Tetramic acid and imidazolidinone syntheses via unexpected base induced cyclisations of alanine derived Weinreb amides

Reactions of N-protected derivatives of Weinreb amides of alanine with strong base unexpectedly gave tetramic acid derivatives or an imidazolidinone. The tetramic acid derivatives were obtained by unusual cyclisation of N-acyl N-methoxy derivatives of alanine Weinreb amide upon treatment with potassium hexamethyldisilazide and benzyl bromide. In contrast, treatment of a bromobenzylidine alanine Weinreb amide with potassium hexamethyldisilazide gave rise to cyclisation to form an imidazolidinone.     

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%.     

High-yielding synthesis of Weinreb amides via homogeneous catalytic carbonylation of iodoalkenes and iodoarenes

Iodoarenes (iodobenzene and 2-iodothiophene) and iodoalkenes (1-iodocyclohexene, 1-iodo-4-tert-butylcyclohexene, 1-iodo-2-methylcyclohexene and 1-iodo-1-(1-naphthyl)ethene) were used as substrates in palladium-catalysed aminocarbonylation with N,O-dimethylhydroxylamine. The corresponding Weinreb amides were prepared in high isolated yields (up to 87%) when forcing conditions (40-60 bar of CO, 50 °C) were used. The aminocarbonylation provides the Weinreb amides as pure products in a chemoselective reaction. No formation of ketocarboxamides, due to double CO insertion, except for 2-iodothiophene, was observed even at 60 bar of CO pressure.     

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.     

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%.     

A Photochemical Protocol for the Synthesis of Weinreb and Morpholine Amides from Carboxylic Acids

In recent years, the development of light-mediated methods for synthetic applications has attracted high interest, because such methods constitute alternative approaches for the production of valuable chemical products. We study herein a photochemical protocol for the synthesis of Weinreb amides and morpholine amides from carboxylic acids. Various carboxylic acids were directly coupled to N,O-dimethylhydroxylamine, upon irradiation with either LED 370 nm or sunlight in the presence of 4-dimethylaminopyridine and bromotrichloromethane, providing Weinreb amides in moderate to high yields. Similarly, morpholine amides were obtained in satisfactory to high yields under sunlight or LED 370 nm irradiation. Thus, the versatile building blocks Weinreb amides and morpholine amides may be efficiently synthesized directly from carboxylic acids by light-mediated approaches, without the need of coupling reagents or pre-activation of carboxylic acids.     

A facile one-pot synthesis of acyclic β-enamino ketones, an important class of versatile synthetic intermediates

A one-pot sequential process consisting of nucleophilic substitution of the lithiated acetylides with Weinreb amides followed by a Michael reaction of the extruded N-methoxy-N-methylamine after quenching with saturated NH₄Cl, provided β-enamino ketones in high yield and in a single geometrical isomeric form. It has been demonstrated that this method is applicable to a wide variety of such amides and to different acetylides.     

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.     

Asymmetric synthesis of cyclic β-amino acids and cyclic amines via sequential diastereoselective conjugate addition and ring closing metathesis

Diastereoselective conjugate addition of lithium (S)-N-allyl-N-α-methylbenzylamide to a range of α,β-unsaturated esters followed by ring closing metathesis is used to afford efficiently a range of substituted cyclic β-amino esters in high d.e. Alternatively, conjugate addition to α,β-unsaturated Weinreb amides, functional group conversion and ring closing metathesis affords cyclic amines in high d.e. The further application of this methodology to the synthesis of a range of carbocyclic β-amino esters via conjugate addition, enolate alkylation and ring closing metathesis is also described. Application of this methodology affords, after deprotection, (S)-homoproline, (S)-homopipecolic acid, (S)-coniine and (1S,2S)-trans-pentacin.     

Design and synthesis of a new indazole library: direct conversion of N-methoxy-N-methylamides (Weinreb amides) to 3-keto and 3-formylindazoles

Nucleophilic addition of Grignard or lithiated reagents on the new Weinreb amides 3 and 4 afforded efficiently the corresponding ketones and allowed the design and synthesis of a new indazole library. These 3-ketoindazoles were obtained by a direct and original conversion of N-methoxy-N-methylamides with good yields. Furthermore, the reduction of 3 with LiAlH₄ furnished the corresponding aldehydes as a versatile and efficient pathway to 3-formylindazoles.     

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.     

Stereoselective synthesis of 2-aryl-4-en-1-ols,promising synthons for the preparation of oxygen heterocycles

Reactions of arylacetic acids with N-methoxymethanamine afford corresponding Weinreb amides which at alkenylation with methallyl and prenyl bromides in the presence of (Me₃Si)₂N^–Na⁺ form unsaturated amides ArCHRCONMe(OMe) (R = CH₂CMe=CH₂, CH₂C=CMe₂). Amides readily react with BuLi and BnMgCl to give ketones ArCHRCOR' (R' = Bu, Bn). A stereoselective reduction of the latter with LiBH(s-Bu)₃ leads to a quantitative formation of syn-isomers of 2-aryl-4-en-1-ols.     

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.     

An expedient conversion of α-amino acids into Weinreb amides using COMU® as a coupling agent

The use of COMU®, as a non-hazardous partner, in the coupling of N-protected α-amino acids to N-methoxy-N-methylamine to afford the corresponding Weinreb amides is discussed. From a practical point of view the reaction can be monitored visually by virtue of the colour change associated with the conversion of substrates (yellow) into the products (orange). As the by-products of the reaction are conveniently water-soluble the products are isolated relatively pure and with minimal racemisation. These factors coupled with the short reaction time make this a very useful procedure.     

Cross-metathesis of allyl halides with olefins bearing an α-alkoxy amide group

We have examined whether the allyl halide cross-metathesis reaction tolerates α-alkoxy amide groups. Ruthenium-based catalysts I-III did not catalyze the cross-metathesis of allyl halides in the presence of an α-alkoxy N,N-dimethylamide group to any appreciable extent, but the reaction could tolerate either a bulky N,N-diisopropylamide or Weinreb amide group. In particular, the Grubbs-Hoveyda-Blechert 2nd generation catalyst (III) efficiently catalyzed the cross-metathesis of allyl halides with olefins bearing a Weinreb amide group.     

Stereospecific synthesis of conjugated (1E,3E)- and (1Z,3Z)-1,4-di(n-N,N-dimethylaminophenyl)-1,3-butadienes from 2-chloro-1-(n-N,N-dimethylaminophenyl)ethenes: fluorescence properties

The conjugated 1,4-di(n-N,N-dimethylaminophenyl)-1,3-butadienes (n=o-, m-, p-) were efficiently synthesised by homocoupling of the appropriate 2-chloro-1-(n-N,N-dimethylaminophenyl)ethene (n=o-, m-, p-) with stoichiometric amounts of zerovalent nickel complexes. The 1,3-butadienes were obtained as a mixture of stereoisomers, with independence of the starting E or Z chlorovinyl isomer. Moreover, the stereospecific (Z,Z) stereoisomer was obtained by partial hydrogenation of the corresponding 1,3-butadiyne, while the stereospecific (E,E) stereoisomer was obtained by exposure to the sunlight radiation of the (Z,Z) or the (Z,E) compound in ethanol.     

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.     

Intramolecular electrophilic cyclization of functional derivatives of unsaturated compounds: II. Synthesis and transformation of N-{(2Z)-5-[(arylsulfanyl)methyl]dihydrofuran-2(3H)-ylidene}-N-alkyl(aryl)aminium perchlorates

N-Alkyl(aryl)amides of allylacetic acid when reacting with arylsulfenyl chlorides in acetic acid in the presence of lithium perchlorate undergo a selective cyclization to form N-{(2Z)-5-[(arylsulfanyl)methyl] dihydrofuran-2(3H)-ylidene}-N-alkyl-(aryl)aminium perchlorates. Treating of the latter with sodium acetate leads to the formation of the corresponding 5-[(arylsulfanyl)methyl]lactones, and with sodium ethylate, to 5-[(arylsulfanyl) methyl]-2-iminolactones. In reaction with secondary cycloalkylamines in the presence of water a transamidation and tetrahydrofuran ring opening occurs to afford 5-arylsulfanyl-4-hydroxypentanoic acid amides.     

Protease-catalysed synthesis of Z-l-aminoacyl-l-caprolactam amides from Z-protected amino acid esters and dl-α-amino-ε-caprolactam

The enzymatic synthesis of Z-l-aminoacyl-l-caprolactam amides from Z-protected amino acid esters and dl-α-amino-ε-caprolactam (ACL) was accomplished by the thiol proteases papain, bromelain and ficin in aqueous-organic media. Product yields of 96% and 87% for Z-Gly-l-ACL and Z-Ala-l-ACL, respectively, could be obtained. The products were purified and characterised by polarimetry, NMR and LC-MS. The suitability to accept a bulky 1,2-amino ketone as a nucleophile expands the general knowledge of thiol proteases and their catalytic potential.     

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.