Direct transformation of N,N-disubstituted amides and isopropyl esters to nitriles

Various N,N-dimethyl amides, N-methoxy-N-methyl amides, and isopropyl esters were smoothly transformed into the corresponding nitriles in good to moderate yields by the treatment with diisobutylaluminium hydride, followed by treatment with molecular iodine in aq ammonia. The present reactions are novel one-pot and practical methods for the transformation of N,N-disubstituted amides and isopropyl esters into nitriles, through the formation of hemiaminal O-AlBu₂ and hemiacetal O-AlBu₂, respectively.     

Base-promoted aromatic [3,3] sigmatropic rearrangement of N-acyl-O-arylhydroxylamine derivatives

The base-promoted aromatic [3,3] sigmatropic rearrangement of N-acyl-O-arylhydroxylamines giving α-(2-hydroxyphenyl)amides was successfully demonstrated. The substrates were prepared from N-substituted hydroxylamines by N-acylation followed by copper(I)-mediated O-arylation with boronic acids. Treatment of the substrates with lithium hexamethyldisilazide (LiHMDS) in THF at 0?°C to room temperature generated the corresponding amide enolates. The aromatic [3,3] rearrangement of the enolates provided the desired products in moderate to good yields. A crossover experiment produced only intramolecular products and clarified that the reaction proceeds via the aromatic [3,3] sigmatropic rearrangement, not a bond-cleavage–recombination process. Our method is a formal α-arylation of amides.     

Selective N-debenzylation of amides with p-TsOH

N-Benzylamides were debenzylated efficiently with 4 equiv. of p-TsOH in refluxing toluene. Good to quantitative yields of the desired primary amides were obtained within 2-4 h from a wide variety of N-2,4-dimethoxybenzylamides. N-4-Methoxylbenzyl amides and N-benzylamides were also debenzylated cleanly. In the case of N-2,4-dimethoxylbenzylamides, selective N-debenzylation was possible in the presence of N-Fmoc, N-t-BOC or N-trityl-protection. Protected amino acid amides survived these conditions without any detectable epimerization.     

Structure and dynamics of t-butyldimethylsilyl amides

A series of N-alkyl- and N-aryl-t-butyldimethylsilyl amides have been prepared by amination and their structures determined by IR and NMR spectroscopy. Like their trimethylsilyl counterparts, the N-alkyl derivatives exist as amides while the N-aryl derivates exist as amide/imidate mixtures. The percentage of imidate and the free energies of activation for the imidate/amide exchange in the aryl derivatives are greater than those in the trimethylsilyl derivatives. The barriers to rotation in the amide form of the aryl derivatives are similar to those of the trimethylsilyl derivatives. The barrier for rotation in t-butyldimethylsilyl-N-methyl formamide, however, is lower than that of the trimethylsilyl derivative. Isomer ratios and free energies of activation are rationalized in terms of the steric effect of the t-butyl group.     

Simple and efficient cleavage of the N-(1-phenylethyl) unit of carboxamides with methanesulfonic acid

Cleavage of the N-(1-phenylethyl) unit of carboxamides using less than 1 equiv of MsOH in refluxing toluene was found to be simple and very efficient leading to the desired amides in good to excellent yields, and also proved to be more effective compared with reductive methods using hydrogen sources, or acid hydrolysis reagents such as TFA and TsOH. The method selectively cleaved only the N-(1-phenylethyl) group of N-benzyl-N-(1-phenylethyl)amides.     

Hydro-amination/-amidation of 1,3-diynes with indoles/azoles/amides under modified Ullmann conditions: stereo- and regio-selective synthesis of N-alkenynes via N-H bond activation

An efficient strategy for the stereo- and regio-selective synthesis of N-alkenynes has been described. The salient feature of the reaction involves hydro-amination/amidation of 1,3-diynes with indoles/azoles/amides via transition-metal catalyzed activation of N-H bond. The resulting N-alkenynes derived from N-heterocycles and cyclic amides were obtained as a mixture of Z/E isomers with Z-stereoselectivity ranging from 60% to 95%. In contrast, acyclic amides afforded N-alkenynes with exclusive E-stereoselectivity, albeit in reduced yield ranging from ∼10% to 41%.     

Ligand‐free CuTC‐catalyzed N‐arylation of amides,anilines and 4‐aminoantipyrine: synthesis of N‐arylacrylamides, 4‐amido‐N‐phenylbenzamides and 4‐amino(N‐phenyl)antipyrenes

N‐Arylation of amides and anilines with aryl iodides was efficiently catalyzed by copper thiophenecarboxylate under ligand‐free conditions with good to excellent yields. A variety of substituted aryl iodides, amides, anilines and 4‐aminoantipyrine were found to be applicable to the simple catalytic system. Furthermore, some practical, unique secondary amides, such as N‐arylacrylamides and 4‐amido‐N‐phenylbenzamides, and 4‐amino(N‐phenyl)antipyrenes, which are difficult to obtain by the classical methods, were prepared. Copyright © 2013 John Wiley & Sons, Ltd.     

Effects of steric bulk and stereochemistry on the rates of diketopiperazine formation from N-aminoacyl-2,2-dimethylthiazolidine-4-carboxamides (Dmt dipeptide amides)—a model for a new prodrug linker system

A peptide-like self-immolative molecular clip is required for release of active drugs from prodrugs by endopeptidases. Upon cleavage from the carrier, this clip must collapse and release the drug rapidly. A series of aminoacyl-5,5-dimethylthiaproline (Aaa-Dmt) N-(2-(4-nitrophenyl)ethyl)amides were designed. Boc-l-aminoacyl fluorides were coupled with R-DmtOH to give Boc-l-Aaa-R-DmtOH, which were converted to the Boc-l-Aaa-R-Dmt N-(2-(4-nitrophenyl)ethyl)amides. The l,S diastereomeric series was prepared by the reaction of Boc-Aaa PFP esters with S-DmtOH. The l-Aaa-Dmt N-(2-(4-nitrophenyl)ethyl)amides were allowed to cyclise to diketopiperazines (DKPs) in aqueous buffers, expelling 2-(4-nitrophenyl)ethylamine as a model for amine-containing drugs. Reaction rates were dependant on pH. In the l,R diastereomeric series, increasing steric bulk of the Aaa side-chain (Gly, Ala, Phe, Val) led to decrease in the reaction rate. However, in the l,S series, the greatest rate of reaction was observed for the most bulky amino-acid (Val), with t_½=15 min at pH 8.0. The effects of steric bulk and stereochemistry are rationalised through conformational analysis (NMR and X-ray crystallography) of the starting dipeptide amides, the product diketopiperazines and key analogues. Since the dipeptides are (almost) exclusively in the cis-amide conformation, trans-cis interconversion is not relevant. The data suggest that steric interactions in the reacting conformations of the dipeptide amides, as they form the tetrahedral intermediates, are the controlling factors. Thus, l-Aaa-S-Dmt amides are shown to be excellent candidates for incorporation into the design of novel prodrugs.     

Synthesis of new enantiomerically pure N-methyl-N-arylsulfonyl-α-aminonitriles from amino acids

New enantiomerically pure N-methyl-N-arylsulfonyl-α-aminonitriles were prepared starting from the corresponding α-amino acids by way of N-methyl-N-arylsulfonyl-α-amino amides. The key step of this sequence consists of the dehydration of amides by thionyl chloride which proceeded without a significant racemization. Enantiomeric purity of nitriles was determined by HPLC analysis.     

Synthesis of N,N-dialkylaminobenzonitriles and halo-(N,N-dialkyl)benzamidines by reaction of halobenzonitriles with lithium amides

3- and 4-N,N-Dialkylaminobenzonitriles and 4-chloro-(N,N-dialkyl)benzamidines were isolated by reacting 4-chlorobenzonitrile with hindered lithium amides under thermodynamic (0 °C) and kinetic control conditions (−78 °C), respectively. As previously reported, a benzyne mechanism seems to be confirmed since N,N-dialkylaminobenzonitriles are formed. Only benzamidines were isolated in fair to high yields at both 0 °C and −78 °C with non-hindered lithium amides. Exploitation and mechanistic rationale of the reaction of different halobenzonitriles are also reported.     

Preparation and hydrophobizing properties of carboxylic acid <Emphasis Type="Italic">N</Emphasis>-[3-(dimethylamino)propyl]amide hydrochlorides

Carboxylic acid N-[3-(dimethylamino)propyl]amides were prepared in 90–95% yield by the reaction of carboxylic acid esters with N,N-dimethyl-1,3-diaminopropane in the presence of zeolites as catalysts. Hydrochlorides of these amides show promise as cationic surfactants for hydrophobization of the bottomhole formation zone of oil fields.     

Synthesis and conformational analysis of N-aryl-N-(3-thienyl)acetamides

The cis-trans conformational equilibrium of amides is of interest because it can be used to control functional activity. Here, we designed and synthesized a series of N-(3-thienyl)amides in order to study the factors affecting their conformational equilibrium. NMR studies showed that the major conformer of N-methyl-N-(3-thienyl)amide in solution is the E-form (cis form), as is the case for N-methylacetamide. For N-aryl-N-(3-thienyl)amides bearing an N-phenyl moiety, the major conformers differ depending on not only the relative π-electron density of the N-aryl moiety, but also its size. X-ray analysis showed that their solid-state conformational preferences were similar to those in solution.     

An efficient process for the bromolactamization of unsaturated acids

Bromolactamization of the N-Boc derivatives of unsaturated amides using N-bromosuccinimide and lithium t-butoxide in tetrahydrofuran occurs smoothly to give excellent yields of bromo N-Boc α-lactams, which are valuable as synthetic intermediates.     

Synthesis,Quantification, and Characterization of Fatty Acid Amides from In Vitro and In Vivo Sources

Fatty acid amides are a diverse family of underappreciated, biologically occurring lipids. Herein, the methods for the chemical synthesis and subsequent characterization of specific members of the fatty acid amide family are described. The synthetically prepared fatty acid amides and those obtained commercially are used as standards for the characterization and quantification of the fatty acid amides produced by biological systems, a fatty acid amidome. The fatty acid amidomes from mouse N₁₈TG₂ cells, sheep choroid plexus cells, Drosophila melanogaster, Bombyx mori, Apis mellifera, and Tribolium castaneum are presented.     

Highly efficient synthesis of aryl ketones by PEPPSI-palladium catalyzed acylative Suzuki coupling of amides with diarylborinic acids

An improved acylative cross-coupling of various N-methyl-N-tosyl amides with diarylborinic acids for synthesis of aryl ketones is developed. In most cases, aryl ketones could be obtained in excellent yields by using 1?mol% 2,6-diisopropylphenylimidazolylidene and 3-chloropyridine co-supported palladium chloride as catalyst in the presence of 3 equiv. K₂CO₃ as base in refluxing THF. The readily prepared and cost-effective substrates, N-methyl-N-tosylamides and diarylborinic acids, and the commercially available catalyst system promise a practical and efficient access to aryl ketones.     

Untersuchungen zur molekülstruktur von Carbon-Säureamid-Verbindungen der säure H2TeBr6

The compounds of general formula (amide)₄H₂(TeBr₆), prepared by reaction of amides with hexabromotelluric acid, have been investigated spectroscopically. The spectral data are consistent with the crystal structure of (N,N-dimethylformamide)₄H₂(TeBr₆), in which short hydrogen bonds (O ? O 2.44(2) Å) are present.     

Convenient synthesis of C-terminal di- and tri-peptide amides from N-protected dipeptidoylbenzotriazoles

N-Protected dipeptidoylbenzotriazoles react with aqueous ammonia to give dipeptide primary amides (77-98%) and with N-unprotected α-amino amides to afford tripeptide primary amides (82-86%).     

Acyl derivatives of 5-amino-2-azabicyclo[3.2.2]nonanes

5-Amino-2-azabicyclo[3.2.2]nonanes possess activity against the causative organisms of Human African trypanosomiasis and Malaria tropica. Their newly prepared N-acyl derivatives were inactive against Trypanosoma b. rhodesiense, but some of them showed good antiplasmodial activity against a multiresistant strain of Plasmodium falciparum. The results are compared to the activities of the N-unsubstituted compounds and N-sulfonyl analogues. The diastereomeric character of the formed amides was elucidated by NMR spectroscopy.     

Synthesis of modified Weinreb amides: N-tert-butoxy-N-methylamides as effective acylating agents

An efficient preparation of N-methyl-O-tert-butylhydroxylamine hydrochloride has been settled, which allowed the synthesis of modified Weinreb amides. Nucleophilic addition of organolithium and Grignard reagents on these N-tert-butoxy-N-methylamides afforded efficiently the corresponding ketones and reduction with DIBAL furnished the corresponding aldehydes in good yields up to 97%.     

Diastereoselective Ti-mediated preparation of bicyclic aminocyclopropanes from N-alkenyl amides

Intramolecular Ti-mediated alkene-amide couplings of a range of N-alk-3-enyl amides fitted with a substituent at the homoallylic position are described. CF₃-substituted compounds are suitable substrates and bicyclic aminocyclopropanes bearing a CF₃ group can be prepared in this way. Good diastereoselectivities can be observed depending on the substitution pattern, and best results are obtained in diethyl ether rather than in THF.