl derivatives prefer 5‐exo‐cyclization, while methacryloyl amides are transformed to the corresponding lactams with tetra‐substituted carbons at the alpha‐position via 6‐endo‐cyclization. Both reactions include syn‐cyanopalladation to carboncarbon triple bonds in the initial step, and sequential cyclization followed by reductive elimination in one operation enables the construction of the highly functionalized nitrogen heterocycles. The scope of suitable substrates and a proposed mechanism are also described.     

3, 4‐Dihydroxymandelic acid amides of alkylamines as antioxidants for lipids

The antioxidative and radical scavenging activity of the 3, 4‐dihydroxymandelic acid (DHMA) amides of hexylamine, 2‐ethylhexylamine, octylamine, and cyclohexylamine was determined by several physicochemical test systems. The amides were synthesized by protecting group‐free coupling of in situ prepared N‐hydroxysuccinimidylester of DHMA and the amines. The radical scavenging activity was determined using the DPPH (2, 2‐diphenyl‐1‐picrylhydrazyl) method and by quenching superoxide anions generated using a horse radish peroxidase/H₂O₂ system. In the DPPH assay, all amides show higher radical scavenging activity (EC₅₀ 0.09‐0.12 mol/mol_DPPH) compared to the standard antioxidants ascorbic acid (EC₅₀ 0.27 mol/mol_DPPH) and tocopherol (EC₅₀ 0.25 mol/mol_DPPH). The amides are also more potent superoxide radical scavengers (IC₅₀ < 600 nm) than standard ascorbic acid (IC₅₀ 700 nm). Activity against lipid peroxidation was determined by accelerated autoxidation of highly unsaturated oils and squalene using the Rancimat. Again, the antioxidative potentials of the DHMA amides against lipid oxidation as determined by the Rancimat, are at least equal or higher compared to the standard lipid antioxidants tocopherol, BHT, BHA, and ascorbylpalmitate (concentration in soybean oil 0.05%, all other oils 0.025%, squalene 0.005%). In squalene, an equi‐amount mixture of DHMA octylamide and α‐tocopherol shows a synergistic effect. Last but not least, the amides are able to protect an emulsion of linoleic acid/β‐carotene against oxidation initiated by N, N‐azodiisobutyramidine dihydrochloride (IC₅₀ 0.19‐0.77 mmol/l, ascorbic acid > 0.9, tocopherol 0.08). The DHMA octylamide in combination with ascorbic acid shows a synergistic antioxidative effect in the emulsion model. In conclusion, the new alkylamides of DHMA are easy to synthesize, potent radical scavengers and protect lipids, in particular the highly unsaturated, both in bulk and in emulsions against autoxidation.     

Rhodium‐Catalyzed C?H Olefination of Aryl Weinreb Amides

A rhodium(III)‐catalyzed oxidative C H olefination directed by Weinreb amides, a class of well developed versatile building blocks in organic synthesis, has been developed with air as the terminal oxidant. The reactions proceed with excellent reactivity, good functional group tolerance and high yields.     

Volatile compounds from ponerine ants in the genusMesoponera

Volatile constituents have been characterized from two species of ponerine ants in the genusMesoponera. 2,5-Dimethyl-3-isopentyl-pyrazine has been identified from cephalic extracts ofM. castanea andM. castaneicolor, by gas chromatography-mass spectrometry. Combined gasters and thoraces of both species are also characterized by the presence of nonanal, nonanoic acid, isovaleric acid, phenylacetic acid, and undecanal, as well as a series of aliphatic amines and amides.N-Isoamylnonylamine was a major constituent that was accompanied byN-isoamylnonenylamine,N,N-diisoamylnonylamine,N-acetyl nonylamine,N-formyl isoamylnonylamine,N-isovaleroyl nonylamine, and several other secondary and tertiary amines. The possible significance of the amines and amides as idiosyncratic natural products ofMesoponera species is discussed.     

Fully Enzymatic Resolution of Chiral Amines: Acylation and Deacylation in the Presence of Candida antarctica Lipase B

A fully enzymatic methodology for the resolution of chiral amines has been demonstrated. Candida antarctica lipase B (CaLB)‐catalyzed acylation with N‐methyl‐ and N‐phenylglycine, as well as analogues having the general formula R¹ X CH₂CO₂R² (R¹=Me, Ph; X=O, S) afforded the corresponding enantioenriched amides, which were subsequently enzymatically hydrolyzed. Surprisingly, CaLB also proved to be the catalyst of choice for this latter step. The heteroatom in the acyl donor profoundly influences both the enzymatic acylation and deacylation; the O‐substituted reagents performed best with regard to enantioselectivity as well as reaction rate in synthesis and hydrolysis.